Editorial of the 2019 Workshop on Very Large Internet of Things (VLIoT)

We are proud of presenting the outcome of this third edition of the "Very Large Internet of Things" (VLIoT) workshop, which was held in Los Angeles (USA) in August 2019, in conjunction with the 45th International Conference on Very Large Data Bases (VLDB). Following the success path of the two previous workshop editions - in Munich (2017) and in Rio de Janeiro (2018) - VLIoT 2019 kept its tradition to be a vivid and high-quality technical forum for researchers and practitioners working with Internet of Things to share their experiences, visions and latest findings, most of them regarding the design, implementation, deployment and management of IoT systems at very large and scale. This editorial of the special issue introduces and introduces all papers presented at the workshop

Importance of Anatomical Efficacy for Disease Control in Neovascular AMD: An Expert Opinion

BACKGROUND: Neovascular age-related macular degeneration (nAMD) presents a significant treatment burden for patients, carers and medical retina services. However, significant debate remains regarding how best to manage nAMD when assessing disease activity by optical coherence tomography (OCT), and particularly the significance of different types of fluid and how the understanding of anatomical efficacy can influence treatment strategies. This article provides opinion on the practical implications of anatomical efficacy and significance of fluid in the management of nAMD and proposes recommendations for healthcare professionals (HCPs) to improve understanding and promote best practice to achieve disease control. METHODS: An evidence-based review was performed and an expert panel debate from the Retina Outcomes Group (ROG), a forum of retinal specialists, provided insights and recommendations on the definition, role and practical implications of anatomical efficacy and the significance of fluid at the macula in the management of nAMD. RESULTS: The ROG has developed recommendations for achieving disease control through a zero-tolerance approach to the presence of fluid in nAMD as patients who avoid fluctuations in fluid at the macula have better visual outcomes. Recommendations cover five key areas: service protocol, training, regimen, multidisciplinary teams and engagement. This approach facilitates more standardised protocol-based treatment strategies. CONCLUSIONS: Targeting a fluid-free macula and aiming for disease control are essential to improve outcomes. As new therapies and technologies become available, drying the macula and maintaining disease control will become even more achievable. The outlined recommendations aim to promote best practice among HCPs and medical retina services to improve patient outcomes

DIAbetic macular oedema aNd diode subthreshold micropulse laser (DIAMONDS) : Ppotocol for a randomised clinical trial

Background In the UK, macular laser is the treatment of choice for people with diabetic macular oedema with central retinal subfield thickness (CST) < 400 μm, as per National Institute for Health and Care Excellence guidelines. It remains unclear whether subthreshold micropulse laser is superior and should replace standard threshold laser for the treatment of eligible patients. Methods DIAMONDS is a pragmatic, multicentre, allocation-concealed, randomised, equivalence, double-masked clinical trial that aims to determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser compared with standard threshold laser, for the treatment of diabetic macular oedema with CST < 400 μm. The primary outcome is the mean change in best-corrected visual acuity in the study eye from baseline to month 24 post treatment. Secondary outcomes (at 24 months) include change in binocular best corrected visual acuity; CST; mean deviation of the Humphrey 10–2 visual field; change in percentage of people meeting driving standards; European Quality of Life-5 Dimensions, National Eye Institute Visual Functioning Questionnaire-25 and VisQoL scores; incremental cost per quality-adjusted life year gained; side effects; number of laser treatments and use of additional therapies. The primary statistical analysis will be per protocol rather than intention-to-treat analysis because the latter increases type I error in non-inferiority or equivalence trials. The difference between lasers for change in best-corrected visual acuity (using 95% CI) will be compared to the permitted maximum difference of five Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear and logistic regression models will be used to compare outcomes between treatment groups. A Markov-model-based cost-utility analysis will extend beyond the trial period to estimate longer-term cost-effectiveness. Discussion This trial will determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser, when compared with standard threshold laser, for the treatment of diabetic macular oedema, the main cause of sight loss in people with diabetes mellitus

Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema : the DIAMONDS non-inferiority RCT

Background: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. Objectives: Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. Design: A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. Setting: Hospital eye services in the UK. Participants: Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of  24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. Interventions: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. Main outcome measures: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10–2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire – 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. Results: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was –2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and –0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (–3.9 to –0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. Future work: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. Limitations: The majority of participants enrolled had poorly controlled diabetes. Conclusions: Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. Trial registration: This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 50. See the NIHR Journals Library website for further project information

Retinal gene therapy in patients with choroideremia: Initial fi ndings from a phase 1/2 clinical trial

BACKGROUND: Choroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease. METHODS: In a multicentre clinical trial, six male patients (aged 35–63 years) with choroideremia were administered AAV.REP1 (0·6–1·0×10(10) genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213. FINDINGS: Despite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3·8 letters (SE 4·1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23·0 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment (increase 2·3 dB [95% CI 0·8–3·8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1·7 [SE 1·0]) was correlated with the vector dose administered per mm(2) of surviving retina (r=0·82, p=0·04). By contrast, small non-significant reductions (p>0·05) were noted in the control eyes in both maximal sensitivity (–0·8 dB [1·5]) and mean sensitivity (–1·6 dB [0·9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector. INTERPRETATION: The initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. These findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as age-related macular degeneration, for which intervention should ideally be applied before the onset of retinal thinning. FUNDING: UK Department of Health and Wellcome Trust

Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia

Retinal gene therapy is increasingly recognised as a novel molecular intervention that has huge potential in treating common causes of blindness, the majority of which have a genetic aetiology. Choroideremia is a chronic X-linked retinal degeneration that was first described in 1872. It leads to progressive blindness due to deficiency of Rab-escort protein 1 (REP1). We designed an adeno-associated viral vector to express REP1 and assessed it in a gene therapy clinical trial by subretinal injection in 14 patients with choroideremia. The primary endpoint was vision change in treated eyes two years after surgery compared to unoperated fellow eyes. Despite complications in two patients, visual acuity improved in the 14 treated eyes over controls (median 4.5 letter gain, vs 1.5 letter loss, p=0.04), with six treated eyes gaining more than one line of vision (&gt;5 letters). The results suggest that retinal gene therapy can sustain and improve visual acuity in a cohort of predominantly late stage choroideremia patients in whom rapid visual acuity loss would ordinarily be predicted

DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser (DIAMONDS) : a randomized double-masked non-inferiority clinical trial

Purpose Determine clinical-effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) <400μ. Design Pragmatic, multicenter, allocation-concealed, double-masked, randomized, non-inferiority trial. Participants Adults with 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. Intervention Randomisation 1:1 to 577nm SML or SL; retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if >10 ETDRS-letter-loss and/or CRT increased >400μ. Outcomes Primary: Mean change in BCVA in the study eye at 24 months (non-inferiority margin 5 ETDRS-letters). Secondary: mean change from baseline to month-24 in binocular BCVA; CRT and mean deviation (MD) of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL (EQ-5D-5L), National Eye Institute-Visual Function Questionnaire (NEI-VFQ25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life year (QALY) gained; adverse effects; number of laser and rescue treatments. Results DIAMONDS recruited fully (n=266); 87% SML and 86% SL had primary outcome data. Mean BCVA change from baseline to month-24 was -2.43 (Standard Deviation [SD] 8.20) and -0.45 (SD 6.72) in SML and SL, respectively. SML was deemed not only non-inferior but also equivalent to SL as the 95% confidence interval (CI) (-3.9 to -0.04) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS-letters). There was no statistically significant difference in binocular BCVA (0.32 ETDRS letters; 95% CI -0.99, 1.64; p = 0.63), CRT (-0.64 microns; 95% CI -14.25, 12.98; p = 0.93), MD (0.39 dB; 95% CI -0.23, 1.02; p = 0.21), meeting driving standards (% point difference 1.6, 95% CI -25.3, 28.5; p=0.91), adverse effects (Risk Ratio 0.28, 95% CI 0.06, 1.34; p=0.11), rescue treatments (% point difference -2.8, 95% CI -13.1, 7.5; p=0.59) or EQ-5D/VFQ-25/VisQoL scores. Number of laser treatments was higher in SML (0.48; 95% CI 0.18, 0.79; p = 0.002). Base-case analysis indicated no differences in costs or QALYs. Conclusions SML was equivalent to SL, requiring slightly higher laser treatments