Intraretinal Hyper-Reflective Foci Are Almost Universally Present and Co-Localize With Intraretinal Fluid in Diabetic Macular Edema.

Purpose: In diabetic macular edema (DME), hyper-reflective foci (HRF) has been linked to disease severity and progression. Using an automated approach, we aimed to investigate the baseline distribution of HRF in DME and their co-localization with cystoid intraretinal fluid (IRF). Methods: Baseline spectral-domain optical coherence tomography (SD-OCT) volume scans (N = 1527) from phase III clinical trials YOSEMITE (NCT03622580) and RHINE (NCT03622593) were segmented using a deep-learning-based algorithm (developed using B-scans from BOULEVARD NCT02699450) to detect HRF. The HRF count and volume were assessed. HRF distributions were analyzed in relation to best-corrected visual acuity (BCVA), central subfield thickness (CST), and IRF volume in quartiles, and Diabetic Retinopathy Severity Scores (DRSS) in groups. Co-localization of HRF with IRF was calculated in the central 3-mm diameter using the en face projection. Results: HRF were present in most patients (up to 99.7%). Median (interquartile range [IQR]) HRF volume within the 3-mm diameter Early Treatment Diabetic Retinopathy Study ring was 1964.3 (3325.2) pL, and median count was 64.0 (IQR = 96.0). Median HRF volumes were greater with decreasing BCVA (nominal P = 0.0109), and increasing CST (nominal P < 0.0001), IRF (nominal P < 0.0001), and DRSS up to very severe nonproliferative diabetic retinopathy (nominal P < 0.0001). HRF co-localized with IRF in the en face projection. Conclusions: Using automated HRF segmentation of full SD-OCT volumes, we observed that HRF are a ubiquitous feature in DME and exhibit relationships with BCVA, CST, IRF, and DRSS, supporting a potential link to disease severity. The spatial distribution of HRF closely followed that of IRF.

Understanding Multilevel Selection May Facilitate Management of Arbuscular Mycorrhizae in Sustainable Agroecosystems.

Studies in natural ecosystems show that adaptation of arbuscular mycorrhizal (AM) fungi and other microbial plant symbionts to local environmental conditions can help ameliorate stress and optimize plant fitness. This local adaptation arises from the process of multilevel selection, which is the simultaneous selection of a hierarchy of groups. Studies of multilevel selection in natural ecosystems may inform the creation of sustainable agroecosystems through developing strategies to effectively manage crop microbiomes including AM symbioses. Field experiments show that the species composition of AM fungal communities varies across environmental gradients, and that the biomass of AM fungi and their benefits for plants generally diminish when fertilization and irrigation eliminate nutrient and water limitations. Furthermore, pathogen protection by mycorrhizas is only important in environments prone to plant damage due to pathogens. Consequently, certain agricultural practices may inadvertently select for less beneficial root symbioses because the conventional agricultural practices of fertilization, irrigation, and use of pesticides can make these symbioses superfluous for optimizing crop performance. The purpose of this paper is to examine how multilevel selection influences the flow of matter, energy, and genetic information through mycorrhizal microbiomes in natural and agricultural ecosystems, and propose testable hypotheses about how mycorrhizae may be actively managed to increase agricultural sustainability.

Resource Use and Real-World Outcomes for Ranibizumab Treat and Extend for Neovascular Age-Related Macular Degeneration in the UK: Interim Results from TERRA.

INTRODUCTION: Ranibizumab is an inhibitor of vascular endothelial growth factor-A (anti-VEGF) approved for the treatment of neovascular age-related macular degeneration (nAMD). The treat and extend (T&E) regimen can potentially reduce the burden of clinic visits compared with a pro re nata (PRN) regimen. Retrospective, interim analyses of clinical effectiveness, treatment and resource use patterns were conducted using real-world data in England and Wales from the TERRA study. METHODS: Two cohorts, those switching from a PRN to a T&E regimen ('prior PRN') and those initiating ranibizumab on the T&E regimen as their first anti-VEGF therapy ('anti-VEGF-naïve') were enrolled in TERRA. Retrospective clinical assessments were gathered from medical records, while resource use patterns were collected via an operating cost questionnaire completed by each study site. RESULTS: At the interim analysis cut-off date (15 November 2016), 11 sites had enrolled 145 patients (prior PRN: n = 110; anti-VEGF-naïve: n = 35). Mean change from baseline (date of first injection) in visual acuity and central subfield retinal thickness to 12 months was +7.6 Early Treatment Diabetic Retinopathy Study letters [95% confidence interval (CI) 2.8, 12.4; p = 0.003; n = 27] and -67.7 µm (95% CI -106.5, -28.9; p = 0.001, n = 29), respectively, in the anti-VEGF-naïve cohort. Most T&E clinics were run as one-stop services (same-day monitoring and injection), whereas 4/10 PRN clinics were run as two-stop services (monitoring and injection on different days). In general, one-stop clinics used less staff resources and were likely to be shorter in duration for healthcare providers than the cumulative time spent for two-stop clinics. CONCLUSION: This is the first real-world observational study conducted in England and Wales demonstrating the effectiveness of the ranibizumab T&E regimen in anti-VEGF-naïve patients. T&E is compatible with one-stop clinic services, which these real-world data suggest to be less resource intensive than two-stop clinic services, possibly providing a dosing regimen beneficial to both patients and resource burden in UK clinical practice. FUNDING: Novartis Pharmaceuticals UK Limited.

Tetanus in developing countries: a case series and review.

PURPOSE: Few anesthesiologists have expertise in the diagnosis and treatment of tetanus, a disease that remains prevalent in developing countries. We report on a series of four cases of tetanus cases recently encountered in Rwanda. We review the clinical epidemiology, pathophysiology, diagnosis and the treatment of tetanus, and provide implications for anesthesiologists and critical care physicians. CLINICAL FEATURES: We report four cases, two involving adults who were inadequately vaccinated and experienced injuries, and two involving neonates, both of whom underwent umbilical cord transection using unsterilized equipment. All patients required tracheal intubation, and were mechanically ventilated when equipment was available. One adult and one neonate succumbed to the disease. These cases highlight the difficulties of diagnosis and management of complicated diseases in the resource-challenged health care setting of developing countries. CONCLUSIONS: The differential diagnosis of tetanus may be confusing, and survival depends on the rapidity of treatment with antitoxin, as well as adequate supportive care. High doses of sedatives and muscle relaxants, as well as prolonged mechanical ventilation, are usually necessary. Mortality remains high, usually resulting from late respiratory failure and cardiovascular collapse, associated with autonomic instability. Anesthesiologists and critical care physicians have an important role to play in the management of these patients. Increased involvement in humanitarian health organizations, immigration from developing countries, and emergence of high risk groups in developed countries will likely result in more exposure of anesthesiologists to the complexities of this disease.

Corrected QT interval prolongation after an overdose of escitalopram, morphine, oxycodone, zopiclone and benzodiazepines.

Escitalopram is the recently marketed S-enantiomer of the widely used antidepressant citalopram. Data from intentional overexposure to this medication are limited. Twelve-lead electrocardiogram (ECG) effects from racemic citalopram have been described; however, the present report is the first, to the best of the authors' knowledge, that describes all the reported abnormalities in a single patient receiving escitalopram. A 52-year-old man with a history of depression treated with escitalopram 10 mg/day, extended-release morphine 30 mg/day and zopiclone 15 mg/day was found unconscious at his home. He was known to have attempted suicide three weeks previously. Partially emptied bottles of escitalopram, morphine, oxycodone, zopiclone, lorazepam and diazepam were found close to the patient. He was transferred to the emergency department, where airway management and other supportive care were initiated. The patient was transferred to the intensive care unit. The initial 12-lead ECG demonstrated junctional rhythm at 48 beats/min, a wide complex escape (145 ms) with right bundle branch morphology and a prolonged corrected QT interval at 650 ms. Cardiac monitoring was undertaken. No ventricular arrhythmias or torsade de pointes were detected. No specific treatment for shortening the QT was implemented. Another 12-lead ECG performed 48 h later demonstrated sinus tachycardia with a normal corrected QT, normal PR interval and normal QRS duration. The effects of the overdose of escitalopram on the ECG and its interactions with other drugs are reviewed.