description of the methodological approach

publishersversionpublishe

Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy:Results of the EUROCONDOR Clinical Trial

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit

Functional Implication of Dp71 in Osmoregulation and Vascular Permeability of the Retina

Functional alterations of Müller cells, the principal glia of the retina, are an early hallmark of most retina diseases and contribute to their further progression. The molecular mechanisms of these reactive Müller cell alterations, resulting in disturbed retinal homeostasis, remain largely unknown. Here we show that experimental detachment of mouse retina induces mislocation of the inwardly rectifying potassium channels (Kir4.1) and a downregulation of the water channel protein (AQP4) in Müller cells. These alterations are associated with a strong decrease of Dp71, a cytoskeleton protein responsible for the localization and the clustering of Kir4.1 and AQP4. Partial (in detached retinas) or total depletion of Dp71 in Müller cells (in Dp71-null mice) impairs the capability of volume regulation of Müller cells under osmotic stress. The abnormal swelling of Müller cells In Dp71-null mice involves the action of inflammatory mediators. Moreover, we investigated whether the alterations in Müller cells of Dp71-null mice may interfere with their regulatory effect on the blood-retina barrier. In the absence of Dp71, the retinal vascular permeability was increased as compared to the controls. Our results reveal that Dp71 is crucially implicated in the maintenance of potassium homeostasis, in transmembraneous water transport, and in the Müller cell-mediated regulation of retinal vascular permeability. Furthermore, our data provide novel insights into the mechanisms of retinal homeostasis provided by Müller cells under normal and pathological conditions

A evolução clínica do paciente portador de abscesso pulmonar: Clinical evolution of patients with lung abscess

Atualmente, com a era da antibioticoterapia e demais meios terapêuticos, o abscesso pulmonar decaiu em termos de morbimortalidade, mas ainda permanece como um desafio em termos diagnósticos e manejo clínico. O abscesso pulmonar corresponde a uma cavidade com pus no pulmão, envolvido por tecido inflamado e geralmente oriunda de uma infecção. O artigo objetivou descrever de modo narrativo a evolução clínica do portador de abscesso pulmonar, ressaltando os principais dados para a compreensão deste fenômeno. Um abscesso pulmonar é causado principalmente por bactérias existentes na boca ou garganta, a qual são aspiradas até os pulmões. A sintomatologia é inespecífica, abordando fadiga, inapetência, sudorese noturna, febre, perda ponderal e tosse com expectoração. O quadro clínico geralmente necessita do complemento de exames de imagem, principalmente a radiografia torácica para diagnóstic

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p&lt;0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p&lt;0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

A social and ecological assessment of tropical land uses at multiple scales: the Sustainable Amazon Network

Science has a critical role to play in guiding more sustainable development trajectories. Here, we present the Sustainable Amazon Network (Rede Amazonia Sustentavel, RAS): a multidisciplinary research initiative involving more than 30 partner organizations working to assess both social and ecological dimensions of land-use sustainability in eastern Brazilian Amazonia. The research approach adopted by RAS offers three advantages for addressing land-use sustainability problems: (i) the collection of synchronized and co-located ecological and socioeconomic data across broad gradients of past and present human use; (ii) a nested sampling design to aid comparison of ecological and socioeconomic conditions associated with different land uses across local, landscape and regional scales; and (iii) a strong engagement with a wide variety of actors and non-research institutions. Here, we elaborate on these key features, and identify the ways in which RAS can help in highlighting those problems in most urgent need of attention, and in guiding improvements in land-use sustainability in Amazonia and elsewhere in the tropics. We also discuss some of the practical lessons, limitations and realities faced during the development of the RAS initiative so far.Keywords: Social–ecological systems, Tropical forests, Land use, Interdisciplinary research, Sustainability, Trade-off

Reproducibility of evaluation of optic disc change for glaucoma with stereo optic disc photographs

To determine the reproducibility of the assessment for glaucomatous change in serial optic disc stereo-slides. Masked interobserver variability study. Serial optic disc stereo-slides from 40 patients. Three independent ophthalmologists evaluated for change a set of two serial 20 degrees optic disc color stereo-slides of 40 patients. This test set was not from European Glaucoma Prevention Study (EGPS) patients. Each observer performed two evaluations at least 30 days apart and was masked from the temporal sequence of the slides and his or her previous evaluation. Each patient was graded as changed or stable by two-out-of-three agreement. A kappa statistic was used to calculate the intra- and interobserver reproducibility as well as the assignment reproducibility (first consensus versus second consensus). The same procedure was followed to test the reproducibility when another experienced ophthalmologist was added to one of the three reading centers. Reproducibility in evaluating glaucomatous optic disc change. The intraobserver reproducibility (95% confidence interval [CI]) in the evaluation of change ranged between 0.79 (0.45-1.14) and 1.00 (0.69-1.31). The interobserver reproducibility (95% CI) in the evaluation of change ranged between 0.45 (0.15-0.75) and 0.75 (0.44-1.06). The assignment reproducibility (first consensus versus second consensus in the evaluation of change) between the senior EGPS readers was 0.94 (0.63-1.25). The assignment reproducibility when another experienced ophthalmologist replaced one of the readers was 0.94 (0.63-1.25). The assignment reproducibility of three expert readers looking for glaucomatous change in serial optic disc stereo-slides was excellent. It remained so when one of the three experts was replaced by another experienced reader

Reproducibility of evaluation of optic disc change for glaucoma with stereo optic disc photographs

To determine the reproducibility of the assessment for glaucomatous change in serial optic disc stereo-slides. Masked interobserver variability study. Serial optic disc stereo-slides from 40 patients. Three independent ophthalmologists evaluated for change a set of two serial 20 degrees optic disc color stereo-slides of 40 patients. This test set was not from European Glaucoma Prevention Study (EGPS) patients. Each observer performed two evaluations at least 30 days apart and was masked from the temporal sequence of the slides and his or her previous evaluation. Each patient was graded as changed or stable by two-out-of-three agreement. A kappa statistic was used to calculate the intra- and interobserver reproducibility as well as the assignment reproducibility (first consensus versus second consensus). The same procedure was followed to test the reproducibility when another experienced ophthalmologist was added to one of the three reading centers. Reproducibility in evaluating glaucomatous optic disc change. The intraobserver reproducibility (95% confidence interval [CI]) in the evaluation of change ranged between 0.79 (0.45-1.14) and 1.00 (0.69-1.31). The interobserver reproducibility (95% CI) in the evaluation of change ranged between 0.45 (0.15-0.75) and 0.75 (0.44-1.06). The assignment reproducibility (first consensus versus second consensus in the evaluation of change) between the senior EGPS readers was 0.94 (0.63-1.25). The assignment reproducibility when another experienced ophthalmologist replaced one of the readers was 0.94 (0.63-1.25). The assignment reproducibility of three expert readers looking for glaucomatous change in serial optic disc stereo-slides was excellent. It remained so when one of the three experts was replaced by another experienced reader

The Effect of the Oral PKC β Inhibitor Ruboxistaurin on Vision Loss in Two Phase 3 Studies

Purpose.: To assess the effect of ruboxistaurin (RBX) on vision loss through a prospectively defined combined analysis of two phase 3 trials (MBDL and MBCU). Methods.: Patients in both of these 3-year randomized, placebo-controlled, double-masked trials had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) ≥ 75 letters (∼20/32 Snellen), ETDRS retinopathy level 20 to 47D (MBDL) or 35B to 53E (MBCU), and no prior panretinal or focal photocoagulation in at least one eye at baseline. Patients received oral placebo (N = 508 total from both studies) or RBX 32 mg/d (N = 520 total). Best-corrected ETDRS VA was measured at 6-month intervals for 3 years (MBDL) or for 18 to 48 months (MBCU). Sustained moderate visual loss (SMVL) was defined as a 15-letter or more reduction from baseline in VA sustained for a patient's last 6 months of study participation. Results.: In the combined studies (N = 1028 total), SMVL occurred in 4.4% of placebo- versus 2.3% of RBX-treated patients (P = 0.069). In patients with a minimum of 2 years of follow-up (N = 825 total), there was less SMVL in the RBX group (4.4% placebo versus 2.1% RBX, P = 0.045). Other VA-related measures (mean VA, contrast sensitivity, Visual Functioning Questionnaire 25 [VFQ-25]) either trended toward a benefit for RBX or were also statistically significant in favor of RBX. In contrast, diabetic macular edema (DME) morphology-related measures (occurrence of significant center of macula involvement, optical coherence tomography [OCT]-determined center of macula thickness, application of focal photocoagulation) did not show a consistent trend in favor of or against RBX. Conclusions.: SMVL data in a prospectively defined combined analysis from these two phase 3 trials suggest a magnitude of effect of RBX on vision loss similar to that seen in two prior studies (approximately 50% reduction above standard care). However, event rates were low and statistical significance was not achieved. (ClinicalTrials.gov numbers, NCT00133952, NCT00090519.