Factors Affecting Intraocular Pressure Measurement and New Methods for Improving Accuracy; What Can IOP Tell Us about Glaucoma? How Can Practitioners Improve IOP Utility and Glaucoma Outcomes?

An increased awareness of how central corneal thickness (CCT) and corneal material properties such as corneal hysteresis has changed both tonometry accuracy and the resultant understanding of glaucoma risk. New research findings and methods of tonometry provide differing information on the diagnosis and treatment of ocular conditions which should be understood to appropriately incorporate this information into individual patient care. Additionally, a useful re-examination of what IOP can tell us about glaucoma empowers practitioners to improve glaucoma outcomes. All clinically utilized tonometry methods are estimates of true IOP, which is only assessed using direct intracameral techniques. Different described tonometry techniques are associated with their own overall bias and interpatient variability, due most typically to tissue biomechanics

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial

BackgroundAnterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability.MethodsWe did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score—4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367.FindingsBetween Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5–13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications.InterpretationSurgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Analysis and Application of Opto-Mechanics to the Etiology of Sub-Optimal Outcomes in Laser Corrective Eye Surgery and Design Methodology of Deformable Surface Accommodating Intraocular Lenses

Overview: Optical concepts as they relate to the ophthalmologic correction of vision in corneal laser vision correction and intraocular lens design was examined. Purpose: The interaction between the excimer laser and residual corneal tissue in laser vision correction produces unwanted side effects. Understanding the origin of these artifacts can lead to better procedures. Furthermore, accommodating intraocular lenses offer a potential for eliminating presbyopia. Understanding the properties of a new accommodating intraocular lens incorporating a deformable interface may lead to advances in cataract surgery. Introduction: Corneal surface irregularities following laser refractive procedures are commonly seen. They regularly result in a patient’s decreased best corrected visual acuity and decreased contrast sensitivity. These changes are only seen in biologic tissue and the etiology has been elusive. A thermal response has been theorized and was investigated in this research. In addition, intraocular lenses using a mechanically deforming interface to change their power in order to duplicate natural accommodation have been developed. The deforming interface(s) induce optical aberrations due to irregular deformations. Design efforts have centered on minimizing these deformations. Both of the ophthalmic applications have been analyzed using finite element analysis (FEA) to understand their inherent optical properties. Methods: FEA modeling of thermal theory has been applied to verify that excimer laser induced collagen contraction creates corneal surface irregularities and central islands. A mathematical model which indicates the viability of the theory was developed. The modeling results were compared to post ablation changes in eyes utilizing an excimer (ArF 193 nm), as well as non-ablative thermal heating in eyes with a CO₂ laser. Addition modeling was performed on an Intraocular lens prototype measuring of actuation force, lens power, interface contour, optical transfer function, and visual Strehl ratio. Prototype verified mathematical models were utilized to optimize optical and mechanical design parameters to maximize the image quality and minimize the required force. Results: The predictive model shows significant irregular central buckling formation and irregular folding. The amount of collagen contraction necessary to cause significant surface changes is very small (0.3%). Uniform scanning excimer laser ablation to corneal stroma produces a significant central steepening and peripheral flattening in the central 3mm diameter. Isolated thermal load from uniform CO₂ laser irradiation without ablation also produces central corneal steepening and paracentral flattening in the central 3mm diameter. The iterative mathematical modeling based upon the intraocular lens prototype yielded maximized optical and mechanical performance through varied input mechanical and optical parameters to produce a maximized visual Strehl ratio and a minimized force requirement. Conclusions: The thermal load created by laser irradiation creates a characteristic spectrum of morphologic changes on the porcine corneal stromal surface which correlates to the temperature rise and is not seen inorganic, isotropic material. The highly similar surface changes seen with both lasers are likely indicative of temperature induced transverse collagen fibril contraction and stress re-distribution. Refractive procedures which produce significant thermal load should be cognizant of these morphological changes. The optimized intraocular lens operates within the physiologic constraints of the human eye including the force available for full accommodative amplitude using the eye’s natural focusing feedback, while maintaining image quality in the space available. Optimized optical and mechanical performance parameters were delineated as those which minimize both asphericity and actuation pressure. The methodology combines a multidisciplinary basic science approach from biomechanics, optical science, and ophthalmology to optimize an intraocular lens design suitable for preliminary trials

Lethal crossroads: The evolution of Taliban violence in response to counterinsurgency strategies in Afghanistan 2006-2021

Lethal Crossroads: The Evolution of Taliban Violence in Response to Counterinsurgency Strategies in Afghanistan 2006-2021. July 2022 Presented in partial fulfilment for the Degree of International Master in Security, Intelligence and Strategic Studies Word Count: 21861 Date of Submission: 24/07/2022 Student Number Glasgow: 2188272M Dublin: 20109547 Prague: 19142078 Supervisor Dr Erika Biagini Abstract This thesis examines how the Taliban's use of the Improvised Explosive Device (IED) evolved in response to changing counterinsurgency strategies in Afghanistan between 2006 and 2021. The work aims to identify the role of state counterinsurgency strategies in affecting variation in IED use by insurgents. The evolution of methods of violence in Afghanistan has rarely been focused on. Yet, the Taliban's return to power in 2021 amid the withdrawal of the last coalition forces necessitates reflection on the conflict across academia and policy making. To investigate the evolution of the IED this research employs a longitudinal case study design applying qualitative research methodologies such as the constant comparative method to analyse three distinct phases of insurgent and counterinsurgent violent competition in Afghanistan between 2006 and 2021. An evolutionary theoretical framework outlined by Veilleux-Lepage..

Analysis and application of opto-mechanics to the etiology of sub-optimal outcomes in laser corrective eye surgery and design methodology of deformable surface accommodating intraocular lenses

Overview: Optical concepts as they relate to the ophthalmologic correction of vision in corneal laser vision correction and intraocular lens design was examined. Purpose: The interaction between the excimer laser and residual corneal tissue in laser vision correction produces unwanted side effects. Understanding the origin of these artifacts can lead to better procedures. Furthermore, accommodating intraocular lenses offer a potential for eliminating presbyopia. Understanding the properties of a new accommodating intraocular lens incorporating a deformable interface may lead to advances in cataract surgery. Introduction: Corneal surface irregularities following laser refractive procedures are commonly seen. They regularly result in a patient’s decreased best corrected visual acuity and decreased contrast sensitivity. These changes are only seen in biologic tissue and the etiology has been elusive. A thermal response has been theorized and was investigated in this research. In addition, intraocular lenses using a mechanically deforming interface to change their power in order to duplicate natural accommodation have been developed. The deforming interface(s) induce optical aberrations due to irregular deformations. Design efforts have centered on minimizing these deformations. Both of the ophthalmic applications have been analyzed using finite element analysis (FEA) to understand their inherent optical properties. Methods: FEA modeling of thermal theory has been applied to verify that excimer laser induced collagen contraction creates corneal surface irregularities and central islands. A mathematical model which indicates the viability of the theory was developed. The modeling results were compared to post ablation changes in eyes utilizing an excimer (ArF 193 nm), as well as non-ablative thermal heating in eyes with a CO2 laser. Addition modeling was performed on an Intraocular lens prototype measuring of actuation force, lens power, interface contour, optical transfer function, and visual Strehl ratio. Prototype verified mathematical models were utilized to optimize optical and mechanical design parameters to maximize the image quality and minimize the required force. Results: The predictive model shows significant irregular central buckling formation and irregular folding. The amount of collagen contraction necessary to cause significant surface changes is very small (0.3%). Uniform scanning excimer laser ablation to corneal stroma produces a significant central steepening and peripheral flattening in the central 3mm diameter. Isolated thermal load from uniform CO2 laser irradiation without ablation also produces central corneal steepening and paracentral flattening in the central 3mm diameter. The iterative mathematical modeling based upon the intraocular lens prototype yielded maximized optical and mechanical performance through varied input mechanical and optical parameters to produce a maximized visual Strehl ratio and a minimized force requirement. Conclusions: The thermal load created by laser irradiation creates a characteristic spectrum of morphologic changes on the porcine corneal stromal surface which correlates to the temperature rise and is not seen inorganic, isotropic material. The highly similar surface changes seen with both lasers are likely indicative of temperature induced transverse collagen fibril contraction and stress re-distribution. Refractive procedures which produce significant thermal load should be cognizant of these morphological changes. The optimized intraocular lens operates within the physiologic constraints of the human eye including the force available for full accommodative amplitude using the eye’s natural focusing feedback, while maintaining image quality in the space available. Optimized optical and mechanical performance parameters were delineated as those which minimize both asphericity and actuation pressure. The methodology combines a multidisciplinary basic science approach from biomechanics, optical science, and ophthalmology to optimize an intraocular lens design suitable for preliminary trials