Prolyl Endopeptidase Is Involved in Filaggrinolysis and Cornification.

FLG is a well-known biomarker of atopic dermatitis and skin dryness. Its full proteolysis (or filaggrinolysis) produces the major constituents of the natural moisturizing factor. Some proteases/peptidases remain to be identified in this multistep process.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

Background: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA).

Apixaban versus no anticoagulation for the prevention of venous thromboembolism in children with newly diagnosed acute lymphoblastic leukaemia or lymphoma (PREVAPIX-ALL): a phase 3, open-label, randomised, controlled trial.

Background: Paediatric patients with acute lymphoblastic leukaemia or lymphoma are at increased risk of venous thromboembolism resulting in increased mortality and morbidity. We hypothesised that apixaban, a direct oral anticoagulant, would safely reduce venous thromboembolism in this patient population.

Methods: PREVAPIX-ALL was a phase 3, open-label, randomised, controlled trial conducted in 74 paediatric hospitals in 9 countries.

Poroelastic behavior and water permeability of human skin at the nanoscale.

Topical skin care products and hydrating compositions (moisturizers or injectable fillers) have been used for years to improve the appearance of, for example facial wrinkles, or to increase "plumpness". Most of the studies have addressed these changes based on the overall mechanical changes associated with an increase in hydration state. However, little is known about the water mobility contribution to these changes as well as the consequences to the specific skin layers.

Mindfulness and Imagery Enhanced Behavioral Parenting: Effectiveness Pilot of the Confident Carers Cooperative Kids Program.

Mindfulness is increasingly offered to parents of children presenting with behavioral problems, either as a stand-alone intervention, or integrated within existing behavioral parenting interventions. There is relatively modest support for mindful parenting, with small to medium effect size improvements demonstrated across child and parent outcome measures. Here we introduce a mindfulness and imagery enhanced behavioral parenting program.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention.

Background: Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding.

Mindful Parent Training for Parents of Children Aged 3-12 Years with Behavioral Problems: a Scoping Review.

Objectives: While mindfulness-based parenting programs (MPPs) are increasingly popular for reducing child behavior problems, the evidence for the advantages of MPP over existing behavioral parent training is unclear. Existing systematic reviews have largely excluded the breadth of MPP protocols, including those that integrate behavioral skills components. Therefore, a scoping review was conducted to map the nature and extent of research on MPPs for parents of children aged 3 to 12 years with behavioral problems.

Author Correction: Reconstructed Skin Models Revealed Unexpected Differences in Epidermal African and Caucasian Skin.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Filaggrin and filaggrin 2 processing are linked together through skin aspartic acid protease activation.

Skin aspartic acid protease (SASPase) is believed to be a key enzyme involved in filaggrin processing during epidermal terminal differentiation. Since little is known about the regulation of SASPase function, the aim of this study was to identify involved protein partners in the process. Yeast two hybrid analyses using SASPase as bait against a human reconstructed skin library identified that the N-terminal domain of filaggrin 2 binds to the N-terminal fragment of SASPase.

Hyaluronic-Acid-Presenting Self-Assembled Nanoparticles Transform a Hyaluronidase HYAL1 Substrate into an Efficient and Selective Inhibitor.

In this study, an original method of macromolecular design was used to develop a hyaluronidase-1 (HYAL1) inhibitor from its principal substrate, hyaluronic acid (HA). HA-based nanoparticles (HA-NP) were obtained by copolymer self-assembly and their effects on HYAL1 activity were investigated by combining different analytical tools. Compared to HA, HA-NP exhibited an enhanced stability against HYAL1 degradation while maintaining its interaction with the HA receptors CD44 and aggrecan.

Reconstructed Skin Models Revealed Unexpected Differences in Epidermal African and Caucasian Skin.

Clinical observations of both normal and pathological skin have shown that there is a heterogeneity based on the skin origin type. Beside external factors, intrinsic differences in skin cells could be a central element to determine skin types. This study aimed to understand the in vitro behaviour of epidermal cells of African and Caucasian skin types in the context of 3D reconstructed skin.

Anisotropic cellular forces support mechanical integrity of the Stratum Corneum barrier.

The protective function of biological surfaces that are exposed to the exterior of living organisms is the result of a complex arrangement and interaction of cellular components. This is the case for the most external cornified layer of skin, the stratum corneum (SC). This layer is made of corneocytes, the elementary 'flat bricks' that are held together through adhesive junctions.

Multivalent and multifunctional polysaccharide-based particles for controlled receptor recognition.

Polysaccharides represent a versatile class of building blocks that are used in macromolecular design. By choosing the appropriate saccharide block, various physico-chemical and biological properties can be introduced both at the level of the polymer chains and the resulting self-assembled nanostructures. Here, we synthetized amphiphilic diblock copolymers combining a hydrophobic and helical poly(γ-benzyl-L-glutamate) PBLG and two polysaccharides, namely hyaluronic acid (HA) and laminarin (LAM).

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations.

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans.

Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials.

Background: It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs.

Methods: Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method).

Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus.

Background: A post hoc pooled analysis was undertaken to evaluate the safety of saxagliptin in patients with type 2 diabetes mellitus, with attention to events of special interest for dipeptidyl peptidase-4 inhibitors.

Methods: Pooled analyses were performed for 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy, and a subset of 11 saxagliptin + metformin studies. Adverse events and events of special interest (gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, worsening renal function, and specific laboratory events) were assessed; incidence rates (events/100 person-years) and incidence rates ratios (saxagliptin/control) were calculated (Mantel-Haenszel method).

Calmodulin-like skin protein level increases in the differentiated epidermal layers in atopic dermatitis.

In atopic dermatitis (AD), the skin barrier is disturbed, and the expression of calcium-dependent S100 proteins and the calcium gradient is also altered in the epidermis. The calmodulin-like skin protein (CLSP), which is expressed in the differentiated epidermis, is believed to modulate the function of calcium-dependent proteins involved in barrier formation and is significantly increased in the epidermis of psoriatic patients. We, therefore, investigated the CLSP level in skin biopsies taken from patients with acute exacerbated and non-exacerbated AD as well as from healthy control subjects.

Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy.

Background: Achievement of glycemic control is an important objective in the management of type 2 diabetes mellitus (T2DM).

Objective: The objective of this study was to evaluate the safety and efficacy of the dipeptidyl peptidase-4 inhibitor saxagliptin versus placebo as add-on therapy in patients with T2DM inadequately controlled with insulin alone or insulin plus metformin.

Methods: This was a long-term (28-week) extension of a short-term (24-week), randomized, double-blind, parallel-group trial of saxagliptin 5 mg once daily versus placebo as add-on therapy to open-label insulin or insulin plus metformin therapy totaling 52 weeks of treatment.

Proteomic analysis identifies new biomarkers for postmenopausal and dry skin.

A proteomic analysis of stratum corneum (SC) samples of normal healthy skin revealed the presence of more than 70 proteins by 2D electrophoresis. The majority of these proteins to our knowledge have not yet been described in normal SC. We analysed by Western blot the levels of 25 proteins in the SC taken from postmenopausal and dry skin compared with young and normal skin, respectively.

Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin.

Objective: To evaluate efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control on insulin alone or combined with metformin.

Methods: Adults (n = 455) with HbA(1c) 7.5-11% on stable insulin therapy (30-150 U/day ± metformin) for at least 8 weeks were stratified by metformin use and randomly assigned 2:1 to receive saxagliptin 5 mg or placebo once daily for 24 weeks.