Quantifying intra-tumoral genetic heterogeneity of glioblastoma toward precision medicine using MRI and a data-inclusive machine learning algorithm.

BACKGROUND AND OBJECTIVE: Glioblastoma (GBM) is one of the most aggressive and lethal human cancers. Intra-tumoral genetic heterogeneity poses a significant challenge for treatment. Biopsy is invasive, which motivates the development of non-invasive, MRI-based machine learning (ML) models to quantify intra-tumoral genetic heterogeneity for each patient. This capability holds great promise for enabling better therapeutic selection to improve patient outcome. METHODS: We proposed a novel Weakly Supervised Ordinal Support Vector Machine (WSO-SVM) to predict regional genetic alteration status within each GBM tumor using MRI. WSO-SVM was applied to a unique dataset of 318 image-localized biopsies with spatially matched multiparametric MRI from 74 GBM patients. The model was trained to predict the regional genetic alteration of three GBM driver genes (EGFR, PDGFRA and PTEN) based on features extracted from the corresponding region of five MRI contrast images. For comparison, a variety of existing ML algorithms were also applied. Classification accuracy of each gene were compared between the different algorithms. The SHapley Additive exPlanations (SHAP) method was further applied to compute contribution scores of different contrast images. Finally, the trained WSO-SVM was used to generate prediction maps within the tumoral area of each patient to help visualize the intra-tumoral genetic heterogeneity. RESULTS: WSO-SVM achieved 0.80 accuracy, 0.79 sensitivity, and 0.81 specificity for classifying EGFR; 0.71 accuracy, 0.70 sensitivity, and 0.72 specificity for classifying PDGFRA; 0.80 accuracy, 0.78 sensitivity, and 0.83 specificity for classifying PTEN; these results significantly outperformed the existing ML algorithms. Using SHAP, we found that the relative contributions of the five contrast images differ between genes, which are consistent with findings in the literature. The prediction maps revealed extensive intra-tumoral region-to-region heterogeneity within each individual tumor in terms of the alteration status of the three genes. CONCLUSIONS: This study demonstrated the feasibility of using MRI and WSO-SVM to enable non-invasive prediction of intra-tumoral regional genetic alteration for each GBM patient, which can inform future adaptive therapies for individualized oncology.

Image-localized biopsy mapping of brain tumor heterogeneity: A single-center study protocol.

Brain cancers pose a novel set of difficulties due to the limited accessibility of human brain tumor tissue. For this reason, clinical decision-making relies heavily on MR imaging interpretation, yet the mapping between MRI features and underlying biology remains ambiguous. Standard (clinical) tissue sampling fails to capture the full heterogeneity of the disease. Biopsies are required to obtain a pathological diagnosis and are predominantly taken from the tumor core, which often has different traits to the surrounding invasive tumor that typically leads to recurrent disease. One approach to solving this issue is to characterize the spatial heterogeneity of molecular, genetic, and cellular features of glioma through the intraoperative collection of multiple image-localized biopsy samples paired with multi-parametric MRIs. We have adopted this approach and are currently actively enrolling patients for our 'Image-Based Mapping of Brain Tumors' study. Patients are eligible for this research study (IRB #16-002424) if they are 18 years or older and undergoing surgical intervention for a brain lesion. Once identified, candidate patients receive dynamic susceptibility contrast (DSC) perfusion MRI and diffusion tensor imaging (DTI), in addition to standard sequences (T1, T1Gd, T2, T2-FLAIR) at their presurgical scan. During surgery, sample anatomical locations are tracked using neuronavigation. The collected specimens from this research study are used to capture the intra-tumoral heterogeneity across brain tumors including quantification of genetic aberrations through whole-exome and RNA sequencing as well as other tissue analysis techniques. To date, these data (made available through a public portal) have been used to generate, test, and validate predictive regional maps of the spatial distribution of tumor cell density and/or treatment-related key genetic marker status to identify biopsy and/or treatment targets based on insight from the entire tumor makeup. This type of methodology, when delivered within clinically feasible time frames, has the potential to further inform medical decision-making by improving surgical intervention, radiation, and targeted drug therapy for patients with glioma.

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

Image-based models of T-cell distribution identify a clinically meaningful response to a dendritic cell vaccine in patients with glioblastoma.

BACKGROUND: Glioblastoma is an extraordinarily heterogeneous tumor, yet the current treatment paradigm is a "one size fits all" approach. Hundreds of glioblastoma clinical trials have been deemed failures because they did not extend median survival, but these cohorts are comprised of patients with diverse tumors. Current methods of assessing treatment efficacy fail to fully account for this heterogeneity. METHODS: Using an image-based modeling approach, we predicted T-cell abundance from serial MRIs of patients enrolled in the dendritic cell (DC) vaccine clinical trial. T-cell predictions were quantified in both the contrast-enhancing and non-enhancing regions of the imageable tumor, and changes over time were assessed. RESULTS: A subset of patients in a DC vaccine clinical trial, who had previously gone undetected, were identified as treatment responsive and benefited from prolonged survival. A mere two months after initial vaccine administration, responsive patients had a decrease in model-predicted T-cells within the contrast-enhancing region, with a simultaneous increase in the T2/FLAIR region. CONCLUSIONS: In a field that has yet to see breakthrough therapies, these results highlight the value of machine learning in enhancing clinical trial assessment, improving our ability to prospectively prognosticate patient outcomes, and advancing the pursuit towards individualized medicine.

Antlions of formerly recognized tribe Gnopholeontini (Neuroptera: Myrmeleontidae: Brachynemurini) from Peninsula of Baja California, with a new species of Tyttholeon Adams

ABSTRACT A new antlion species, Tyttholeon froehlichi Tavares, Marquez and Contreras sp. n., is described from the Baja California Peninsula, Mexico, an area biogeographically significant for its high number of endemic species. Previously monotypic, Tyttholeon Adams now comprises two Nearctic species. Three of the four genera within the formerly recognized tribe Gnopholeontini and their respective species, all present in the Peninsula of Baja California (Gnopholeon barberi Currie, G. delicatulus Currie, G. zapotecus Stange, Menkeleon bellulus Banks, and Tyttholeon puerilis Adams), are herein diagnosed, illustrated, and have their distribution updated and analyzed. A taxonomic key is provided for Tyttholeon.

Personalized paroxysmal atrial fibrillation ablation by tailoring ablation index to the left atrial wall thickness: the 'Ablate by-LAW' single-centre study-a pilot study.

AIMS: To determine if adapting the ablation index (AI) to the left atrial wall thickness (LAWT), which is a determinant of lesion transmurality, is feasible, effective, and safe during paroxysmal atrial fibrillation (PAF) ablation. METHODS AND RESULTS: Consecutive patients referred for PAF first ablation. Left atrial wall thickness three-dimensional maps were obtained from multidetector computed tomography and integrated into the CARTO navigation system. Left atrial wall thickness was categorized into 1 mm layers and AI was titrated to the LAWT. The ablation line was personalized to avoid thicker regions. Primary endpoints were acute efficacy and safety, and freedom from atrial fibrillation (AF) recurrences. Follow-up (FU) was scheduled at 1, 3, 6, and every 6 months thereafter. Ninety patients [60 (67%) male, age 58 ± 13 years] were included. Mean LAWT was 1.25 ± 0.62 mm. Mean AI was 366 ± 26 on the right pulmonary veins with a first-pass isolation in 84 (93%) patients and 380 ± 42 on the left pulmonary veins with first-pass in 87 (97%). Procedure time was 59 min (49-66); radiofrequency (RF) time 14 min (12.5-16); and fluoroscopy time 0.7 min (0.5-1.4). No major complication occurred. Eighty-four out of 90 (93.3%) patients were free of recurrence after a mean FU of 16 ± 4 months. CONCLUSION: Personalized AF ablation, adapting the AI to LAWT allowed pulmonary vein isolation with low RF delivery, fluoroscopy, and procedure time while obtaining a high rate of first-pass isolation, in this patient population. Freedom from AF recurrences was as high as in more demanding ablation protocols. A multicentre trial is ongoing to evaluate reproducibility of these results.

Very low prevalence of ultrasound-detected tenosynovial abnormalities in healthy subjects throughout the age range: OMERACT ultrasound minimal disease study.

OBJECTIVES: This study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range. METHODS: Adult HS (age 18-80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1-5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort. RESULTS: 939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups. CONCLUSIONS: Ultrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.

Left atrial wall thickness of the pulmonary vein reconnection sites during atrial fibrillation redo procedures.

BACKGROUND: Left atrial wall thickness (LAWT) has been related to pulmonary vein (PV) reconnections after atrial fibrillation (AF) ablation. The aim was to integrate 3D-LAWT maps in the navigation system and analyze the relationship with local reconnection sites during AF-redo procedures. METHODS: Consecutive patients referred for AF-redo ablation were included. Procedure was performed using a single catheter technique. LAWT maps obtained from multidetector computerized tomography (MDCT) were imported into the navigation system. LAWT of the circumferential PV line, the reconnected segment and the reconnected point, were analyzed. RESULTS: Sixty patients [44 (73%) male, age 61 ± 10 years] were included. All reconnected veins were isolated using a single catheter technique with 55 min (IQR 47-67) procedure time and 75 s (IQR 50-120) fluoroscopy time. Mean LAWT of the circumferential PV line was 1.46 ± 0.22 mm. The reconnected segment was thicker than the rest of segments of the circumferential PV line (2.05 + 0.86 vs. 1.47 + 0.76, p < .001 for the LPVs; 1.55 + 0.57 vs. 1.27 + 0.57, p < .001 for the RPVs). Mean reconnection point wall thickness (WT) was at the 82nd percentile of the circumferential line in the LPVs and at the 82nd percentile in the RPVs. CONCLUSION: A single catheter technique is feasible and efficient for AF-redo procedures. Integrating the 3D-LAWT map into the navigation system allows a direct periprocedural estimation of the WT at any point of the LA. Reconnection points were more frequently present in thicker segments of the PV line. The use of 3D-LAWT maps can facilitate reconnection point identification during AF-redo ablation.

Days gained response discriminates treatment response in patients with recurrent glioblastoma receiving bevacizumab-based therapies.

BACKGROUND: Accurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze days gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies. METHODS: DG response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N = 62). Kaplan-Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM. RESULTS: In patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan-Meier analysis showed significant differences in OS and PFS at DG cutoffs consistent with previously identified values from newly diagnosed GBM using T1-weighted gadolinium-enhanced magnetic resonance imaging (T1Gd). DG scores for bevacizumab monotherapy patients only approached significance for PFS. Cox regression showed that increases of 25 DG on T1Gd imaging were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy patients. CONCLUSION: DG has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

Sex-specific impact of patterns of imageable tumor growth on survival of primary glioblastoma patients.

BACKGROUND: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. METHODS: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). RESULTS: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR = 1.027, p = 0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR = 1.011, p < 0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p = 0.010 t-test), but tumor size was not correlated with female overall survival (p = 0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p = 0.004, F p = 0.001, t-test). CONCLUSION: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Protocolo de rehabilitación multimodal en pacientes sometidos a cirugía electiva del tracto gastrointestinal. Estudio prospectivo comparativo multicéntrico / Multimodal rehabilitation protocol in patients undergoing elective surgery of the gastrointestinal tract. Prospective multicentre comparative study

Los protocolos de rehabilitación multimodal están diseñados para minimizar la disfunción de órganos y lograr la recuperación acelerada en el postoperatorio. Objetivo General: Determinar si la aplicación del protocolo de rehabilitación multimodal favorece la recuperación acelerada en pacientes quirúrgicos electivos en comparación con el manejo tradicional. Metodología: Se realizó un estudio multicéntrico aleatorizado con la participación de cuatro hospitales en diferentes regiones del país. La investigación fue de tipo prospectivo de corte longitudinal, comparativo, donde los pacientes fueron asignados al azar, un grupo estudio (n=142) a quienes se les aplicó el protocolo y un grupo control (n=100) manejados de acuerdo con conductas tradicionales. Resultados: La estancia hospitalaria para el grupo estudio fue de 1,8 ± 1,2 días, mientras que para el grupo control fue de 6,3 ± 3,87 días (p < 0,05). En cuanto a las complicaciones post operatorias el 88,7% de los pacientes del grupo estudio evolucionaron favorablemente y 11,26% presentaron complicaciones menores, mientras que 30% de los pacientes del grupo control presentaron complicaciones tales como infección de sitio quirúrgico 13%, dehiscencia de anastomosis 5% y vómitos 12% (p < 0,05). Conclusión: Con la aplicación del protocolo de rehabilitación multimodal se logró que la tasa de complicaciones fuera significativamente menor en el grupo estudio al compararla con el grupo control, por ello se sugiere la aplicación del mismo dentro de las realidades de nuestros hospitales, además de ser una excelente herramienta para lograr una recuperación más temprana en el post operatorio y disminuir la estancia hospitalaria(AU)

The multimodal rehabilitation protocols are designed to minimize organ dysfunction in the postoperative period and achieve accelerated postoperative recovery. General Objective: To determine whether the application of multimodal rehabilitations protocols promotes rapid recovery in elective surgical patients compared with traditional management. Methodology: A multicenter randomized involving four hospitals in different regions of the country study was conducted. The research was prospective, longitudinal, comparative court, patients were randomized in study group (n = 142) who applied the protocol and a control group (n = 100) managed according to traditional behaviors. Results: The hospital stay for the study group was 1.8 ± 1.2 days, while the control group the average was 6.3 ± 3.87 days (p < 0.05). Regarding postoperative complications, 88.7% of the study group patients evolved favorably and 11.26% presented minor complications, while 30% of the control group patients presented complications such as surgical site infection 13%, anastomotic dehiscence 5 % and vomiting 12% (p < 0.05).Conclusion: With the application of the multimodal rehabilitation protocol, it was achieved that the rate of complications was significantly lower in the study group when compared with the control group, therefore it is suggested to apply it within the realities of our hospitals, in addition to being an excellent tool to achieve an earlier recovery in the postoperative period and reduce hospital stay(AU)

Longterm Safety and Efficacy of Subcutaneous Abatacept in Patients with Rheumatoid Arthritis: 5-year Results from a Phase IIIb Trial.

OBJECTIVE: To assess 5-year safety, tolerability, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA). METHODS: The Abatacept Comparison of sub[QU]cutaneous versus intravenous in Inadequate Responders to methotrexatE (ACQUIRE) phase IIIb, randomized, double-dummy, multinational trial compared efficacy and safety of SC and intravenous (IV) ABA in patients with RA. In the initial 6-month double-blind (DB) period, patients received IV or SC ABA, plus MTX, and in the subsequent open-label longterm extension (LTE) period, all patients received SC ABA (125 mg/wk). The final 5-year safety, tolerability, and efficacy analyses are reported. RESULTS: Of 1385 patients who completed the DB period, 1372 entered LTE and 945 (68.8%) completed ≥ 5 years of treatment. During LTE, 97 (7.1%) patients discontinued treatment because of an adverse event (AE). Incidence rate (IR; event/100 patient-yrs of exposure; based on LTE data, 95% CI) for AE of interest were the following: serious AE 7.73 (6.96-8.58), infection 38.60 (36.24-41.12), serious infection 1.68 (1.35-2.07), malignancies 1.09 (0.84-1.42), and autoimmune disorders 1.33 (1.05-1.69), and were stable over time. No association between immunogenicity and either worsening of ABA safety or loss of efficacy was noted. Efficacy in the LTE was consistent with the DB period and was maintained to the end of the study. CONCLUSION: These 5-year data establish that SC ABA (125 mg/wk) has a consistent safety profile and durable efficacy for longterm treatment of patients with RA who had an inadequate response to MTX.

Distinct Phenotypic Clusters of Glioblastoma Growth and Response Kinetics Predict Survival.

PURPOSE: Despite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype-growth before treatment and during each treatment to recurrence -has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK. PATIENTS AND METHODS: From our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment. RESULTS: There was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%). CONCLUSION: Dichotomizing the heterogeneity of GBMs into two populations-one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival-suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.

Plasma B-type natriuretic peptide levels are poorly related to the occurrence of ischemia or ventricular arrhythmias during symptom-limited exercise in low-risk patients.

INTRODUCTION: The usefulness of B-type natriuretic peptide (BNP) as a marker of ischemia is controversial. BNP levels have predicted arrhythmias in various settings, but it is unknown whether they are related to exercise-induced ischemic ventricular arrhythmias. MATERIAL AND METHODS: We analyzed in 63 patients (64 ±14 years, 65% male, 62% with known coronary disease) undergoing exercise stress single-photon emission computed tomography (SPECT) the association between plasma BNP values (before and 15 min after exercise) and the occurrence of ischemia or ventricular arrhythmias during the test. RESULTS: Exercise test (8.1 ±2.7 min, 7.4 ±8.1 metabolic equivalents, 82 ±12% of maximal predicted heart rate) induced reversible perfusion defects in 23 (36%) patients. Eight (13%) patients presented significant arrhythmias (≥ 7 ventricular premature complexes/min, couplets, or non-sustained ventricular tachycardia during exercise or in the first minute of recovery). Median baseline BNP levels were 17.5 (12.4-66.4) pg/ml in patients developing scintigraphic ischemia and 45.6 (13.2-107.4) pg/ml in those without ischemia (p = 0.137). The BNP levels increased after exercise (34.4 (15.3-65.4)% increment over baseline, p < 0.001), but the magnitude of this increase was not related to SPECT positivity (35.7 (18.8-65.4)% vs. 27.9 (5.6-64.0)% in patients with and without ischemia, respectively, p = 0.304). No significant association was found between BNP values (at baseline or their change during the test) and ventricular arrhythmias. CONCLUSIONS: Plasma BNP values - at baseline or after exercise - were not associated with myocardial ischemia or with ventricular arrhythmia during exercise SPECT. These results highlight the limited usefulness of this biomarker to assess acute ischemia.

Restitución intestinal precoz para el manejo integral de pacientes sometidos a ostomía derivativa / Early intestinal restitution for integral management of patients undergoing derivative ostomy

Analizar la factibilidad de la generalización de este procedimiento y las ventajas del mismo. Métodos:Se realizó un estudio descriptivo, retrospectivo y transversal, en el cual se incluyeron 6 pacientes entre 28 y 76 años, con enfermedad de Fournier por distintas etiologías, aparte, algunos con comorbilidades, intervenidos en el Servicio de Cirugía del Hospital Luis Razetti, desde junio de 2013 hasta junio de 2015. El procedimiento consiste en la restitución precoz posterior a una colostomía protectora por una lesión en la región genitoperineal resuelta. El tiempo promedio dela restitución fue de 18 días. Resultados:Seis pacientes con una media de 50 años, 83% masculino y 17% femenino. Antecedentes quirúrgicos de lesiones genitoperineales por distintas causas. Del total de pacientes el 50% padecían DM II; 83,3% presentaron cultivos positivos. Se tomó en cuenta la albúmina sérica para la anastomosis la cual fue término terminal en todos los pacientes. En el 50% de los pacientes se dejó abierta la herida de la piel para un cierre por segunda intención, ya que la principal complicación fue infección del sitio quirúrgico, un 17% de complicaciones crónicas.El tiempo promedio fue de 70 minutos en la primera cirugía y 80 minutos la cirugía definitiva. Se inició la vía oral en el 50% de los pacientes dentro de las primeras 72 horas. Conclusión:La restitución intestinal precoz se considera un procedimiento quirúrgico simple, sin embargo es una intervención relacionada con elevada morbilidad, más aun cuando existen comorbilidades como la diabetes mellitus(AU)

To analyze the feasibility of the generalization of this procedure and its advantages. Methods:We conducted a descriptive, retrospective and transversal study, which included 6 patients between 28 and 76 years, with Fournier disease by different etiologies, aside, some with comorbidities, operated in the Service of Surgery of the Hospital Luis Razetti, from June 2013 until June 2015. The procedure consists of early return back to a protective colostomy by a lesion in the resolute perineal genital region. The average time of the refund was 18 days. Results:Six patients with an average of 50 years, 83% male and 17% female. There was a surgical history of perineal genital injuries for various reasons. Of the total of patients 50% had DM II; 83.3% were positive. It took into account the serum albumin for anastomosis, which was end to end in all patients. In 50% of patients the skin for a close wound left open by second intention, since the main complication was infection of the surgical site, 17% of chronic complications. The average time was 70 minutes in the first surgery and 80 minutes definitive surgery. It was started the oral route in 50% of patients within 72 hours. Conclusion:Early intestinal restitution is considered a simple surgical procedure; it is however an intervention associated with high morbidity, even more so when there are comorbidities such as diabetes mellitus(AU)

Effect of nesting environment on incubation temperature and hatching success of Morelet's crocodile (Crocodylus moreletii) in an urban lake of Southeastern Mexico.

Incubation temperature is an important aspect in terms of biological performance among crocodiles, and several controlled experiments have demonstrated a significant relationship between incubation temperature, success in hatching and survival of hatchlings. However, a few studies have tested these relationships in the wild. The objective of this study was to determine the relationship of nest characteristics and environment (hatch year, nest basal area and height, clutch size, distance to shore line, and vegetation cover), to incubation temperature and hatching success among Morelet's crocodile (Crocodylus moreletii). The study was carried out during the nesting seasons of Morelet's crocodile, from 2007 to 2009 in the Laguna de Las Ilusiones, an urban lake located in Villahermosa, Tabasco, Mexico. We physically characterized 18 nests and inserted a temperature data logger in each nest chamber. At the end of the nesting season and prior to hatching, we recovered the crocodile eggs and data loggers and calculated hatching success, under laboratory conditions. We related the environmental variables of the nest with the mean and fluctuation (standard deviation) of nest temperature, using linear models. We also related the environmental variables affecting the nest, to mean nest temperature and fluctuation in incubation temperature and to hatching success, using linear models. Although we found differences in incubation temperature between nests, mean incubation temperature did not differ between years, but there were differences in nest thermal fluctuation between years. The mean incubation temperature for 11 nests (61.1%) was lower than the suggested Female-Male pivotal temperature (producing 50% of each sex) for this species, and all hatchlings obtained were males. There were no differences in clutch size between years, but hatching success varied. Our study indicates that hatching success depends on certain environmental variables and nest conditions to which the eggs are subjected, including season, nest size and clutch size. We also discuss the importance of the fluctuation of incubation temperature on hatching success and sex determination.

Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy. METHODS: Patients taking MTX were randomized (1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS). RESULTS: In this study, 918 patients were randomized and received ≥1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P = 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P = 0.25 and P = 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (≥140/90 mm Hg) occurred at ≥1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group. CONCLUSION: With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at 24 weeks, whereas a significant difference in the SHS was not seen. The overall level of response to treatment with fostamatinib was lower than had been observed in the phase II program, but similar adverse events were reported.

Rediscovery of an endemic vertebrate from the remote Islas Revillagigedo in the eastern Pacific Ocean: the Clarión nightsnake lost and found.

Vertebrates are currently going extinct at an alarming rate, largely because of habitat loss, global warming, infectious diseases, and human introductions. Island ecosystems are particularly vulnerable to invasive species and other ecological disturbances. Properly documenting historic and current species distributions is critical for quantifying extinction events. Museum specimens, field notes, and other archived materials from historical expeditions are essential for documenting recent changes in biodiversity. The Islas Revillagigedo are a remote group of four islands, 700-1100 km off the western coast of mainland México. The islands are home to many endemic plants and animals recognized at the specific- and subspecific-levels, several of which are currently threatened or have already gone extinct. Here, we recount the initial discovery of an endemic snake Hypsiglena ochrorhyncha unaocularus Tanner on Isla Clarión, the later dismissal of its existence, its absence from decades of field surveys, our recent rediscovery, and recognition of it as a distinct species. We collected two novel complete mitochondrial (mt) DNA genomes and up to 2800 base-pairs of mtDNA from several other individuals, aligned these with previously published mt-genome data from samples throughout the range of Hypsiglena, and conducted phylogenetic analyses to infer the biogeographic origin and taxonomic status of this population. We found the Isla Clarión population to be most closely related to populations in the Sonora-Sinaloa state border area of mainland México and Isla Santa Catalina, in the Gulf of California. Based on genetics, morphology, and geographic distributions, we also recognize these two other lineages as distinct species. Our study shows the importance of museum specimens, field notes, and careful surveys to accurately document biodiversity and brings these island endemics (Clarión and Santa Catalina nightsnakes) and mainland population near the Sonora-Sinaloa state border to the attention of conservation biologists currently monitoring biodiversity in these fragile subtropical ecosystems.

Subcutaneous abatacept for the treatment of rheumatoid arthritis: longterm data from the ACQUIRE trial.

OBJECTIVE: Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA). METHODS: The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (∼3.5 yrs of exposure) are reported. RESULTS: Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8-44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA. CONCLUSION: These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).