Talaromycosis in a renal transplant recipient returning from South China.

Talaromycosis is a fungal infection endemic in Southeast Asia. We report a case of a renal transplant recipient who developed infection after a trip to South China. She presented with constitutional symptoms and was found to have an FDG-avid lung mass. Histopathology demonstrated small yeast cells and culture grew Talaromyces marneffei. The patient was treated with 2 weeks of liposomal amphotericin B followed by itraconazole. The dose of tacrolimus was significantly reduced because of the interaction with itraconazole. Mycophenolate mofetil was discontinued. After 12 months of treatment, the mass had completely resolved. Talaromycosis has mainly been reported in patients with AIDS and is uncommon among solid organ transplant recipients. The immune response against T. marneffei infection is mediated predominantly by T cells and macrophages. The diagnosis may not be suspected outside of endemic areas. We propose a therapeutic approach in transplant patients by extrapolating the evidence from the HIV literature and following practices applied to other endemic mycoses.

Patient Strategies for Managing the Vicious Cycle of Fatigue, Pain and Urgency in Inflammatory Bowel Disease: Impact, Planning and Support.

BACKGROUND: Inflammatory bowel disease (IBD) causes inter-related symptoms of fatigue, pain and urgency which can persist in remission. AIM: To understand how people with IBD experience and self-manage these symptoms and to inform the future development of an online self-management programme. METHODS: Using exploratory qualitative methods, we recruited participants from clinic and community settings. Focus groups, conducted across the UK, were audio-recorded and professionally transcribed. Transcripts were analysed over four rounds using framework analysis. Eight patients were consulted to agree the final structure of data and themes. RESULTS: Seven focus groups were held; five gave useable data. Twenty-six participants (15 female; ages 21-60 years; disease duration 2-40 years) with Crohn's disease (n = 10), ulcerative colitis (n = 14) and IBD-unclassified (n = 2) attended one of these five focus groups. Three core themes emerged: The Negative Impact of Symptoms, Positively Taking Control and Seeking and Receiving Support. The persistent, often stark impact of multiple co-existing symptoms on physical and emotional wellbeing can force unwanted adjustments and limitations in working, social and intimate arenas of life. Unpredictable symptoms are challenging and impact each other in negative vicious cycles. Managing diet, pacing, accepting background levels of fatigue, pain and urgency, seeking support, exercising and attending to mental wellbeing, are all perceived as helpful in self-managing symptoms. CONCLUSION: Fatigue, pain and urgency are troublesome for patients, especially in combination, suggesting that these should be addressed simultaneously by clinicians. Participants reported several strategies for self-management, providing patient-focused evidence to inform future development of a self-management intervention programme.

Effective nebulization of interferon-γ using a novel vibrating mesh.

BACKGROUND: Interferon gamma (IFN-γ) is a clinically relevant immunomodulatory cytokine that has demonstrated significant potential in the treatment and management of respiratory diseases such as tuberculosis and pulmonary fibrosis. As with all large biomolecules, clinical translation is dependent on effective delivery to the disease site and delivery of IFN-γ as an aerosol offers a logical means of drug targeting. Effective localization is often hampered by instability and a lack of safe and efficient delivery systems. The present study sought to determine how effectively IFN-γ can be nebulized using two types of vibrating mesh nebulizer, each with differing mesh architectures, and to investigate the comparative efficiency of delivery of therapeutically active IFN-γ to the lungs. METHODS: Nebulization of IFN-γ was carried out using two different Aerogen vibrating mesh technologies with differing mesh architectures. These technologies represent both a standard commercially available mesh type (Aerogen Solo®) and a new iteration mesh (Photo-defined aperture plate (PDAP®). Extensive aerosol studies (aerosol output and droplet analysis, non-invasive and invasive aerosol therapy) were conducted in line with regulatory requirements and characterization of the stability and bioactivity of the IFN-γ post-nebulization was confirmed using SDS-PAGE and stimulation of Human C-X-C motif chemokine 10 (CXCL 10) also known as IFN-γ-induced protein 10KDa (IP 10) expression from THP-1 derived macrophages (THP-1 cells). RESULTS: Aerosol characterization studies indicated that a significant and reproducible dose of aerosolized IFN-γ can be delivered using both vibrating mesh technologies. Nebulization using both devices resulted in an emitted dose of at least 93% (100% dose minus residual volume) for IFN-γ. Characterization of aerosolized IFN-γ indicated that the PDAP was capable of generating droplets with a significantly lower mass median aerodynamic diameter (MMAD) with values of 2.79 ± 0.29 µm and 4.39 ± 0.25 µm for the PDAP and Solo respectively. The volume median diameters (VMD) of aerosolized IFN-γ corroborated this with VMDs of 2.33 ± 0.02 µm for the PDAP and 4.30 ± 0.02 µm for the Solo. SDS-PAGE gels indicated that IFN-γ remains stable after nebulization by both devices and this was confirmed by bioactivity studies using a THP-1 cell model in which an alveolar macrophage response to IFN-γ was determined. IFN-γ nebulized by the PDAP and Solo devices had no significant effect on the key inflammatory biomarker cytokine IP-10 release from this model in comparison to non-nebulized controls. Here we demonstrate that it is possible to combine IFN-γ with vibrating mesh nebulizer devices and facilitate effective aerosolisation with minimal impact on IFN-γ structure or bioactivity. CONCLUSIONS: It is possible to nebulize IFN-γ effectively with vibrating mesh nebulizer devices without compromising its stability. The PDAP allows for generation of IFN-γ aerosols with improved aerodynamic properties thereby increasing its potential efficiency for lower respiratory tract deposition over current technology, whilst maintaining the integrity and bioactivity of IFN-γ. This delivery modality therefore offers a rational means of facilitating the clinical translation of inhaled IFN-γ.

'Symptom-free' when inflammatory bowel disease is in remission: Expectations raised by online resources.

OBJECTIVES: Up to 60% of patients with inflammatory bowel disease (IBD) experience symptoms when in remission. Qualitative research suggests patients seldom feel they receive adequate explanations for these. This study explores how, and how often, ongoing symptoms during remission are represented on readily searchable patient websites. METHODS: Bing, Google, and Yahoo were searched for websites providing medical information about IBD. Thematic analysis was used to inductively explore themes around symptoms during quiescent IBD, followed by deductive content analysis to quantify core themes. RESULTS: Results indicated that remission is commonly defined as "few or no symptoms" and that there is limited information available on symptoms during remission. 55.6% of IBD websites provided a definition of remission based on symptom control only, while 44.4% also incorporated inflammatory control. The few websites that mentioned that symptoms may continue during remission (21.7%) related these to IBS. CONCLUSIONS: Current website information is predominantly biomedical and fails to adequately explain how symptoms may persist during remission and how IBS and IBD may be linked. PRACTICE IMPLICATIONS: Lack of explanatory models of symptoms in remission may lead to distress and increase anxiety about symptoms. Clearer explanations of these symptoms are needed.

Development and preliminary evaluation of a suicidal risk assessment protocol in a randomised controlled trial using the Patient Health Questionnaire (PHQ-9).

BACKGROUND: Participants in research trials often disclose severe depression symptoms, including thoughts of self-harm and suicidal ideation, in validated self-administered questionnaires such as the Patient Health Questionnaire (PHQ-9). However, there is no standard protocol for responding to such disclosure, and the opportunity to support people at risk is potentially missed. We developed and evaluated a risk assessment protocol for the IBD-BOOST randomised controlled trial (ISRCTN71618461 09/09/2019). METHODS: Participants completed the PHQ-9 at baseline and 6-month and 12-month follow-ups. The trial database automatically alerted the research team to risk assess participants. Trial researchers, trained in the protocol, contacted participants by telephone, completed the risk assessment, and signposted participants to appropriate professional services. RESULTS: Seven hundred eighty participants were randomised in the trial; 41 required risk assessment. One participant declined assessment, so 40 risk assessments were completed. Twenty-four participants were assessed as low-risk and 16 participants as medium-risk, with 12 declaring previous suicide attempts. None were rated as high-risk. Trial participants expressed appreciation for being contacted, and all except two wished to receive information about professional support services. Trial risk assessors reported positive experiences of conducting the risk assessment with suggestions for improvement, which resulted in minor modifications to the protocol. DISCUSSION: Our evaluation demonstrated that it was viable for a research trial team to successfully conduct a risk-assessment protocol for trial participants reporting thoughts of self-harm, with training and support from senior colleagues. Resources are required for training and delivery, but it is not unduly onerous. Trial participants appeared to find completing the assessment acceptable.

Systematic review: the role of psychological stress in inflammatory bowel disease.

BACKGROUND: Psychological stress is a possible factor in the disease course and poor psychosocial outcomes in inflammatory bowel disease (IBD). Understanding the exact relationship between stress and health has been hampered by methodological issues and how stress has been defined and measured. AIMS: To explore the association between stress and disease outcomes, investigate the impact of stress on psychosocial outcomes, and evaluate the efficacy of interventions in reducing stress for people with IBD METHODS: We performed a systematic review, searching Medline, CINAHL, Embase and PsycInfo databases on 21 January 2021. We included prospective studies that recruited people with IBD who were aged 16 or over and that measured psychological stress or distress. Analyses included Critical Appraisal Skills Programme quality assessments of included studies and narrative analyses against each research question. RESULTS: We reviewed 38 studies with 4757 people with IBD, and included 23 observational and 15 interventional studies using 36 different instruments to measure stress. Perceived stress was the most frequently studied concept and preceded IBD exacerbation. Only three studies examined the relationship between stress and psychosocial factors. Cognitive behavioural interventions may reduce stress and other interventions with disease-specific stress, but more studies are needed where groups have comparable baseline characteristics and potential harms are considered alongside benefits. CONCLUSION: Psychological stress appears to precede IBD exacerbation, although what role it plays in psychosocial outcomes and how it is best managed is unclear. Further research needs to examine the differential effects of stress on disease subtypes and IBD in flare and remission.

A Novel Digital Self-management Intervention for Symptoms of Fatigue, Pain, and Urgency in Inflammatory Bowel Disease: Describing the Process of Development.

BACKGROUND: Empirical studies and systematic reviews have demonstrated the role of biological, cognitive, behavioral, and emotional factors in fatigue, pain, and urgency in inflammatory bowel disease (IBD). Behavioral management that addresses the cognitive, behavioral, and emotional factors offered alongside medical treatment is seldom available to people with IBD. Digital interventions provide a potentially scalable and cost-effective way of providing behavioral support to patients. OBJECTIVE: This paper aimed to describe the process of developing a supported digital self-management intervention for fatigue, pain, and urgency in IBD using theory and evidence-based approaches and stakeholder input. METHODS: The Medical Research Council framework for complex health interventions and a person-based approach were used to guide intervention development, consulting with 87 patients with IBD and 60 nurses. These frameworks informed the selection and use of a theoretical model that subsequently guided cognitive behaviorally based intervention content. They also guided the design of tailored digital intervention pathways for individuals with IBD that matched the predominant symptoms. RESULTS: A transsymptomatic cognitive behavioral framework of symptom perpetuation was developed for the symptoms of fatigue, pain, and urgency in IBD. A logic model was used to define the intervention techniques. Patient feedback and qualitative interviews refined the website content and functionalities, including the use of visual aids, email reminders, and graphical tracking of symptoms. Nurse focus groups informed the volume and delivery model of the therapist facilitator support. Ratings of acceptability out of 10 following feasibility testing (31/87, 36%) demonstrated accessibility (scoring 9.43, SD 1.040), ease (scoring 8.07, SD 3.205), clarity, and the relevant tone of the intervention. The final intervention comprised 12 web-based sessions (8 core and 4 symptom-specific), with one 30-minute facilitator phone call following session 1 and subsequent on-site messaging. CONCLUSIONS: The use of theory and integration of stakeholders' views throughout informed the development of an evidence-based digital intervention for fatigue, pain, and urgency in IBD. This is the first web-based self-management intervention designed to address these multiple symptoms with the aim of improving the quality of life and reducing the symptom burden of IBD. The intervention is being tested in a large multicenter randomized controlled trial. TRIAL REGISTRATION: ISRCTN Registry ISRCTN71618461; https://www.isrctn.com/ISRCTN71618461.

Pain management in inflammatory bowel disease: feasibility of an online therapist-supported CBT-based self-management intervention.

BACKGROUND: Chronic pain is a poorly managed symptom of inflammatory bowel disease (IBD). Cognitive behavioural therapy (CBT) has an evidence base in functional gastrointestinal conditions and chronic pain. This study aimed to test the feasibility and acceptability of a 9-week online facilitator-supported CBT intervention, tailored for people with chronic IBD-related pain. DESIGN: A single-arm pre-post design with nested qualitative interviews was used. Twenty individuals with IBD and chronic pain were recruited through an online IBD charity and had consented to research in a previous survey or responded to an online charity advert. Individuals who indicated a pain-interference score of ≥ 4/10 (Brief Pain Inventory) and met inclusion criteria were invited to take part. Outcomes included recruitment and retention rates, pain interference and severity, quality of life (QoL) and psychosocial measures. RESULTS: Of 145 individuals contacted, 55 (37.9%) responded. Two individuals were recruited from the study advertisement. Twenty out of 57 (35.1%) met screening and eligibility criteria. Eighty-five percent of the sample engaged with intervention sessions and 55% completed at least 5/9 sessions. Eighty percent of recruited participants completed the post-intervention questionnaire at week 9. The mean score for overall acceptability was 43.4 (0-70). Qualitative feedback demonstrated the value of thought monitoring and facilitator support. Scores improved for QoL and pain self-efficacy and reduced for depression, anxiety, pain catastrophising and avoidance resting behaviour. CONCLUSIONS: Online CBT for chronic IBD-related pain appears feasible and acceptable. The study suggests positive effects for improving QoL and reducing psychological distress; however, online and face-to-face recruitment methods are recommended and establishing efficacy through larger randomised controlled trials is required.

Supported online self-management versus care as usual for symptoms of fatigue, pain and urgency/incontinence in adults with inflammatory bowel disease (IBD-BOOST): study protocol for a randomised controlled trial.

BACKGROUND: Despite being in clinical remission, many people with inflammatory bowel disease (IBD) live with fatigue, chronic abdominal pain and bowel urgency or incontinence that limit their quality of life. We aim to test the effectiveness of an online self-management programme (BOOST), developed using cognitive behavioural principles and a theoretically informed logic model, and delivered with facilitator support. PRIMARY RESEARCH QUESTION: In people with IBD who report symptoms of fatigue, pain or urgency and express a desire for intervention, does a facilitator-supported tailored (to patient needs) online self-management programme for fatigue, pain and faecal urgency/incontinence improve IBD-related quality of life (measured using the UK-IBDQ) and global rating of symptom relief (0-10 scale) compared with care as usual? METHODS: A pragmatic two-arm, parallel group randomised controlled trial (RCT), of a 12-session facilitator-supported online cognitive behavioural self-management programme versus care as usual to manage symptoms of fatigue, pain and faecal urgency/incontinence in IBD. Patients will be recruited through a previous large-scale survey of unselected people with inflammatory bowel disease. The UK Inflammatory Bowel Disease Questionnaire and global rating of symptom relief at 6 months are the co-primary outcomes, with multiple secondary outcomes measured also at 6 and 12 months post randomisation to assess maintenance. The RCT has an embedded pilot study, health economics evaluation and process evaluation. We will randomise 680 patients, 340 in each group. Demographic characteristics and outcome measures will be presented for both study groups at baseline. The UK-IBDQ and global rating of symptom relief at 6 and 12 months post randomisation will be compared between the study groups. DISCUSSION: The BOOST online self-management programme for people with IBD-related symptoms of fatigue, pain and urgency has been designed to be easily scalable and implemented. If it is shown to improve patients' quality of life, this trial will enable clinicians and patients to make informed management decisions. This is the first trial, to our knowledge, focused on multiple symptoms prioritised by both people with IBD and health professionals. TRIAL REGISTRATION: ISRCTN71618461 . Registered on 9 September 2019.

Developing a better biopsychosocial understanding of pain in inflammatory bowel disease: a cross-sectional study.

OBJECTIVE: Pain is frequently reported by patients with inflammatory bowel disease (IBD). Pain in IBD is not fully explained by disease activity or other clinical findings, and a recent systematic review suggested that psychosocial factors have an important role in IBD-pain. The aim of this study was to investigate psychosocial factors associated with pain in IBD. METHODS: 297 adults (>16 years) with IBD were recruited from outpatient clinics (n = 114) and online (n = 183). Participants completed validated questionnaires assessing pain and potential emotional, cognitive and behavioural correlates. Socio-demographic and clinical factors including disease activity were also recorded. RESULTS: 243 (81.8%) of participants reported pain. Of these 243, mean age was 36 years; 153 (63%) had Crohn's disease, 90 (37%) had ulcerative colitis, and 165 (67.9%) were female. 62.6% reported mild, 31.6% moderate and 5.8% severe pain. 40.3% of participants with pain met established criteria for chronic pain and 18.5% reported opioid use. Female gender, smoking, surgery and steroid use were associated with greater pain severity. Psychosocial factors associated with pain-related interference included depression, catastrophising, fear avoidance, lower self-efficacy and worse mental well-being. Regression models explained 45.6% of the variance in pain severity and 49.7% of pain interference. Psychosocial factors explained 9.5% and 24% of this variance respectively when controlling for demographic and clinical variables. CONCLUSIONS: Pain in IBD is significantly associated with cognitive and behavioural factors as well as low mood. This study contributes to a biopsychosocial understanding of pain in IBD and identifies important targets for future interventions.

Optic nerve sheath ultrasound in the assessment of paediatric hydrocephalus.

OBJECTS: Optic nerve sheath diameter has been linked with intracranial pressure in previous studies. Measurement of sheath diameter using transorbital ultrasound is proposed as a clinical assessment indicator of developing hydrocephalus in the paediatric population. METHODS: A retrospective review of optic nerve sheath ultrasound examinations performed in a clinical setting between 2000 and 2006 for assessment of hydrocephalus in a single institution. RESULTS: A total of 331 examinations were performed in 160 patients over the study period. A satisfactory image was possible in all cases. Sheath diameters were correlated with clinical case data from concurrent case records. CONCLUSION: Transorbital ultrasound is a reproducible, non-invasive technique for the assessment of optic nerve sheath diameter and is well tolerated in children. Our series revealed asymptomatic baseline value higher than in previous reports. Variation from individual case asymptomatic baseline was the most sensitive variable in the series in determining development of hydrocephalus. This technique is felt to be a useful adjunct in the assessment of hydrocephalus in the paediatric neurosurgical population.

In Vitro Study of the Effect of Breathing Pattern on Aerosol Delivery During High-Flow Nasal Therapy.

INTRODUCTION: The use of concurrent aerosol delivery during high-flow nasal therapy (HFNT) may be exploited to facilitate delivery of a variety of prescribed medications for inhalation. The study assessed the effect of tidal volume, breath rate, and inspiratory:expiratory (I:E) ratio on the quantity of aerosol captured at the level of the trachea during simulated HFNT. METHODS: Testing was completed according to a factorial statistical design of experiments (DOE) approach. Tracheal dose was characterized with a vibrating mesh nebulizer (Aerogen Solo, Aerogen Ltd) using simulated adult, small child, and infant HFNT models. Furthermore, aerosol delivery was evaluated across a range of adult patient profiles with clinically representative test setups. RESULTS: Aerosol delivery increased with a large tidal volume, a rapid breath rate, and a long inspiratory time. Tidal volume, breath rate, and I:E ratio each had a significant effect on tracheal dose across simulated adult, small child, and infant breathing. CONCLUSION: The main trends that were identified in the statistical DOE predicted aerosol delivery across adult patient breathing profiles, in terms of tidal volume, breath rate, and I:E ratio. Therefore, patients with distressed breathing profiles may be expected to receive a larger aerosol dose than those with normal breathing rates. FUNDING: Aerogen Limited.

An unusual presentation of Legionella pneumonia in a returning traveller.

A male patient in his mid-60s presented with a severe pneumonia following return to the UK after travel to Crete. He was diagnosed with Legionnaire's disease (caused by an uncommon serogroup of Legionella pneumophila). He was pancytopenic on admission, and during a long stay on critical care he was diagnosed with a disseminated Aspergillus infection. Bone marrow aspiration revealed an underlying hairy cell leukaemia that undoubtedly contributed to his acute presentation and subsequent invasive fungal infection.

Vibrating Mesh Nebulisation of Pro-Antimicrobial Peptides for Use in Cystic Fibrosis.

BACKGROUND: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung by a vibrating mesh nebuliser (VMN) and whether the pro-AMP modification has any effect on delivery. METHODS: Physical characteristics of the peptides (AMP and pro-AMP) and antimicrobial activity were compared before and after nebulisation. Droplet size distribution was determined by laser diffraction and cascade impaction. Delivery to a model lung was determined in models of spontaneously-breathing and mechanically-ventilated patients. RESULTS: The physical characteristics and antimicrobial activities were unchanged after nebulisation. Mean droplet size diameters were below 5 µm in both determinations, with the fine particle fraction approximately 67% for both peptides. Approximately 25% of the nominal dose was delivered in the spontaneously-breathing model for both peptides, with higher deliveries observed in the mechanically-ventilated model. Delivery times were approximately 170 s per mL for both peptides and the residual volume in the nebuliser was below 10% in nearly all cases. CONCLUSIONS: These results demonstrate that the delivery of (pro-)AMPs to the lung using a VMN is feasible and that the prodrug modification is not detrimental. They support the further development of pro-AMPs as therapeutics in CF.

'It's about willpower in the end. You've got to keep going': a qualitative study exploring the experience of pain in inflammatory bowel disease.

BACKGROUND: Pain is a widely experienced symptom of inflammatory bowel disease (IBD), which has significant psychological and functional impacts on patients. Understanding the aetiology and management of chronic pain is a poorly understood area of IBD research. This qualitative study aimed to explore the experiences of individuals with IBD and pain, the pain management strategies they use and any needs for future pain management interventions. METHODS: In all, 14 individuals with IBD were purposively recruited and interviewed (face-to-face or telephone) using a topic guide. Interviews were transcribed and analysed using inductive thematic analysis. RESULTS: Themes identified were 'vicious cycles', 'findings solutions' and 'attitudes'. The experience and impact of pain were rarely viewed in isolation, but rather within the context of a cycle of IBD symptoms. Other 'vicious cycles' identified included anxiety, avoidance and inactivity, and poor understanding and communication. Pain management included short- and long-term strategies. Searching for a solution for pain had an emotional impact on individuals. There were contrasting attitudes from participants, including defeat, tolerance and acceptance. CONCLUSION: This study provides an understanding of the experience of pain in IBD. The interaction of pain with accompanying IBD symptoms has an emotional and physical impact on individuals, and creates a barrier to adequate assessment, understanding and treatment of pain. Patients rely on their own experiences, and a trial and error approach to apply helpful strategies. Adjuvant behavioural therapies may be beneficial for patients experiencing pain and psychological distress, and to facilitate self-management.

Behaviour change techniques associated with adherence to prescribed exercise in patients with persistent musculoskeletal pain: Systematic review.

PURPOSE: Exercise (planned, structured, repetitive movement) improves pain and function in people with persistent musculoskeletal pain (PMSK), but adherence is often poor. This systematic review evaluates the evidence from randomized controlled trials (RCTs) on the effectiveness of interventions to improve exercise adherence in people with PMSK and describes the content, context, and theoretical underpinning of behaviour change interventions designed to increase adherence. METHODS: Nine electronic databases were searched from inception dates to August 2017. Studies were included if they were RCTs that included adults with PMSK ≥3 months; ≥one measure of exercise adherence, exercise prescribed to both groups, and employed ≥one behaviour change technique (BCT) in the treatment group. Independent data extraction, theory coding, BCT taxonomy coding, and quality assessment using Cochrane Risk of Bias (RoB) tool was conducted by two reviewers. RESULTS: Eight RCTs (five low, three high RoB) met inclusion criteria. Five trials reported between-group differences in exercise adherence, favouring the treatment group. Three trials reported theoretical underpinning. There was moderate evidence that five BCTs, social support, goal setting, instruction of behaviour, demonstration of behaviour, and practice/rehearsal, improved exercise adherence. Interventions employing ≤seven BCTs, unique to those included in the control group, were most effective at enhancing exercise adherence. CONCLUSIONS: Limited moderate-quality evidence supports using a small number of BCTs to enhance exercise adherence in people with PMSK. Further research should explore the associations and synergies between BCTs and explicitly report how theory was utilized. This may inform recommendations for health care professionals working with this population. Statement of contribution What is already known on this subject? Exercise (i.e., planned, structured, repetitive movements) improves pain and function in people with persistent musculoskeletal pain (PMSK). Many people with PMSK do not adhere to exercises prescribed by a health care professional. Little research has explored how to enhance adherence to prescribed exercise in people with PMSK. What does this study add? Moderate-quality evidence from eight trials suggests behaviour change interventions enhance exercise adherence. Social support, goal setting, demonstration, instruction, and rehearsal were employed in effective interventions. Interventions with ≤7 behaviour change techniques were more effective at improving adherence than those employing >7.

Adolescent and parent factors related to fatigue in paediatric multiple sclerosis and chronic fatigue syndrome: A comparative study.

BACKGROUND: Fatigue is a disabling, poorly understood symptom in children and adolescents with multiple sclerosis (caMS), for which effective treatments are lacking. In paediatric Chronic Fatigue Syndrome (CFS), effective psychological interventions have been developed based on psychosocial factors associated with fatigue. This study aimed to identify potentially modifiable factors of fatigue in caMS by comparing caMS, adolescents with CFS, healthy adolescents and their parents on measures of fatigue, psychosocial factors, and neurocognitive functioning. METHODS: 175 participants including 30 caMS (15 fatigued, 15 non-fatigued), 30 adolescents with CFS, 30 healthy controls, and their parents were compared on measures of self- and parent-reported fatigue, adolescent and parent cognitive behavioural responses to symptoms, sleep, psychological difficulties, parental distress and objectively measured neurocognitive functioning. RESULTS: Fatigue severity, functional impairment and cognitive behavioural responses to symptoms were equivalent in fatigued caMS and adolescents with CFS, and were significantly higher than in healthy controls and non-fatigued caMS. Neurocognitive functioning was impaired in both caMS groups, but was normal in adolescents with CFS and healthy controls. No between-group differences were identified in adolescent sleep behaviour or psychological difficulties. Parents of all illness groups had more unhelpful cognitions than parents of healthy controls. Psychological distress was elevated in parents of both fatigued groups. CONCLUSIONS: Fifty percent of caMS reported clinically significant fatigue. Similarities between adolescent and parent cognitive behavioural factors in fatigued caMS and adolescents with CFS suggest important potential targets for intervention. Both fatigued and non-fatigued caMS had cognitive difficulties, suggesting that fatigue may need targeted intervention.

Nebulised lipid-polymer hybrid nanoparticles for the delivery of a therapeutic anti-inflammatory microRNA to bronchial epithelial cells.

Modulation of microRNAs (miRNAs), endogenous regulators of gene expression, is a promising strategy for tackling inflammatory lung diseases. In this proof-of-concept study, we tested delivery of miR-17 to bronchial epithelial cells (BECs) using nebulised lipid-polymer hybrid nanoparticles (LPNs). The primary aim was to reduce the induced secretion of miR-17's target, i.e. the pro-inflammatory chemokine interleukin (IL)-8. Synthetic miR-17 mimics were loaded into LPNs composed of poly(dl-lactic-co-glycolic acid) (PLGA) and the cationic lipid 1,2-dioleoyloxy-3-(trimethylammonium)propane (DOTAP) using a double emulsion solvent evaporation method and nebulised using the Aerogen Solo nebuliser. The physicochemical, aerosol, inflammatory and cytotoxic properties of LPNs were characterised. The effect of LPNs on lipopolysaccharide (LPS)-induced IL-8 production from human NuLi-1 BECs was tested by ELISA. The z-average, polydispersity index and ζ-potential of the LPNs and the aerodynamic properties of nebulised suspensions were in a range optimal for deposition in the bronchi and bronchioles post-inhalation. Cytotoxic and pro-inflammatory effects were minimal for LPNs loaded with a model cargo. Nebulisation did not affect the physicochemical or functional properties of the LPNs. Nebulised miR-17-loaded LPNs downregulated LPS-induced IL-8 secretion by >40% in BECs. This study suggests that DOTAP-modified PLGA LPNs are efficient and well-tolerated carriers for delivery of miRNA mimics to BECs.

In Vitro Determination of the Main Effects in the Design of High-Flow Nasal Therapy Systems with Respect to Aerosol Performance.

INTRODUCTION: The use of concurrent aerosol delivery during high-flow nasal therapy (HFNT) may be exploited to facilitate the delivery of a variety of prescribed medications for inhalation. Until now, a systematic approach to determine the conditions required to yield an optimal emitted dose has not been reported. The aim of this study was to establish the effects of gas flow rate, input droplet size, and nebulizer position on the amount of aerosol exiting the nasal cannula during HFNT and thus becoming available for inhalation. METHODS: Testing was completed according to a factorial statistical design of experiments (DOE) approach. Emitted dose was characterized with a vibrating mesh nebulizer (Aerogen Solo, Aerogen Ltd) for an adult model of HFNT at three clinically relevant gas flow rates, using three nebulizers producing varying input droplet sizes and placed at two different nebulizer positions. RESULTS: Increasing the gas flow rate significantly lowered the emitted dose, with a dose of 7.10% obtained at 10 LPM, 2.67% at 25 LPM, and 1.30% at 40 LPM (p < 0.0001). There was a significant difference in emitted dose between nebulizers with different input droplet sizes, with increasing input droplet size associated with a reduced emitted dose (6.11% with an input droplet size of 3.22 µm, 2.76% with 4.05 µm, and 2.38% with 4.88 µm, p = 0.0002, Pearson's r = - 0.2871). In addition, the droplet size exiting the nasal cannula interface was lower than that produced by the aerosol generator for all devices under test. Positioning the nebulizer immediately after the humidification chamber yielded a marginally greater emitted dose (3.79%) than when the nebulizer was placed immediately upstream of the nasal cannula (3.39%). Flow rate, input droplet size, and nebulizer position were at the 0.10 level of significance, indicating that all three factors had significant effects on emitted dose. According to the DOE model, flow rate had the greatest influence on emitted dose, followed by input droplet size and then nebulizer position. CONCLUSION: Our findings indicate that in order to optimize the amount of aerosol exiting the nasal cannula interface during HFNT, it is necessary for gas flow rate to be low and the input droplet size to be small, while the nebulizer should be positioned immediately after the humidification chamber. FUNDING: Aerogen Limited.