Medicinal Plants, Phytochemicals and Regulation of the NLRP3 Inflammasome in Inflammatory Bowel Diseases: A Comprehensive Review.

Ongoing research explores the underlying causes of ulcerative colitis and Crohn's disease. Many experts suggest that dysbiosis in the gut microbiota and genetic, immunological, and environmental factors play significant roles. The term "microbiota" pertains to the collective community of microorganisms, including bacteria, viruses, and fungi, that reside within the gastrointestinal tract, with a particular emphasis on the colon. When there is an imbalance or disruption in the composition of the gut microbiota, it is referred to as dysbiosis. Dysbiosis can trigger inflammation in the intestinal cells and disrupt the innate immune system, leading to oxidative stress, redox signaling, electrophilic stress, and inflammation. The Nod-like Receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome, a key regulator found in immunological and epithelial cells, is crucial in inducing inflammatory diseases, promoting immune responses to the gut microbiota, and regulating the integrity of the intestinal epithelium. Its downstream effectors include caspase-1 and interleukin (IL)-1ß. The present study investigated the therapeutic potential of 13 medicinal plants, such as Litsea cubeba, Artemisia anomala, Piper nigrum, Morus macroura, and Agrimonia pilosa, and 29 phytocompounds such as artemisitene, morroniside, protopine, ferulic acid, quercetin, picroside II, and hydroxytyrosol on in vitro and in vivo models of inflammatory bowel diseases (IBD), with a focus on their effects on the NLRP3 inflammasome. The observed effects of these treatments included reductions in IL-1ß, tumor necrosis factor-alpha, IL-6, interferon-gamma, and caspase levels, and increased expression of antioxidant enzymes, IL-4, and IL-10, as well as regulation of gut microbiota. These effects could potentially provide substantial advantages in treating IBD with few or no adverse effects as caused by synthetic anti-inflammatory and immunomodulated drugs. However, additional research is necessary to validate these findings clinically and to develop effective treatments that can benefit individuals who suffer from these diseases.

Polyketide Synthase-Mediated O-Methyloxime Formation in the Biosynthesis of the Oximidine Anticancer Agents.

Bacterial trans-acyltransferase polyketide synthases (trans-AT PKSs) are modular megaenzymes that employ unusual catalytic domains to assemble diverse bioactive natural products. One such PKS is responsible for the biosynthesis of the oximidine anticancer agents, oxime-substituted benzolactone enamides that inhibit vacuolar H+ -ATPases. Here, we describe the identification of the oximidine gene cluster in Pseudomonas baetica and the characterization of four novel oximidine variants, including a structurally simpler intermediate that retains potent anticancer activity. Using a combination of in vivo, in vitro and computational approaches, we experimentally elucidate the oximidine biosynthetic pathway and reveal an unprecedented mechanism for O-methyloxime formation. We show that this process involves a specialized monooxygenase and methyltransferase domain and provide insight into their activity, mechanism and specificity. Our findings expand the catalytic capabilities of trans-AT PKSs and identify potential strategies for the production of novel oximidine analogues.

Phytochemicals and Regulation of NF-kB in Inflammatory Bowel Diseases: An Overview of In Vitro and In Vivo Effects.

Inflammatory bowel diseases (IBD) are chronic relapsing idiopathic inflammatory conditions affecting the gastrointestinal tract. They are mainly represented by two forms, ulcerative colitis (UC) and Crohn's disease (CD). IBD can be associated with the activation of nuclear factors, such as nuclear factor-kB (NF-kB), leading to increased transcription of pro-inflammatory mediators that result in diarrhea, abdominal pain, bleeding, and many extra-intestinal manifestations. Phytochemicals can interfere with many inflammation targets, including NF-kB pathways. Thus, this review aimed to investigate the effects of different phytochemicals in the NF-kB pathways in vitro and in vivo models of IBD. Fifty-six phytochemicals were included in this study, such as curcumin, resveratrol, kaempferol, sesamol, pinocembrin, astragalin, oxyberberine, berberine hydrochloride, botulin, taxifolin, naringin, thymol, isobavachalcone, lancemaside A, aesculin, tetrandrine, Ginsenoside Rk3, mangiferin, diosgenin, theanine, tryptanthrin, lycopene, gyngerol, alantolactone, mangostin, ophiopogonin D, fisetin, sinomenine, piperine, oxymatrine, euphol, artesunate, galangin, and nobiletin. The main observed effects related to NF-kB pathways were reductions in tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1ß, IL-6, interferon-gamma (IFN-γ), and cyclooxygenase-2 (COX-2), and augmented occludin, claudin-1, zonula occludens-1, and IL-10 expression levels. Moreover, phytochemicals can improve weight loss, stool consistency, and rectal bleeding in IBD. Therefore, phytochemicals can constitute a powerful treatment option for IBD in humans.

Characterisation of progression of macular oedema in the initial stages of diabetic retinopathy: a 3-year longitudinal study.

BACKGROUND/OBJECTIVES: To characterise the prevalence and three-year progression of centre-involving diabetic macular oedema (CI-DMO) in minimal to moderate non-proliferative diabetic retinopathy, using optical coherence tomography (OCT) and measurements of retinal fluid using tissue optical reflectivity ratios (OCT-Leakage). METHODS/METHODS: Seventy-four eyes from 74 patients were followed in a 3-year prospective longitudinal observational cohort of type 2 diabetes (T2D) patients using spectral-domain optical coherence tomography (SD-OCT), OCT-Angiography (OCT-A) and OCT-Leakage (OCT-L). Eyes were examined four times with 1-year intervals. Sixteen eyes (17.8%) were excluded from the analysis due to quality control standards. Retinal oedema was measured by central retinal thickness and retinal fluid by using optical reflectivity ratios obtained with the OCT-L algorithm. Vessel density was measured by OCT-A. Thinning of the ganglion cell and inner plexiform layers (GCL + IPL) was examined to identify retinal neurodegenerative changes. Diabetic retinopathy ETDRS classification was performed using the seven-field ETDRS protocol. RESULTS: CI-DMO was identified in the first visit in 9% of eyes in ETDRS groups 10-20, 10% of eyes in ETDRS group 35 and 15% of eyes in ETDRS groups 43-47. The eyes with CI-DMO and subclinical CI-DMO showed a progressive increase in retinal extracellular fluid during the 3-year period of follow-up. The eyes with CI-DMO and increased retinal extracellular fluid accumulation were associated with vision loss. CONCLUSIONS: The prevalence of subclinical CI-DMO and CI-DMO in the initial stages of NPDR occurs independently of severity grading of the retinopathy, showing progressive increase in retinal extracellular fluid and this increase is associated with vision loss (82% 9 out of 11 cases).

Efficacy Evaluation of SDF-1α-Based Polypeptides in an Acute Myocardial Infarction Model Using Structure-Based Drug Design.

Stromal cell-derived factor-1 alpha (SDF-1α, CXCL12) mediates the migration of circulating cells to desired sites for tissue development, homeostasis, and regeneration and can be used to promote cardiac regeneration by recruiting stem cells. However, the use of SDF-1α in the injured heart necessitates not only higher binding affinity to its receptor, CXCR4+, but also better robustness against enzymatic degradation than other SDF-1 isoforms. Here, we conduct a screening of SDF-1α analog peptides that were designed by structure-based drug design (SBDD), a type of computer-aided drug design (CADD). We have developed in vitro and in vivo methods that enable us to estimate the effect of peptides on the migration of human mesenchymal stem cells (hMSCs) and cardiac regeneration in acute myocardial infarction (AMI)-induced animals, respectively. We demonstrate that one type of SDF-1α analog peptide, SDP-4, among the four analog peptides preselected by SBDD, is more potent than native SDF-1α for cardiac regeneration in myocardial infarction. It is interesting to note that the migratory effects of SDP-4 determined by a wound healing assay, a Transwell assay, and a 2D migration assay are comparable to those of SDF-1α. These results suggest that in vivo, as well as in vitro, screening of peptides developed by SBDD is a quintessential process to the development of a novel therapeutic compound for cardiac regeneration. Our finding also has an implication that the SDP-4 peptide is an excellent candidate for use in the regeneration of an AMI heart.

Statins are associated with reduced likelihood of sarcopenia in a sample of heart failure outpatients: a cross-sectional study.

BACKGROUND: Sarcopenia is prevalent in heart failure (HF) patients, contributing to its poor prognosis. Statin use is postulated as a probable risk for developing sarcopenia, but little is known regarding this association in HF patients. This work aims at classifying and characterising sarcopenia and at describing the association of statin use with sarcopenia in a sample of Portuguese HF outpatients. METHODS: In this cross-sectional study, a sample of 136 HF patients (median age: 59 years, 33.8% women) was recruited from an HF outpatients' clinic of a University Hospital in Portugal. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People 2. Clinical, nutritional, and dietary data were collected. RESULTS: A total of 25 (18.4%) individuals were categorised as sarcopenic, ranging from 12.2% in younger (< 65 years) participants vs. 30.4% in older ones and from 3.3% in men vs. 47.8% in women. Severe sarcopenia accounted for 7.4% of the sample and sarcopenic obesity was identified in 5.1% of the individuals. A total of 65.4% of the participants were statin users. In multivariable analysis (n = 132, 25 sarcopenic), the use of statins was inversely associated with sarcopenia (OR = 0.03; 95% CI = 0.01, 0.30). Each additional age year was associated with a 9% increase in the likelihood of being sarcopenic (OR = 1.09; 95% CI = 1.01, 1.17), and each Kg.m-2 increment in body mass index was associated with a 21% decrease in the likelihood of sarcopenia (OR = 0.79; 95% CI = 0.65, 0.96). The daily use of five or more medicines was also directly associated with sarcopenia (OR = 26.87; 95% CI = 2.01, 359.26). On the other hand, being a man and being physically active were inversely associated with sarcopenia (OR = 0.01; 95% CI = 0.00, 0.07 and OR = 0.09; 95% CI = 0.01, 0.65, respectively). CONCLUSIONS: Contrary to what was expected, patients medicated with statins were less likely to be sarcopenic. Although this finding deserves further research, we hypothesise that this might be related to the pleiotropic effects of statins on endothelial function, contributing to better neuromuscular fitness.

DESCENDING NECROTIZING MEDIASTINITIS - A MULTIDISCIPLINARY PATHOLOGY.

A 23-year-old man presented with fever and cervical swelling. Contrast-enhanced CT-scan with oblique sagittal planes reconstructions with extensive collection with gaseous areas, involving multiple cervical and mediastinal spaces is shown, reflecting a cervical-mediastinal necrotizing fasciitis. Note the circumference to the laryngotracheal axis. He underwent combined surgery by ENT and thoracic surgery and was discharged without sequelae after long hospitalization. This case demonstrates the importance of working in a multidisci- plinary team to treat complex pathologies.

Panax ginseng and aging related disorders: A systematic review.

The aging process predisposes numerous homeostatic disorders, metabolic disorders, cardiovascular diseases, neurodegenerative diseases, and cancer. Changes in diet and lifestyle and therapeutic adjuvants are essential to minimize the effects of comorbidities associated with aging. Natural products such as Panax ginseng have been used to treat and prevent diseases related to aging. This review aims to investigate the effects of Panax ginseng in various conditions associated with aging, such as inflammation, oxidative stress, mitochondrial dysfunction, apoptosis, neurodegenerative and metabolic disorders, cardiovascular diseases, and cancer. The ginsenosides, chemical constituents found in Panax ginseng, can inhibit the effects of inflammatory cytokines, inhibit signaling pathways that induce inflammation, and inhibit cells that participate in inflammatory processes. Besides, ginsenosides are involved in neuroprotective effects on the central nervous system due to anti-apoptotic, antioxidant, and anti-inflammatory effects. The use of ginseng extract showed actions on lipid homeostasis, positively regulating high-density lipoprotein, down-regulating low-density lipoprotein and triglyceride levels, and producing beneficial effects on vascular endothelial function. The use of this plant in cancer resulted in improved quality of life and mood. It decreased symptoms of fatigue, nausea, vomiting, and dyspnea, reducing anxiety. Panax ginseng has been shown to exert potent therapeutic benefits that can act as a complementary treatment in managing patients with chronic diseases related to aging.

Relationship of Inflammatory Markers and Metabolic Syndrome in Postmenopausal Women.

The increased deposition of visceral fat in the postmenopause period increases the production of inflammatory cytokines and the release of tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), and decrease in IL-10. This study investigated the relationship between inflammatory biomarkers and metabolic syndrome (MS) in postmenopausal women considering different diagnostic criteria. We conducted a cross-sectional observational study based on STROBE. Data were collected regarding the diagnostic criteria for MS (International Diabetes Federation; NCEP (International Diabetes Federation (IDF), National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III), and Harmonized criteria), body composition, comorbidities, time without menstruation, values of IL-6, IL-10, and TNF-α. ANOVA, Kruskal-Wallis, Levene tests, ROC, and odds ratio were performed to analyze the data. The results showed no significant difference between the methods and no interaction between the method and the presence of MS. However, for the values of WC, body fat percentage, TNF-α, and IL-10/TNF-α ratio, a significant effect of MS was observed. In subjects with MS, lower values of body fat percentage and TNF-α and higher values of the IL-10/TNF-α ratio were also observed. The higher IL-10/TNF-α ratio in the MS group is related to the greater anti-inflationary action of IL-10. The IL-10/TNF-α ratio showed significant accuracy to discriminate patients with MS according to the NCEP-ATP III criteria.

Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions.

Adipose, skeletal, and hepatic muscle tissues are the main endocrine organs that produce adipokines, myokines, and hepatokines. These biomarkers can be harmful or beneficial to an organism and still perform crosstalk, acting through the endocrine, paracrine, and autocrine pathways. This study aims to review the crosstalk between adipokines, myokines, and hepatokines. Far beyond understanding the actions of each biomarker alone, it is important to underline that these cytokines act together in the body, resulting in a complex network of actions in different tissues, which may have beneficial or non-beneficial effects on the genesis of various physiological disorders and their respective outcomes, such as type 2 diabetes mellitus (DM2), obesity, metabolic syndrome, and cardiovascular diseases (CVD). Overweight individuals secrete more pro-inflammatory adipokines than those of a healthy weight, leading to an impaired immune response and greater susceptibility to inflammatory and infectious diseases. Myostatin is elevated in pro-inflammatory environments, sharing space with pro-inflammatory organokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), resistin, and chemerin. Fibroblast growth factor FGF21 acts as a beta-oxidation regulator and decreases lipogenesis in the liver. The crosstalk mentioned above can interfere with homeostatic disorders and can play a role as a potential therapeutic target that can assist in the methods of diagnosing metabolic syndrome and CVD.

Microperimetry and mfERG as functional measurements in diabetic macular oedema undergoing intravitreal ranibizumab treatment.

PURPOSE: To evaluate Microperimetry (MP) and multifocal electroretinogram (mfERG) as whole-macula functional markers of treatment response in naive diabetic macular oedema (DMO) patients undergoing ranibizumab treatment. METHODS: An exploratory sub-analysis of a prospective study (NCT01947881-CHARTRES). Patients received three monthly ranibizumab injections (loading dose) followed by pro re nata (PRN) regimen during 1 year. At baseline, during and after treatment (Months 0, 3, 6 and 12), subjects were tested using BCVA, OCT, MP and mfERG. MP was performed in the central 12°, and retinal sensitivity was measured overall (mean sensitivity (MS)), and in three concentric rings (R1-R3). mfERG P1 amplitude and implicit time were measured over six concentric rings (R1-R6). RESULTS: Thirty-two eyes were included. MP mean and rings sensitivity were significantly lower in DMO (p < 0.001). After loading dose, a significant improvement in retina sensitivity was observed, particularly in good BCVA responders (MS = +2.28 dB; R1 = +2.33 dB, R2 = +2.20 dB, R3 = +2.25 dB; p = 0.049). Overall retinal sensitivity was significantly correlated with BCVA improvement (r = 0.54; p = 0.026) and inversely correlated with OCT central subfield thickness improvement (r = -0.39; p = 0.026). mfERG amplitude and implicit time were also lower in DMO (p < 0.011). An improvement of mfERG P1 amplitude and implicit time in R1 was noted in good responders after ranibizumab loading dose (+16.49 nV/deg2; p = 0.013 and -0.005 ms; p = 0.048, respectively). When changing to PRN treatment regimen, BCVA was maintained during the 12 months of follow-up but worsening of the visual function was detected by MP and mfERG. CONCLUSIONS: Microperimetry and mfERG were able to demonstrate DMO functional improvement after treatment loading dose, as well as early visual changes when treatment regimen was switched to PRN.

Influence of the background, substrate and thickness in light behaviour and colour of zirconia-reinforced lithium silicate (ZLS) glass-ceramic / Influência do fundo, substrato e espessura no comportamento da luz e cor das cerâmicas de dissilicato de lítio reforçadas com zircónia (ZLS)

Objective: To evaluate the influence of background, substrates and thickness on the color and light behaviour of two ZLS glass ceramics. Material and Methods: Standardized disc-shape specimens (12 x 1.2 mm), color A1 HT, of Celtra Duo and Vita Suprinity (n=30), were tested over a white/black background, and divided in five groups (n=6) to be tested over five substrates (polished gold alloy, white zirconia and composite, dentine and enamel A1 colour). The L*, C*, h*, a*, b* and Δ E values, were recorded in two thicknesses (1.2 and 2.4 mm). Translucency parameter (TP), contrast ratio (CR) and opalescence parameter (OP) were calculated. Data was analysed with non­parametric tests: Mann Whitney between ceramic materials for thickness, Wilcoxon for thicknesses in substrates and ceramic material and Kruskal­Wallis with Bonferroni corrections tests (p<0,01) for substrates. Results: For 2.4 mm, the Δ E values were always higher independently of ceramic material or substrates. Vita Suprinity registered lower values than Celtra Duo. Zirconia substrate registered the lower values. For 1.2 mm, dentine registered the lower values. Gold alloy and composite substrates registered the lower Δ E values for 1.2 mm Celtra Duo and 2.4 mm Vita Suprinity specimens. CT and OP higher values and TP lower values were registered for 2.4 mm Vita Suprinity. It was impossible to calculate for Celtra Duo specimens. Conclusions: Background, substrate and thickness had significant influence in light behaviour and final color of ZLS glass ceramics. Substrates Gold alloy and dentine exhibited clinical acceptable Δ E values for 1.2 mm Celtra Duo specimens. (AU)

Objetivo: Avaliar a influência do fundo, do substrato e da espessura no comportamento da luz e na cor de duas cerâmicas ZLS. Material e métodos: Discos de cerâmica (12 x 1.2 mm) de cor A1 HT, de Celtra Duo e Suprinity (n=30), foram testados sobre fundo branco/preto e cinco substratos (liga Ag-Au-Pt polida; zircónia branca; compósito, dentina e esmalte de cor A1). Os valores L*, C*, h*, a*, b* e Δ E foram registados em duas espessuras (1.2 mm e 2.4 mm). O parâmetro de translucidez (TP), o parâmetro de opalescência (OP) e o índice de contraste (CR) foram determinados. Foram realizados testes não paramétricos: Mann Whitney entre cerâmicas por espessura, Wilcoxon entre categoria de espessura por substrato e cerâmica; Kruskal­Wallis com correção de Bonferroni para substratos (p <0,01). Resultados: Para 2,4 mm, o Δ E foi sempre superior independentemente do material ou substrato. Os valores de Suprinity foram inferiores aos de Celtra Duo. O substrato zirconia obteve o Δ E mais baixo. Para 1,2 mm, a dentina obteve o Δ E mais baixo. A liga dourada e o compósito obtiveram Δ E mais baixo para Celtra Duo 1,2 mm e Suprinity 2,4 mm. Para Suprinity, CT e OP foram maiores para 2,4 mm e menores para TP. Não foi possível calcular para Celtra Duo. Conclusão: O fundo, substrato e espessura tiveram influência significativa no comportamento da luz e cor das restaurações de cerâmica ZLS. Apenas os substratos metal e dentina apresentaram valores clinicamente aceitáveis, para Celtra Duo na espessura de 1.2 mm.(AU)

Targeting Neuropilin-1 with Nanobodies Reduces Colorectal Carcinoma Development.

Neuropilin-1 (NRP-1) is a co-receptor for semaphorins and vascular endothelial growth factor (VEGF) family members that can be expressed on cancer cells and tumor-infiltrating myeloid, endothelial and lymphoid cells. It has been linked to a tumor-promoting environment upon interaction with semaphorin 3A (Sema3A). Nanobodies (Nbs) targeting NRP-1 were generated for their potential to hamper the NRP-1/Sema3A interaction and their impact on colorectal carcinoma (CRC) development was evaluated in vivo through the generation of anti-NRP-1-producing CRC cells. We observed that tumor growth was significantly delayed and survival prolonged when the anti-NRP-1 Nbs were produced in vivo. We further analyzed the tumor microenvironment and observed that the pro-inflammatory MHC-IIhigh/trophic MHC-IIlow macrophage ratio was increased in tumors that produce anti-NRP-1 Nbs. This finding was corroborated by an increase in the expression of genes associated with MHC-IIhigh macrophages and a decrease in the expression of MHC-IIlow macrophage-associated genes in the macrophage pool sorted from anti-NRP-1 Nb-producing tumors. Moreover, we observed a significantly higher percentage of tumor-associated antigen-specific CD8+ T cells in tumors producing anti-NRP-1 Nbs. These data demonstrate that an intratumoral expression of NRP-1/Sema3A blocking biologicals increases anti-tumor immunity.

Pretreatment hemoglobin level as a prognostic factor in patients with locally advanced head and neck squamous cell carcinoma.

AIM: Evaluate pretreatment hemoglobin values as a prognostic factor in patients with locally advanced head and neck squamous cell carcinoma treated with concurrent chemoradiotherapy. BACKGROUND: Anemia is one of the most prevalent laboratory abnormalities in oncological disease. It leads to a decrease in cellular oxygen supply, altering radiosensitivity of tumor cells and compromising therapeutic outcomes. MATERIALS AND METHODS: Retrospective evaluation of patients with HNSCC treated with cCRT. Primary and secondary endpoint was to evaluate the correlation of Hb levels (≥12.5 g/dL or <12.5 g/dL) at the beginning of cCRT with overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: A total of 108 patients were identified. With a median follow-up of 16.10 months median OS was 59.70 months for Hb ≥12.5 g/dL vs. 14.13 months for Hb <12.5 g/dL (p = 0.004). PFS was 12.29 months for Hb ≥12.5 g/dL and 1.68 months for Hb <12.5 g/dL (p = 0.016). CONCLUSIONS: In this analysis, Hb ≥12.5 g/dL correlated with significantly better OS and PFS. Further studies are needed to validate these findings.

Characterization of Disease Progression in the Initial Stages of Retinopathy in Type 2 Diabetes: A 2-Year Longitudinal Study.

Purpose: To characterize 2-year changes occurring in neurodegeneration, edema, and capillary dropout in nonproliferative diabetic retinopathy. Methods: Two-year prospective longitudinal observational cohort of eyes/patients with type 2 diabetes using spectral domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCTA). Eyes were examined three times with intervals of 1 year. Thickness of the full retina and layer-by-layer measurements were used to identify edema or neurodegeneration. OCTA vessel density maps of the retina were used to identify capillary dropout. Early Treatment Diabetic Retinopathy Study (ETDRS) classification was performed using the seven-field ETDRS protocol. Results: A total of 62 eyes from 62 patients with diabetes were followed for 2 years. After verification for image quality, a total of 44 eyes from 44 patients (30% women) aged 52 to 80 years were retained for data analysis. There were 18 eyes with ETDRS grades 10 to 20, 17 eyes with ETDRS grade 35, and 9 eyes with ETDRS grades 43 to 47. During the 2-year follow-up period, there was a progressive increase in capillary dropout, whereas edema and neurodegeneration remained stable. In multivariate analysis, considering a model adjusted for age, sex, hemoglobin A1C, visual acuity, and diabetes duration, vessel density remained significantly different between Diabetic Retinopathy Severity Scale groups (Wilks' λ = 0.707; P = 0.015) showing association with disease progression. Conclusions: Capillary dropout increased in a period of 2 years in eyes with minimal, mild, and moderate diabetic retinopathy, whereas the presence of edema and neurodegeneration remained stable.

Baseline predictors for visual acuity loss during observation in diabetic macular oedema with good baseline visual acuity.

PURPOSE: To investigate clinical baseline characteristics and optical coherence tomography biomarkers predicting visual loss during observation in eyes with diabetic macular oedema (DMO) and good baseline visual acuity (VA). METHODS: A sub-analysis of a 12-month, retrospective study, including patients with baseline VA ≤0.1 logMAR (≥20/25 Snellen) and centre-involving DMO. The primary outcome measure was the correlation between baseline characteristics and VA loss ≥10 letters during follow-up. RESULTS: A total of 249 eyes were included in the initial study, of which 147 eyes were observed and 80 eyes received anti-vascular endothelial growth factor (VEGF) treatment at baseline. Visual acuity (VA) loss ≥10 letters occurred in 21.8% (observed cohort) and in 24.3% (treated cohort), respectively. Within observed eyes, presence of hyperreflective foci [HRF; odds ratio (OR): 3.18, p = 0.046], and disorganization of inner retina layers (DRIL; OR: 2.71, p = 0.026) were associated with a higher risk of VA loss ≥10 letters. In observed eyes with a combined presence of HRF, DRIL and ellipsoid zone (EZ) disruption, the risk of VA loss was further increased (OR: 3.86, p = 0.034). In eyes with combined presence of DRIL, HRF and EZ disruption, risk of VA loss was 46.7% (7/15 eyes) in the observed cohort, and 26.3% (5/19 eyes) in the treated cohort (p = 0.26). CONCLUSION: Patients with DMO and good baseline VA, managed by observation, are of increased risk for VA loss if DRIL, HRF and EZ disruption are present at baseline. Earlier treatment with anti-VEGF in these patients may potentially decrease the risk of VA loss at 12 months.

OPTICAL COHERENCE TOMOGRAPHY LEAKAGE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Identification of Choroidal Neovascularization Activity by Location and Quantification of Abnormal Fluid Under Anti-Vascular Endothelial Growth Factor Therapy.

PURPOSE: To test optical coherence tomography leakage in the identification and quantification of choroidal neovascularization-related fluid, its change after anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration eyes and its relation to functional outcome. METHODS: Prospective analysis of a cohort of neovascular age-related macular degeneration cases treated with 2.0-mg intravitreal aflibercept. Eyes included were analyzed before, 1-week, and 1-month after one injection. Best-corrected visual acuity was assessed using Early Treatment Diabetic Retinopathy Study method. Optical coherence tomography leakage maps depicting low optical reflectivity (LOR) sites were acquired with OCT Cirrus AngioPlex (Zeiss, Dublin, CA). The LOR area ratio was correlated to retinal thickness and best-corrected visual acuity. Optical coherence tomography angiography was simultaneously performed. RESULTS: Twenty-two eyes of 18 patients with neovascular age-related macular degeneration were included. The LOR ratio of the full retina scan and retinal pigment epithelium-Bruch layer decreased from baseline to Month 1 (P < 0.05). Changes in retinal thickness and LOR ratio were positively correlated (P < 0.05). Best-corrected visual acuity change correlated with the outer segment layer LOR change (rho = -0.53, P = 0.014), and LOR was inferior in better responders (P = 0.021). Optical coherence tomography leakage identified eyes with recurrent fluid in the external layers. CONCLUSION: Optical coherence tomography leakage identified and quantified the fluid related to choroidal neovascularization activity. Low optical reflectivity change in the outer segment layer correlates with functional outcome and increasing LOR in the external layers may be a marker of early recurrence. Combining optical coherence tomography angiography and optical coherence tomography leakage allows both for choroidal neovascularization morphology and activity analysis.

New-Onset Atrial Fibrillation in St-Segment Elevation Myocardial Infarction: Predictors and Impact on Therapy And Mortality / Fibrilação Auricular de Novo no Infarto Agudo do Miocárdio com Supradesnível do Segmento ST: Preditores e Impacto na Terapêutica e Mortalidade

Abstract Backgrund: New-onset atrial fibrillation complicating acute myocardial infarction represents an important challenge, with prognostic significance. Objective: To study the incidence, impact on therapy and mortality, and to identify predictors of development of new-onset atrial fibrillation during hospital stay for ST-segment elevation myocardial infarction. Methods: We studied all patients with ST-elevation myocardial infarction included consecutively, between 2010 and 2017, in a Portuguese national registry and compared two groups: 1 - no atrial fibrillation and 2 - new-onset atrial fibrillation. We adjusted a logistic regression model data analysis to assess the impact of new-onset atrial fibrillation on in-hospital mortality and to identify independent predictors of its development. A p value < 0.05 was considered significant. Results: We studied 6325 patients, and new-onset atrial fibrillation was found in 365 (5.8%). Reperfusion was successfully accomplished in both groups with no difference regarding type of reperfusion. In group 2, therapy with beta-blockers and angiotensin-conversion enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) was less frequent, 20.6% received anticoagulation at discharge and 16.1% were on triple therapy. New-onset atrial fibrillation was associated with more in-hospital complications and mortality. However, it was not found as an independent predictor of in-hospital mortality. We identified age, prior stroke, inferior myocardial infarction and complete atrioventricular block as independent predictors of new-onset atrial fibrillation. Conclusion: New-onset atrial fibrillation remains a frequent complication of myocardial infarction and is associated with higher rate of complications and in-hospital mortality. Age, prior stroke, inferior myocardial infarction and complete atrioventricular block were independent predictors of new onset atrial fibrillation. Only 36.7% of the patients received anticoagulation at discharge.

Resumo Fundamento: A fibrilação auricular de novo no contexto de infarto agudo do miocárdio representa um importante desafio com potencial impacto prognóstico. Objetivo: Determinar a incidência, impacto na terapêutica e mortalidade, e identificar possíveis preditores do aparecimento de fibrilação auricular de novo durante o internamento por infarto agudo do miocárdio com supradesnivelamento do segmento ST. Métodos: Estudamos todos os pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento ST inseridos consecutivamente de 2010 a 2017 num registro nacional português e comparamos dois grupos: 1 - sem fibrilação auricular; 2- com fibrilação auricular de novo. Efetuamos análise com modelo de regressão logística para avaliar o impacto de fibrilação auricular de novo na mortalidade intra-hospitalar e identificar preditores independentes para o seu aparecimento. Para teste de hipóteses, considerou-se significativo p < 0,05. Resultados: Estudamos 6325 pacientes, dos quais 365 (5.8%) apresentaram fibrilação auricular de novo. Não houve diferença no número de pacientes reperfundidos nem na estratégia de reperfusão. No grupo 2, terapêutica com betabloqueadores e IECA/ARA foi menos frequente, 20.6% tiveram alta sob anticoagulação oral e 16.1% sob terapêutica tripla. A fibrilação auricular de novo associou-se a maior incidência de complicações e mortalidade intra-hospitalar, mas não foi preditor independente de mortalidade intra-hospitalar. Identificamos idade, acidente vascular cerebral prévio, infarto inferior e bloqueio auriculoventricular completo como preditores independentes de fibrilação auricular de novo. Conclusões: A fibrilação auricular de novo continua sendo uma complicação frequente do infarto agudo do miocárdio, estando associada a aumento das complicações e mortalidade intra-hospitalar. Apenas 36.7% desses pacientes teve alta sob anticoagulação.

Real-world outcomes of non-responding diabetic macular edema treated with continued anti-VEGF therapy versus early switch to dexamethasone implant: 2-year results.

AIMS: To provide 2-year follow-up data on eyes with diabetic macular edema (DME) that were non-responsive after three initial anti-vascular endothelial growth factor (VEGF) injections, comparing functional and anatomical outcomes under continued anti-VEGF therapy versus dexamethasone (DEX) implant. METHODS: Multicenter, retrospective chart review comparing eyes with treatment-naïve DME and a suboptimal response to a loading phase of anti-VEGF therapy (3 injections given monthly) which were then treated with (a) further anti-VEGF (n = 72) or (b) initially switched to DEX implant (n = 38). Main outcome measures were change in visual acuity (VA) and central subfield thickness (CST) from the end of the loading phase to 24 months. RESULTS: In 79% of the 12-month study population (87/110 eyes), 24-month data were available. One quarter of eyes in each group switched treatments during the second year. Eyes that were switched early to DEX implant maintained the functional and anatomical improvements at 24 months which were seen in the first year (from month 3: + 8.9 letters, - 214 µm). Eyes that were switched from anti-VEGF therapy to steroids in the second year improved VA and reduced CST at 24 months (from month 12: + 6.8 letters, p = 0.023; - 226 µm, p = 0.004). In eyes continued on anti-VEGF therapy, VA and CST were stable at 24 months (from month 3: + 2.8 letters, p = 0.254; - 24 µm, p = 0.243). Eyes that were non-responsive to anti-VEGF therapy for 12 months had similar chances to experience a VA gain from further therapy as eyes that were non-responsive for 3 months only (23.8 vs. 31.0%, p = 0.344). CONCLUSIONS: The beneficial effect of an early switch to DEX implant in DME non-responders seen at month 12 was maintained during the second year. A later switch from anti-VEGF to steroids still provided significant improvement. Eyes continued on anti-VEGF over a period of 24 months maintained vision. A quarter of eyes, which had not improved vision at 12 months, exhibited a delayed response to treatment.

Characterization of Initial Stages of Diabetic Macular Edema.

PURPOSE: This study is aimed at characterizing the type of retinal edema in the initial stages of retinopathy in type 2 diabetes. METHODS: In this retrospective cross-sectional study, spectral domain optical coherence tomography (OCT) layer by layer analysis of the retina in association with OCT-Leakage, an algorithm to detect sites of low optical reflectivity, were used to examine eyes with minimal, mild, and moderate diabetic retinopathy (DR). RESULTS: A total of 142 eyes from 142 patients (28% women) aged 52-88 years were imaged. Macular edema, either subclinical (SCME) or central-involved macular edema (CIME), was present in 43% of eyes in group 10-20, 41% of eyes in group 35, and 38% of eyes in group 43-47. The inner nuclear layer (INL) was the layer showing higher and most frequent increases in retinal thickness (79%). The edema was predominantly intracellular in group 10-20 (65%) and extracellular in groups 35 (77%) and 43-47 (69%). CONCLUSIONS: Eyes from diabetic patients in the initial stages of DR with different Early Treatment Diabetic Retinopathy Study gradings show similar prevalence of SCME and CIME, independent of the severity of the retinopathy. Retinal edema is located mainly in the INL and appears to be mostly extracellular except in the earliest stages of diabetic retinal disease where intracellular edema predominates.