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Off‐label repurposing of empagliflozin allows pathomechanism‐based treatment of neutropenia/neutrophil‐dysfunction in glycogen storage disease type Ib (GSDIb). From a value‐based healthcare (VBHC) perspective, we here retrospectively studied patient‐reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity‐analysis, and systematic benefit–risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality‐of‐life‐scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony‐stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482–14 190 (NL) and € 1281–41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062–225 716 (NL) and € 37 697–231 790 (AT), based on conservative assumptions. The systematic benefit‐risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit‐risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems. [ABSTRACT FROM AUTHOR]

Background: Wound management is a critical factor when treating patients with the inherited skin fragility disease dystrophic epidermolysis bullosa (DEB). Due to genetic defects in structural proteins, skin and mucous epithelia are prone to blistering and chronic wounding upon minor trauma. Furthermore, these wounds are commonly associated with excessive pruritus and predispose to the development of life-threatening squamous cell carcinomas, underscoring the unmet need for new therapeutic options to improve wound healing in this patient cohort. Vitamin D3 is acknowledged to play an important role in wound healing by modulating different cellular processes that impact epidermal homeostasis and immune responses. In this study, we evaluate the safety and efficacy of low-dose calcipotriol, a vitamin D3 analogue, in promoting wound healing and reducing itch and pain in patients with DEB.Methods: Eligible DEB patients, aged ≥ 6 years and with a known mutation in the COL7A1 gene, were recruited to a placebo-controlled, randomized, double blind, cross-over phase II monocentric clinical trial. Patients were required to have at least two wounds with a minimum size of 6 cm2 per wound. The primary objective was to evaluate efficacy of daily topical application of a 0.05 µg/g calcipotriol ointment in reducing wound size within a 4-week treatment regimen. Secondary objectives were to assess safety, as well as the impact of treatment on pruritus, pain, and bacterial wound colonization in these patients.Results: Six patients completed the clinical trial and were included into the final analysis. Topical low-dose calcipotriol treatment led to a significant reduction in wound area at day 14 compared to placebo (88.4% vs. 65.5%, P < 0.05). Patients also reported a significant reduction of pruritus with calcipotriol ointment compared to placebo over the entire course of the treatment as shown by itch scores of 3.16 vs 4.83 (P < 0.05) and 1.83 vs 5.52 (P < 0.0001) at days 14 and 28, respectively. Treatment with low-dose calcipotriol did not affect serum calcium levels and improved the species richness of the wound microbiome, albeit with no statistical significance.Conclusions: Our results show that topical treatment with low-dose calcipotriol can accelerate wound closure and significantly reduces itch, and can be considered a safe and readily-available option to improve local wound care in DEB patients. Trial Registration EudraCT: 2016-001,967-35. Registered 28 June 2016, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001967-35/AT. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation are a genetically and phenotypically heterogeneous family of diseases affecting the co‐ and posttranslational modification of proteins. Using exome sequencing, we detected biallelic variants in GFUS (NM_003313.4) c.[632G>A];[659C>T] (p.[Gly211Glu];[Ser220Leu]) in a patient presenting with global developmental delay, mild coarse facial features and faltering growth. GFUS encodes GDP‐L‐fucose synthase, the terminal enzyme in de novo synthesis of GDP‐L‐fucose, required for fucosylation of N‐ and O‐glycans. We found reduced GFUS protein and decreased GDP‐L‐fucose levels leading to a general hypofucosylation determined in patient's glycoproteins in serum, leukocytes, thrombocytes and fibroblasts. Complementation of patient fibroblasts with wild‐type GFUS cDNA restored fucosylation. Making use of the GDP‐L‐fucose salvage pathway, oral fucose supplementation normalized fucosylation of proteins within 4 weeks as measured in serum and leukocytes. During the follow‐up of 19 months, a moderate improvement of growth was seen, as well as a clear improvement of cognitive skills as measured by the Kaufmann ABC and the Nijmegen Pediatric CDG Rating Scale. In conclusion, GFUS‐CDG is a new glycosylation disorder for which oral L‐fucose supplementation is promising. Synopsis: A novel type of congenital disorder of glycosylation (CDG) was identified in a child carrying biallelic variants in GDP‐L‐fucose synthase (GFUS). Oral L‐fucose supplementation resulted in clinical improvements. The index patient presented with stunted growth and no speech at the age of 3 6/12 years, coarse facial features, aversion to feeding, and recurrent vomiting on tube feeding.Biallelic variants in GFUS lead to a reduced level of GDP‐L‐fucose and subsequently to a general hypofucosylation of proteins.GFUS deficiency can be bypassed by oral L‐fucose supplementation triggering the salvage pathway for the generation of GDP‐L‐fucose.After the fucose therapy, the growth parameters have stabilized, and the patient started to speak and showed improved attention span and cognitive skills. [ABSTRACT FROM AUTHOR]

Meat yield, proximate composition, pH and drip loss of breast and thigh muscles were studied in 29 hunted male and 32 slaughtered female pheasants. In the breast muscles of additional 14 hunted male pheasants, colour, cooking loss and shear force were measured. Weight of muscles of hunted male pheasants was higher than that of slaughtered females, but the percentages of breast and thigh muscles relative to the dressed carcass did not differ. Average protein concentrations in lean muscles were above 22%, and average fat was below 1.2%. In breast muscles, pH was lower than in thigh (ca. 5.6 vs. 6.0), and, consequently, drip loss was higher (2.2-3.0% vs. 1.0-1.5%). Colour of breast muscles was characterised by L*a*b* values of about 55, 4 and 8-9, respectively. The shear force of breast muscles was about 30 N/cm. [ABSTRACT FROM AUTHOR]

Blistering in epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is associated with an inflammatory phenotype, which can be disrupted by diacerein in vitro. In this pilot study we hypothesized, that a topical formulation of diacerein 1% reduces blistering. Five patients initially applied diacerein underneath both armpits. Then, each participant received 1% diacerein-cream for one armpit, and placebo for the other (randomized withdrawal). The number of blisters was reduced significantly (left: -78%; right: -66% of baseline) within two weeks and remained significantly below the initial level even during withdrawal in four patients. These findings point to a relevant effect of diacerein and provide important information for a confirmative study. [ABSTRACT FROM AUTHOR]

The LSI process, that is, the infiltration of molten silicon into porous structures, is one of the most economical techniques for the production of dense C/SiC composites. However, despite decades of development, the phenomena at the infiltration front have not been understood sufficiently. Consequently, a comprehensive model of the reactive infiltration process, which would help to optimize the production process of C/SiC components, has not been established yet. A special thermo‐optical measuring furnace, TOM_ac, enables in situ inspection during liquid silicon infiltration in a controlled atmosphere. Using a novel experimental set‐up, temperatures and atmospheres were varied during silicon melt infiltration into gap capillaries incorporated in glassy carbon. Results clearly demonstrate that the capillary effect is not the rate controlling process as commonly believed but show the importance of gas phase reactions. Besides optical inspection of the infiltration process, quenching experiments combined with SEM analyses of the samples provided a detailed insight into reaction mechanisms and transport processes. [ABSTRACT FROM AUTHOR]

Generalized severe epidermolysis bullosa simplex (EBS-gen sev) is caused by mutations within either the KRT5 or KRT14 gene, phenotypically resulting in blistering and wounding of the skin and mucous membranes after minor mechanical friction. In a clinical phase 2/3 trial, diacerein has recently been shown to significantly reduce blister numbers upon topical application. In this study we addressed basic pharmacokinetic parameters of locally applied diacerein in vitro and in vivo. Ex vivo experiments using a Franz diffusion cell confirmed the uptake and bio-transformation of diacerein to rhein in a porcine skin model. Rhein, the active metabolite of diacerein, was also detected in both urine and serum samples of two EBS-gen sev patients who topically applied a 1% diacerein ointment over a period of 4 weeks. The accumulated systemic levels of rhein in EBS-gen sev patients were lower than reported levels after oral application. These preliminary findings point towards the uptake and prolonged persistance of diacerein / rhein within the intended target organ - the skin. Further, they imply an acceptable safety profile at the systemic level. TRIAL REGISTRATION: DRKS. DRKS00005412 . Registered 6 November 2013. [ABSTRACT FROM AUTHOR]

Blistering in epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is associated with an inflammatory phenotype, which can be disrupted by diacerein in vitro. In this pilot study we hypothesized, that a topical formulation of diacerein 1% reduces blistering. Five patients initially applied diacerein underneath both armpits. Then, each participant received 1% diacerein-cream for one armpit, and placebo for the other (randomized withdrawal). The number of blisters was reduced significantly (left: -78%; right: -66% of baseline) within two weeks and remained significantly below the initial level even during withdrawal in four patients. These findings point to a relevant effect of diacerein and provide important information for a confirmative study. [ABSTRACT FROM AUTHOR]