One-year outcome of bevacizumab therapy for chronic macular edema in central and branch retinal vein occlusions in real-world clinical practice in the UK

Background: The purpose of this study was to investigate the 12-month outcome of macular edema secondary to both chronic and new central and branch retinal vein occlusions treated with intravitreal bevacizumab in the real-life clinical setting in the UK. Methods: Retrospective case notes analysis of consecutive patients with retinal vein occlusions treated with bevacizumab in 2010 to 2012. Outcome measures were visual acuity (measured with Snellen, converted into logMAR [logarithm of the minimum angle of resolution] for statistical calculation) and central retinal thickness at baseline, 4 weeks post-loading phase, and at 1 year. Results: There were 56 and 100 patients with central and branch retinal vein occlusions, respectively, of whom 62% had chronic edema and received prior therapies and another 32% required additional laser treatments post-baseline bevacizumab. Baseline median visual acuity was 0.78 (interquartile range [IQR] 0.48–1.22) in the central group and 0.6 (IQR 0.3–0.78) in the branch group. In both groups, visual improvement was statistically significant from baseline compared to post-loading (P,0.001 and P=0.03, respectively), but was not significant by month 12 (P=0.058 and P=0.166, respectively); 30% improved by at least three lines and 44% improved by at least one line by month 12. Baseline median central retinal thickness was 449 μm (IQR 388–553) in the central group and 441 µm (IQR 357–501) in the branch group. However, the mean reduction in thickness was statistically significant at post-loading (P,0.001) and at the 12-month time point (P,0.001) for both groups. The average number of injections in 1 year was 4.2 in the central group and 3.3 in the branch group. Conclusion: Our large real-world cohort results indicate that bevacizumab introduced to patients with either new or chronic edema due to retinal vein occlusion can result in resolution of edema and stabilization of vision in the first year.

Mobility changes in older age: neuropsychological, neurophysiological and cognitive predictors of successful adaptation in a real world scenario

The aims of this thesis were to investigate the neuropsychological, neurophysiological, and cognitive contributors to mobility changes with increasing age. In a series of studies with adults aged 45-88 years, unsafe pedestrian behaviour and falls were investigated in relation to i) cognitive functions (including response time variability, executive function, and visual attention tests), ii) mobility assessments (including gait and balance and using motion capture cameras), iii) motor initiation and pedestrian road crossing behavior (using a simulated pedestrian road scene), iv) neuronal and functional brain changes (using a computer based crossing task with magnetoencephalography), and v) quality of life questionnaires (including fear of falling and restricted range of travel). Older adults are more likely to be fatally injured at the far-side of the road compared to the near-side of the road, however, the underlying mobility and cognitive processes related to lane-specific (i.e. near-side or far-side) pedestrian crossing errors in older adults is currently unknown. The first study explored cognitive, motor initiation, and mobility predictors of unsafe pedestrian crossing behaviours. The purpose of the first study (Chapter 2) was to determine whether collisions at the near-side and far-side would be differentially predicted by mobility indices (such as walking speed and postural sway), motor initiation, and cognitive function (including spatial planning, visual attention, and within participant variability) with increasing age. The results suggest that near-side unsafe pedestrian crossing errors are related to processing speed, whereas far-side errors are related to spatial planning difficulties. Both near-side and far-side crossing errors were related to walking speed and motor initiation measures (specifically motor initiation variability). The salient mobility predictors of unsafe pedestrian crossings determined in the above study were examined in Chapter 3 in conjunction with the presence of a history of falls. The purpose of this study was to determine the extent to which walking speed (indicated as a salient predictor of unsafe crossings and start-up delay in Chapter 2), and previous falls can be predicted and explained by age-related changes in mobility and cognitive function changes (specifically within participant variability and spatial ability). 53.2% of walking speed variance was found to be predicted by self-rated mobility score, sit-to-stand time, motor initiation, and within participant variability. Although a significant model was not found to predict fall history variance, postural sway and attentional set shifting ability was found to be strongly related to the occurrence of falls within the last year. Next in Chapter 4, unsafe pedestrian crossing behaviour and pedestrian predictors (both mobility and cognitive measures) from Chapter 2 were explored in terms of increasing hemispheric laterality of attentional functions and inter-hemispheric oscillatory beta power changes associated with increasing age. Elevated beta (15-35 Hz) power in the motor cortex prior to movement, and reduced beta power post-movement has been linked to age-related changes in mobility. In addition, increasing recruitment of both hemispheres has been shown to occur and be beneficial to perform similarly to younger adults in cognitive tasks (Cabeza, Anderson, Locantore, & McIntosh, 2002). It has been hypothesised that changes in hemispheric neural beta power may explain the presence of more pedestrian errors at the farside of the road in older adults. The purpose of the study was to determine whether changes in age-related cortical oscillatory beta power and hemispheric laterality are linked to unsafe pedestrian behaviour in older adults. Results indicated that pedestrian errors at the near-side are linked to hemispheric bilateralisation, and neural overcompensation post-movement, 4 whereas far-side unsafe errors are linked to not employing neural compensation methods (hemispheric bilateralisation). Finally, in Chapter 5, fear of falling, life space mobility, and quality of life in old age were examined to determine their relationships with cognition, mobility (including fall history and pedestrian behaviour), and motor initiation. In addition to death and injury, mobility decline (such as pedestrian errors in Chapter 2, and falls in Chapter 3) and cognition can negatively affect quality of life and result in activity avoidance. Further, number of falls in Chapter 3 was not significantly linked to mobility and cognition alone, and may be further explained by a fear of falling. The objective of the above study (Study 2, Chapter 3) was to determine the role of mobility and cognition on fear of falling and life space mobility, and the impact on quality of life measures. Results indicated that missing safe pedestrian crossing gaps (potentially indicating crossing anxiety) and mobility decline were consistent predictors of fear of falling, reduced life space mobility, and quality of life variance. Social community (total number of close family and friends) was also linked to life space mobility and quality of life. Lower cognitive functions (particularly processing speed and reaction time) were found to predict variance in fear of falling and quality of life in old age. Overall, the findings indicated that mobility decline (particularly walking speed or walking difficulty), processing speed, and intra-individual variability in attention (including motor initiation variability) are salient predictors of participant safety (mainly pedestrian crossing errors) and wellbeing with increasing age. More research is required to produce a significant model to explain the number of falls.

Self-efficacy in depression: Bridging the gap between competence and real-world functioning

Background: Depression is the largest contributing factor to years lost to disability, and symptom remission does not always result in functional improvement. Comprehensive analysis of functioning requires investigation both of the competence to perform behaviours, as well as actual performance in the real world. Further, two independent domains of functioning have been proposed: adaptive (behaviours conducive to daily living skills and independent functioning) and interpersonal (behaviours conducive to the successful initiation and maintenance of social relationships). To date, very little is known about the relationship between these constructs in depression, and the factors that may play a key role in the disparity between competence and real-world performance in adaptive and interpersonal functioning. Purpose: This study used a multidimensional (adaptive and interpersonal functioning), multi-level (competence and performance) approach to explore the potential discrepancy between competence and real-world performance in depression, specifically investigating whether self-efficacy (one’s beliefs of their capability to perform particular actions) predicts depressed individuals’ underperformance in the real world relative to their ability. A comparison sample of healthy participants was included to investigate the level of depressed individuals’ impairment, across variables, relative to healthy individuals. Method: Forty-two participants with depression and twenty healthy participants without history of, or current, psychiatric illness were recruited in the Kingston, Ontario community. Competence, self-efficacy, and real-world functioning all in both adaptive and interpersonal domains, and symptoms were assessed during a single-visit assessment. Results: Relative to healthy individuals, depressed individuals showed significantly poorer adaptive and interpersonal competence, adaptive and interpersonal functioning, and significantly lower self-efficacy for adaptive and interpersonal behaviours. Self-efficacy significantly predicted functional disability both in the domain of adaptive and interpersonal functioning. Interpersonal self-efficacy accounted for significant variance in the discrepancy between interpersonal competence and functioning. Conclusions: The current study provides the first data regarding relationships among competence, functioning, and self-efficacy in depression. Self-efficacy may play an important role in the deployment of functional skills in everyday life. This has implications for therapeutic interventions aimed at enhancing depressed individuals’ engagement in functional activities. There may be additional intrinsic or extrinsic factors that influence the relationships among competence and functioning in depression.

Patient-reported outcomes and visual acuity after 12 months of anti-VEGF-treatment for sight-threatening diabetic macular edema in a real world setting

Aims To examine objective visual acuity measured with ETDRS, retinal thickness (OCT), patient reported outcome and describe levels of glycated hemoglobin and its association with the effects on visual acuity in patients treated with anti-VEGF for visual impairment due to diabetic macular edema (DME) during 12 months in a real world setting. Methods In this cross-sectional study, 58 patients (29 females and 29 males; mean age, 68 years) with type 1 and type 2 diabetes diagnosed with DME were included. Medical data and two questionnaires were collected; an eye-specific (NEI VFQ-25) and a generic health-related quality of life questionnaire (SF-36) were used. Results The total patient group had significantly improved visual acuity and reduced retinal thickness at 4 months and remains at 12 months follow up. Thirty patients had significantly improved visual acuity, and 27 patients had no improved visual acuity at 12 months. The patients with improved visual acuity had significantly improved scores for NEI VFQ-25 subscales including general health, general vision, near activities, distance activities, and composite score, but no significant changes in scores were found in the group without improvements in visual acuity. Conclusions Our study revealed that anti-VEGF treatment improved visual acuity and central retinal thickness as well as patient-reported outcome in real world 12 months after treatment start.

Assessing the resilience of a real-world social-ecological system: lessons from a multidisciplinary evaluation of a South African pastoral system

In the past decades, social-ecological systems (SESs) worldwide have undergone dramatic transformations with often detrimental consequences for livelihoods. Although resilience thinking offers promising conceptual frameworks to understand SES transformations, empirical resilience assessments of real-world SESs are still rare because SES complexity requires integrating knowledge, theories, and approaches from different disciplines. Taking up this challenge, we empirically assess the resilience of a South African pastoral SES to drought using various methods from natural and social sciences. In the ecological subsystem, we analyze rangelands’ ability to buffer drought effects on forage provision, using soil and vegetation indicators. In the social subsystem, we assess households’ and communities’ capacities to mitigate drought effects, applying agronomic and institutional indicators and benchmarking against practices and institutions in traditional pastoral SESs. Our results indicate that a decoupling of livelihoods from livestock-generated income was initiated by government interventions in the 1930s. In the post-apartheid phase, minimum-input strategies of herd management were adopted, leading to a recovery of rangeland vegetation due to unintentionally reduced stocking densities. Because current livelihood security is mainly based on external monetary resources (pensions, child grants, and disability grants), household resilience to drought is higher than in historical phases. Our study is one of the first to use a truly multidisciplinary resilience assessment. Conflicting results from partial assessments underline that measuring narrow indicator sets may impede a deeper understanding of SES transformations. The results also imply that the resilience of contemporary, open SESs cannot be explained by an inward-looking approach because essential connections and drivers at other scales have become relevant in the globalized world. Our study thus has helped to identify pitfalls in empirical resilience assessment and to improve the conceptualization of SES dynamics.

Fingolimod real world experience

Fingolimod is a Multiple Sclerosis treatment licensed in Europe since 2011. Its efficacy has been demonstrated in three large phase III trials, used in the regulatory submissions throughout the world. As usual, in these trials the inclusion and exclusion criteria were designed to obtain a homogeneous population, with interchangeable characteristics in the different treatment arms. Although this is the best strategy to achieve a robust answer to the investigation question, it does not guaranty the treatment efficacy in the clinical practice, since in the real world there are concomitant treatments, comorbidities, adherence and persistence challenges. But, to make informed treatment decision for a real life patient, we need to have evidence of the treatment efficacy, what has been called treatment effectiveness. This work aims to review fingolimod effectiveness, using as source of information abstracts, posters and manuscripts. This unorthodox strategy was developed because more than half of the published experience with fingolimod is still on abstracts and posters. Only a small part of the studies reviewed are already published in peer reviewed journals. Fingolimod seems to be, at least, as effective and safe as it was on clinical trials, and with its long term experience no new safety signals were observed. In the Portuguese hospital perspective, early treatment with fingolimod is expected to result in better clinical outcomes associated with a more efficient healthcare resources allocation.

Efficient Secure Computation for Real-world Settings and Security Models

Secure computation involves multiple parties computing a common function while keeping their inputs private, and is a growing field of cryptography due to its potential for maintaining privacy guarantees in real-world applications. However, current secure computation protocols are not yet efficient enough to be used in practice. We argue that this is due to much of the research effort being focused on generality rather than specificity. Namely, current research tends to focus on constructing and improving protocols for the strongest notions of security or for an arbitrary number of parties. However, in real-world deployments, these security notions are often too strong, or the number of parties running a protocol would be smaller. In this thesis we make several steps towards bridging the efficiency gap of secure computation by focusing on constructing efficient protocols for specific real-world settings and security models. In particular, we make the following four contributions: - We show an efficient (when amortized over multiple runs) maliciously secure two-party secure computation (2PC) protocol in the multiple-execution setting, where the same function is computed multiple times by the same pair of parties. - We improve the efficiency of 2PC protocols in the publicly verifiable covert security model, where a party can cheat with some probability but if it gets caught then the honest party obtains a certificate proving that the given party cheated. - We show how to optimize existing 2PC protocols when the function to be computed includes predicate checks on its inputs. - We demonstrate an efficient maliciously secure protocol in the three-party setting.

Use of flucinolone acetonide for patients with diabetic macular oedema:patient selection criteria and early outcomes in real world setting

Introduction: Fluocinolone acetonide slow release implant (Iluvien®) was approved in December 2013 in UK for treatment of eyes which are pseudophakic with DMO that is unresponsive to other available therapies. This approval was based on evidence from FAME trials which were conducted at a time when ranibizumab was not available. There is a paucity of data on implementation of guidance on selecting patients for this treatment modality and also on the real world outcome of fluocinolone therapy especially in those patients that have been unresponsive to ranibizumab therapy. Method: Retrospective study of consecutive patients treated with fluocinolone between January and August 2014 at three sites were included to evaluate selection criteria used, baseline characteristics and clinical outcomes at 3-month time point. Results: Twenty two pseudophakic eyes of 22 consecutive patients were included. Majority of patients had prior therapy with multiple intravitreal anti-VEGF injections. Four eyes had controlled glaucoma. At baseline mean VA and CRT were 50.7 letters and 631 μm respectively. After 3 months, 18 patients had improved CRT of which 15 of them also had improved VA. No adverse effects were noted. One additional patient required IOP lowering medication. Despite being unresponsive to multiple prior therapies including laser and anti-VEGF injections, switching to fluocinolone achieved treatment benefit. Conclusion: The patient level selection criteria proposed by NICE guidance on fluocinolone appeared to be implemented. This data from this study provides new evidence on early outcomes following fluocinolone therapy in eyes with DMO which had not responded to laser and other intravitreal agents.

Clinical characteristics and selection of treatment modality for patients with vitreomacular traction:real-world implementation of NICE guidance (TA297)

Aim: To investigate the qualitative aspects in patient selection and the quantitative impact of disease burden in real world treatment of vitreomacular traction (VMT) and implementation of the National Institute for Health and Care Excellence (NICE) guidance (TA297). Methods: A monocentric, retrospective review of consecutive patients undergoing optical coherence tomography (OCT) imaging over a 3 month period. Patients with VMT in at least one eye were identified for further data collection on laterality, visual acuity, symptoms, presence of epiretinal membrane, macular hole and treatment selection. Results: A total of 3472 patients underwent OCT imaging with a total of 6878 eyes scanned. Out of 87 patients, 74 patients had unilateral VMT (38 right, 36 left) and 13 patients had bilateral VMT. Eighteen patients with unilateral VMT satisfied NICE criteria of severe sight problems in the affected eye. Eight were managed for a coexisting pathology, one refused treatment, one patient did not attend, two closed spontaneously, and one received ocriplasmin prior to the study start date. Only two patients with unilateral VMT received ocriplasmin and three underwent vitrectomy. Those failing to meet NICE criteria for unilateral VMT were predominantly asymptomatic (n=49) or had coexisting ERM (n=5) or both (n=2). Conclusion: Ocriplasmin provides an alternative treatment for patients with symptomatic VMT. Our data shows that the majority of patients with VMT do not meet NICE TA297 primarily due to lack of symptoms. Those meeting NICE criteria, but not treated, tended to have coexisting macular pathology. Variation in patient selection due to subjective factors not outlined in NICE guidance suggests that real world outcomes of ocriplasmin therapy should be interpreted with caution.

The blue side of diabetes: assessing the impact of depression in people with type 2 diabetes using real-world data

The aim of the thesis is to assess the impact of depression in people with type 2 diabetes. Using Healthcare Utilization Databases, I estimated in a large population-based cohort with type 2 diabetes the incidence of depression over 10 year-period, identified the demographic and clinical predictors of depression, and determined the extent to which depression is a risk factor for acute and long-term complications and mortality. In the context of COVID-19 pandemic, I evaluated whether the presence of a history of depression in type 2 diabetes increased the Emergency Department (ED) access rate for diabetes-related complications, and I investigated changes in the incidence of depression during the first year of the pandemic. Findings from the first study indicated that developing depression was associated with being a woman, being over 65 years, living in rural areas, having insulin as initial diabetes medication and having comorbid conditions; the study also confirmed that depression was associated with an increased risk for acute and long-term diabetes complications and all-cause mortality. The second observational study showed a higher rate of ED access for diabetes-related complications during the pandemic in people with type 2 diabetes and a history of depression than in those without a history of depression, similar to what was observed in a pre-pandemic period. As shown in the third population-based study, the incidence of depression decreased in 2020 compared to 2019, mainly during the first and the second waves of the COVID-19 pandemic, when people probably had difficulty reaching healthcare services. This new real-world evidence will help healthcare professionals identify timely patients at high risk of developing depression. Lastly, policymakers and physicians will benefit from new evidence of the effects of the COVID-19 pandemic on depression in people with type 2 diabetes to ensure a high level of care during crisis periods.

Models and algorithms for real-world optimization problems

This thesis deals with efficient solution of optimization problems of practical interest. The first part of the thesis deals with bin packing problems. The bin packing problem (BPP) is one of the oldest and most fundamental combinatorial optimiza- tion problems. The bin packing problem and its generalizations arise often in real-world ap- plications, from manufacturing industry, logistics and transportation of goods, and scheduling. After an introductory chapter, I will present two applications of two of the most natural extensions of the bin packing: Chapter 2 will be dedicated to an application of bin packing in two dimension to a problem of scheduling a set of computational tasks on a computer cluster, while Chapter 3 deals with the generalization of BPP in three dimensions that arise frequently in logistic and transportation, often com- plemented with additional constraints on the placement of items and characteristics of the solution, like, for example, guarantees on the stability of the items, to avoid potential damage to the transported goods, on the distribution of the total weight of the bins, and on compatibility with loading and unloading operations. The second part of the thesis, and in particular Chapter 4 considers the Trans- mission Expansion Problem (TEP), where an electrical transmission grid must be expanded so as to satisfy future energy demand at the minimum cost, while main- taining some guarantees of robustness to potential line failures. These problems are gaining importance in a world where a shift towards renewable energy can impose a significant geographical reallocation of generation capacities, resulting in the ne- cessity of expanding current power transmission grids.

ICE Emissions Estimation through Machine-learning techniques to support real-world R&D experiments

The emissions estimation, both during homologation and standard driving, is one of the new challenges that automotive industries have to face. The new European and American regulation will allow a lower and lower quantity of Carbon Monoxide emission and will require that all the vehicles have to be able to monitor their own pollutants production. Since numerical models are too computationally expensive and approximated, new solutions based on Machine Learning are replacing standard techniques. In this project we considered a real V12 Internal Combustion Engine to propose a novel approach pushing Random Forests to generate meaningful prediction also in extreme cases (extrapolation, very high frequency peaks, noisy instrumentation etc.). The present work proposes also a data preprocessing pipeline for strongly unbalanced datasets and a reinterpretation of the regression problem as a classification problem in a logarithmic quantized domain. Results have been evaluated for two different models representing a pure interpolation scenario (more standard) and an extrapolation scenario, to test the out of bounds robustness of the model. The employed metrics take into account different aspects which can affect the homologation procedure, so the final analysis will focus on combining all the specific performances together to obtain the overall conclusions.

Robotic grasping: State of the art and modular real-world implementation

Robotic Grasping is an important research topic in robotics since for robots to attain more general-purpose utility, grasping is a necessary skill, but very challenging to master. In general the robots may use their perception abilities like an image from a camera to identify grasps for a given object usually unknown. A grasp describes how a robotic end-effector need to be positioned to securely grab an object and successfully lift it without lost it, at the moment state of the arts solutions are still far behind humans. In the last 5–10 years, deep learning methods take the scene to overcome classical problem like the arduous and time-consuming approach to form a task-specific algorithm analytically. In this thesis are present the progress and the approaches in the robotic grasping field and the potential of the deep learning methods in robotic grasping. Based on that, an implementation of a Convolutional Neural Network (CNN) as a starting point for generation of a grasp pose from camera view has been implemented inside a ROS environment. The developed technologies have been integrated into a pick-and-place application for a Panda robot from Franka Emika. The application includes various features related to object detection and selection. Additionally, the features have been kept as generic as possible to allow for easy replacement or removal if needed, without losing time for improvement or new testing.

Vardagsanknuten matematikundervisning : En systematisk litteraturstudie om en vardagsanknuten matematikundervisnings betydelse för mellanstadieelevers matematikförståelse

Syftet med denna studie har varit att klargöra och undersöka huruvida mellanstadieelevers matematikförståelse ökar eller inte om de ser nyttan av att lära sig skolans matematik. Detta har gjorts med hjälp av en systematisk litteraturstudie där aktuell vetenskaplig forskning inom området tagits fram genom sökning, granskning och analys. Resultaten som framkommit visar att det finns samband mellan en vardagsanknuten matematik och elevers förståelse, men att detta samband inte alltid är effektivt. Det är dock inte enbart en vardagsanknuten matematik som kan kopplas ihop med och har betydelse för elevers förståelse och utveckling inom matematik, utan också vilken kognitiv nivå uppgifterna har. De resultat studierna påvisar behandlar vikten av grundläggande kunskaper inom matematik som en förutsättning för elevers matematiska utveckling och förståelse. Forskarna menar att en ökad förståelse gynnas om de problem som ska lösas har ett tydligt beskrivet syfte.