Adolescents with Rett syndrome at critical care pathway junctures: Examining clinicians' decision to initiate invasive long-term ventilation.

BACKGROUND: The initiation of invasive long-term ventilation (I-LTV) for an adolescent with Rett Syndrome (RTT) involves many serious bioethical considerations. In moving towards a more inclusive model of patient participation, transparency surrounding the main influencing factors around this decision is important. OBJECTIVE: We aimed to identify the main drivers influencing a clinician's decision to support initiation of I-LTV for an adolescent with RTT. METHOD: We used an anonymous online vignette-based factorial survey. The survey was distributed internationally through eight professional multi-disciplinary organisations to reach clinicians working in paediatrics. RESULTS: We analysed 504 RTT vignettes completed by 246 clinicians using mixed effect regression modelling. The main three significant influencing factors identified were: parental agreement with the decision to support initiation, the family's support network, and proximity to a tertiary care centre. Additional comments from participants focused on family support, and the importance of on-going communication with the family. CONCLUSION: As the rights of those with disabilities improve and participation of adolescents in decision-making becomes more established, effective communications with the family around goals of care and particular sensitivity and reflective practice around methods of consensus building will likely contribute to a positive decision-making process at this difficult time.

C-Reactive Protein, Interleukin-6, and Vascular Recurrence According to Stroke Subtype: An Individual Participant Data Meta-Analysis

BACKGROUND AND OBJECTIVES: Anti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention. METHODS: Using individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by stroke mechanism, per quarter and per biomarker unit increase after loge transformation. We then did study-level meta-analysis with comparable published studies not providing IPD. Preferred Reporting Items for Systematic Review and Meta-Analyses IPD guidelines were followed. RESULTS: IPD was obtained from 10 studies (8,420 patients). After adjustment for vascular risk factors and statins/antithrombotic therapy, IL-6 was associated with recurrent MACE in stroke caused by large artery atherosclerosis (LAA) (risk ratio [RR] 2.30, 95% CI 1.21-4.36, p = 0.01), stroke of undetermined cause (UND) (RR 1.78, 1.19-2.66, p = 0.005), and small vessel occlusion (SVO) (RR 1.71, 0.99-2.96, p = 0.053) (quarter 4 [Q4] vs quarter 1 [Q1]). No association was observed for stroke due to cardioembolism or other determined cause. Similar results were seen for recurrent stroke and when analyzed per loge unit increase for MACE (LAA, RR 1.26 [1.06-1.50], p = 0.009; SVO, RR 1.22 [1.01-1.47], p = 0.04; UND, RR 1.18 [1.04-1.34], p = 0.01). High-sensitivity CRP was associated with recurrent MACE in UND stroke only (Q4 vs Q1 RR 1.45 [1.04-2.03], p = 0.03). Findings were consistent on study-level meta-analysis of the IPD results with 2 other comparable studies (20,136 patients). DISCUSSION: Our data provide new evidence for the selection of patients in future RCTs of anti-inflammatory therapy in stroke due to large artery atherosclerosis, small vessel occlusion, and undetermined etiology according to inflammatory marker profile.

Impact of serum sodium concentrations, and effect modifiers on mortality in the Irish Health System.

BACKGROUND: Abnormalities of serum sodium are associated with increased mortality risk in hospitalised patients, but it is unclear whether, and to what extent other factors influence this relationship. We investigated the impact of dysnatraemia on total and cause-specific mortality in the Irish health system while exploring the concurrent impact of age, kidney function and designated clinical work-based settings. METHODS: A retrospective cohort study of 32,666 participants was conducted using data from the National Kidney Disease Surveillance System. Hyponatraemia was defined as < 135 mmol/L and hypernatraemia as > 145 mmol/L with normal range 135-145 mmol/L. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR's) and 95% Confidence Intervals (CIs) while penalised spline models further examined patterns of risk. RESULTS: There were 5,114 deaths (15.7%) over a median follow up of 5.5 years. Dysnatraemia was present in 8.5% of patients overall. In multivariable analysis, both baseline and time-dependent serum sodium concentrations exhibited a U-shaped association with mortality. Hyponatremia was significantly associated with increased risk for cardiovascular [HR 1.38 (1.18-1.61)], malignant [HR: 2.49 (2.23-2.78)] and non-cardiovascular/non-malignant causes of death [1.36 (1.17-1.58)], while hypernatremia was significantly associated with cardiovascular [HR: 2.16 (1.58-2.96)] and non-cardiovascular/ non-malignant deaths respectively [HR: 3.60 (2.87-4.52)]. The sodium-mortality relationship was significantly influenced by age, level of kidney function and the clinical setting at baseline (P < 0.001). For hyponatraemia, relative mortality risks were significantly higher for younger patients (interaction term P < 0.001), for patients with better kidney function, and for patients attending general practice [HR 2.70 (2.15-3.36)] than other clinical settings. For hypernatraemia, age and kidney function remained significant effect modifiers, with patients attending outpatient departments experiencing the greatest risk [HR 9.84 (4.88-18.62)] than patients who attended other clinical locations. Optimal serum sodium thresholds for mortality varied by level of kidney function with a flattening of mortality curve observed for patients with poorer kidney function. CONCLUSION: Serum sodium concentrations outside the standard normal range adversly impact mortality and are associated with specific causes of death. The thresholds at which these risks appear to vary by age, level of kidney function, and are modified in specific clinical settings within the health system.

C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: An Individual Participant Data Meta-Analysis.

BACKGROUND: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. METHODS: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. RESULTS: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase logeIL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09-1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04-1.21], per unit increase logehsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04-1.21]; hsCRP, RR, 1.09 [95% CI, 1.04-1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00-1.19]; hsCRP, RR, 1.05 [95% CI, 1.00-1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09-1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07-1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08-1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93-1.43]). CONCLUSIONS: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Patient and hospital-level factors associated with time to surgery after hip fracture in Ireland: Analysis of national audit data 2016-2020.

INTRODUCTION: In hip fracture care, time to surgery (TTS) is a commonly used quality indicator associated with patient outcomes including mortality. This study aimed to identify patient and hospital-level characteristics associated with TTS in Ireland. METHODS: National data from the Irish Hip Fracture Database (IHFD) (2016-2020) were analysed along with hospital-level characteristics obtained from a 2020 organisational survey. Generalised linear model regression was used to explore the association of TTS with case-mix, surgical details, hospital-level staffing and specific protocols recommended to expedite surgery. RESULTS: A total of 14,951 patients with surgically treated hip fracture from 16 hospitals were included (Mean age= 80.6 years (SD=8.8), 70.4% female). Mean TTS was 40.9 h (SD=60.3 h). Case-mix factors associated with longer TTS were male sex and higher American Society of Anaesthesiologists (ASA) grade. Other factors found to be associated with longer TTS included low pre-morbid mobility, inter-hospital transfer, weekday presentation, pre-operative medical physician assessment, intracapsular fracture type, arthroplasty surgery, general anaesthesia, consultant grade of surgeon and lower hospital-level orthopaedic surgical capacity. The oldest age-group and pre-fracture nursing home residence were associated with shorter TTS when adjusted for other case-mix factors. None of four explored protocols for expediting surgery were associated with TTS. CONCLUSION: Patients with more comorbidity experience longer surgical delay after hip fracture in Ireland, in line with international research. Low availability of senior orthopaedic surgeons in Ireland may be delaying hip fracture surgery. Pathway of presentation, including via inter-hospital transfer or hospital bypass, is an important factor that requires further exploration. Further research is required to identify successful system-level protocols and interventions that may expedite hip fracture surgery within this setting.

Steps Ahead: Optimising physical activity in adults with cystic fibrosis: A pilot randomised trial using wearable technology, goal setting and text message feedback.

BACKGROUND: Regular participation in physical activity (PA) is encouraged for people with Cystic Fibrosis (CF). This study aimed to assess the effectiveness of an intervention using wearable technology, goal setting and text message feedback on PA and health outcomes in people with CF. METHODS: This was a pilot randomised trial conducted at University Hospital Limerick. Participants were randomly assigned to the intervention (INT) or active comparator (AC). The 12-week intervention consisted of wearable technology (Fitbit Charge 2) which was remotely monitored, and participants set step count goals. Participants were sent a one-way text message once a week over 12 weeks to positively reinforce and encourage PA participation. The AC group received the wearable technology alone. Follow up was assessed at 24 weeks. Outcomes assessed were PA, aerobic capacity, lung function, sleep, quality of life and wellbeing. RESULTS: Step count increased significantly for the INT group over 12 weeks when compared to the AC group (p=0.019). The INT group had a 28% week-to-week percentage change (Weeks 1-12), while the AC group reduced by 1%, p=0.023. Within group changes demonstrated that VO2 peak (ml/kg/min) significantly increased for the INT group at 12 weeks (24.4 ±7.65 to 26.13 ±7.79, p=0.003) but not at 24 weeks (24.45 ±7.05, p=0.776). There were no significant differences observed for VO2 peak (ml/kg/min) for the AC group. There was no significant effect on lung function, sleep, well-being, or quality of life for either group. CONCLUSIONS: A personalised PA intervention using wearable technology, goal setting and text message feedback increased PA and aerobic capacity in people with CF. Integration of this intervention into usual care may encourage regular PA participation for people with CF.

Comparative effectiveness of neutralising monoclonal antibodies in high risk COVID-19 patients: a Bayesian network meta-analysis.

The purpose of this work was to review and synthesise the evidence on the comparative effectiveness of neutralising monoclonal antibody (nMAB) therapies in individuals exposed to or infected with SARS-CoV-2 and at high risk of developing severe COVID-19. Outcomes of interest were mortality, healthcare utilisation, and safety. A rapid systematic review was undertaken to identify and synthesise relevant RCT evidence using a Bayesian Network Meta-Analysis. Relative treatment effects for individual nMABs (compared with placebo and one another) were estimated. Pooled effects for the nMAB class compared with placebo were estimated. Relative effects were combined with baseline natural history models to predict the expected risk reductions per 1000 patients treated. Eight articles investigating four nMABs (bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab) were identified. All four therapies were associated with a statistically significant reduction in hospitalisation (70-80% reduction in relative risk; absolute reduction of 35-40 hospitalisations per 1000 patients). For mortality, ICU admission, and invasive ventilation, the risk was lower for all nMABs compared with placebo with moderate to high uncertainty due to small event numbers. Rates of serious AEs and infusion reactions were comparable between nMABs and placebo. Pairwise comparisons between nMABs were typically uncertain, with broadly comparable efficacy. In conclusion, nMABs are effective at reducing hospitalisation among infected individuals at high-risk of severe COVID-19, and are likely to reduce mortality, ICU admission, and invasive ventilation rates; the effect on these latter outcomes is more uncertain. Widespread vaccination and the emergence of nMAB-resistant variants make the generalisability of these results to current patient populations difficult.

Association between vitamin D deficiency and the risk of prevalent type 2 diabetes and incident prediabetes: A prospective cohort study using data from The Irish Longitudinal Study on Ageing (TILDA).

Background: It is hypothesized that vitamin D contributes to the aetiology of type 2 diabetes mellitus (diabetes). This study's objective was to examine the relationships between baseline vitamin D status (as measured by plasma 25-hydroxyvitamin D concentration) and both prevalent diabetes and prospective risk of developing diabetes, including prediabetes, in a population with historically low levels of vitamin D. Methods: In this prospective cohort study, data from The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort of adults aged ≥50 years residing in Ireland were analysed, including wave 1 (October 2009-June 2011) (n = 5272) and wave 3 (March 2014-October 2015) (n = 3828). Those aged <50 years at baseline or who did not complete the health assessment were excluded. Logistic regression models examined the associations between baseline vitamin D concentration (nmol/L) with prevalent diabetes status and incident diabetes/prediabetes collected at a 4-year follow-up. Models were adjusted for age, sex, education, body mass index, smoking history, physical activity, use of statins, and the season in which the vitamin D concentration was sampled. Findings: Deficient baseline vitamin D concentration was cross-sectionally associated with an increased likelihood of having prevalent diabetes (Relative Risk Ratio [RRR] 1·5, 95% CI: 1·03, 2·18; p = 0·037). In longitudinal analyses evaluating diabetes status 4 years later, there was a 62% increased likelihood (RRR: 1·62, 95% CI: 1·12, 2·35; p = 0·011) of developing prediabetes for those with vitamin D <30 nmol/L compared to those with ≥75 nmol/L. The rate of progression from prediabetes to diabetes between wave 1 and 3 was observed to be 32·5%. Interpretation: Those with lower concentrations of vitamin D, as measured by 25-hydroxyvitamin D, may have different risk profiles with regards to their glycaemic status. Our study had limited power due to the low incidence of diabetes but showed strong associations with incident prediabetes, so further research is required. Optimising vitamin D status at a population level may significantly reduce diabetes. Funding: TILDA is funded by Atlantic Philanthropies, the Irish Department of Health, and Irish Life, while additional funding was provided by the Irish Department of Agriculture, Food and the Marine (13F492) to cover the cost of 25-hydroxyvitamin D analysis.

The association between ambient UVB dose and ANCA-associated vasculitis relapse and onset.

BACKGROUND: The aetiology of ANCA-associated vasculitis (AAV) and triggers of relapse are poorly understood. Vitamin D (vitD) is an important immunomodulator, potentially responsible for the observed latitudinal differences between granulomatous and non-granulomatous AAV phenotypes. A narrow ultraviolet B spectrum induces vitD synthesis (vitD-UVB) via the skin. We hypothesised that prolonged periods of low ambient UVB (and by extension vitD deficiency) are associated with the granulomatous form of the disease and an increased risk of AAV relapse. METHODS: Patients with AAV recruited to the Irish Rare Kidney Disease (RKD) (n = 439) and UKIVAS (n = 1961) registries were studied. Exposure variables comprised latitude and measures of ambient vitD-UVB, including cumulative weighted UVB dose (CW-D-UVB), a well-validated vitD proxy. An n-of-1 study design was used to examine the relapse risk using only the RKD dataset. Multi-level models and logistic regression were used to examine the effect of predictors on AAV relapse risk, phenotype and serotype. RESULTS: Residential latitude was positively correlated (OR 1.41, 95% CI 1.14-1.74, p = 0.002) and average vitD-UVB negatively correlated (0.82, 0.70-0.99, p = 0.04) with relapse risk, with a stronger effect when restricting to winter measurements (0.71, 0.57-0.89, p = 0.002). However, these associations were not restricted to granulomatous phenotypes. We observed no clear relationship between latitude, vitD-UVB or CW-D-UVB and AAV phenotype or serotype. CONCLUSION: Our findings suggest that low winter ambient UVB and prolonged vitD status contribute to AAV relapse risk across all phenotypes. However, the development of a granulomatous phenotype does not appear to be directly vitD-mediated. Further research is needed to determine whether sufficient vitD status would reduce relapse propensity in AAV.

Accuracy of the ActivPAL and Fitbit Charge 2 in measuring step count in Cystic Fibrosis.

BACKGROUND: Physical activity (PA) is important in Cystic Fibrosis (CF) management. Fitness wearables are becoming increasingly popular as measurement tools of PA; however, the accuracy of these devices should first be evaluated. OBJECTIVE: The purpose of this study was to assess the accuracy of the ActivPAL and Fitbit Charge 2 as a measure of step count in Cystic Fibrosis. METHODS: Twenty-one participants were recruited from an adult CF Center in Ireland for a single session of testing. Participants walked for 5 min at five pre-determined speeds in a controlled testing environment (2, 2.5, 3, 3.5 and 4 miles per hour on a treadmill) and at three self-selected speeds in a corridor (slow, medium, and fast). They concurrently wore an accelerometer (ActivPAL) and fitness wearable (Fitbit Charge 2), and both were compared to visual observations. Step count is the outcome being assessed. RESULTS: The ActivPAL under-estimated step count by 0.63% across treadmill speeds and 1.1% across self-selected walking speeds. The Fitbit Charge 2 underestimated the step count by 2.97% across treadmill speeds and by 6.3% across self-selected walking speeds. Very strong correlations were found between the ActivPAL and visual observations (r: 0.93 to 0.99), while the Fitbit Charge 2 ranged from weak to very strong correlations when compared to visual observations (r: 0.34 to 0.84). CONCLUSION: The ActivPAL and Fitbit Charge 2 demonstrated acceptable validity for step count measurement in CF. These devices can be used for tracking PA during interventions in people with CF.

Efficacy and safety of electronic cigarettes as a smoking cessation intervention: A systematic review and network meta-analysis.

INTRODUCTION: This systematic review of randomized controlled trials (RCTs) evaluated the efficacy and safety of electronic cigarettes (e-cigarettes, ENDS) in helping people who smoke to achieve abstinence compared with electronic non-nicotine delivery systems (ENNDS, no nicotine) or any smoking cessation comparator treatment or combination of treatments at 24-26 weeks and at 52 weeks. METHODS: Systematic review techniques involved searches of three databases in February 2020 with update searches run on 14 May 2021, two-person independent screening, two-person independent assessment of bias, formal extraction of data with verification by a second person, a feasibility assessment to decide if meta-analysis was appropriate, and network meta-analysis (NMA) of data at 24-26 weeks. Data at 52 weeks were narratively summarized. RESULTS: Ten RCTs met the inclusion criteria, eight for efficacy and ten for safety. Eight of the nine RCTs were assessed as at high risk of bias. The sample sizes of the RCTs were 30-2012. Using nicotine replacement therapy (NRT) as the reference treatment, the incidences of smoking cessation at 24-26 weeks were comparable between ENDS and NRT groups (RR=1.17; 95% CrI: 0.66-1.86). Three sensitivity analyses were carried out indicating the main findings for 24-26 weeks were robust to assumptions. The findings at 52 weeks were inconclusive. CONCLUSIONS: This systematic review and NMA indicates that there is no clear evidence of a difference in effect between nicotine containing e-cigarettes and NRT on incidences of smoking cessation at 24-26 weeks, and substantial uncertainty remains.

Estimating the conditional probability of developing human papilloma virus related oropharyngeal cancer by combining machine learning and inverse Bayesian modelling.

The epidemic increase in the incidence of Human Papilloma Virus (HPV) related Oropharyngeal Squamous Cell Carcinomas (OPSCCs) in several countries worldwide represents a significant public health concern. Although gender neutral HPV vaccination programmes are expected to cause a reduction in the incidence rates of OPSCCs, these effects will not be evident in the foreseeable future. Secondary prevention strategies are currently not feasible due to an incomplete understanding of the natural history of oral HPV infections in OPSCCs. The key parameters that govern natural history models remain largely ill-defined for HPV related OPSCCs and cannot be easily inferred from experimental data. Mathematical models have been used to estimate some of these ill-defined parameters in cervical cancer, another HPV related cancer leading to successful implementation of cancer prevention strategies. We outline a "double-Bayesian" mathematical modelling approach, whereby, a Bayesian machine learning model first estimates the probability of an individual having an oral HPV infection, given OPSCC and other covariate information. The model is then inverted using Bayes' theorem to reverse the probability relationship. We use data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, SEER Head and Neck with HPV Database and the National Health and Nutrition Examination Surveys (NHANES), representing the adult population in the United States to derive our model. The model contains 8,106 OPSCC patients of which 73.0% had an oral HPV infection. When stratified by age, sex, marital status and race/ethnicity, the model estimated a higher conditional probability for developing OPSCCs given an oral HPV infection in non-Hispanic White males and females compared to other races/ethnicities. The proposed Bayesian model represents a proof-of-concept of a natural history model of HPV driven OPSCCs and outlines a strategy for estimating the conditional probability of an individual's risk of developing OPSCC following an oral HPV infection.

A cohort study to investigate sex-specific differences in ANCA-associated glomerulonephritis outcomes.

Data surrounding sex-specific differences in ANCA-associated vasculitis glomerulonephritis (ANCA-GN) outcomes is sparse. We hypothesised that the previously observed increased risk of end-stage kidney disease (ESKD) in males is driven by sex-specific variation in immunosuppression dosing. Patients were recruited to the Irish Rare Kidney Disease Registry or followed by the Royal Free Hospital vasculitis team (2012-2020). Inclusion criteria: prior diagnosis of ANCA-GN (biopsy proven pauci-immune glomerulonephritis) and positive serology for anti-MPO or -PR3 antibodies. Renal and patient survival, stratified by sex and Berden histological class, was analysed. The cumulative- and starting dose/kilogram of induction agents and prednisolone, respectively, was compared between sexes. 332 patients were included. Median follow-up was time 40.2 months (IQR 17.3-69.2). 73 (22%) reached ESKD and 47 (14.2%) died. Overall 1- and 5-year renal survival was 82.2% and 76.7% in males and 87.1% and 82.0% in females, respectively (p 0.13). The hazard ratio for ESKD in males versus females, after adjustment for age, ANCA serology, baseline creatinine and histological class was 1.07 (95% CI 0.59-1.93). There was no difference between sexes in the dose/kilogram of any induction agent. We did not observe a strong impact of sex on renal outcome in ANCA-GN. Treatment intensity does not vary by sex.

Steps Ahead: optimising physical activity in adults with cystic fibrosis: Study Protocol for a pilot randomised trial using wearable technology, goal setting and text message feedback.

Background: Physical activity (PA) and exercise are widely documented as key components in the management of cystic fibrosis (CF). In recent years there have been significant improvements in telehealth, in particular; fitness tracking, smartphone use and remote monitoring, all of which may have potential to impact on positive health outcomes in people with CF. The objective of this pilot randomised trial is to explore the potential efficacy of a fitness tracker, which is remotely monitored, combined with personalised text message feedback and goal setting, on lung function, aerobic capacity and PA in adults with CF. Secondary endpoints include quality of life, body composition and wellbeing. Methods: This is a pilot randomised trial which will be conducted at the University Hospital Limerick, Ireland. Participants will be randomised to the intervention or active comparator after their baseline assessment. The 12-week intervention will consist of a fitness tracker (Fitbit Charge 2) which is linked to an online monitoring system (Fitabase) for data collection purposes that enables the physiotherapist to remotely monitor participant data. The CF physiotherapist will set short- and long-term goals with participants and will send one-way text message feedback on Fitbit data and weekly progress. This message will consist of positive reinforcement and re-assess participant goals. The active comparator group will receive a fitness tracker which is also linked to Fitabase; however, no feedback will be provided to participants in this group. Both groups will be re-assessed at 12 weeks. After this point, both groups will continue with the Fitbit alone for a further 12 weeks. Both groups will be re-assessed at 24 weeks. Discussion: This is a novel concept which utilises modern technology, remote monitoring and personalised feedback to investigate the effect on health outcomes in people with CF.  Trial registration: ClinicalTrials.gov NCT03672058 (14/09/2018).

Assessing the impact of a matching-adjusted indirect comparison in a Bayesian network meta-analysis.

If IPD is available for some or all trials in a network meta-analysis (NMA), then incorporating this IPD into an NMA is routinely considered to be preferable. However, the situation often arises where a researcher has IPD for trials concerning a particular treatment (eg, from a sponsor) but none for other trials. Therefore, one can reweight the IPD so that the covariate characteristics in the IPD trials match that of the aggregate data (AgD) trials, using a matching-adjusted indirect comparison (MAIC). We assess the impact of using the reweighted aggregated data, obtained by the MAIC, in a Bayesian NMA for a connected treatment network. We apply this method to a network of multiple myeloma treatments in newly diagnosed patients (ndMM), where the outcome is progression free survival. We investigate the reliability of the methods and results through a simulation study. The ndMM network consists of three IPD studies comparing lenalidomide to placebo (Len-Placebo), one AgD study comparing Len-Placebo, and one AgD study comparing thalidomide to placebo (Thal-Placebo). We therefore investigate two options of weighting the covariates: (a) All three studies are weighted separately to match the AgD Thal-Placebo trial. (b) Patients are weighted across all three IPD studies to match the AgD Thal-Placebo trial, but the NMA considers each trial separately. We observe limited benefit to MAIC in the full network population. While MAIC can be beneficial as a sensitivity analysis to confirm results across patient populations, we advise that MAIC is used and interpreted with caution.

Carotid Plaque Inflammation Imaged by 18F-Fluorodeoxyglucose Positron Emission Tomography and Risk of Early Recurrent Stroke.

Background and Purpose- Plaque inflammation contributes to stroke and coronary events. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) identifies plaque inflammation-related metabolism. Almost no prospective data exist on the relationship of carotid 18F-FDG uptake and early recurrent stroke. Methods- We did a multicenter prospective cohort study BIOVASC (Biomarkers/Imaging Vulnerable Atherosclerosis in Symptomatic Carotid disease) of patients with carotid stenosis and recent stroke/transient ischemic attack with 90-day follow-up. On coregistered carotid 18F-FDG PET/computed tomography angiography, 18F-FDG uptake was expressed as maximum standardized uptake value (SUVmax) in the axial single hottest slice. We then conducted a systematic review of similar studies and pooled unpublished individual-patient data with 2 highly similar independent studies (Dublin and Barcelona). We analyzed the association of SUVmax with all recurrent nonprocedural stroke (before and after PET) and with recurrent stroke after PET only. Results- In BIOVASC (n=109, 14 recurrent strokes), after adjustment (for age, sex, stenosis severity, antiplatelets, statins, diabetes mellitus, hypertension, and smoking), the hazard ratio for recurrent stroke per 1 g/mL SUVmax was 2.2 (CI, 1.1-4.5; P=0.025). Findings were consistent in the independent Dublin (n=52, hazard ratio, 2.2; CI, 1.1-4.3) and Barcelona studies (n=35, hazard ratio, 2.8; CI, 0.98-5.5). In the pooled cohort (n=196), 37 recurrent strokes occurred (29 before and 8 after PET). Plaque SUVmax was higher in patients with all recurrence ( P<0.0001) and post-PET recurrence ( P=0.009). The fully adjusted hazard ratio of any recurrent stroke was 2.19 (CI, 1.41-3.39; P<0.001) and for post-PET recurrent stroke was 4.57 (CI, 1.5-13.96; P=0.008). Recurrent stroke risk increased across SUVmax quartiles (log-rank P=0.003). The area under receiver operating curve for all recurrence was 0.70 (CI, 0.59-0.78) and for post-PET recurrence was 0.80 (CI, 0.64-0.96). Conclusions- Plaque inflammation-related 18F-FDG uptake independently predicted future recurrent stroke post-PET. Although further studies are needed, 18F-FDG PET may improve patient selection for carotid revascularization and suggest that anti-inflammatory agents may have benefit for poststroke vascular prevention.

The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma.

BACKGROUND: Network meta-analysis (NMA) allows for the estimation of comparative effectiveness of treatments that have not been studied in head-to-head trials; however, relative treatment effects for all interventions can only be derived where available evidence forms a connected network. Head-to-head evidence is limited in many disease areas, regularly resulting in disconnected evidence structures where a large number of treatments are available. This is also the case in the evidence of treatments for relapsed or refractory multiple myeloma. METHODS: Randomised controlled trials (RCTs) identified in a systematic literature review form two disconnected evidence networks. Standard Bayesian NMA models are fitted to obtain estimates of relative effects within each network. Observational evidence was identified to fill the evidence gap. Single armed trials are matched to act as each other's control group based on a distance metric derived from covariate information. Uncertainty resulting from including this evidence is incorporated by analysing the space of possible matches. RESULTS: Twenty five randomised controlled trials form two disconnected evidence networks; 12 single armed observational studies are considered for bridging between the networks. Five matches are selected to bridge between the networks. While significant variation in the ranking is observed, daratumumab in combination with dexamethasone and either lenalidomide or bortezomib, as well as triple therapy of carfilzomib, ixazomib and elozumatab, in combination with lenalidomide and dexamethasone, show the highest effects on progression free survival, on average. CONCLUSIONS: The analysis shows how observational data can be used to fill gaps in the existing networks of RCT evidence; allowing for the indirect comparison of a large number of treatments, which could not be compared otherwise. Additional uncertainty is accounted for by scenario analyses reducing the risk of over confidence in interpretation of results.

Examining the Feasibility and Utility of Estimating Partial Expected Value of Perfect Information (via a Nonparametric Approach) as Part of the Reimbursement Decision-Making Process in Ireland: Application to Drugs for Cancer.

BACKGROUND: In Ireland, all new drugs for which reimbursement by the healthcare payer is sought undergo a health technology assessment by the National Centre for Pharmacoeconomics. The National Centre for Pharmacoeconomics estimate expected value of perfect information but not partial expected value of perfect information (owing to computational expense associated with typical methodologies). OBJECTIVE: The objective of this study was to examine the feasibility and utility of estimating partial expected value of perfect information via a computationally efficient, non-parametric regression approach. METHODS: This was a retrospective analysis of evaluations on drugs for cancer that had been submitted to the National Centre for Pharmacoeconomics (January 2010 to December 2014 inclusive). Drugs were excluded if cost effective at the submitted price. Drugs were excluded if concerns existed regarding the validity of the applicants' submission or if cost-effectiveness model functionality did not allow required modifications to be made. For each included drug (n = 14), value of information was estimated at the final reimbursement price, at a threshold equivalent to the incremental cost-effectiveness ratio at that price. The expected value of perfect information was estimated from probabilistic analysis. Partial expected value of perfect information was estimated via a non-parametric approach. Input parameters with a population value at least €1 million were identified as potential targets for research. RESULTS: All partial estimates were determined within minutes. Thirty parameters (across nine models) each had a value of at least €1 million. These were categorised. Collectively, survival analysis parameters were valued at €19.32 million, health state utility parameters at €15.81 million and parameters associated with the cost of treating adverse effects at €6.64 million. Those associated with drug acquisition costs and with the cost of care were valued at €6.51 million and €5.71 million, respectively. CONCLUSION: This research demonstrates that the estimation of partial expected value of perfect information via this computationally inexpensive approach could be considered feasible as part of the health technology assessment process for reimbursement purposes within the Irish healthcare system. It might be a useful tool in prioritising future research to decrease decision uncertainty.

Harms of off-label erythropoiesis-stimulating agents for critically ill people.

BACKGROUND: Anaemia is a common problem experienced by critically-ill people. Treatment with erythropoiesis-stimulating agents (ESAs) has been used as a pharmacologic strategy when the blunted response of endogenous erythropoietin has been reported in critically-ill people. The use of ESAs becomes more important where adverse clinical outcomes of transfusing blood products is a limitation. However, this indication for ESAs is not licensed by regulatory authorities and is called off-label use. Recent studies concern the harm of ESAs in a critical care setting. OBJECTIVES: To focus on harms in assessing the effects of erythropoiesis-stimulating agents (ESAs), alone or in combination, compared with placebo, no treatment or a different active treatment regimen when administered off-label to critically-ill people. SEARCH METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO via OvidSP, CINAHL, all evidence-based medicine (EBM) reviews including IPA and SCI-Expanded, Conference Proceedings Citation Index- Science, BIOSIS Previews and TOXLINE up to February 2017. We also searched trials registries, checked reference lists of relevant studies and tracked their citations by using SciVerse Scopus. SELECTION CRITERIA: We considered randomized controlled trials (RCTs) and controlled observational studies, which compared scheduled systemic administration of ESAs versus other effective interventions, placebo or no treatment in critically-ill people. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and evaluated the eligibility of retrieved records, extracted data and assessed the risks of bias and quality of the included studies. We resolved differences in opinion by consensus or by involving a third review author. We assessed the evidence using GRADE and created a 'Summary of findings' table. We used fixed-effect or random-effects models, depending on the heterogeneity between studies. We fitted three-level hierarchical Bayesian models to calculate overall treatment effect estimates. MAIN RESULTS: Of the 27,865 records identified, 39 clinical trials and 14 observational studies, including a total of 945,240 participants, were eligible for inclusion. Five studies are awaiting classification. Overall, we found 114 adverse events in 33 studies (30 RCTs and three observational studies), and mortality was reported in 41 studies (32 RCTs and nine observational studies). Most studies were at low to moderate risk of bias for harms outcomes. However, overall harm assessment and reporting were of moderate to low quality in the RCTs, and of low quality in the observational studies. We downgraded the GRADE quality of evidence for venous thromboembolism and mortality to very low and low, respectively, because of risk of bias, high inconsistency, imprecision and limitations of study design.It is unclear whether there is an increase in the risk of any adverse events (Bayesian risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.21; 3099 participants; 9 studies; low-quality evidence) or venous thromboembolism (Bayesian RR 1.04, 95% CI 0.70 to 1.41; 18,917 participants; 18 studies; very low-quality evidence).There was a decreased risk of mortality with off-label use of ESAs in critically-ill people (Bayesian RR 0.76, 95% CI 0.61 to 0.92; 930,470 participants; 34 studies; low-quality evidence). AUTHORS' CONCLUSIONS: Low quality of evidence suggests that off-label use of ESAs may reduce mortality in a critical care setting. There was a lack of high-quality evidence about the harm of ESAs in critically-ill people. The information for biosimilar ESAs is less conclusive. Most studies neither evaluated ESAs' harm as a primary outcome nor predefined adverse events. Any further studies of ESA should address the quality of evaluating, recording and reporting of adverse events.

Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease.

BACKGROUND AND OBJECTIVES: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.