Paediatric atopic dermatitis and treatment adherence: Exploring factors contributing to topical corticosteroid phobia as a contributor to poor treatment adherence

Atopic dermatitis (AD), also known as eczema or atopic eczema, is the most common chronic inflammatory dermatosis (skin condition) affecting paediatric patients in the western world. There continues to be a rapid rise in incidence of this condition worldwide with a doubling of prevalence in children under age five years in the past 30 years. It also remains one of the most treatable with correct management. Topical corticosteroids (TCS), which have a topical anti-inflammatory action, remain central to this management. However, parent and patient poor adherence to prescribed treatment plans often leads to less effective control of their AD. A review of the literature demonstrated that one of the commonly cited contributing factors to treatment non-adherence in paediatric AD is a fear or anxiety regarding the use of TCS, a condition termed ‘TCS phobia’ (Chapter 2). Although moderate to severe atopic dermatitis is disabling and highly disruptive for patients and their families, TCS phobia is a significant barrier to effective treatment. This thesis presents a body of work that aims to identify the sources of information or misinformation about the safety and efficacy of TCS, as well as assessing the impact of this information on parents’ and patients’ perception on the long term use of TCS to manage their AD. Previous research has identified that parents of children with AD highlight the role of family and friends, the Internet, pharmacists and general practitioners as key sources of information that contribute to fear and anxiety towards using TCS to manage AD. This can create conflicting information leading to confusion and ultimately poor or non-adherence to prescribed treatment plans. This is especially the case when the conflicting information comes from different members of the multidisciplinary treatment team. A multidisciplinary treatment team incorporates health care professionals from different disciplines who provide a specific service and associated health information to the patients, and in the setting of AD in Australia includes general practitioners, dermatologists, and pharmacists. Therefore, it is important to investigate the knowledge and attitudes of these health professionals about the safety and efficacy of TCS that forms the advice provided to parents and patients in paediatric AD. This is because treatment adherence is directly related to risk/benefit of treating a condition as well as the perception of disease severity. If the perceived risks associated with treatment, such as TCS in paediatric AD, out way the perceived benefits or perceived disease severity, then there is significant risk of treatment non-adherence. A consensus statement and systematic review of the adverse effects arising from the use of TCS in children with atopic dermatitis was performed (Chapter 3). The aim of the consensus meeting was to identify the potential and perceived adverse effects and systematically review the literature for each. Dermatologists play a key role as clinical educators around the use, safety and efficacy of TCS. A cross-sectional survey of all Australian dermatologists was performed to assess their attitudes towards the use and safety of TCS in paediatric AD (Chapter 4). Close to half (44%) of the 455 dermatologists in Australia completed the survey (n=198). Nearly all responders prescribed potent or super-potent TCS in the management of paediatric AD. The most common side-effect cited by over two-thirds of the respondents was peri-orificial dermatitis with only a minority (6%) citing cutaneous atrophy. Most dermatologists stated that pharmacists were the most common source of misinformation leading to TCS phobia. Of the respondents, 75% strongly agreed that TCS do not cause skin atrophy when used appropriately and under clinical supervision. Furthermore, 77% agreed or strongly agreed that the words ‘use sparingly’ should be removed from pharmacist labels on TCS prescriptions. This study indicates that dermatologists comfortably manage paediatric AD with potent or super-potent TCS and believe that TCS do not cause skin atrophy in paediatric AD. This is in keeping with the current up to date literature on the safety and efficacy of TCS in this setting and represents the baseline against which other healthcare professionals should refer to when providing advice about the treatment of paediatric AD. Parents and dermatologists commonly cite conflicting information provided by pharmacists on the safety and efficacy of TCS in paediatric AD as contributing to TCS phobia and serving as a major impediment to treatment adherence. Consequently, a study was conducted to assess pharmacists’ beliefs and information on the safety of TCS in paediatric AD treatment (Chapter 5). A cross-sectional survey to assess attitudes and knowledge on the use of TCS in paediatric AD was completed by Australian pharmacists (n=292) who attended a continuing professional development conference. The mean response rate for each question was 86% of the 292 surveyed. Of the responders, 64% recognised that treatment non-adherence was a major reason for treatment failure in paediatric AD. Only a quarter (27%) of the pharmacists would instruct parents/patients to apply TCS until the eczema is clear. Over half (54%) of the responders indicated they would instruct patients to use TCS sparingly. Nearly half (46%) of the responders believed that cutaneous atrophy was the commonest side-effect from use and over half (56%) indicated that side-effects would occur, even if used appropriately. This study demonstrated the existence of significant knowledge gaps about the use and safety of TCS in paediatric AD in Australian pharmacists. Furthermore, their advice to patients potentially contributes to poor treatment adherence because of this misinformation which can contribute to the fear and anxiety around using TCS. Parents cite general practitioners and pharmacists as a source of information that contributes to TCS phobia which can in turn affect treatment adherence. The previous study demonstrated the knowledge gap amongst Australian pharmacists. Therefore, a study was conducted to assess general practitioners’ beliefs and information on the safety of TCS in paediatric AD treatment (Chapter 6). A cross-sectional survey was performed on Australian general practitioners (n=257) participating in continuing professional development programs. Over a third (40.7%) instruct parents to apply TCS for two weeks or less. Nearly half (47.7%) instruct parents to apply TCS sparingly or with the smallest amount possible. Furthermore, nearly a third (30.2%) reported skin atrophy as the most common TCS side effect. Therefore, this study demonstrates that advice from their general practitioner may carry unintentional risk messages contributing to a fear and anxiety about using TCS and ultimately can lead to treatment non-adherence. The studies in chapters 4 to 6 demonstrate the potential for conflicting advice from healthcare professionals in a patient’s multi-disciplinary treatment team. However, an investigation was needed to assess the actual impact of the advice from healthcare professionals on patients and parents’ perception of the safety and efficacy of TCS in AD. Furthermore, it is important to assess the advice provided by pharmacists and general practitioners as related to and reported by patients and parents of patients using TCS on a long-term basis for AD (Chapter 7). A multi-centre cross-sectional survey was performed on a total of 123 adult patients and 78 parents (n=201). Of the total respondents, three quarters (76.6%) reported consistently (“Often” or “Always”) receiving one or more message(s) regarding TCS “risk” from a general practitioner (GP) and/ or pharmacist (n=192). Respondents reported being told to “try natural or complementary and alternative therapies before resorting to the use of TCS” significantly more often by pharmacists than by GPs (p=0.039). This study demonstrates that high rates of consistently delivered messages about TCS “risk” from GPs and pharmacists do affect patient/parent understanding about TCS safety. This “risk” messaging can contribute to fear and anxiety about using TCS and may lead to treatment non-adherence. Chapters 4 to 7 provide evidence that conflicting information from different healthcare professionals in the multi-disciplinary treatment team leads to the delivery of negative risk messaging to parents and patients with AD. This contributes to TCS phobia and can lead to poor treatment outcomes due to non-adherence. However, non-health professional such as parents, family and friends, and the Internet are others sources of knowledge about AD and its treatment. This was also investigated. The perception of TCS safety in the management of AD is influenced by family/friends of the patient or parent of children with AD. This means these are another potential source of misinformation on TCS which can negatively impact perceptions of TCS safety. A multicentre cross-sectional survey of patients (aged >18years old) and parents of patients (aged <18years old) with a history of a chronic inflammatory dermatosis was performed to assess information they receive from family/friends and the Internet about TCS use (Chapter 8). A total of 123 patients and 78 parents completed the survey (n=201). Parents/Patients reported that they were more likely to be informed by the Internet “[having] my [child’s] skin condition means that [I/he/she] will need to use topical corticosteroids” (p <0.001) and that “inflamed skin conditions will improve with the topical corticosteroids” (p = 0.007). On the other hand, family/friends were more likely to recommend parents/patients “try nonprescription creams/ointments before resorting to the use of prescription topical corticosteroids” (p = 0.014). This study highlights that high rates of messages about TCS ‘risk’ from family/friends and the Internet may affect patient/parent understanding about TCS safety. Furthermore, this may contribute to treatment non-adherence. Chapters 3 to 8 have demonstrated external influence that can deliver negative biases that contribute to fear and anxiety about TCS use and ultimately lead to non-adherence in the treatment of paediatric AD. However, a parent’s perception of disease severity, representing an ‘internal’ influence bias, can contribute to whether or not they treat their child’s AD. If a parent assesses their child’s AD to be less severe than it actually is, they are much more likely to undertreat and more likely to be non-adherent with the prescribed management plan. A study was performed comparing parent reported disease severity compared to physician assessed disease severity (Chapter 9). A prospective cohort study recruited fifty paediatric patients and their caregivers from an outpatient dermatology clinic. Two clinicians completed ratings on the Eczema Area and Severity Index (EASI) tool and caregivers completed ratings on the Self-Administered EASI (SA-EASI) and Dermatology Quality of Life Index (DLQI) tools. EASI scores between clinicians were compared and there was good inter-clinician reliability (p = 0.351 ). There was a strong, positive statistically significant correlation between EASI and SA-EASI (r = 0.865, p= <0.01). The EASI score mean was statistically significantly higher than the SA-EASI mean (p = <0.001) for a given patient. This study looked to establish a discrepancy between clinician and caregiver perception of atopic dermatitis severity. It showed that caregivers significantly underestimate the severity of their child’s atopic dermatitis. This provides the clinician with a greater understanding into poor treatment compliance commonly observed in clinical practice and highlights a need to provide parents with a greater understanding of their child’s disease. By establishing the severity of the eczema to the caregiver, the clinician is empowered to provide education about the expectations surrounding treatment, allowing greater insight into noncompliance. This can facilitate an approach to the fears and misconceptions that caregivers may have. Overall, the studies in this thesis contribute to an awareness of the sources of negative risk or misinformation about the safety and efficacy of TCS in the setting of paediatric AD. Furthermore, it demonstrates the direct impact of this information on patients and parents. These findings provide the basis for education programs to help educate the healthcare professional members of the multi-disciplinary treatment team. It is through consistent positive messaging from these healthcare professionals that patients and parents will be better equipped and supported to combat the negative risk messaging from non-healthcare professional sources such as family, friends and the Internet. Ultimately, this has the capacity to positively impact treatment adherence and outcomes for both the patient with AD and their entire family unit

Bdellovibrio bacteriovorus HD100 guards against Pseudomonas tolaasii brown-blotch lesions on the surface of post-harvest Agaricus bisporus supermarket mushrooms

BACKGROUND: Pseudomonas tolaasii is a problematic pathogen of cultured mushrooms, forming dark brown 'blotches' on mushroom surfaces and causing spoilage during crop growth and post-harvest . Treating P. tolaasii infection is difficult, as other, commensal bacterial species such as Pseudomonas putida are necessary for mushroom growth, so treatments must be relatively specific. RESULTS: We have found that P. tolaasii is susceptible to predation in vitro by the δ-proteobacterium Bdellovibrio bacteriovorus. This effect also occurred in funga, where B. bacteriovorus was administered to post-harvest mushroom caps before and after administration of the P. tolaasii pathogen. A significant, visible improvement in blotch appearance, after incubation, was observed on administration of Bdellovibrio. A significant reduction in viable P. tolaasii cell numbers, recovered from the mushroom tissue, was detected. This was accompanied by a more marked reduction in blotch severity on Bdellovibrio administration. We found that there was in some cases an accompanying overgrowth of presumed-commensal, non-Pseudomonas bacteria on post-harvest mushroom caps after Bdellovibrio-treatment. These bacteria were identified (by 16SrRNA gene sequencing) as Enterobacter species, which were seemingly resistant to predation. We visualised predatory interactions occuring between B. bacteriovorus and P. tolaasii on the post-harvest mushroom cap surface by Scanning Electron Microscopy, seeing predatory invasion of P. tolaasii by B. bacteriovorus in funga. This anti-P. tolaasii effect worked well in post-harvest supermarket mushrooms, thus Bdellovibrio was not affected by any pre-treatment of mushrooms for commercial/consumer purposes. CONCLUSIONS: The soil-dwelling B. bacteriovorus HD100 preys upon and kills P. tolaasii, on mushroom surfaces, and could therefore be applied to prevent spoilage in post-harvest situations where mushrooms are stored and packaged for sale

How should we evaluate research on counselling and the treatment of depression? A case study on how NICE’s draft 2018 guideline considered what counts as best evidence

Background: Health guidelines are developed to improve patient care by ensuring the most recent and “best available evidence” is used to guide treatment recommendations (NICE Guidance, 2017). NICE’s revised guideline development methodology acknowledges that evidence needed to answer one question (treatment efficacy) may be different from evidence needed to answer another (cost effectiveness, treatment acceptability to patients; NICE, 2014/2017). This review uses counselling in the treatment of depression as a case study, and interrogates the constructs of ‘best’ evidence and ‘best’ guideline methodologies. Method: The review comprises six sections: (1) the implications of diverse definitions of counselling in research; (2) research findings from meta-analyses and randomised controlled trials (RCTs); (3) limitations to trials-based evidence; (4) findings from large routine outcome datasets; (5) the inclusion of qualitative research that emphasises service-user voices; and (6) conclusions and recommendations. Results: Research from meta-analyses and RCTs reviewed in the draft 2018 NICE guideline is limited but positive in relation to the effectiveness of counselling in the treatment for depression. The weight of evidence suggests little, if any, advantage to CBT over counselling once bias and researcher allegiance are taken into account. A growing body of evidence from large NHS datasets also evidences that counselling is both effective and cost-effective when delivered in NHS settings. Conclusion: Recommendations in NICE’s own updated procedures suggest that sole reliance on RCTs and meta-analyses as best methodologies is no longer adequate. There is a need to include large standardised collected datasets from routine practice as well as the voice of patients via high-quality qualitative research

Intermittent applied mechanical loading induces subchondral bone thickening that may be intensified locally by contiguous articular cartilage lesions

Objectives: Changes in subchondral bone (SCB) and cross-talk with articular cartilage (AC) have been linked to osteoarthritis (OA). Using micro-computed tomography (micro-CT) this study: (1) examines changes in SCB architecture in a non-invasive loading mouse model in which focal AC lesions are induced selectively in the lateral femur, and (2) determines any modifications in the contralateral knee, linked to changes in gait, which might complicate use of this limb as an internal control. Methods: Right knee joints of CBA mice were loaded: once with 2weeks of habitual use (n=7), for 2weeks (n=8) or for 5weeks (n=5). Both left (contralateral) and right (loaded) knees were micro-CT scanned and the SCB and trabecular bone analysed. Gait analysis was also performed. Results: These analyses showed a significant increase in SCB thickness in the lateral compartments in joints loaded for 5weeks, which was most marked in the lateral femur; the contralateral non-loaded knee also showed transient SCB thickening (loaded once and repetitively). Epiphyseal trabecular bone BV/TV and trabecular thickness were also increased in the lateral compartments after 5 weeks of loading, and in all joint compartments in the contralateral knee. Gait analysis showed that applied loading only affected gait in the contralateral himd-limb in all groups of mice from the second week after the first loading episode. Conclusions: These data indicate a spatial link between SCB thickening and AC lesions following mechanical trauma, and the clear limitations associated with the use of contralateral joints as controls in such OA models, and perhaps in OA diagnosis

Revision of the African cichlid fish genus Ctenochromis (Teleostei, Cichliformes), including a description of the new genus Shuja from Lake Tanganyika and the new species Ctenochromis scatebra from northern Tanzania

Molecular phylogenetic evidence clearly resolves the African cichlid fish genus Ctenochromis, as defined by Greenwood (1979), as paraphyletic. Here, we redefine the genus Ctenochromis and assign Ctenochromis horei, a member of the Tropheini from Lake Tanganyika, to a new genus Shuja gen. nov. We restrict Ctenochromis to Ctenochromis pectoralis and Ctenochromis scatebra sp. nov., both of which are endemic to the Pangani River catchment in northern Tanzania, and are resolved as sister taxa in a phylogenetic analysis using genome-wide data. Ctenochromis pectoralis is the type species of the genus and described from specimens collected near Korogwe, Tanzania. The species was declared extinct in a 2016 IUCN Red List Assessment. We confirm the continued presence of a population of C. pectoralis within the Ruvu tributary linking Lake Jipe to Nyumba ya Mungu Reservoir. The new taxon Ctenochromis scatebra sp. nov. is described from Chemka Springs, and recognised on the basis of differences from C. pectoralis in tooth and jaw morphology

Lateral line system diversification during the early stages of ecological speciation in cichlid fish

Background: The mechanosensory lateral line system is an important sensory modality in fishes, informing multiple behaviours related to survival including finding food and navigating in dark environments. Given its ecological importance, we may expect lateral line morphology to be under disruptive selection early in the ecological speciation process. Here we quantify the lateral line system morphology of two ecomorphs of the cichlid fish Astatotilapia calliptera in crater Lake Masoko that have diverged from common ancestry within the past 1,000 years. Results: Based on geometric morphometric analyses of CT scans, we show that the zooplanktivorous benthic ecomorph that dominates the deeper waters of the lake has large cranial lateral line canal pores, relative to those of the nearshore invertebrate-feeding littoral ecomorph found in the shallower waters. In contrast, fluorescence imaging revealed no evidence for divergence between ecomorphs in the number of either superficial or canal neuromasts. We illustrate the magnitude of the variation we observe in Lake Masoko A. calliptera in the context of the neighbouring Lake Malawi mega-radiation that comprises over 700 species. Conclusions: These results provide the first evidence of divergence in this often-overlooked sensory modality in the early stages of ecological speciation, suggesting that it may have a role in the broader adaptive radiation process

Sustainable Harvesting of Tropical Rainforests: Reply to Keto, Scott and Olsen

This paper refutes the Keto et al. proposition that the Queensland selection logging system is neither ecologically nor economically sustainable. The key requirements of this system are: (1) that logging guidelines are sympathetic to the silvicultural characteristics of the forest, ensuring adequate regeneration of commercial species and discouraging invasion by weeds; (2) tree-marking by trained staff specifies trees to be retained, trees to be removed and the direction of felling to ensure minimal damage to the residual stand; (3) logging equipment is appropriate and driven by trained operators to ensure minimal damage and soil disturbance, compaction and erosion; (4) prescriptions ensure that adequate stream buffers and steep slopes are excluded from logging; (5) sufficient areas for scientific reference, feature protection and recreation are identified and excluded from logging; and (6) that deficiencies in an evolving system are recognized and remedied, leading to an improved system. Many studies of the effects of logging in these forests have been published and collectively provide a unique demonstration of one possible approach to sustainable timber harvesting