Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

ß-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain.

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify ß-hydroxybutyrate (ßHB), a ketone body, as a regulator of protein solubility in the aging brain. ßHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate ßHB-induced protein insolubility across in vitro, ex vivo, and in vivo mouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brain in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-ß, and exogenous ßHB ameliorates pathology in nematode models of amyloid-ß aggregation toxicity. We have generated a comprehensive atlas of the ßHB-induced protein insolublome ex vivo and in vivo using mass spectrometry proteomics, and have identified common protein domains within ßHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among ßHB targets and the clearance of these targets from mouse brain, likely via ßHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.

Resilience as a Buffering Variable Between the Big Five Components and Factors and Symptoms of Academic Stress at University.

The aim of this cross-sectional study was to establish predictive relationships of the Big Five personality factors (according to their self-regulatory level), together with resilience (proactive and reactive factors), for factors and symptoms of academic stress related to teaching and learning in the University context. A total of 405 female undergraduate students were selected, and completed questionnaires that had been previously validated in Spanish University students (Big Five personality factors, resilience, and academic stress symptoms and factors). A linear, ex-post facto design was used, including linear regression, Structural Equation Modeling (SEM), and mediational analyses. Specific linear regression showed the expected gradation: that self-regulatory personality factors (conscientiousness, extraversion) were positive linear predictors of proactive resilience, as well as significant negative predictors of stress factors and symptoms of academic stress; while the non-regulatory personality factors (openness to experience, agreeableness) showed little relationship. By contrast, the dysregulatory personality factor (neuroticism) was a negative predictor of proactive resilience, a positive predictor of reactive resilience, and positively predicted academic stress factors in the teaching and learning process, as well as stress symptoms. SEM general analysis showed that personality factors positively predicted resilience, and resilience negatively predicted factors and symptoms of academic stress. Specific mediational model analysis, with each personality factor, confirmed the different mediating relationships that appeared in the linear regression analyses. These results are discussed from the perspective of promoting resilience and healthy personalities in the University context. Implications for addressing academic stress at University are discussed.

Feasibility, tolerability, and safety of hysterosalpingo-foam sonography (hyfosy). multicenter, prospective Spanish study.

OBJECTIVE: To determine the feasibility,tolerability, and safety of the ultrasound assessment of tubal patency using foam as contrast. METHODS: This was a prospective multicenter study of 915 infertile nulliparous women scheduled for sonohysterosalpingography with foam instillation (HYFOSY) for tubal patency testing as a part of the fertility workup. Clinical and sonographic data were recorded into a web-shared database. Tubal patency, cervical catheterization, pain during the procedure and post-procedural complications were collected. Patients reported discomfort or pain experienced during the procedure with a visual analogue scale (VAS) score. RESULTS: Nine hundred fifteen women were included in the final analysis. Median age was 34 (range, 21-45) years and median body mass index was 23 (range, 16-41) kg/m2. Of 839 women, only 8(0.95 %) cases were abandoned due to impossibility of introducing the intracervical catheter. Most of the cervical os were easily cannulated with either paediatric nasogastric probes or special catheter for intrauterine insemination / sonohysterosalpingography 688/914(75.3 %). With a median instillation of 4 mL (range 1-16) of foam, both tubes were identified in 649/875 (70.9 %) patients, while unilateral patency was observed in 190/875 (20.8 %). Only 36/875 (3.9 %) of the women had bilateral tubal obstruction. The median VAS score for perception of pain during HyFoSy examination was 2 (range 0-10), and only 17 (1.9 %) of women reported severe pain (VAS ≥ 7). Pain was unrelated to tubal patency or tubal blockage. Unexpectedly, difficult cervical catheterizations that needed tenaculum, were more likely associated with mild pain during procedure [nasogastric probe group 176/289 (70.9 %) vs. insemination catheter group 166/399 (41.6 %) vs. tenaculum group 190/218(87.2 %) p < 0.001]. Finally, among 915 patients, we only noticed 3 (0.32 %) complications of the technique: two vasovagal episodes and a mild urinary infection. CONCLUSION: HYFOSY is a feasible, well-tolerated and safe technique for the evaluation of tubal patency in infertile women.

A multi-inverse approach for a holistic understanding of applied animal science systems.

Technological and mathematical advances have provided opportunities to investigate new approaches for the holistic quantification of complex biological systems. One objective of these approaches, including the multi-inverse deterministic approach proposed in this paper, is to deepen the understanding of biological systems through the structural development of a useful, best-fitted inverse mechanistic model. The objective of the present work was to evaluate the capacity of a deterministic approach, that is, the multi-inverse approach (MIA), to yield meaningful quantitative nutritional information. To this end, a case study addressing the effect of diet composition on sheep weight was performed using data from a previous experiment on saccharina (a sugarcane byproduct), and an inverse deterministic model (named Paracoa) was developed. The MIA successfully revealed an increase in the final weight of sheep with an increase in the percentage of corn in the diet. Although the soluble fraction also increased with increasing corn percentage, the effective nonsoluble degradation increased fourfold, indicating that the increased weight gain resulted from the nonsoluble substrate. A profile likelihood analysis showed that the potential best-fitted model had identifiable parameters, and that the parameter relationships were affected by the type of data, number of parameters and model structure. It is necessary to apply the MIA to larger and/or more complex datasets to obtain a clearer understanding of its potential.

Ki67 Labelling Index of Neoplastic Epithelial Cells Differentiates Canine Acanthomatous Ameloblastoma from Oral Squamous Cell Carcinoma.

Canine acanthomatous ameloblastoma (CAA) and oral squamous cell carcinoma (OSCC) are the most common oral tumours of epithelial origin in dogs. Overlapping clinical, radiographical and histological features can make distinction between CAA and OSCC difficult. The ability to distinguish tumour identity is critical due to their different biological behaviour and recommended treatment modalities, as well as respective comparative and translational applications as potential models of human disease. Based on marked differences in biological behaviour (i.e. benign versus malignant), it is reasonable to predict that the tumour cell proliferation activity is lower in CAA than in OSCC. However, to our knowledge, the epithelial cell proliferation activity of CAA has not been studied or compared with that of OSCC. Therefore, the aims of this study were to (1) compare the neoplastic epithelial cell proliferation activity of CAA and OSCC based on conventional mitotic index (MI) and Ki67 labelling index (LI), and (2) correlate these findings with clinical parameters including patient signalment, anatomical tumour location and degree of local invasion at the time of diagnosis as determined by computed tomography. We found that (1) the Ki67 LI of OSSC (n = 14) was significantly higher than that of CAA (n = 25), (2) the Ki67 LI correlated with a more aggressive locally invasive behaviour, and (3) the MI was not associated with tumour type. We conclude that the Ki67 LI, but not the MI, is a useful differential marker of CAA from OSCC, and that the epithelial cell proliferation activities of OSCC and CAA correlate with their known differences in biological behaviour.

Lipid profile of cerebrospinal fluid in multiple sclerosis patients: a potential tool for diagnosis.

Multiple sclerosis (MS) is a complex multifactorial neuropathology. Although its etiology remains unclear, it has been demonstrated that the immune system attacks myelin, leading to demyelination and axonal damage. The involvement of lipids as one of the main components of myelin sheaths in MS and other demyelinating diseases has been postulated. However, it is still a matter of debate whether specific alteration patterns exist over the disease course. Here, using a lipidomic approach, we demonstrated that, at the time of diagnosis, the cerebrospinal fluid of MS patients presented differences in 155 lipid species, 47 of which were identified. An initial hierarchical clusterization was used to classify MS patients based on the presence of 25 lipids. When a supervised method was applied in order to refine this classification, a lipidomic signature was obtained. This signature was composed of 15 molecules belonging to five different lipid families including fatty acids (FAs). An FA-targeted approach revealed differences in two members of this family: 18:3n3 and 20:0 (arachidic acid). These results reveal a CSF lipidomic signature in MS patients at the time of diagnosis that might be considered as a potential diagnostic tool.

Emerging from gastroesophageal reflux (EMERGE): an Italian survey - I the viewpoint of the gastroenterologist.

Gastroesophageal reflux disease (GERD) is defined as a "disease that develops when the reflux of stomach contents induces troublesome symptoms and/or complications". From a therapeutic point of view, many options have been proposed, including proton pump inhibitors (PPI), antihistamines (H2- receptor antagonists), antacid chemical compounds, antireflux barrier (using alginates), prokinetics, inhibitors of gastric sphincters, protection of mucosal tissue, neuromodulators, nociceptor antagonists, lifestyle modification, and surgery. A new medical compound has been recently launched in Italy: Marial® (manufactured by Aurora, Milan, Italy) containing magnesium alginate and E-Gastryal®. The aim of this survey was to analyse the patients' characteristics and the prescriptive approach considering both the past or current treatments and clinical features during a visit in 56 gastroenterological centers, distributed in the whole of Italy. One thousand eight hundred forty-nine patients (46.5% males, and 53.5% females, mean age 48.59 years) were visited. Patients with positive reflux symptoms index (RSI+) had higher GIS scores than RSI- subjects. PPIs (both as monotherapy or plus add-on) were the most common medication prescribed before the visit. There was a significant change of prescription to Marial® at the visit. More precisely,, Marial® was preferentially prescribed to about a quarter of the patients, particularly to those with lower GIS score, whereas PPI plus add-on option was preferred for patients with higher GIS score. In conclusion, the current experience demonstrated that GERD may be managed considering a patient-centred work-up by using the GIS questionnaire. GIS score may be able to define the medication choice that includes also the new medical compound Marial®.

Emerging from gastroesophageal reflux (EMERGE): An Italian survey - II the viewpoint of the patient.

Gastroesophageal reflux disease (GERD) is a very common disease, as about a quarter of the Western population has GERD symptoms at least weekly and GERD is the most frequent reason for outpatient gastroenterology consultation. GERD treatment is based on proton pump inhibitor (PPI) use, but PPI may be ineffective in some patients and potentially unsafe if administered for very long time. A new medical compound (Marial®) has been introduced on the Italian market. This product contains magnesium alginate and a phytopolymer: it may be able to repair ulcer/erosion, protect mucosal tissue, and contrast acid contents. The current survey was conducted on a large group of GERD patients visited at 56 Italian gastroenterological offices. Patients were treated with PPI alone, PPI plus add-on, or Marial® for 4 weeks: the choice was decided by each gastroenterologist on the basis of the best practice criterion. A reflux symptoms index (RSI) questionnaire was used to weekly assess the clinical features. Marial® and PPI plus add-on significantly reduced RSI scores, from the second week. Noteworthy, Marial® was more effective than PPI plus add-on. In conclusion, the current survey demonstrated that patients with GERD perceived a significant improvement of GERD symptoms measured by the RSI questionnaire. Marial® was as effective as PPI plus add-on.

Correlation between the reflux finding score and the GERD impact scale in patients with gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a very common disorder. As there is no gold standard diagnostic tool, patient-based strategy is adopted in clinical practice. In this regard, there are questionnaires able to easily and rapidly assess symptom severity directly by the patient. The GERD Impact Scale (GIS) and the Reflux Symptom Index (RSI) have been validated as diagnostic tools in routine clinical care. The present study aimed to correlate RIS values with GIS scores in a large cohort of GERD patients visited at gastroenterological clinics. Globally, 785 subjects (51.2% males, 48.8% females, mean age: 49.59 years) were visited in 56 Italian gastroenterological offices. The current study demonstrates that a GIS value >19 may be a reliable cut-off to define the positivity of the test, and GIS and RSI were significantly correlated. Therefore, both tests may be recommended for GERD patients in clinical practice.

Frecuencia de Chlamydia trachomatis en mujeres de edad fértil al usar PCR en tiempo real en el Servicio de Laboratorio del Hospital Carlos Andrade Marín / Recurrence of Chlamydia Trachomatis in women of childbearing age when using CRP in real time in the Laboratory Department of Carlos Andrade Marin Hospital

Introducción: Chlamydia trachomatis es una bacteria patógena comúnmente reportada como causante de infecciones del tracto urogenital. Materiales y métodos: Mediante este estudio se determinó la frecuencia de infección por C. trachomatis utilizando PCR en tiempo real en mujeres de edad fértil (18 ­ 45) que acudieron al laboratorio del Hospital Carlos Andrade Marín. Para el estudio se colectaron 200 muestras de orina y se identificó el patógeno utilizando un kit comercial que identificó el plásmido críptico y al gen ompA presentes en la bacteria. Resultados: Se detectaron 3 muestras positivas que correspondieron al 1.5% de frecuencia. Los casos positivos se encontraron dentro de grupo de edad de 25 a 26 años. Discusión: Los resultados obtenidos en la presente investigación son comparables con estudios similares realizados en Latinoamérica con grupos de bajo riesgo.

Introduction: Chlamydia trachomatis is a pathogenic bacterium commonly reported as cause of infections of the urogenital tract. Methods: This study determined the frequency of C. trachomatis infection using real-time PCR. Two hundred urine samples from women in reproductive age were analyzed (range: 18 ­ 45 years old), which have attended at Carlos Andrade Marín Hospital. In order to test the samples, a commercial kit that identifies the criptic plasmid and the ompA gene from C. trachomatis was used. Results: From the 200 samples, three were positive that corresponed to a frequency of 1.5%. All positive cases were found within the group of 25 and 26 years old. Discussion: The results obtained in this research are comparable with similar studies obtained in several Latin American countries in low risk population

Improving risk assessment for post-surgical low cardiac output syndrome in patients without severely reduced ejection fraction undergoing open aortic valve replacement. The role of global longitudinal strain and right ventricular free wall strain.

Low cardiac output syndrome (LCOS) after surgical aortic valve replacement (SAVR) is related to increased mortality and treatment related costs. We aimed to evaluate whether echocardiography-derived left ventricular global longitudinal strain (LV-GLS) relates to the occurrence of postoperative LCOS in patients undergoing SAVR. We prospectively enrolled 75 patients with symptomatic severe aortic stenosis, left ventricular ejection fraction (LVEF) >40%, NYHA Class

Clinical and Histopathologic Characterization of Canine Chronic Ulcerative Stomatitis.

Canine chronic ulcerative stomatitis, also known as chronic ulcerative paradental stomatitis, is a painful condition of the oral cavity. The purpose of this study was to determine if there are commonalities in clinical and radiographic features among patients, whether the histopathologic evaluation might inform the pathogenesis, and whether the condition appears similar to human oral mucosal diseases. To do this, we prospectively collected clinical, radiographic, and histopathologic data from 20 dogs diagnosed with the disease. Clinical data were based on a clinical disease activity index, oral and periodontal examination parameters, and full-mouth dental radiographs. The histopathological and immunohistochemical data were based on oral mucosal samples obtained from erosive or ulcerated areas. Our findings revealed that canine chronic stomatitis is clinically characterized by painful oral mucosal ulcers of varying size, pattern, appearance, and distribution, most often associated with teeth with early periodontitis. Histologic examination revealed a subepithelial lichenoid band (interface mucositis) where B cells, T cells, and Forkhead-box protein 3 (FoxP3)- and interleukin-17-expressing cells were present. These cells might play a role in the underlying immune response and an immune-mediated pathogenesis is suspected. The clinical and histopathologic features of this chronic inflammatory mucosal disease in dogs resemble those of oral lichen planus in humans.

Antiviral RNA silencing suppression activity of Tomato spotted wilt virus NSs protein.

In addition to regulating gene expression, RNA silencing is an essential antiviral defense system in plants. Triggered by double-stranded RNA, silencing results in degradation or translational repression of target transcripts. Viruses are inducers and targets of RNA silencing. To condition susceptibility, most plant viruses encode silencing suppressors that interfere with this process, such as the Tomato spotted wilt virus (TSWV) NSs protein. The mechanism by which NSs suppresses RNA silencing and its role in viral infection and movement remain to be determined. We cloned NSs from the Hawaii isolate of TSWV and using two independent assays show for the first time that this protein restored pathogenicity and supported the formation of local infection foci by suppressor-deficient Turnip mosaic virus and Turnip crinkle virus. Demonstrating the suppression of RNA silencing directed against heterologous viruses establishes the foundation to determine the means used by NSs to block this antiviral process.

Self-etching dental adhesive containing a natural essential oil: anti-biofouling performance and mechanical properties.

This study assessed the anti-biofouling performance of an experimental adhesive system containing a naturally occurring essential vegetable oil and examined the following physical and mechanical properties: water sorption (WS) and solubility (SL), microtensile bond strength to dentin (µTBS), and degree of conversion. The following six groups were tested: a self-etching experimental adhesive containing refined essential oil from the seeds of the Butia capitata tree (EAO); an oil-free version of the experimental adhesive (EANO); one group without adhesive as the control (C); and the three following commercial self-etching adhesives: Clearfil Protect Bond (CPB), Clearfil SE Bond, and Adper SE Plus. The antibacterial effect was estimated by microbiological culture on selective/non-selective media, and the results expressed as colony-forming units per unit weight of dry biofilm (CFU mg(-1)). The data were submitted to ANOVA and Tukey's post hoc test (α = 0.05). After 24 h, pH changes were similar in the storage medium of all tested adhesive systems. EAO showed similar levels of antimicrobial activity in a model biofilm microcosm as the commercial self-etching adhesive CPB. Both were effective against total microorganisms, aciduric bacteria, lactobacilli, and Streptococcus mutans. WS and SL were not affected by the presence of the essential oil; the values of EAO were similar to or less than those of commercial equivalents. The incorporation of an essential oil into an experimental adhesive did not influence its monomer conversion result. Immediate µTBS values of EAO and EANO were similar and were greater than those of commercial equivalents. After storage for 6 months, the µTBS of the EAO decreased significantly and became similar to the values of commercial equivalents, while the strength of the EANO was not affected.

Dispersion of luminescent nanoparticles in different derivatives of poly(ethyl methacrylate).

Gd2O3:Tb(5%) nanoparticles were prepared via the polyol route and dispersed without any stabilizer in several ethyl methacrylate derivatives matrices such as poly(ethyl methacrylate), poly(2-methoxyethyl methacrylate) and poly(2-hydroxyethyl methacrylate) (PHEMA). Nanocomposites were obtained via free-radical polymerization of methacrylic monomers with ethylene glycol dimethacrylate as crosslinker and colloidal solution of Gd2O3:Tb(5%) nanoparticles. Best results are obtained with PHEMA in which the dispersed Gd2O3:Tb(5%) nanoparticles are spherical with a mean diameter of 15 nm, as measured by TEM. The obtained solid Gd2O3:Tb(5%)/PHEMA nanocomposites are highly transparent (in the visible spectral range) and exhibit characteristic photoluminescence of Tb3+ 5D4-7F(J) (J = 6-3), with 5D4-7F5 strong green emission at 536 nm upon UV excitation. The nanoparticles and nanocomposites have been well characterized by high-resolution transmission electron microscope (TEM), UV/Vis transmission spectra, photoluminescence excitation, and emission spectra.