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2.
Australas J Dermatol ; 65(4): 373-377, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38445760

ABSTRACT

As with adults, paediatric patients may benefit from a number of advanced targeted therapies for inflammatory skin disease. This brief report aims to be an accessible reference tool with respect to regulatory approval and reimbursement of these treatments within Australia.


Subject(s)
Dermatologic Agents , Humans , Australia , Child , Dermatologic Agents/administration & dosage , Dermatologic Agents/therapeutic use , Psoriasis/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Ustekinumab/therapeutic use , Ustekinumab/administration & dosage , Skin Diseases/drug therapy
4.
Skin Health Dis ; 4(1): e314, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38312260

ABSTRACT

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin fragility disorder requiring multidisciplinary management. Information regarding costs of current standard treatment is scant. Objectives: As part of a longitudinal natural history study, we explored the community care costs of UK patients with different forms of RDEB. Methods: Fifty-nine individuals with RDEB provided detailed information on multiple facets of RDEB including disease severity scores (iscorEB, BEBS) and patient reported outcomes (quality of life evaluation in epidermolysis bullosa, iscorEB patient questionnaire). Costs data included time spent doing dressings, frequency of dressing changes, details of materials used, and paid and unpaid care. Results: Overall costs of dressing materials and associated care were high in RDEB. Median annual costs across all subtypes for those using dressings (n = 51) were over £26 000. For severe RDEB (RDEB-S), median costs were almost £90 000 per annum, with a median of 18 h per week spent on dressing changes. Half of working-age adults with RDEB were unemployed and 39% of carers were unable to take on full-time or part-time paid employment, adding to indirect costs and the financial burden from RDEB on families and society. Conclusions: The findings demonstrate the high costs of care of RDEB, particularly for RDEB-S. The current expense supports the drive to develop new therapies which accelerate wound healing and diminish total wound burden, thereby reducing costs of dressings and care. While costly to bring to market, these might ultimately reduce the overall cost of treatment and also the impact on individuals living with this rare disease. The data also highlight the need for adequate reimbursement for EB care which can place significant financial strain on families.

6.
Orphanet J Rare Dis ; 18(1): 235, 2023 08 09.
Article in English | MEDLINE | ID: mdl-37559055

ABSTRACT

BACKGROUND: Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes. OBJECTIVES: As part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and correlation with disease severity and quality of life. METHODS: Fifty individuals with RDEB aged 8 years and above completed the Leuven Itch Scale (LIS) (total 243 reviews over a 7-year period). Data included itch frequency, severity, duration, distress, circumstances, consequences, itch surface area and medications for itch. The iscorEB disease severity score and the validated EB quality of life tool, QOLEB, were compared to LIS domains and analysed by RDEB subtype. RESULTS: Itch was frequent, present in the preceding month in 93% of reviews. Itch severity and distress were significantly greater in severe (RDEB-S) and pruriginosa (RDEB-Pru) subtypes compared to intermediate RDEB (RDEB-I). Itch medications were reported in just over half of reviews including emollients, topical corticosteroids and antihistamines; the proportion of participants not using medication despite frequent pruritus suggests limited efficacy. In inversa RDEB (RDEB-Inv) and RDEB-I, LIS domains correlated with iscorEB and QOLEB. In contrast to previous studies, correlations were lacking in RDEB-S suggesting that global disease burden relatively reduces the contribution of itch. CONCLUSIONS: This comprehensive study of RDEB-associated itch highlights differences between RDEB subtypes, suggests an unmet need for effective treatments and could serve as control data for future clinical trials incorporating itch as an endpoint.


Subject(s)
Epidermolysis Bullosa Dystrophica , Epidermolysis Bullosa , Humans , Epidermolysis Bullosa Dystrophica/complications , Quality of Life , Epidermolysis Bullosa/complications , Pruritus , Prospective Studies
8.
Cell Rep Med ; 4(5): 101051, 2023 05 16.
Article in English | MEDLINE | ID: mdl-37196633

ABSTRACT

Alterations in the microbiome correlate with improved metabolism in patients following bariatric surgery. While fecal microbiota transplantation (FMT) from obese patients into germ-free (GF) mice has suggested a significant role of the gut microbiome in metabolic improvements following bariatric surgery, causality remains to be confirmed. Here, we perform paired FMT from the same obese patients (BMI > 40; four patients), pre- and 1 or 6 months post-Roux-en-Y gastric bypass (RYGB) surgery, into Western diet-fed GF mice. Mice colonized by FMT from patients' post-surgery stool exhibit significant changes in microbiota composition and metabolomic profiles and, most importantly, improved insulin sensitivity compared with pre-RYGB FMT mice. Mechanistically, mice harboring the post-RYGB microbiome show increased brown fat mass and activity and exhibit increased energy expenditure. Moreover, improvements in immune homeostasis within the white adipose tissue are also observed. Altogether, these findings point to a direct role for the gut microbiome in mediating improved metabolic health post-RYGB surgery.


Subject(s)
Bariatric Surgery , Gastrointestinal Microbiome , Insulin Resistance , Mice , Animals , Adipose Tissue, Brown , Obesity/surgery , Energy Metabolism
9.
Mucosal Immunol ; 16(2): 135-152, 2023 04.
Article in English | MEDLINE | ID: mdl-36792009

ABSTRACT

The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.


Subject(s)
Autophagy-Related Proteins , Crohn Disease , Intestinal Mucosa , Animals , Mice , Autophagy/genetics , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Cell Death/genetics , Crohn Disease/genetics , Crohn Disease/pathology , Interferon-gamma/metabolism , Interferon-gamma/pharmacology , Intestinal Diseases/metabolism , Intestinal Diseases/pathology , Intestinal Mucosa/metabolism , Intestines/metabolism , Intestines/pathology , Tumor Necrosis Factor-alpha
10.
Cancers (Basel) ; 15(3)2023 Jan 17.
Article in English | MEDLINE | ID: mdl-36765529

ABSTRACT

Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4-12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.

11.
Animals (Basel) ; 13(3)2023 Jan 23.
Article in English | MEDLINE | ID: mdl-36766277

ABSTRACT

The management of ewes across southern Australia may vary with breed and can change over time and, as such, a greater understanding of producer management practices and the motivations that influence these practices is required. A cross-sectional study was performed by telephone interview with sheep producers managing Composite, Maternal, Merino or shedding ewe breeds mated in either spring, summer, or autumn. The surveyed producers were a unique subset of southern Australian producers. A large proportion of the surveyed producers followed current best practice guidelines for ewe mating and lambing nutritional management; however, some producers did not align with these targets. Further, some producers did not see the value in attaining the current recommendations. Pregnancy scanning was widely practiced, likely an artefact of the recruitment process; however, a few producers did not utilize this information for nutritional management at lambing time. Finally, most producers were active in their search for new information, seeking information regularly from a wide range of sources and reported making management changes within the last five years. Further work is required to understand why some producers are not adopting best practice where possible and to understand current barriers for adoption. Management guidelines for all sheep breeds are required to best manage sheep across southern Australia.

12.
14.
Animals (Basel) ; 12(21)2022 Oct 24.
Article in English | MEDLINE | ID: mdl-36359032

ABSTRACT

Sheep production in southern Australia may vary by breed, time of year, production output (wool, meat, or both), region and seasonal influence. Sheep producers with flocks of approximately 300-500 ewes (n = 58) were recruited across southern Australia to take part in a survey and mating variables were collected from over 30,000 ewes between October 2020 and August 2021. A Bayesian Network (BN) was developed to identify the interrelatedness and most influential variable on pregnancy and fetal number (of pregnant ewes) outcomes under different scenarios. The BN analysis indicated a low association between the variables explored, however, were breed dependent. In wool-based breeds a mating liveweight of 60-69.5 kg predicted the lowest non-pregnant and greatest number of fetuses, and in shedding ewes 70-79.5 kg predicted the lowest non-pregnant rate and 90-99.5 kg the greatest number of fetuses. Pregnancy rate and fetuses per ewe were optimized at ram percentages of 1.5% for Composite and Merino ewes and 2% for Maternal ewes. A mating BCS 4 resulted in greatest pregnancy rate and number of fetuses across all breeds. Curvilinear relationships between mating liveweight, BCS and ram percentage were observed with pregnancy rate and fetal number. Practically, reproductive potential is best managed on a breed basis and with consideration of all variables explored.

16.
Australas J Dermatol ; 63(4): e289-e296, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36057946

ABSTRACT

Discoid (nummular) eczema is a common and distinctive eczema variant, which has not been studied in depth. Although the principles of management are similar to that of classic atopic dermatitis, distinctions are made due to its unique presentation and persistent clinical course in children. Australian and New Zealand dermatologists with an interest in paediatric eczema developed a consensus narrative to assist clinicians in diagnosing and treating this subtype of eczema. Identifying triggers, potent topical corticosteroids under occlusion, skin barrier support and management of pruritus are first-line therapies, however, many eventually require systemic immunomodulatory agents.


Subject(s)
Dermatitis, Atopic , Dermatologic Agents , Eczema , Child , Humans , New Zealand , Australia , Eczema/diagnosis , Eczema/drug therapy , Dermatitis, Atopic/drug therapy , Dermatologic Agents/therapeutic use
17.
Gut Microbes ; 14(1): 2104087, 2022.
Article in English | MEDLINE | ID: mdl-35912530

ABSTRACT

Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to glycolipid antigens found in microbes in a CD1d-dependent manner. iNKT cells exert innate-like functions and produce copious amounts of cytokines, chemokines and cytotoxic molecules within only minutes of activation. As such, iNKT cells can fuel or dampen inflammation in a context-dependent manner. In addition, iNKT cells provide potent immunity against bacteria, viruses, parasites and fungi. Although microbiota-iNKT cell interactions are not well-characterized, mounting evidence suggests that microbiota colonization early in life impacts iNKT cell homeostasis and functions in disease. In this study, we showed that CD1d-/- and Vα14 Tg mice, which lack and have increased numbers of iNKT cells, respectively, had no significant alterations in gut microbiota composition compared to their littermate controls. Furthermore, specific iNKT cell activation by glycolipid antigens only resulted in a transient and minimal shift in microbiota composition when compared to the natural drift found in our colony. Our findings demonstrate that iNKT cells have little to no influence in regulating commensal bacteria at steady state.Abbreviations: iNKT: invariant Natural Killer T cell; αGC: α-galactosylceramide.


Subject(s)
Gastrointestinal Microbiome , Microbiota , Natural Killer T-Cells , Animals , Cytokines , Glycolipids , Mice
18.
Pediatr Dermatol ; 39(5): 752-756, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35896169

ABSTRACT

Segmental infantile hemangiomas affecting the upper body are associated with PHACE(S) (Posterior fossa anomalies, Hemangioma, Arterial anomalies, Cardiac anomalies, Eye anomalies, and Sternal defects) syndrome, whereas segmental infantile hemangiomas affecting the lower body are the cutaneous hallmark of LUMBAR (Lower body hemangioma and other skin defects, Urogenital anomalies and Ulceration, Myelopathy, Bony deformities, Anorectal malformations and Arterial anomalies, and Renal anomalies) syndrome. We present two individuals with concurrent features of both PHACE and LUMBAR syndromes demonstrating an overlap phenotype. The overlapping features seen in our patients suggest that these syndromes occur on the same phenotypic spectrum and derive from a common embryonic pathophysiology.


Subject(s)
Abnormalities, Multiple , Aortic Coarctation , Eye Abnormalities , Hemangioma , Neurocutaneous Syndromes , Abnormalities, Multiple/diagnosis , Eye Abnormalities/diagnosis , Hemangioma/diagnosis , Humans , Neurocutaneous Syndromes/diagnosis , Syndrome
19.
Br J Dermatol ; 187(5): 730-742, 2022 11.
Article in English | MEDLINE | ID: mdl-35762296

ABSTRACT

BACKGROUND: There is limited evidence on the best available treatment options for capillary malformations (CMs), mainly due to the absence of uniform outcome measures in trials on therapies. A core outcome set (COS) enables standard reporting of trial outcomes, which facilitates comparison of treatment results. OBJECTIVES: To develop a core outcome domain set (CDS), as part of a core outcome set (COS), for clinical research on CMs. METHODS: Sixty-seven potentially relevant outcome subdomains were recognized based on the literature, focus group sessions, and input from the COSCAM working group. These outcome subdomains were presented in an online Delphi study to CM experts (medical specialists and authors of relevant literature) and (parents of) patients with CM (international patient associations). During three e-Delphi study rounds, the participants repeatedly scored the importance of these outcome subdomains on a seven-point Likert scale. Participants could also propose other relevant outcome subdomains. Consensus was defined as ≥ 80% agreement as to the importance of an outcome subdomain among both stakeholder groups. The CDS was finalized during an online consensus meeting. RESULTS: In total 269 participants from 45 countries participated in the first e-Delphi study round. Of these, 106 were CM experts from 32 countries, made up predominantly of dermatologists (59%) and plastic surgeons (18%). Moreover, 163 (parents of) patients with CM from 28 countries participated, of whom 58% had Sturge-Weber syndrome. During the two subsequent e-Delphi study rounds, 189 and 148 participants participated, respectively. After the entire consensus process, consensus was reached on 11 outcome subdomains: colour/redness, thickness, noticeability, distortion of anatomical structures, glaucoma, overall health-related quality of life, emotional functioning, social functioning, tolerability of intervention, patient satisfaction with treatment results, and recurrence. CONCLUSIONS: We recommend the CDS to be used as a minimum reporting standard in all future trials of CM therapy. Our next step will be to select suitable outcome measurement instruments to score the core outcome subdomains. What is already known about this topic? Besides physical and functional sequelae, capillary malformations (CMs) often cause emotional and social burden. The lack of uniform outcome measures obstructs proper evaluation and comparison of treatment strategies. As a result, there is limited evidence on the best available treatment options. The development of a core outcome set (COS) may improve standardized reporting of trial outcomes. What does this study add? A core outcome domain set (CDS), as part of a COS, was developed for clinical research on CMs. International consensus was reached on the recommended core outcome subdomains to be measured in CM trials: colour/redness, thickness, noticeability, distortion of anatomical structures, glaucoma, overall health-related quality of life, emotional functioning, social functioning, tolerability of intervention, patient satisfaction with treatment results, and recurrence. This CDS enables the next step in the development of a COS, namely to reach consensus on the core outcome measurement instruments to score the core outcome subdomains. What are the clinical implications of this work? The obtained CDS will facilitate standardized reporting of treatment outcomes, thereby enabling proper comparison of treatment results. This comparison is likely to provide more reliable information for patients about the best available treatment options.


Subject(s)
Glaucoma , Quality of Life , Humans , Consensus , Delphi Technique , Outcome Assessment, Health Care , Research Design , Treatment Outcome , Clinical Trials as Topic
20.
Int J Clin Pharm ; 44(3): 663-672, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35320485

ABSTRACT

Background General practice in the UK is experiencing a crisis. Greater multidisciplinary working is a potential solution. The new general practice contract in Scotland encourages this and includes a new pharmacotherapy service to be delivered by General Practice Clinical Pharmacists (GPCPs). Consensus is lacking for the standards of practice for delivery of pharmacotherapy medication reviews (which are polypharmacy and chronic medication reviews) as part of this service. Aim To identify and validate standards of practice for polypharmacy and chronic disease medication (pharmacotherapy level 3) reviews conducted by GPCPs. Method A two-phased mixed-methods consensus methodology was used. Phase 1: An expert group of GPCPs (n = 4) and clinical pharmacist managers (n = 2) responsible for delivering the pharmacotherapy service used a Modified Nominal Group Technique to generate potential standards. Phase 2: Two-round Delphi survey involving GPCPs with ≥ 1 year of experience of working in general practice (n = 159). Results The expert group identified 44 potential standards of practice for polypharmacy and chronic disease reviews. Practicing GPCPs indicated during the Delphi phase that the 44 standards were applicable to practice. The standards of practice covered seven main categories: skills, environment, qualifications, qualities and behaviours, knowledge, process and experience. Conclusion Practicing GPCPs indicated that the standards identified by the expert group are acceptable and valid for current practice and the delivery of polypharmacy and chronic medication reviews. The application of these standards to practice may help GPCPs and general practices to ensure equitable delivery of patient care.


Subject(s)
General Practice , Pharmacists , Chronic Disease , General Practice/methods , Humans , Medication Review , Pharmaceutical Preparations , Polypharmacy
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