Congenital heart defects caused by FOXJ1.

FOXJ1 is expressed in ciliated cells of the airways, testis, oviduct, central nervous system and the embryonic left-right organizer. Ablation or targeted mutation of Foxj1 in mice, zebrafish and frogs results in loss of ciliary motility and/or reduced length and number of motile cilia, affecting the establishment of the left-right axis. In humans, heterozygous pathogenic variants in FOXJ1 cause ciliopathy leading to situs inversus, obstructive hydrocephalus and chronic airway disease. Here, we report a novel truncating FOXJ1 variant (c.784_799dup; p.Glu267Glyfs*12) identified by clinical exome sequencing from a patient with isolated congenital heart defects (CHD) which included atrial and ventricular septal defects, double outlet right ventricle (DORV) and transposition of the great arteries. Functional experiments show that FOXJ1 c.784_799dup; p.Glu267Glyfs*12, unlike FOXJ1, fails to induce ectopic cilia in frog epidermis in vivo or to activate the ADGB promoter, a downstream target of FOXJ1 in cilia, in transactivation assays in vitro. Variant analysis of patients with heterotaxy or heterotaxy-related CHD indicates that pathogenic variants in FOXJ1 are an infrequent cause of heterotaxy. Finally, we characterize embryonic-stage CHD in Foxj1 loss-of-function mice, demonstrating randomized heart looping. Abnormal heart looping includes reversed looping (dextrocardia), ventral looping and no looping/single ventricle hearts. Complex CHDs revealed by histological analysis include atrioventricular septal defects, DORV, single ventricle defects as well as abnormal position of the great arteries. These results indicate that pathogenic variants in FOXJ1 can cause isolated CHD.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials.

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 µm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.

BACKGROUND: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING: F Hoffmann-La Roche.

The importance of cancer prevention policies to inform and guide preventative and screening measures for people with intellectual disabilities: The COST project "Cancer- Understanding Prevention in Intellectual Disabilities".

Cancer is a global public health problem, but its exact prevalence in people with intellectual disabilities is still uncertain. This population, with limited health skills and complex health needs, faces many challenges in cancer prevention, screening, timely diagnosis and treatment. Furthermore, they are often underrepresented in general cancer prevention and screening policies across Europe, leading to widened disparities in health outcomes and premature mortality. Thus, unified national and local policies are needed to reduce inequalities and promoting a pan-European inclusion of people with intellectual disabilities. Our goal is to raise public awareness of this issue, including the involvement of people with intellectual disabilities, and promote engagement from relevant stakeholders. The COST Action 'Cancer- Understanding Prevention in Intellectual Disabilities' (CUPID) project will address health inequalities faced by people with intellectual disabilities in relation to cancer, and support the development of policy recommendations specifically tailored to their unique cognitive and healthcare needs, having a positive long-term impact on quality of life.

Preparing for hybrid warfare and cyberattacks on health services' digital infrastructure: What nurse managers need to know.

AIM: This article aims to outline the key concepts in hybrid warfare and cyberattack to better inform nurse managers in their strategic contribution to the defence of critical digital infrastructure. BACKGROUND: Hybrid warfare often targets a nation's critical digital infrastructure including that of health services. Hybrid warfare against national health services, primarily through cyberattack, is likely to increase in a more destabilized and conflictual international environment. EVALUATION: Key literature, reports and assessments on hybrid warfare, advanced persistent threats and cyberattack referenced to health services were analysed. KEY ISSUE: Health services are a key element of a nation's critical digital infrastructure and as such are a strategic target in hybrid warfare. Cyberattack through exploiting clinicians', such as nurses, online susceptibilities is a key route of attack. Nurse managers, to be effective planners, need to be fully informed about the context and specific nature of cyberattack. CONCLUSION(S): Articles about the relationship between hybrid warfare and cyberattack on health services digital infrastructure are rarely aimed at nurse managers. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers need to be fully informed about the geopolitical nature of cyberattacks if they are to be fully consulted and listened to in response planning in defence of health services' digital infrastructure.

Exploring user empowerment and service improvement within an Irish epilepsy service using Checkland's 'Soft Systems' approach.

AIM: To illustrate the value of Checkland's 'Soft Systems' approach to explore and analyse the interaction of human and organisational factors that affect service delivery and patient experience in one specialist epilepsy service. BACKGROUND: Checkland's approach is underutilized in relation to health service improvement. One epilepsy service in Ireland is used as an example to illustrate the value of his approach to improve service delivery, particularly when what needs to change is not clear. METHOD: Checkland's 'Soft Systems' seven-stage approach was used collaboratively to explore patients' and clinicians' experience of service delivery and how to improve it. RESULTS: The research identified the practice of empowerment affected the quality of the service experience. Checkland's concept of a human activity system was particularly pertinent in identifying this issue and providing a 'map' for change. CONCLUSION: Wider inferences for the use of Checkland's approach by nurse managers are discussed, as is the value of using Checkland's approach to improve services. IMPLICATIONS FOR NURSING MANAGEMENT: Checkland's 'Soft Systems' is an underutilized approach in health care that could be used by managers to initiate and embed change within a health care service.

Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study).

PURPOSE: Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial. DESIGN: Multicenter cohort study. PARTICIPANTS: Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion). METHODS: Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit. MAIN OUTCOME MEASURES: Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST). RESULTS: Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range [IQR], 0-12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 µm (95% CI, 142-166) and was stable between 2 and 5 years (-1 µm; 95% CI, -12 to 9). CONCLUSIONS: Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.

An exploratory non-randomized study of a 3-month electronic nicotine delivery system (ENDS) intervention with people accessing a homeless supported temporary accommodation service (STA) in Ireland.

BACKGROUND: Smoking is endemic amongst people accessing homeless services, and they are disproportionately affected by smoking-related diseases. This paper reports on the results of a 3-month small scale intervention which explored the efficacy, challenges and opportunities of using electronic nicotine delivery systems (ENDS) to support cessation of tobacco smoking with people accessing an Irish supported temporary accommodation (STA) homeless service. It considers the results of this intervention with reference to the balance of harms between the use of vaping to support smoking cessation and continued smoking. METHODS: Twenty-three participants were recruited. Demographic data, carbon monoxide (CO) measurements, homelessness status and smoking history were recorded. Participants were given an ENDS device and two 10-ml bottles containing e-liquid available in several flavours and at several strengths. Participants could pick up new bottles on a weekly basis. At weeks 1, 4, 8 and 12, the Fagerström Test and Mood and Physical Symptoms Scale (MPSS) were administered. RESULTS: Over 75% of the residents in the participating hostel were recruited (23/30). However, there was a substantial loss to follow-up (n = 14) as a result of data protection issues, the transient nature of the population of interest and non-compliance with the intervention. Self-reported reductions in cigarette consumption were found to be statistically significant (p < 0.001). However, reductions in carbon monoxide measurements were not statistically significant. Decreases in Fagerström Nicotine Dependence Test were statistically significant (p = 0.001), but decreases in MPSS "urge to smoke" and "strength of urges" composite scores were not. Reported side effects included coughing, runny nose, bleeding nose, slight sweating, dizziness, increased phlegm and a burning sensation at the back of the throat. Barriers to engagement were peer norms, vaping restrictions in accommodation and adverse life events. Positive effects reported included increased energy, less coughing, better breathing and financial benefits. An improvement in the domain "poor concentration" was also found to be statistically significant (p = 0.040). CONCLUSION: ENDS-based interventions may be effective with this population. Future research should aim to improve follow-up, consider including behavioural components and monitor health effects in relation to ongoing concerns around risks and the balance of harms. TRIAL REGISTRATION: Registered retrospectively ISRCTN14767579.

Effect of Intravitreous Aflibercept vs Vitrectomy With Panretinal Photocoagulation on Visual Acuity in Patients With Vitreous Hemorrhage From Proliferative Diabetic Retinopathy: A Randomized Clinical Trial.

Importance: Vitreous hemorrhage from proliferative diabetic retinopathy can cause loss of vision. The best management approach is unknown. Objective: To compare initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation for vitreous hemorrhage from proliferative diabetic retinopathy. Design, Setting, and Participants: Randomized clinical trial at 39 DRCR Retina Network sites in the US and Canada including 205 adults with vison loss due to vitreous hemorrhage from proliferative diabetic retinopathy who were enrolled from November 2016 to December 2017. The final follow-up visit was completed in January 2020. Interventions: Random assignment of eyes (1 per participant) to aflibercept (100 participants) or vitrectomy with panretinal photocoagulation (105 participants). Participants whose eyes were assigned to aflibercept initially received 4 monthly injections. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol criteria. Main Outcomes and Measures: The primary outcome was mean visual acuity letter score (range, 0-100; higher scores indicate better vision) over 24 weeks (area under the curve); the study was powered to detect a difference of 8 letters. Secondary outcomes included mean visual acuity at 4 weeks and 2 years. Results: Among 205 participants (205 eyes) who were randomized (mean [SD] age, 57 [11] years; 115 [56%] men; mean visual acuity letter score, 34.5 [Snellen equivalent, 20/200]), 95% (195 of 205) completed the 24-week visit and 90% (177 of 196, excluding 9 deaths) completed the 2-year visit. The mean visual acuity letter score over 24 weeks was 59.3 (Snellen equivalent, 20/63) (95% CI, 54.9 to 63.7) in the aflibercept group vs 63.0 (Snellen equivalent, 20/63) (95% CI, 58.6 to 67.3) in the vitrectomy group (adjusted difference, -5.0 [95% CI, -10.2 to 0.3], P = .06). Among 23 secondary outcomes, 15 showed no significant difference. The mean visual acuity letter score was 52.6 (Snellen equivalent, 20/100) in the aflibercept group vs 62.3 (Snellen equivalent, 20/63) in the vitrectomy group at 4 weeks (adjusted difference, -11.2 [95% CI, -18.5 to -3.9], P = .003) and 73.7 (Snellen equivalent, 20/40) vs 71.0 (Snellen equivalent, 20/40) at 2 years (adjusted difference, 2.7 [95% CI, -3.1 to 8.4], P = .36). Over 2 years, 33 eyes (33%) assigned to aflibercept received vitrectomy and 34 eyes (32%) assigned to vitrectomy received subsequent aflibercept. Conclusions and Relevance: Among participants whose eyes had vitreous hemorrhage from proliferative diabetic retinopathy, there was no statistically significant difference in the primary outcome of mean visual acuity letter score over 24 weeks following initial treatment with intravitreous aflibercept vs vitrectomy with panretinal photocoagulation. However, the study may have been underpowered, considering the range of the 95% CI, to detect a clinically important benefit in favor of initial vitrectomy with panretinal photocoagulation. Trial Registration: ClinicalTrials.gov Identifier: NCT02858076.

A Qualitative Examination of the Physical Activity Needs of People with Severe Mental Illness.

It is recognised that physical activity has a positive impact on quality of life, social well-being and overall health of people with severe mental illness. However, there is a lack of theory informed programmes that support people with mental illness to adopt regular physical activity behaviour. The aim of this case study was to identify determinants of long-term physical activity among people with severe mental illness that may then inform the development of more suitable physical activity programmes. Semi-structured interviews were conducted with 15 people (13 men and 2 women) with a mean age of 36.7 [standard deviation (SD)=11.8] who had a diagnosed mental illness and were attending a physical activity programme run by a mental health non-governmental organisation. Interview data was analysed using the documentary method to emphasise the perspective of people with severe mental illness. Three participation types were generated in the context of individuals' physical activity orientation and social background-first 'rehabilitative orientated' (physical activity as a supportive measure to re-enter the labour market and develop a daily routine); second 'social-orientated' (social well-being within the group as the primary motive); finally, 'trust-orientated' (a sense of trust that encourages participation). Based on these type-specific categories, it is suggested that different settings (mental health care centres and sport clubs) might be needed to attract and maintain the physical activity engagement of people with severe mental illness. In the context of sport clubs, it is recommended that coaches undergo training in mental health literacy.

Conceptualizing skill mix in nursing and health care: An analysis.

AIM: This paper aims to unpack the concept of "skill mix" into its constituent parts to achieve a better understanding and reduce confusion associated with the term. BACKGROUND: Skill mix is a topic that is widely debated and is foremost on the health policy agenda due to specific local pressures within international health services. At present, however, there is large variation in terms of what is understood by the concept of "skill mix" and there is a paucity of research that attempts to analyse this concept. EVALUATION: Using Rodgers' evolutionary method of concept analysis, this paper provides an analysis of definitions of skill mix, its attributes and associated terms in the literature. KEY ISSUE: Definitions of skill mix are often vague and ambiguous and may refer to one or more attributes of skill mix. CONCLUSION: A lack of understanding of the concept can lead to an ad hoc interpretation of policy recommendations related to skill mix at local level. IMPLICATIONS FOR NURSING MANAGEMENT: A better understanding of the concept of "skill mix" and its attributes can assist both policy makers and stakeholders, including nurse management, to ensure that the potential of skill mix is maximized.

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.

BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

Plasma Vascular Endothelial Growth Factor Concentrations after Intravitreous Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema.

PURPOSE: To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS: Participants with available plasma samples (N = 436). METHODS: Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS: These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.

Purchasing Over The Counter (OTC) Medicinal Products Containing Codeine - Easy Access, Advertising, Misuse and Perceptions of Medicinal Risk.

PURPOSE: Codeine containing medicines can carry a number of health risks associated with the increase in reported misuse and dependence, however they are still readily available over the counter (OTC) in many countries. The aim of this novel study was to report on the results of a survey of customers purchasing OTC codeine containing medicinal products at pharmacies in Ireland, South Africa and England; exploring use, sources of knowledge and perception of risks. METHODS: The study design was an exploratory cross sectional survey. It involved a customer self-administered questionnaire at the point of purchase (n=1230).  Relationships between categorical variables were analysed using Pearson chi-square for bivariate analysis. Continuous scale variables were analysed using one way analysis of variance. RESULTS: In Ireland 6% stated they purchased codeine containing products weekly, in South Africa 13% and in England 16%. In Ireland and England women are more likely to view codeine containing products as harmful. In England older adults are more likely to perceive codeine containing products as harmful. A higher proportion of customers in South Africa opposed restricting codeine containing products to prescription only when compared with people in Ireland and England. CONCLUSIONS: Codeine containing products are widely purchased and used in all three jurisdictions. Whilst the majority of customers appear to have some awareness and knowledge of risks, it does not materially impact on their purchasing behaviour with a substantial minority purchasing/using such products on a weekly basis. This regularity of purchase whilst indicative of the popularity of such products, may also be a potential indicator of misuse. Future research is needed in relation to cultural and gendered differences and targeted information giving and harm reduction initiatives for safe usage of these medicinal products.

Theoretical Perspectives of Adherence to Web-Based Interventions: a Scoping Review.

PURPOSE: The purpose of this paper is to review the literature as this relates to theoretical perspectives of adherence to web-based interventions, drawing upon empirical evidence from the fields of psychology, business, information technology and health care. METHODS: A scoping review of the literature utilising principles outlined by Arksey and O'Malley was undertaken. RESULTS: Several relevant theoretical perspectives have emerged, eight of which are charted and discussed in this review. These are the Internet Intervention Model, Persuasive Systems Design, the 'PERMA' framework, the Support Accountability Model, the Model of User Engagement, the Technology Acceptance Model, the Unified Theory of Acceptance and Use of IT and the Conceptual Model of User Engagement. CONCLUSIONS: The findings of the review indicate that an interdisciplinary approach, incorporating a range of technological, environmental and individual factors, may be needed in order to comprehensively explain user adherence to web-based interventions.

Healthcare Quality Improvement and 'work engagement'; concluding results from a national, longitudinal, cross-sectional study of the 'Productive Ward-Releasing Time to Care' Programme.

BACKGROUND: Concerns about patient safety and reducing harm have led to a particular focus on initiatives that improve healthcare quality. However Quality Improvement (QI) initiatives have in the past typically faltered because they fail to fully engage healthcare professionals, resulting in apathy and resistance amongst this group of key stakeholders. Productive Ward: Releasing Time to Care (PW) is a ward-based QI programme created to help ward-based teams redesign and streamline the way that they work; leaving more time to care for patients. PW is designed to engage and empower ward-based teams to improve the safety, quality and delivery of care. METHODS: The main objective of this study was to explore whether PW sustains the 'engagement' of ward-based teams by examining the longitudinal effect that the national QI programme had on the 'work-engagement' of ward-based teams in Ireland. Utilising the Utrecht Work Engagement Scale questionnaire (UWES-17), we surveyed nine PW (intervention) sites from typical acute Medical/Surgical, Rehabilitation and Elderly services (representing the entire cohort of a national phase of PW implementation in Ireland) and a cohort of matched control sites. The numbers surveyed from the PW group at T1 (up to 3 months after commencing the programme) totalled 253 ward-team members and 249 from the control group. At T2 (12 months later), the survey was repeated with 233 ward-team members from the PW sites and 236 from the control group. RESULTS: Overall findings demonstrated that those involved in the QI initiative had higher 'engagement' scores at T1 and T2 in comparison to the control group. Total 'engagement' score (TES), and its 3 dimensions, were all significantly higher in the PW group at T1, but only the Vigour dimension remained significantly higher at T2 (p = 0.006). CONCLUSION: Our results lend some support to the assertions of the PW initiative itself and suggest that when compared to a control group, ward-based teams involved in the QI programme are more likely to be 'engaged' by it and its associated improvement activities and that this is maintained over time. However, only the Vigour dimension of 'engagement' remained significantly higher in the PW over time.

Reported implementation lessons from a national quality improvement initiative; Productive Ward: Releasing Time to Care™. A qualitative, ward-based team perspective.

AIM: To explore the experiences of participants involved in the implementation of the Productive Ward: Releasing Time to Care™ initiative in Ireland, identifying key implementation lessons. BACKGROUND: A large-scale quality improvement programme Productive Ward: Releasing Time to Care™ was introduced nationwide into Ireland in 2011. We captured accounts from ward-based teams in an implementation phase during 2013-14 to explore their experiences. METHODS: Semi-structured, in-depth interviews with a purposive sample of 24 members of ward-based teams from nine sites involved in the second national phase of the initiative were conducted. Interviews were analysed and coded under themes, using a seven-stage iterative process. RESULTS: The predominant theme identified was associated with the implementation and management of the initiative and included: project management; training; preparation; information and communication; and participant's negative experiences. The most prominent challenge reported related to other competing clinical priorities. CONCLUSIONS: Despite the structured approach of Productive Ward: Releasing Time to Care™, it appears that overstretched and busy clinical environments struggle to provide the right climate and context for ward-based teams to engage and interact actively with quality improvement tools, methods and activities. IMPLICATIONS FOR NURSING MANAGEMENT: Findings highlight five key aspects of implementation and management that will help facilitate successful adoption of large-scale, ward-based quality improvement programmes such as Productive Ward: Releasing Time to Care™. Utilising pre-existing implementation or quality frameworks to assess each ward/unit for 'readiness' prior to commencing a quality improvement intervention such as Productive Ward: Releasing Time to Care™ should be considered.

A Phase 1 Study of Intravitreous E10030 in Combination with Ranibizumab in Neovascular Age-Related Macular Degeneration.

PURPOSE: To assess the safety and tolerability of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, when administered in combination with an anti-vascular endothelial growth factor (VEGF) agent, ranibizumab (Lucentis; Genentech, South San Francisco, CA) 0.5 mg, by intravitreal injection in participants with neovascular age-related macular degeneration (NVAMD). DESIGN: Prospective phase 1 clinical trial. PARTICIPANTS: A total of 23 participants diagnosed with NVAMD and aged 50 years or older were enrolled. METHODS: Part 1 included 15 participants. Three participants received a single intravitreal E10030 (0.03 mg) injection and were subsequently given intravitreal ranibizumab (0.5 mg) injections at weeks 2, 6, and 10. Twelve participants (3 per group) received E10030 (0.03, 0.3, 1.5, or 3.0 mg) in combination with ranibizumab (0.5 mg) at day 0, month 1, and month 2 in an ascending manner. In Part 2 (8 participants), E10030 (0.3, 1.5, or 3.0 mg) in combination with ranibizumab (0.5 mg) was injected at day 0, month 1, and month 2. MAIN OUTCOME MEASURES: Safety at week 12 was the primary outcome and included assessment of vital signs, laboratory tests, and serial eye examinations. Other safety metrics included assessment through week 24 of Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA) and biomarker changes evaluated by optical coherence tomography (OCT) and fluorescein angiography (FA). RESULTS: All doses of intravitreal E10030 administered in combination with ranibizumab were well tolerated. No dose-limiting toxicities or relevant safety events were noted at any dose level during the study. Investigators did not report adverse events related to E10030 or ranibizumab. Mean VA change was a gain of 14 letters, and 59% of participants gained ≥15 letters from baseline at week 12. On FA at week 12, there was an 85.5% mean reduction from baseline in choroidal neovascularization (CNV) size. On OCT at the week 12 visit, there was a mean decrease in center point thickness and central subfield thickness of 38.9% and 33.7%, respectively. CONCLUSIONS: Intravitreal E10030 administered at doses up to 3 mg in combination with ranibizumab was well tolerated without evidence of systemic or ocular toxicity in participants with NVAMD. The changes in both mean VA and imaging biomarkers suggest a favorable short-term safety profile for the combination therapy of E10030 and ranibizumab.

Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial.

PURPOSE: To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. DESIGN: Randomized clinical trial. PARTICIPANTS: Six hundred sixty participants with visual acuity (VA) impairment from DME. METHODS: Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. MAIN OUTCOME MEASURES: Change in VA, adverse events, and retreatment frequency. RESULTS: Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders). CONCLUSIONS: All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.