A mixed methods investigation of trial design for measuring glaucoma medication adherence

Sub-optimal adherence to glaucoma therapy has negative health and financial implications. The Norwich Adherence Glaucoma Study (NAGS) adopted gold-standard methods including randomisation and objective outcome measurement to investigate an adherence intervention. Patients were randomised to standard care alone (control group) or additional glaucoma and medication related information provision using Behaviour Change Counselling. A Travalert Dosing Aid® (TDA) was used to collect 8 months of adherence data. For the 208 patients randomised, adherence was higher than expected in the control group and there was no significant difference in adherence between intervention and control. Two qualitative studies collected user experiences from NAGS and established patient experiences of administering eye drops using the TDA. Potential NAGS experimental design errors were identified that might have inadvertently introduced changes in patient behaviour, causing bias in the observed study outcomes; a phenomenon known as a reactivity effect. Thus, the React study was designed to quantify the magnitude of reactivity effects on observed adherence behaviour, but the study required the use of a modified consent method. Focus groups informed the content of a questionnaire that was piloted using cognitive interviewing methods. The subsequent questionnaire was distributed to 400 members of the public attending an out-patient NHS hospital. From the 208 questionnaires returned, the majority of respondents felt that the proposed React study used an acceptable consent method in order to investigate reactivity effects. Work continues with the React study to recruit the target sample size. Participants with lower measured adherence were less likely to participate and this self-selecting bias compromised estimates of the true magnitude of reactivity effects. However, the evidence collected to date confirmed the presence of reactivity effects. This research suggests that objective measures coupled with modified consent procedures may be an appropriate methodological strategy to minimise reactivity effects in trials designed to change behaviour

A pilot study to assess the feasibility of using the Travalert® dosing aid to measure adherence

A pilot study to assess the feasibility of using the Travalert® dosing aid to measure adherence Heidi Cate, 2011 Glaucoma is a chronic condition, leading to progressive visual field loss and eventual blindness if left untreated. With adequate medical therapy, progression of the disease can be reduced. Non-adherence to glaucoma medication is a significant issue requiring further research. However, rigorous evidence for novel adherence interventions requires a valid and reliable measure of adherence. A gold standard for measuring adherence to glaucoma therapy has yet to be established. This study evaluated the Travalert® dosing aid (TDA) as an effective measure of adherence to travoprost. One hundred patients prescribed travoprost for glaucoma or ocular hypertension, were approached and stratified by phase of travoprost use: newly prescribed or follow-up. At baseline, self-reported adherence to travoprost was obtained from follow-up participants using questionnaires (Morisky Medication Adherence Scale and Frequency of Missed Dose). All participants were given a TDA and daily adherence data were collected for 2 months. Self-reported adherence was obtained from both newly prescribed and follow-up participants. Satisfaction with information received about travoprost was assessed using the Satisfaction with Information about Medications Scale questionnaire. The results suggested that future adherence studies should monitor adherence in excess of 100 days to overcome initial monitoring effects. Furthermore, the use of intraocular pressure as a short-term clinical outcome measure to assess adherence to glaucoma medication was found to be unreliable and thus requires further investigation. This study has provided preliminary evidence that the TDA does not significantly alter patient eye drop use behaviour. It has been demonstrated as a feasible, objective adherence measure revealing that 40.9% of participants deviated from their prescribed treatment regimen. A further application of the TDA could be investigation of patient medication usage patterns to advance understanding of the complex area of non-adherence to glaucoma medication and aid the design of future adherence interventions

Development of an evidence-based regimen of prednisolone to treat giant cell arteritis - the Norwich regimen

We have reviewed the literature to form a bespoke regimen for daily oral prednisolone (DP) in GCA. Initial DP in clinical trials is 40-60 mg daily, but relapse rates are 67-92%. Cumulative prednisolone (CP) of 3.2 and 3.9 g (at 6 months) resulted in a relapse rate of 83 and 67%, respectively; and 3 and 3.9 g (at 12 months) resulted in 92 and 82% relapse, respectively. CP was 6.2-7.1 g in the first year. Mean DP was 18.8 mg at 3 months and 6.6-7.4 mg at 12 months. The duration of treatment with prednisolone for GCA was 22-26 months. The CP to achieve discontinuation was 6.5-12.1 g. Using these data, the Norwich regimen starts DP at 1 mg/kg/day of lean body mass, discontinuing over 100 weeks. For the average UK woman, initial DP is 45 mg daily, reaching 21 mg daily by 12 weeks and 6 mg daily by 52 weeks. The CP for the average UK woman would be 6.5 g at 52 weeks and 7.4 g to discontinuation

A history of late and very late stent thrombosis is not associated with increased activation of the contact system, a case control study

Background: The pathophysiological pathways resulting in Late Stent Thrombosis (LST) remain uncertain. Findings from animal studies indicate a role of the intrinsic coagulation pathway in arterial thrombus formation, while clinical studies support an association with ischemic cardiovascular disease. It is currently unknown whether differences in the state of the contact system might contribute to the risk of LST or Very Late Stent Thrombosis (VLST). We assessed the relation between levels of several components involved in the contact system and a history of LST and VLST, termed (V)LST in a cohort of 20 patients as compared to a matched control group treated with PCI. Methods and Results: Activated factor XII (FXIIa), FXII zymogen (FXII), FXIIa-C1-esterase inhibitor (C1-inhibitor), Kallikrein-C1-inhibitor, FXIa-C1-inhibitor and FXIa-α1-antitrypsin (AT-inhibitor) complexes were measured by Enzyme-linked immunosorbent assy (ELISA) methodology. Cases and controls showed similar distributions in sex, age, baseline medications and stent type. Patients with a history of (V)LST had a significantly greater stent burden and a higher number of previous myocardial infarctions than the control patients. There were no significant between-group differences in the plasma levels of the components of the contact system. Conclusion: In a cohort of patients with a history of (V)LST, we did not observe differences in the activation state of the intrinsic coagulation system as compared to patients with a history of percutaneous coronary intervention without stent thrombosis

Improving adherence to glaucoma medication: a randomised controlled trial of a patient-centred intervention (The Norwich Adherence Glaucoma Study)

Background Improving adherence to ocular hypertension (OH)/glaucoma therapy is highly likely to prevent or reduce progression of optic nerve damage. The present study used a behaviour change counselling intervention to determine whether education and support was beneficial and cost-effective in improving adherence with glaucoma therapy. Methods A randomised controlled trial with a 13-month recruitment and 8-month follow-up period was conducted. Patients with OH/glaucoma attending a glaucoma clinic and starting treatment with travoprost were approached. Participants were randomised into two groups and adherence was measured over 8 months, using an electronic monitoring device (Travalert® dosing aid, TDA). The control group received standard clinical care, and the intervention group received a novel glaucoma education and motivational support package using behaviour change counselling. Cost-effectiveness framework analysis was used to estimate any potential cost benefit of improving adherence. Results Two hundred and eight patients were recruited (102 intervention, 106 control). No significant difference in mean adherence over the monitoring period was identified with 77.2% (CI, 73.0, 81.4) for the control group and 74.8% (CI, 69.7, 79.9) for the intervention group (p = 0.47). Similarly, there was no significant difference in percentage intraocular pressure reduction; 27.6% (CI, 23.5, 31.7) for the control group and 25.3% (CI, 21.06, 29.54) for the intervention group (p = 0.45). Participants in the intervention group were more satisfied with information about glaucoma medication with a mean score of 14.47/17 (CI, 13.85, 15.0) compared with control group which was 8.51 (CI, 7.72, 9.30). The mean intervention cost per patient was GB£10.35 (<US$16) and not cost-effective. Conclusions Adherence with travoprost was high and not further increased by the intervention. Nevertheless, the study demonstrated that provision of information, tailored to the individual, was inexpensive and able to achieve high patient satisfaction with respect to information about glaucoma medication. Measurement of adherence remains problematic since awareness of study participation may cause a change in participant behaviour

Emerging pneumococcal carriage serotypes in a high-risk population receiving universal 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide vaccine since 2001

<p>Abstract</p> <p>Background</p> <p>In Australia in June 2001, a unique pneumococcal vaccine schedule commenced for Indigenous infants; seven-valent pneumococcal conjugate vaccine (7PCV) given at 2, 4, and 6 months of age and 23-valent pneumococcal polysaccharide vaccine (23PPV) at 18 months of age. This study presents carriage serotypes following this schedule.</p> <p>Methods</p> <p>We conducted cross sectional surveys of pneumococcal carriage in Aboriginal children 0 to 6 years of age living in remote Aboriginal communities (RACs) in 2003 and 2005. Nasal secretions were collected and processed according to published methods.</p> <p>Results</p> <p>902 children (mean age 25 months) living in 29 communities in 2003 and 818 children (mean age 35 months) in 17 communities in 2005 were enrolled. 87% children in 2003 and 96% in 2005 had received two or more doses of 7PCV. From 2003 to 2005, pneumococcal carriage was reduced from 82% to 76% and reductions were apparent in all age groups; 7PCV-type carriage was reduced from 11% to 8%, and 23PPV-non-7PCV-type carriage from 31% to 25% respectively. Thus non-23PPV-type carriage increased from 57% to 67%. All these changes were statistically significant, as were changes for some specific serotypes. Shifts could not be attributed to vaccination alone. The top 10 of 40 serotypes identified were (in descending order) 16F, 19A, 11A, 6C, 23B, 19F, 6A, 35B, 6B, 10A and 35B. Carriage of penicillin non-susceptible (MIC > = 0.12 μg/mL) strains (15% overall) was detected in serotypes (descending order) 19A, 19F, 6B, 16F, 11A, 9V, 23B, and in 4 additional serotypes. Carriage of azithromycin resistant (MIC > = 2 μg/mL) strains (5% overall), was detected in serotypes (descending order) 23B, 17F, 9N, 6B, 6A, 11A, 23F, and in 10 additional serotypes including 6C.</p> <p>Conclusion</p> <p>Pneumococcal carriage remains high (~80%) in this vaccinated population. Uptake of both pneumococcal vaccines increased, and carriage was reduced between 2003 and 2005. Predominant serotypes in combined years were 16F, 19A, 11A, 6C and 23B. Antimicrobial non-susceptibility was detected in these and 17 additional serotypes. Shifts in serotype-specific carriage suggest a need more research to clarify the association between pneumococcal vaccination and carriage at the serotype level.</p

Commentary: Obesity and Weight Gain in Pregnancy and Postpartum: an Evidence Review of Lifestyle Interventions to Inform Maternal and Child Health Policies

We read with interest the recent review published in Frontiers in Endocrinology that was focused on obesity and weight gain in pregnancy and postpartum. The review of systematic reviews and meta-analyses, investigating the effects of lifestyle interventions on gestational weight gain (GWG) and postpartum weight retention (PPWR), provides evidence showing that lifestyle interventions can reduce excess weight gain and associated risk factors. We agree unconditionally that the burden of maternal and childhood obesity needs to be reduced urgently.Funding for this research has been provided from the Australian Government's Medical Research Future Fund (MRFF)

Global transpiration data from sap flow measurements : the SAPFLUXNET database

Plant transpiration links physiological responses of vegetation to water supply and demand with hydrological, energy, and carbon budgets at the land-atmosphere interface. However, despite being the main land evaporative flux at the global scale, transpiration and its response to environmental drivers are currently not well constrained by observations. Here we introduce the first global compilation of whole-plant transpiration data from sap flow measurements (SAPFLUXNET, https://sapfluxnet.creaf.cat/, last access: 8 June 2021). We harmonized and quality-controlled individual datasets supplied by contributors worldwide in a semi-automatic data workflow implemented in the R programming language. Datasets include sub-daily time series of sap flow and hydrometeorological drivers for one or more growing seasons, as well as metadata on the stand characteristics, plant attributes, and technical details of the measurements. SAPFLUXNET contains 202 globally distributed datasets with sap flow time series for 2714 plants, mostly trees, of 174 species. SAPFLUXNET has a broad bioclimatic coverage, with woodland/shrubland and temperate forest biomes especially well represented (80 % of the datasets). The measurements cover a wide variety of stand structural characteristics and plant sizes. The datasets encompass the period between 1995 and 2018, with 50 % of the datasets being at least 3 years long. Accompanying radiation and vapour pressure deficit data are available for most of the datasets, while on-site soil water content is available for 56 % of the datasets. Many datasets contain data for species that make up 90 % or more of the total stand basal area, allowing the estimation of stand transpiration in diverse ecological settings. SAPFLUXNET adds to existing plant trait datasets, ecosystem flux networks, and remote sensing products to help increase our understanding of plant water use, plant responses to drought, and ecohydrological processes. SAPFLUXNET version 0.1.5 is freely available from the Zenodo repository (https://doi.org/10.5281/zenodo.3971689; Poyatos et al., 2020a). The "sapfluxnetr" R package - designed to access, visualize, and process SAPFLUXNET data - is available from CRAN.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707