A RCT to explore the effectiveness of supporting adherence to nebuliser medication in adults with cystic fibrosis: fidelity assessment of study interventions.

BACKGROUND: A multi-component self-management intervention 'CFHealthHub' was developed to reduce pulmonary exacerbations in adults with Cystic Fibrosis (CF) by supporting adherence to nebuliser medication. It was evaluated in a randomized controlled trial (RCT) involving 19 CF centres, with 32 interventionists, 305 participants in the intervention group, and 303 participants in the standard care arm. Ensuring treatment fidelity of intervention delivery was crucial to ensure that the intervention produced the expected outcomes. METHODS: Fidelity of the CFHealthHub intervention and standard care was assessed using different methods for each of the five fidelity domains defined by the Borrelli framework: study design, training, treatment delivery, receipt, and enactment. Study design ensured that the groups received the intended intervention or standard care. Interventionists underwent training and competency assessments to be deemed certified to deliver the intervention. Audio-recorded intervention sessions were assessed for fidelity drift. Receipt was assessed by identifying whether participants set Action and Coping Plans, while enactment was assessed using click analytics on the CFHealthHub digital platform. RESULTS: Design: There was reasonable agreement (74%, 226/305) between the expected versus actual intervention dose received by participants in the CFHealthHub intervention group. The standard care group did not include focused adherence support for most centres and participants. Training: All interventionists were trained. Treatment delivery: The trial demonstrated good fidelity (overall fidelity by centre ranged from 79 to 97%), with only one centre falling below the mean threshold (> 80%) on fidelity drift assessments. Receipt: Among participants who completed the 12-month intervention, 77% (205/265) completed at least one action plan, and 60% (160/265) completed at least one coping plan. Enactment: 88% (268/305) of participants used web/app click analytics outside the intervention sessions. The mean (SD) number of web/app click analytics per participant was 31.2 (58.9). Additionally, 64% (195/305) of participants agreed to receive notifications via the mobile application, with an average of 53.6 (14.9) notifications per participant. CONCLUSIONS: The study demonstrates high fidelity throughout the RCT, and the CFHealthHub intervention was delivered as intended. This provides confidence that the results of the RCT are a valid reflection of the effectiveness of the CFHealthHub intervention compared to standard care. TRIAL REGISTRATION: ISRCTN registry: ISRCTN55504164 (date of registration: 12/10/2017).

Better Understanding of the Metamorphosis of Pregnancy (BUMP): protocol for a digital feasibility study in women from preconception to postpartum.

The Better Understanding the Metamorphosis of Pregnancy (BUMP) study is a longitudinal feasibility study aimed to gain a deeper understanding of the pre-pregnancy and pregnancy symptom experience using digital tools. The present paper describes the protocol for the BUMP study. Over 1000 participants are being recruited through a patient provider-platform and through other channels in the United States (US). Participants in a preconception cohort (BUMP-C) are followed for 6 months, or until conception, while participants in a pregnancy cohort (BUMP) are followed into their fourth trimester. Participants are provided with a smart ring, a smartwatch (BUMP only), and a smart scale (BUMP only) alongside cohort-specific study apps. Participant centric engagement strategies are used that aim to co-design the digital approach with participants while providing knowledge and support. The BUMP study is intended to lay the foundational work for a larger study to determine whether participant co-designed digital tools can be used to detect, track and return multimodal symptoms during the perinatal window to inform individual level symptom trajectories.

A machine-learning assisted review of the use of habit formation in medication adherence interventions for long-term conditions.

Adherence to medication in long-term conditions is around 50%. The key components of successful interventions to improve medication adherence remain unclear, particularly when examined over prolonged follow-up periods. Behaviour change theories are increasingly interested in the utility of habit formation for the maintenance of health behaviour change, but there is no documentation on how habit has been conceptualised in the medication adherence intervention literature, or what effect the key technique identified in habit formation theory (context dependent repetition) has in these studies. To examine this, a machine-learning assisted review was conducted. Searches of MEDLINE, EMBASE and PSYCInfo and the reference list of a comprehensive systematic review of medication adherence interventions yielded 5973 articles. Machine learning-assisted title and abstract screening identified 15 independent RCTs published between 1976 and 2021, including 18 intervention comparisons of interest. Key findings indicate that conceptualisations of habit in the medication adherence literature are varied and behaviour change technique coding identified only six studies which explicitly described using habit formation. Future work should aim to develop this evidence base, drawing on contemporary habit theory and with explicit demonstration of what techniques have been used to promote habit formation.

Development of an intervention to increase adherence to nebuliser treatment in adults with cystic fibrosis: CFHealthHub.

BACKGROUND: Cystic fibrosis (CF) is a life-limiting genetic condition in which daily therapies to maintain lung health are critical, yet treatment adherence is low. Previous interventions to increase adherence have been largely unsuccessful and this is likely due to a lack of focus on behavioural evidence and theory alongside input from people with CF. This intervention is based on a digital platform that collects and displays objective nebuliser adherence data. The purpose of this paper is to identify the specific components of an intervention to increase and maintain adherence to nebuliser treatments in adults with CF with a focus on reducing effort and treatment burden. METHODS: Intervention development was informed by the Behaviour Change Wheel (BCW) and person-based approach (PBA). A multidisciplinary team conducted qualitative research to inform a needs analysis, selected, and refined intervention components and methods of delivery, mapped adherence-related barriers and facilitators, associated intervention functions and behaviour change techniques, and utilised iterative feedback to develop and refine content and processes. RESULTS: Results indicated that people with CF need to understand their treatment, be able to monitor adherence, have treatment goals and feedback and confidence in their ability to adhere, have a treatment plan to develop habits for treatment, and be able to solve problems around treatment adherence. Behaviour change techniques were selected to address each of these needs and were incorporated into the digital intervention developed iteratively, alongside a manual and training for health professionals. Feedback from people with CF and clinicians helped to refine the intervention which could be tailored to individual patient needs. CONCLUSIONS: The intervention development process is underpinned by a strong theoretical framework and evidence base and was developed by a multidisciplinary team with a range of skills and expertise integrated with substantial input from patients and clinicians. This multifaceted development strategy has ensured that the intervention is usable and acceptable to people with CF and clinicians, providing the best chance of success in supporting people with CF with different needs to increase and maintain their adherence. The intervention is being tested in a randomised controlled trial across 19 UK sites.

Airway clearance techniques used by people with cystic fibrosis in the UK.

OBJECTIVES: To describe the current use of airway clearance techniques among people with cystic fibrosis (CF) in the UK, and the baseline characteristics for users of different airway clearance techniques. DESIGN: Analysis of the UK CF Registry 2011 data. SETTING AND PARTICIPANTS: All people with CF in the UK aged ≥11 years (n=6372). RESULTS: Of the 6372 people on the UK CF registry in 2011, 89% used airway clearance techniques. The most commonly used primary techniques were forced expiratory techniques (28%) and oscillating positive expiratory pressure (PEP) (23%). Postural drainage and high-frequency chest wall oscillation were used by 4% and 1% of people with CF, respectively. The male:female ratio of individuals who used exercise as their primary airway clearance technique was 2:1, compared with 1:1 for other techniques. Individuals with more severe lung disease tended to use devices such as non-invasive ventilation or high-frequency chest wall oscillation. CONCLUSIONS: Forced expiratory techniques and oscillating PEP are the most common airway clearance techniques used by people with CF in the UK, and postural drainage and high-frequency chest wall oscillation are the least common techniques. This is significant in terms of planning airway clearance technique trials, where postural drainage has been used traditionally as the comparator. The use of airway clearance techniques varies between countries, but the reasons for these differences are unknown.

Exploration of the impact of 'mild phenotypes' on median age at death in the U.K. CF registry.

BACKGROUND: The widespread availability of genetic testing allowing the identification of "milder" individuals with CF coincided with improvements in CF life expectancy but the relative contribution of case mix to that improved survival is uncertain. METHODS: Patients in the U.K. CF registry were divided into 'mild phenotype' defined as pancreatic sufficient and 'typical CF' defined as pancreatic insufficient. Distributions of age at death were compared with Mann-Whitney test. Temporal trends in incidence and prevalence were described. Jonckheere-Terpstra test was used to compare the trend for median age at death from 2007 to 2010. RESULTS: Patients with 'mild phenotype' had significantly higher age at death (32 years, interquartile range 14 years versus 27 years, interquartile range 29 years; Mann-Whitney test p-value = 0.026). The proportion of patients with 'mild phenotype' appeared to be increasing (0.128 in 2007, 0.144 in 2010). The trend for increasing age at death (from 25 years in 2007 to 29 years in 2010, Jonckheere-Terpstra test p-value = 0.012) was independent of the 'mild phenotype' patients. CONCLUSION: The impact of mild phenotypes on the improvement in the median age at death among people with CF was trivial.

Predicting mortality for patients with exacerbations of COPD and Asthma in the COPD and Asthma Outcome Study (CAOS).

INTRODUCTION: Decisions about the intensity of treatment for patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are influenced by predictions about survival and quality of life. Evidence suggests that these predictions are poorly calibrated and tend to be pessimistic. AIM: The aim of this study was to develop an outcome prediction model for COPD patients to support treatment decisions. METHODS: A prospective multi-centre cohort study in Intensive Care Units (ICU) and Respiratory High Dependency Units (RHDU) in the UK recruited patients aged 45 years and older admitted with an exacerbation of obstructive lung disease. Data were collected on patients' characteristics prior to ICU admission, and on their survival and quality of life after 180 days. An outcome prediction model was developed using multivariate logistic regression and bootstrapping. RESULTS: Ninety-two ICUs (53% of those in the UK) and three RHDUs took part. A total of 832 patients were recruited. Cumulative 180-day mortality was 37.9%. Using data available at the time of admission to the units, a prognostic model was developed which had an estimated area under the receiver operating characteristic curve ('c') of 74.7% after bootstrapping that was more discriminating than the clinicians (P = 0.033) and was well calibrated. DISCUSSION: This study has produced an outcome prediction model with slightly better discrimination and much better calibration than the participating clinicians. It has the potential to support risk adjustment and clinical decision making about admission to intensive care.

Survival and quality of life for patients with COPD or asthma admitted to intensive care in a UK multicentre cohort: the COPD and Asthma Outcome Study (CAOS).

BACKGROUND: Non-invasive ventilation is first-line treatment for patients with acutely decompensated chronic obstructive pulmonary disease (COPD), but endotracheal intubation, involving admission to an intensive care unit, may sometimes be required. Decisions to admit to an intensive care unit are commonly based on predicted survival and quality of life, but the information base for these decisions is limited and there is some evidence that clinicians tend to be pessimistic. This study examined the outcomes in patients with COPD admitted to the intensive care unit for decompensated type II respiratory failure. METHODS: A prospective cohort study was carried out in 92 intensive care units and 3 respiratory high dependency units in the UK. Patients aged 45 years and older with breathlessness, respiratory failure or change in mental status due to an exacerbation of COPD, asthma or a combination of the two were recruited. Outcomes included survival and quality of life at 180 days. RESULTS: Of the 832 patients recruited, 517 (62%) survived to 180 days. Of the survivors, 421 (81%) responded to a questionnaire. Of the respondents, 73% considered their quality of life to be the same as or better than it had been in the stable period before they were admitted, and 96% would choose similar treatment again. Function during the stable pre-admission period was a reasonable indicator of function reported by those who survived 180 days. CONCLUSIONS: Most patients with COPD who survive to 180 days after treatment in an intensive care unit have a heavy burden of symptoms, but almost all of them-including those who have been intubated-would want similar intensive care again under similar circumstances.

Duration of intravenous antibiotic therapy in people with cystic fibrosis.

BACKGROUND: Respiratory disease is the major cause of mortality and morbidity in cystic fibrosis (CF). Life expectancy of people with CF has increased dramatically in the last 40 years. One of the major reasons for this increase is the mounting use of antibiotics to treat chest exacerbations caused by bacterial infections. The optimal duration of intravenous antibiotic therapy is not clearly defined. Individuals usually receive intravenous antibiotics for 14 days, but treatment may range from 10 to 21 days. A shorter duration of antibiotic treatment risks inadequate clearance of infection which could lead to further lung damage. Prolonged courses of intravenous antibiotics are expensive and inconvenient and the incidence of allergic reactions to antibiotics also increases with prolonged courses. The use of aminoglycosides requires frequent monitoring to avoid some of their side effects. However, some organisms which infect people with CF are known to be multi-resistant to antibiotics, and may require a longer course of treatment. OBJECTIVES: To assess the optimal duration of intravenous antibiotic therapy for treating chest exacerbations in people with cystic fibrosis. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings. Most recent search of the Group's Cystic Fibrosis Trials Register: February 2008. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different durations of intravenous antibiotic courses for acute respiratory exacerbations in people with CF, either with the same drugs at the same dosage, the same drugs at a different dosage or frequency or different antibiotics altogether, including studies with additional therapeutic agents. DATA COLLECTION AND ANALYSIS: No eligible trials were identified. MAIN RESULTS: No eligible trials were identified. AUTHORS' CONCLUSIONS: There are no clear guidelines on the optimum duration of intravenous antibiotic treatment. Duration of treatment is currently based on unit policies and response to treatment. Shorter duration of treatment should improve quality of life and compliance; result in a reduced incidence of drug reactions; and be less costly. However, this may not be sufficient to clear a chest infection and may result in an early recurrence of an exacerbation. This systematic review identifies the need for a multicentre, randomised controlled trial comparing different durations of intravenous antibiotic treatment as it has important clinical and financial implications.

Sources of variability in uncertain medical decisions in the ICU: a process tracing study.

BACKGROUND: Consistency of medical decision making (equity) is an important component of quality of care. When patients with chronic obstructive pulmonary disease (COPD) present with an exacerbation needing respiratory support they may die if it is not provided. However, if the disease has reached its terminal stage, ventilation will prolong the process of dying. The ventilation outcome is uncertain and there is evidence of variability when this decision is made, the sources of which are not well understood. OBJECTIVES: To identify sources of variability and propose ways of tackling them in order to promote equity in this type of medical decision. METHODS: Six case histories were selected from hospital records of COPD patients. Fourteen senior doctors from seven hospitals in the West Midlands participated. A process tracing approach was used which consisted of (1) withholding case information until specifically requested by the doctors, (2) estimating survival during the decision making process, and (3) concurrent questioning regarding information interpretation and its impact on survival estimates and decisions. RESULTS: The observed decision variability was attributed to doctors attaching importance to different information, gathering different information, and interpreting information differently. There were significant differences between doctors in the amount of information requested. CONCLUSIONS: Differences in information gathering and interpretation by clinicians can result in different decisions being made about the same patient. This variation may exist for other uncertain medical decisions and may be tackled by providing clinicians with prognostic models in the form of usable decision aids.

Variation in intubation decisions for patients with chronic obstructive pulmonary disease in one critical care network.

BACKGROUND: Anecdotal evidence suggests variation in intubation decisions for chronic obstructive pulmonary disease (COPD) patients with respiratory failure, but little is known about the extent of or reasons for this variability. AIM: To describe clinician decision-making for patients with exacerbations of COPD considered for intubation. DESIGN: Telephone simulation study. METHODS: Consultants responsible for COPD admissions in the Heart of England Critical Care network were asked to decide whether or not to admit three patients with COPD to ICU on the basis of information conveyed over the telephone. Consultants were also asked to predict patients survival in ICU hospital and at 180 days on the assumption that the patient did receive ICU care. RESULTS: Of the 120 consultants, 98 (82%) took part; 89% would admit patient 1, 64% patient 2, and 40% patient 3. The prediction of survival if ICU admission had occurred differed significantly between admitters and non-admitters. Mean predicted post-ICU hospital survival for patient 1 was 46% (95%CI 43-49) for admitters, and 13% (95%CI 6-19) for non-admitters (p < 0.001). The respective figures for patient 2 were 38% (95%CI 34-42) vs. 12% (95%CI 8-15) (p < 0.001), and for patient 3, 28% (95%CI 24-33) vs. 13% (95%CI 10-16) (p < 0.001). For a housebound COPD patient in their mid 70s, the mean (SD) threshold of predicted hospital survival below which consultants would recommend not admitting to ICU was 22% (13.2%). CONCLUSIONS: Consultants differed markedly in their admitting decisions about identical patients. Objective outcome prediction models might improve equity in ICU bed use for patients with COPD.

GABA-like immunoreactivity in nonspiking interneurons of the locust metathoracic ganglion.

Nonspiking interneurons are important components of the premotor circuitry in the thoracic ganglia of insects. Their action on postsynaptic neurons appears to be predominantly inhibitory, but it is not known which transmitter(s) they use. Here, we demonstrate that many but not all nonspiking local interneurons in the locust metathoracic ganglion are immunopositive for GABA (gamma-aminobutyric acid). Interneurons were impaled with intracellular microelectrodes and were shown physiologically to be nonspiking. They were further characterized by defining their effects on known leg motor neurons when their membrane potential was manipulated by current injection. Lucifer Yellow was then injected into these interneurons to reveal their cell bodies and the morphology of their branches. Some could be recognised as individuals by comparison with previous detailed descriptions. Ganglia were then processed for GABA immunohistochemistry. Fifteen of the 17 nonspiking interneurons studied were immunopositive for GABA, but two were not. The results suggest that the majority of these interneurons might exert their well-characterized effects on other neurons through the release of GABA but that some appear to use a transmitter other than GABA. These nonspiking interneurons are therefore not an homogeneous population with regard to their putative transmitter.

Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the 1989 UK outbreak cohort.

BACKGROUND: Some patients exposed to Q fever (Coxiella burnetii infection) may develop chronic fatigue. AIM: To determine whether subjects involved in the West Midlands Q fever outbreak of 1989 had increased fatigue, compared to non-exposed controls, 10 years after exposure. DESIGN: Matched cohort study comparing cases to age-, sex- and smoking-history-matched controls not exposed to Q fever. METHODS: A postal questionnaire was sent to subjects at home, followed by further assessment in hospital, including a physical examination and blood tests. RESULTS: Of 108 Q-exposed subjects, 70 (64.8%) had fatigue, 37 idiopathic chronic fatigue (ICF) (34.3%), vs. 29/80 (36.3%) and 12 (15.0%), respectively, in controls. In 77 matched pairs, fatigue was commoner in Q-exposed subjects than in controls: 50 (64.9%) vs. 27 (35.1%), p<0.0001. ICF was found in 25 (32.5%) of Q-exposed patients and 11(14.3%) of controls (p=0.01). There were 36 (46.8%) GHQ cases in Q-exposed subjects, vs. 18 (23.4%) controls (p=0.004). A matched analysis of those more intensively studied showed fatigue in 48 (66.7%) Q-exposed patients and 25 (34.7%) controls, (p<0.0001), ICF in 25 (34.7%) Q-exposed and 10 (13.9%) controls (p=0.004), and chronic fatigue syndrome (CFS) in 14 (19.4%) Q-exposed patients and three (4.2%) controls (p=0.003). Thirty-four (47.2%) Q-exposed patients were GHQ cases compared to 17 (23.6%) controls (p=0.004). DISCUSSION: Subjects who were exposed to Coxiella in 1989 had more fatigue than did controls, and some fulfilled the criteria for CFS. Whether this is due to ongoing antigen persistence or to the psychological effects of prolonged medical follow-up is uncertain.

Long-term follow-up of patients from the 1989 Q fever outbreak: no evidence of excess cardiac disease in those with fatigue.

BACKGROUND: In 1989, an outbreak of Q fever (C. burnetii infection) with 147 confirmed cases occurred in Solihull, West Midlands. Three patients developed cardiomyopathy in the subsequent 10 years. The cohort has been followed up with respect to the development of fatigue and, in this instance, cardiac effects after the original infection. AIM: To determine whether persisting fatigue after Q fever represented sub-clinical cardiomyopathy. DESIGN: Prospective follow-up study. METHODS: All traceable subjects from the original outbreak, and community age-, sex- and smoking-matched controls, were studied. Questionnaires for idiopathic fatigue, 12-lead ECG, echocardiography, spirometry and shuttle walk distance were undertaken, and a subset with CDC-defined chronic fatigue syndrome had gated cardiac scans. RESULTS: Of the original cohort, 19 had died, three had emigrated and 10 were untraceable. Of the remaining 115, 108 responded to a mailed questionnaire and 87 were investigated further, of whom 85 provided complete data. Two developed aortic valve vegetations, one of whom died. Chronic fatigue syndrome was found in 20% of cases and 5.3% of controls (including those with co-morbidities), falling to 8.2% and 0 when excluding those with co-morbidities. There were no significant differences in ECG and echocardiographic investigations or shuttle-walk distance between those with fatigue and those without. Six of the seven patients with CFS had gated cardiac scans: all were within normal limits. CONCLUSIONS: These findings do not support the existence of a sub-clinical cardiomyopathy in the patients in this cohort who suffer from fatigue after acute Q fever, although endocarditis can occur after acute infection.

Choosing the surgical mortality threshold for high risk patients with stage Ia non-small cell lung cancer: insights from decision analysis.

The recent British Thoracic Society guidelines recommend that surgical mortality should not be greater than 8% for pneumonectomy and 4% for lobectomy. These cut offs are advanced as guidelines to inform decision making as to whether or not patients with operable lung cancer should be offered surgery. They have been developed from a notion of what acceptable surgical mortality should be. The planning of care for patients with lung cancer involves making choices between different treatments with different outcomes. While it is accepted that the probability of these outcomes is likely to differ among patients, individual patient preferences for them are also likely to vary. Fixed cut offs for surgical mortality mean ignoring this variation. Decision analysis can be used to assist in the complex task of integrating clinical characteristics and varying patient preferences. By considering high risk patients with potentially curable stage Ia non-small cell lung cancer, it is shown that decision analysis has the potential to illuminate decision making and guideline development within the field of cancer care.

RDX degradation using an integrated Fe(0)-microbial treatment approach.

RDX is a persistent and highly mobile groundwater contaminant that represents a major remediation challenge at numerous munitions manufacturing and load-assemblage-package facilities. This work presents proof of concept that permeable reactive iron barriers might be a viable approach to intercept and degrade RDX plumes. Specifically, RDX was rapidly reduced in aquifier microcosms amended with Fe(0) powder, and in flow-through columns packed with steel wool. The rate and extent of RDX degradation in microcosms was enhanced by anaerobic bacteria that feed on cathodic hydrogen (i.e., H2 produced during anaerobic Fe(0) corrosion by water). Apparently, the hydrogenotrophic consortium that exploits Fe(0) corrosion as a metabolic niche participated in the further degradation of heterocyclic intermediates produced by the reaction of RDX with Fe(0). Reductive treatment of RDX with Fe(0) also reduced its toxicity to microorganisms and enhanced its subsequent biodegradability under either anaerobic or anaerobic conditions. Therefore, a combined or sequential Fe(0)-biological treatment approach might improve treatment efficiency.