Improved predictive diagnosis of diabetic macular edema based on hybrid models: An observational study.

Diabetic Macular Edema (DME) is the most common sight-threatening complication of type 2 diabetes. Optical Coherence Tomography (OCT) is the most useful imaging technique to diagnose, follow up, and evaluate treatments for DME. However, OCT exam and devices are expensive and unavailable in all clinics in low- and middle-income countries. Our primary goal was therefore to develop an alternative method to OCT for DME diagnosis by introducing spectral information derived from spontaneous electroretinogram (ERG) signals as a single input or combined with fundus that is much more widespread. Baseline ERGs were recorded in 233 patients and transformed into scalograms and spectrograms via Wavelet and Fourier transforms, respectively. Using transfer learning, distinct Convolutional Neural Networks (CNN) were trained as classifiers for DME using OCT, scalogram, spectrogram, and eye fundus images. Input data were randomly split into training and test sets with a proportion of 80 %-20 %, respectively. The top performers for each input type were selected, OpticNet-71 for OCT, DenseNet-201 for eye fundus, and non-evoked ERG-derived scalograms, to generate a combined model by assigning different weights for each of the selected models. Model validation was performed using a dataset alien to the training phase of the models. None of the models powered by mock ERG-derived input performed well. In contrast, hybrid models showed better results, in particular, the model powered by eye fundus combined with mock ERG-derived information with a 91 % AUC and 86 % F1-score, and the model powered by OCT and mock ERG-derived scalogram images with a 93 % AUC and 89 % F1-score. These data show that the spontaneous ERG-derived input adds predictive value to the fundus- and OCT-based models to diagnose DME, except for the sensitivity of the OCT model which remains the same. The inclusion of mock ERG signals, which have recently been shown to take only 5 min to record in daylight conditions, therefore represents a potential improvement over existing OCT-based models, as well as a reliable and cost-effective alternative when combined with the fundus, especially in underserved areas, to predict DME.

Detección incidental de niveles de vitamina B12 elevados y su relación con neoplasias / Incidental detection of raised serum levels of vitaminB12 and its association with neoplasms

Antecedentes y objetivo Los niveles elevados de vitaminaB12 se han asociado a enfermedades oncohematológicas. Sin embargo, se desconoce la relevancia de su detección incidental en sujetos sin un diagnóstico previo de cáncer. El objetivo de este estudio es evaluar la relación de la hipercobalaminemia y el diagnóstico de un proceso tumoral y establecer los factores de riesgo. Material y métodos Estudio observacional retrospectivo de una cohorte de pacientes con hipercobalaminemia. Se comparó la incidencia de neoplasias con una cohorte de pacientes con vitaminaB12<1.000pg/ml. Resultados Se seleccionaron 4.800 sujetos con determinaciones de vitaminaB12: 345 (7,1%) presentaban niveles >1.000pg/ml. Se excluyeron 68 (28,4%) por administración exógena, 12 (5%) por datos insuficientes y 15 (3%) por una neoplasia activa, seleccionando 250 pacientes; mediana de seguimiento: 22 (RIQ: 12-39) meses. Se detectó: hepatopatía 59 (23,6%), 44 (18,2%) presentaron cáncer de órgano sólido y 17 (7,1%), hemopatía maligna. El tiempo medio desde la detección de hipercobalaminemia al diagnóstico fue de 10meses. La mediana hasta el diagnóstico fue mayor en el grupo de vitaminaB12 elevada (13 vs 51meses; p<0,001). La hipercobalaminemia (HR_ 11,8; IC95: 2,8-49,6; p=0,001) y el tabaquismo (HR: 4,0; IC95%: 2,15-7,59; p<0,001) resultaron predictores independientes. Conclusiones La detección incidental de niveles séricos de vitaminaB12 >1.000pg/ml es elevada. El diagnóstico de neoplasia órgano sólido y hematológica es frecuente durante el año siguiente de seguimiento, siendo la hipercobalaminemia y el tabaquismo factores predictores de un mayor riesgo de cáncer. (AU)

Background and objective Elevated serum levels of vitaminB12 have been associated with oncohematological diseases. However, the relevance of its incidental detection in subjects without a previous diagnosis of cancer is unknown. The aim of this study was to evaluate the relationship between incidental hypercobalaminemia (vitaminB12 >1000pg/mL) and the diagnosis of a tumor process in patients without a diagnosis and to establish the risk factors. Material and methods Retrospective observational study of a cohort of patients with hypercobalaminemia. The incidence of neoplasms was compared with a cohort of patients with vitaminB12 levels <1000pg/mL. Results Vitamin B12 determinations of 4800 subjects were selected. Of them, 345 (7.1%) had levels >1000pg/ml; 68 (28.4%) were excluded due to exogenous administration, 12 (5%) due to insufficient data, and 15 (3%) due to having an active neoplasia, selecting 250 patients, with a median follow-up of 22 (IQR: 12-39) months. Structural liver disease was detected in 59 (23.6%). 18.2% (44 patients) had solid organ cancer and 17 (7.1%) had malignant hemopathy. The average time from the detection of hypercobalaminemia to the diagnosis of cancer was about 10months. The median until the diagnosis of neoplasia was higher in the high vitaminB12 group (13 vs 51months; P<.001). Hypercobalaminemia (HR: 11.8; 95%CI: 2.8-49.6; P=.001) and smoking (HR: 4.0; 95%CI: 2.15-7.59; P<.001) were independent predictors of neoplasia in the multivariate analysis. Conclusions Incidental detection of serum vitaminB12 levels >1000pg/ml is high in the population. The diagnosis of solid organ and hematological neoplasia is frequent during the following year of follow-up, with hypercobalaminemia and smoking being predictors of a higher risk of cancer. (AU)

Detección incidental de niveles de vitamina B12 elevados y su relación con neoplasias / Incidental detection of raised serum levels of vitaminB12 and its association with neoplasms

Antecedentes y objetivo Los niveles elevados de vitaminaB12 se han asociado a enfermedades oncohematológicas. Sin embargo, se desconoce la relevancia de su detección incidental en sujetos sin un diagnóstico previo de cáncer. El objetivo de este estudio es evaluar la relación de la hipercobalaminemia y el diagnóstico de un proceso tumoral y establecer los factores de riesgo. Material y métodos Estudio observacional retrospectivo de una cohorte de pacientes con hipercobalaminemia. Se comparó la incidencia de neoplasias con una cohorte de pacientes con vitaminaB12<1.000pg/ml. Resultados Se seleccionaron 4.800 sujetos con determinaciones de vitaminaB12: 345 (7,1%) presentaban niveles >1.000pg/ml. Se excluyeron 68 (28,4%) por administración exógena, 12 (5%) por datos insuficientes y 15 (3%) por una neoplasia activa, seleccionando 250 pacientes; mediana de seguimiento: 22 (RIQ: 12-39) meses. Se detectó: hepatopatía 59 (23,6%), 44 (18,2%) presentaron cáncer de órgano sólido y 17 (7,1%), hemopatía maligna. El tiempo medio desde la detección de hipercobalaminemia al diagnóstico fue de 10meses. La mediana hasta el diagnóstico fue mayor en el grupo de vitaminaB12 elevada (13 vs 51meses; p<0,001). La hipercobalaminemia (HR_ 11,8; IC95: 2,8-49,6; p=0,001) y el tabaquismo (HR: 4,0; IC95%: 2,15-7,59; p<0,001) resultaron predictores independientes. Conclusiones La detección incidental de niveles séricos de vitaminaB12 >1.000pg/ml es elevada. El diagnóstico de neoplasia órgano sólido y hematológica es frecuente durante el año siguiente de seguimiento, siendo la hipercobalaminemia y el tabaquismo factores predictores de un mayor riesgo de cáncer. (AU)

Background and objective Elevated serum levels of vitaminB12 have been associated with oncohematological diseases. However, the relevance of its incidental detection in subjects without a previous diagnosis of cancer is unknown. The aim of this study was to evaluate the relationship between incidental hypercobalaminemia (vitaminB12 >1000pg/mL) and the diagnosis of a tumor process in patients without a diagnosis and to establish the risk factors. Material and methods Retrospective observational study of a cohort of patients with hypercobalaminemia. The incidence of neoplasms was compared with a cohort of patients with vitaminB12 levels <1000pg/mL. Results Vitamin B12 determinations of 4800 subjects were selected. Of them, 345 (7.1%) had levels >1000pg/ml; 68 (28.4%) were excluded due to exogenous administration, 12 (5%) due to insufficient data, and 15 (3%) due to having an active neoplasia, selecting 250 patients, with a median follow-up of 22 (IQR: 12-39) months. Structural liver disease was detected in 59 (23.6%). 18.2% (44 patients) had solid organ cancer and 17 (7.1%) had malignant hemopathy. The average time from the detection of hypercobalaminemia to the diagnosis of cancer was about 10months. The median until the diagnosis of neoplasia was higher in the high vitaminB12 group (13 vs 51months; P<.001). Hypercobalaminemia (HR: 11.8; 95%CI: 2.8-49.6; P=.001) and smoking (HR: 4.0; 95%CI: 2.15-7.59; P<.001) were independent predictors of neoplasia in the multivariate analysis. Conclusions Incidental detection of serum vitaminB12 levels >1000pg/ml is high in the population. The diagnosis of solid organ and hematological neoplasia is frequent during the following year of follow-up, with hypercobalaminemia and smoking being predictors of a higher risk of cancer. (AU)

Incidental detection of raised serum levels of vitamin B12 and its association with neoplasms.

BACKGROUND AND OBJECTIVES: Elevated serum levels of vitamin B12 have been associated with oncohematological diseases. However, the relevance of its incidental detection in subjects without a previous diagnosis of cancer is unknown. The aim of this study was to evaluate the relationship between incidental hypercobalaminemia (vitamin B12 > 1000 pg/mL) and the diagnosis of a tumor process in patients without a diagnosis and to establish the risk factors. MATERIAL AND METHODS: Retrospective observational study of a cohort of patients with hypercobalaminemia. The incidence of neoplasms was compared with a cohort of patients with vitamin B12 levels <1000 pg/mL. RESULTS: Vitamin B12 determinations of 4800 subjects were selected. Of them, 345 (7.1%) had levels >1000 pg/mL. 68 (28.4%) were excluded due to exogenous administration, 12 (5%) due to insufficient data and 15 (3%) due to having an active neoplasia, selecting 250 patients, with a median follow-up of 22 (IQR 12-39) months. Structural liver disease was detected in 59 (23.6%). 18.2% (44 patients) had solid organ cancer and 17 (7.1%) had malignant hemopathy. The average time from the detection of hypercobalaminemia to the diagnosis of cancer was about 10 months. The median until the diagnosis of neoplasia was higher in the high vitamin B12 group (13 vs. 51 months p < 0.001). Hypercobalaminemia (HR 11.8; 95% CI 2.8-49.6; p = 0.001) and smoking (HR 4.0; 95% CI, 2.15-7.59; p < 0.001) were independent predictors of neoplasia in the multivariate analysis. CONCLUSIONS: Incidental detection of serum vitamin B12 levels >1000 pg/mL is high in the population. The diagnosis of solid organ and hematological neoplasia is frequent during the following year of follow-up, with hypercobalaminemia and smoking being predictors of a higher risk of cancer.

Constructed pine log piles facilitate plant establishment in mining drylands.

Ecological facilitation, though accepted as a main mechanism of plant community assembly, is just starting to be utilized in restoration programmes. Constructing nurse objects that mimic the effect of natural nurse species can be an option to trigger plant nucleation processes in disturbed stressful ecosystems. We hypothesized that arranged log piles might imitate plant facilitation by alleviating abiotic stress and expanding the regeneration niche of beneficiary species, eventually promoting plant establishment, fitness and diversity. With this aim, within a pilot restoration programme in abandoned mining structures in SE Spain where climatic and edaphic stresses concur, we constructed 133 pine log piles from natural wastes generated by local silvicultural activities. We monitored 51 of them plus their adjacent open areas for 15 months, measuring soil temperature, radiation and humidity. We recorded natural seedling establishment, plant nutritional status and heavy metal accumulation. We further performed a seed sowing experiment to investigate how log piles affect plant taxonomic and functional diversity based on 11 establishment and phytostabilization traits. Pine log piles significantly softened microclimatic conditions and accelerated plant establishment in unfertile and metal-polluted mining substrates, simultaneously capturing water, providing shade and pine seeds. Plant communities that naturally established beneath the piles were 15 times denser and five times taxonomically more diverse than those in open areas, despite being skewed towards pine recruitment. Experimental communities sown under log piles were also 1.4 times functionally more diverse, as theory predicts for relaxed abiotic conditions. Log piles improved seedling nutritional status, in terms of P and K content, at the cost of increased metal accumulation. At the landscape scale, nurse objects triggered plant establishment promoting taxonomic and functional diversity in extremely stressful environments. This study exemplifies how soft restoration tools can be based on mechanisms that are widely accepted in the ecological theory.

MODULACIÓN DE LA RESPUESTA ALÉRGICA POR LOS CAROTENOIDES DE LA DIETA / Modulation of the allergic response by dietary carotenoids

Los carotenoides son pigmentos isoprenoides, que están presentes de manera natural y en altas concentraciones en la mayoría de alimentos vegetales, por ejemplo, aguacate (palta), papaya, tomate y zanahoria, pero también se encuentran como aditivos y colorantes en diversos productos cárnicos, aceites vegetales, salsas, aderezos, harinas, entre otros. En los últimos años, varios grupos de investigación han descrito que los carotenoides de la dieta participan en varios procesos fisiopatológicos, incluyendo, la respuesta inmune de tipo alérgico. Las tasas de prevalencia para este tipo de enfermedades se han incrementado de manera alarmante durante las últimas cinco décadas en todo el mundo, y varios factores e hipótesis se han planteado tratando de explicar este fenómeno. Uno de ellos es la hipótesis de la dieta, la cual plantea que la composición de varios micro- y macronutrientes de la alimentación, así como los cambios en los patrones dietarios, serían los responsables de dicho fenómeno. En adición, evidencia epidemiológica y experimental señala que los carotenoides de la dieta participan en la regulación de la inflamación alérgica y, por ello, se postulan como coadyuvantes en la terapia de estos padecimientos. En el presente manuscrito se revisará el estado del arte en relación con los efectos de los carotenoides de la dieta sobre el estado inflamatorio alérgico.(AU)

The carotenoids are isoprenoids pigments, which are naturally present in high concentrations and in most vegetables foods e.g., avocado, papaya, tomato and carrot, but also as additives and dyes found in various meat products, vegetable oils, sauces, dressings, flour, among others. In recent years, several research groups have reported that dietary carotenoids participate in many pathophysiological processes, including the allergic immune response. The prevalence rates for these diseases have increased alarmingly over the past five decades in the world and a number of factors and assumptions have been proposed trying to explain this phenomenon, one of them is the hypothesis of the diet, which has arisen that the composition of several micro and macronutrients of foods, as well as changes in the dietary patterns would be responsible for thisphenomenon.In addition, epidemiological and experimental evidence indicates that dietary carotenoids are involved in the regulation of allergic inflammation and thus postulated as adjuvants in the therapy of these diseases. In this manuscript, we will review the state of art in relation to the effects of dietary carotenoids on the allergic inflammatory state.(AU)

CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8.

Islet transplantation to treat type 1 diabetes has been limited in part by toxicities of current immunosuppression and recipient humoral sensitization. Blockade of the CD28/CD80/86 and CD40/CD154 pathways has shown promise to remedy both these limitations, but translation has been hampered by difficulties in translating CD154-directed therapies. Prior CD40-directed regimens have led to prolonged islet survival, but fail to prevent humoral allosensitization. We therefore evaluated the addition of CTLA4Ig to a CD40 blockade-based regimen in nonhuman primate (NHP) alloislet transplantation. Diabetic rhesus macaques were transplanted allogeneic islets using the CD40-specific antibody 3A8, basiliximab induction, and sirolimus with or without CTLA4Ig maintenance therapy. Allograft survival was determined by fasting blood glucose levels and flow cytometric techniques were used to test for donor-specific antibody (DSA) formation. CTLA4Ig plus 3A8, basiliximab and sirolimus was well tolerated and induced long-term islet allograft survival. The addition of CTLA4Ig prevented DSA formation, but did not facilitate withdrawal of the 3A8-based regimen. Thus, CTLA4Ig combines with a CD40-specific regimen to prevent DSA formation in NHPs, and offers a potentially translatable calcineurin inhibitor-free protocol inclusive of a single investigational agent for use in clinical islet transplantation without relying upon CD154 blockade.

Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates.

Costimulation blockade of the CD40/CD154 pathway has been effective at preventing allograft rejection in numerous transplantation models. This strategy has largely depended on mAbs directed against CD154, limiting the potential for translation due to its association with thromboembolic events. Though targeting CD40 as an alternative to CD154 has been successful at preventing allograft rejection in preclinical models, there have been no reports on the effects of CD40-specific agents in human transplant recipients. This delay in clinical translation may in part be explained by the presence of cellular depletion with many CD40-specific mAbs. As such, the optimal biologic properties of CD40-directed immunotherapy remain to be determined. In this report, we have characterized 3A8, a human CD40-specific mAb and evaluated its efficacy in a rhesus macaque model of islet cell transplantation. Despite partially agonistic properties and the inability to block CD40 binding of soluble CD154 (sCD154) in vitro, 3A8-based therapy markedly prolonged islet allograft survival without depleting B cells. Our results indicate that the allograft-protective effects of CD40-directed costimulation blockade do not require sCD154 blockade, complete antagonism or cellular depletion, and serve to support and guide the continued development of CD40-specific agents for clinical translation.

Experience with a novel efalizumab-based immunosuppressive regimen to facilitate single donor islet cell transplantation.

Islet transplantation is an experimental therapy for selected patients with type 1 diabetes (T1DM). It remains limited by immunosuppressive drug toxicity, progressive loss of insulin independence, allosensitization and the need for multiple islet donors. We describe our experience with an efalizumab-based immunosuppressive regimen as compared to the prevailing standard regimen, the Edmonton protocol. Twelve patients with T1DM received islet transplants: eight were treated with the Edmonton protocol; four were treated with daclizumab induction, a 6-month course of tacrolimus, and maintenance with efalizumab and mycophenolate mofetil. The primary endpoint was insulin independence after one islet infusion. Only two Edmonton protocol treated patients achieved the primary endpoint; six required islets from multiple donors, and all experienced leukopenia, mouth ulcers, anemia, diarrhea and hypertransaminasemia. Four became allosensitized. All patients treated with the efalizumab-based regimen achieved insulin independence with normal hemoglobin A1c after a single islet cell infusion and remained insulin independent while on efalizumab. These patients experienced significantly fewer side effects and none became allosensitized. Trial continuation was terminated by withdrawal of efalizumab from the market. These data suggest that this efalizumab-based regimen prevents islet rejection, is well tolerated, and allows for single donor islet transplantation.

Analysis of body fluid mixtures by mtDNA sequencing: An inter-laboratory study of the GEP-ISFG working group.

The mitochondrial DNA (mtDNA) working group of the GEP-ISFG (Spanish and Portuguese Group of the International Society for Forensic Genetics) carried out an inter-laboratory exercise consisting of the analysis of mtDNA sequencing patterns in mixed stains (saliva/semen and blood/semen). Mixtures were prepared with saliva or blood from a female donor and three different semen dilutions (pure, 1:10 and 1:20) in order to simulate forensic casework. All labs extracted the DNA by preferential lysis and amplified and sequenced the first mtDNA hypervariable region (HVS-I). Autosomal and Y-STR markers were also analysed in order to compare nuclear and mitochondrial results from the same DNA extracts. A mixed stain prepared using semen from a vasectomized individual was also analysed. The results were reasonably consistent among labs for the first fractions but not for the second ones, for which some laboratories reported contamination problems. In the first fractions, both the female and male haplotypes were generally detected in those samples prepared with undiluted semen. In contrast, most of the mixtures prepared with diluted semen only yielded the female haplotype, suggesting that the mtDNA copy number per cell is smaller in semen than in saliva or blood. Although the detection level of the male component decreased in accordance with the degree of semen dilution, it was found that the loss of signal was not consistently uniform throughout each electropherogram. Moreover, differences between mixtures prepared from different donors and different body fluids were also observed. We conclude that the particular characteristics of each mixed stain can deeply influence the interpretation of the mtDNA evidence in forensic mixtures (leading in some cases to false exclusions). In this sense, the implementation of preliminary tests with the aim of identifying the fluids involved in the mixture is an essential tool. In addition, in order to prevent incorrect conclusions in the interpretation of electropherograms we strongly recommend: (i) the use of additional sequencing primers to confirm the sequencing results and (ii) interpreting the results to the light of the phylogenetic perspective.

Aplicación de un análisis estadístico bayesiano objetivo de un modelo de regresión no lineal a la comparación de las proporciones totales degradadas de varios alimentos / Application of an objective statistical Bayesian analysis of a nonlinear regression model to the comparison of total degraded proportions of several foods

En este trabajo se comparan las proporciones totales degradadas en digestiones in vitro de varios alimentos. Para ello, la proporción de un alimento degradada hasta un tiempo t se modela como una función exponencialno linealizable de t y se realiza un análisis estadístico bayesiano objetivo sobre los parámetros que aparecenen el modelo. Estos parámetros tienen unas restricciones naturales que no se procesan adecuadamente conun análisis estadístico frecuentista mientras que un análisis estadístico bayesiano permite no sólo procesarlas adecuadamente como ya se probó en Cano y Salmerón (2007) sino que además permite comparar las curvasde degradación de varios alimentos. Se presenta una aplicación con datos reales. La metodología estadística utilizada para resolver este modelo es adaptable a la resolución de otros modelos similares en los que aparecen parámetros sometidos a ciertas restricciones

In this paper the total degraded proportions of several foods subject to in vitro digestibility are compared. For it, the degraded proportion of a food up to time t is modelled as an exponential non linearizable function of t and for the parameters appearing in the model an objective Bayesian statistical analysis is carried out. These parameters have natural constraints which are not adequately processed with a frequentist statistical analysis while the Bayesian statistical analysis allows not only to adequately process them as was stated in Cano and Salmerón (2007) but it even allows to compare the degradation curves of several foods. An application with realdata is presented. The statistical methodology we have used to solve this model can be adapted to solve similar models involving parameters subject to certain constraints

Identification of mimotopes of platelet autoantigens associated with autoimmune thrombocytopenic purpura.

GPIIb/IIIa, the human platelet glycoprotein complex, is the autoantigen most commonly recognized by autoantibodies in autoimmune thrombocytopenic purpura (AITP). Two murine monoclonal antibodies (mAbs), namely Y2/51 and 5B12, directed against gpIIIa and gpIIb/IIIa, respectively, and rabbit anti-human platelet polyclonal antibodies have been used to select AITP-related epitopes from a phage display peptide library expressing random dodecapeptides in the pIII coat protein of M13 phage. The selected phage clones were tested by ELISA for binding to rabbit anti-human platelet antibodies as well as to sera from AITP patients. Seven clones reacted strongly with rabbit anti-human platelet antibodies, and four clones reacted with sera from AITP patients. Some homology between peptide inserts sequences of selected clones and human platelet gpIIIa and gpIb were found.