Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study.

BACKGROUND: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. MATERIALS AND METHODS: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. RESULTS: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. CONCLUSIONS: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

Accurate prediction of calving in dairy cows by applying feature engineering and machine learning.

Prediction of calving is key to dairy cow management. Current trends of increasing herd sizes globally can directly impact the time that farmers spend monitoring individual animals. Automated monitoring on behavioural and physiological changes prior to parturition can be used to develop machine learning solutions for calving prediction. In this study, we developed a machine learning algorithm for the prediction of calving in dairy cows. We demonstrated that temperature and activity index information retrieved from a commercial reticuloruminal bolus sensor can accurately predict calving from 1-day to 5-days in advance. The best prediction solution using data from 82 dairy cows, achieved up to 87.81 % in accuracy, 92.99 % in specificity, 75.84 % in sensitivity, 82.99 % in positive predictive value (PPV), 78.85 % in F-score, and 90.02 % in negative predictive value (NPV) on the test dataset when using information from 2-days in advance and all the subsets of feature characteristics (temperature + drinking + activity). The performance only decreased by 2.45 % points in accuracy, 0.74 % points in specificity, 6.41 % points in sensitivity, 2.45 % points in positive predictive value, 4.91 % points in F-score, and 2.44 % points in negative predictive value on the test dataset when using all feature characteristics and 5-days in advance information compared to using all features and information from 2-days in advance. Full evaluation of the performance of the prediction showed an improvement when using all the different subsets of feature characteristics together (temperature, activity, and drinking) compared to using temperature features only. When adding activity and drinking to the subset of temperature features, an average increase of 2.70, 1.52, 5.40, 4.39, 5.02, 2.13 % points in accuracy, specificity, sensitivity, PPV, F-score, and NPV, respectively, was obtained. Notably, evaluation of feature importance (i.e., relative weight of any given feature in relation to model prediction) showed that 3-5 (depending on the selected days in advance model) of the top ten features were derived from drinking behaviour, showing the relevance that this behaviour can have in the prediction of calving. This algorithm can provide a useful tool for automated calving prediction in dairy cows which has potential for improvement of health, welfare, and productivity in the dairy industry.

Epidemic model on a network: Analysis and applications to COVID-19.

We analyze an epidemic model on a network consisting of susceptible-infected-recovered equations at the nodes coupled by diffusion using a graph Laplacian. We introduce an epidemic criterion and examine different isolation strategies: we prove that it is most effective to isolate a node of highest degree. The model is also useful to evaluate deconfinement scenarios and prevent a so-called second wave. The model has few parameters enabling fitting to the data and the essential ingredient of importation of infected; these features are particularly important for the current COVID-19 epidemic.

Developing and evaluating threshold-based algorithms to detect drinking behavior in dairy cows using reticulorumen temperature.

In this study, we assessed for the first time the use of a reticuloruminal temperature bolus and a thresholding method to detect drinking events and investigated different factors that can affect drinking behavior. First, we validated the detection of drinking events using 16 cows that received a reticuloruminal bolus. For this, we collected continuous drinking behavior data for 4 d using video recordings and ambient and water temperature for the same 4 d. After all the data were synchronized, we performed 2 threshold algorithms: a general-fixed threshold and a cow-day specific threshold algorithm. In the general-fixed threshold, a positive test was considered if the temperature of any cow fell below a fixed threshold; in the cow-day specific threshold, a positive test was considered when the temperature of specific cows fell below the threshold value deviations around the mean temperature of the cow for that day. The former was evaluated using a threshold varying between 35.7 and 39.5°C, and the latter using the formula µ-n10σ, where µ = mean of the temperature of each cow for one day, n = 1, 2, …, 20, and σ = standard deviation of the temperature of each cow on that day. The performance of the validation of detection using each of the threshold types was computed using different metrics, including overall accuracy, precision, recall (also known as sensitivity), F-score, positive predictive value, negative predictive value, false discovery rate, false omission rate, and Cohen's kappa statistic. The findings of the first study showed that the cow-day specific threshold of n = 10 performed better (true positives = 466; false positives = 167; false negatives = 165; true negatives = 8,416) than using a general-fixed threshold of 38.1°C (true positives = 449; false positives = 181; false negatives = 182; true negatives = 8,402). With the information gained in this first study, we investigated the different factors associated with temperature drop characteristics per cow: number of drops, mean amplitude of the drop, and mean recovery time. For this, we used data from 54 cows collected for almost 1 yr to build a mixed-effect multilevel model that included days in milk, parity, average monthly milk production, and ambient temperature as explanatory variables. Cow characteristics and ambient temperature had significant effects on drinking events. Our results provide a platform for automated monitoring of drinking behavior, which has potential value in prediction of health and welfare in dairy cattle.

The Effects of Developmental Programming upon Neonatal Mortality.

The greatest loss in ruminant production systems occurs during the neonatal period. The maternal environment (nutrition and physiologic status) influences neonatal mortality and morbidity as it reportedly affects (a) Dystocia, both via increasing birth weight and placental dysfunction; (b) Neonatal thermoregulation, both via altering the amount of brown adipose tissue and its ability to function via effects upon the hypothalamic-pituitary-thyroid axis; (c) Modification of the developing immune system and its symbiotic nutrient sources; (d) Modification of maternal and neonatal behavior.

The immediate effects of cervical spine manipulation on pain and biochemical markers in females with acute non-specific mechanical neck pain: a randomized clinical trial.

Study Design: Randomized clinical trial with pre-test, post-test control group design. Objectives: To examine the immediate effects of cervical spinal manipulation (CSM) on serum concentration of biochemical markers (oxytocin, neurotensin, orexin A, and cortisol). Background: Several studies have found an association between spinal manipulation (SM) and pain perception. However, the mechanism by which SM modulates pain remains undefined. Methods: Twenty-eight female subjects with non-specific mechanical neck pain were randomly assigned to one of two interventions (CSM versus sham CSM). Blood samples were drawn before and immediately after the respective interventions. Oxytocin, neurotensin, orexin A, and cortisol were measured from the blood and serum using the Milliplex Map Magnetic Bead Panel Immunoassay on the Luminex 200 Platform. Results: In the CSM group, there were significant increases in pre- versus post-manipulation mean oxytocin (154.5 ± 60.1 vs. 185.1 ± 75.6, p = .012); neurotensin (116.0 ± 26.5 vs.136.4 ± 34.1, p < . 001); orexin A (52.2 ± 31.1 vs. 73.8 ± 38.8, p < .01) serum concentration; but no significant differences in mean cortisol (p = .052) serum concentration. In the sham group, there were no significant differences in any of the biomarkers (p > .05). Conclusion: The results of the current study suggest that the mechanical stimuli provided through a CSM may modify neuropeptide expression by immediately increasing the serum concentration of nociception-related biomarkers (oxytocin, neurotensin, orexin A, but not cortisol) in the blood of female subjects with non-specific mechanical neck pain.

A retrospective review of conjunctival melanoma: Presentation, treatment and evolution. / Revisión retrospectiva del melanoma conjuntival: presentación, tratamiento y evolución.

OBJECTIVE: The purpose of the present study is to describe the clinical characteristics and outcomes of patients diagnosed and treated for conjunctival melanoma in the Ocular Oncology Unit of the University Hospital Clinic of Valladolid. METHODS: A retrospective observational case series study was conducted on patients diagnosed with conjunctival melanoma in the Ocular Oncology Unit of University Hospital Clinic of Valladolid, from January 1992 to December 2017. Demographic information and tumour features were recorded in a Microsoft Access database. RESULTS: Among a total of 462 consecutive patients, the tumour was classified as melanocytic in 252 cases (54.5%), with 27 patients having the pathological diagnosis of conjunctival melanoma. The mean age at diagnosis was 59.2years (16-88), and there were 41% males and 59% females, with a mean follow-up of 6.1±6.8years. As regards the origin of conjunctival melanoma, 16 cases (59%) arose from primary acquired melanosis, 26% from nevus, and 15% developed de novo. The treatment performed was incisional or excisional biopsy in all patients, local adjuvant chemotherapy in 15 cases (56%) and brachytherapy in 5 patients (18%). The median survival was 18years and the probability of survival at 5 and 10years was 89% and 69%, respectively. CONCLUSIONS: Conjunctival melanoma is a rare disease, usually undervalued by the patient as well as being underdiagnosed, leading to insufficient and delayed treatment. Early diagnosis and treatment are essential to prevent recurrences and systemic extension, as well as to preserve vision and life.

Temporal cardiovascular causality during orthostatic stress by extended partial directed coherence.

The aim of this study was to investigate the temporal dynamic behavior of cardiovascular interactions between heart period and systolic blood pressure during a 20-min head-up tilt test at 70° in young women with orthostatic intolerance compared to healthy women. Methods included the lagged and extended partial directed coherence applied to short-term windows shifted by 5 seconds, extracted from a multivariate set of cardiovascular and respiratory time series. Findings revealed significantly increased information flow (p <; 0.01) in patients from: a) heart period to blood pressure during supine position which subsequently decreased and b) blood pressure to heart period during the progression of orthostatic phase. Controls developed balanced cardiovascular interactions with smaller information flows than patients.

Cardiovascular variability in young male and female subjects in health and orthostatic intolerance.

The aim of this study was to investigate the effect of head-up tilt (HUT) test on male and female young patients, diagnosed with orthostatic intolerance (OI), in comparison to male and female healthy subjects. Twenty seven OI patients (21 women, 6 men) and 26 age-matched healthy subjects (13 women, 13 men) were enrolled in a 70° HUT test. In addition to hemodynamic variables, cardiovascular and respiratory parameters were determined using linear and nonlinear methods to analyze heart rate (HRV) and blood pressure variability (BPV). During the complete test, HRV was lower in healthy men than in female controls. Decreased HRV and increased BPV were observed in female patients compared to healthy women. Furthermore, systolic BPV was increased in male and female patients. However, linear (rmssd) and nonlinear (plvar2) parameters indicated that diastolic BPV decreased in male patients during orthostatic phase, but remained unchanged in female patients. Findings indicated gender dependent mechanisms for the regulation of diastolic blood pressure during orthostatic stress in patients.

Study of impaired cardiovascular and respiratory coupling during orthostatic stress based on joint symbolic dynamics.

The present study investigates the instantaneous coupling among the cardiac, vascular, and respiratory systems, using the heart rate, respiration, and systolic and diastolic blood pressure variability in 12 healthy and 16 vasovagal syncope female subjects during a head-up tilt (HUT) testing protocol at 70° This study contributes to the coupling analysis by using a nonlinear joint symbolic dynamics (JSD) in a high-temporal resolution scheme, based on 5 min segments of the time series that are shifted every minute. For each segment, a bivariate JSD matrix was constructed to obtain global and local coupling indices in accordance to Shannon's entropy and the probability of occurrence of various bivariate words, respectively. The novel approach revealed important findings in the coupling dynamics of the systems, thus allowing the detection of group differences during the early orthostatic phase, and during the HUT test, before the occurrence of any pre-syncopal symptoms. In patients, the global indices indicated a significant decrease of cardiovascular coupling, starting at 10 min after the tilt-up, manifested by reduced baroreflex sensitivity and cardiorespiratory coupling that was initiated 8 min after the onset of the orthostatic phase (OP). A decreased autonomic control on cardiovascular-respiratory couplings was further evidenced by increased alterations of the JSD indices during the OP compared to the supine position in patients compared to controls. Furthermore, findings based on local indices demonstrated that female patients showed reductions and disengagements in cardiovascular (p < 0.001) and cardiorespiratory (p < 0.01) couplings, as early as the first 5 min and during the complete OP.

Divertículo duodenal simulando neoplasia quística de páncreas / Duodenal diverticulum as a cystis neoplasm of pancreas

Resumen Objetivo: El divertículo duodenal se presenta con una frecuencia del 1 al 23% según series radiológicas y de autopsias. La localización más frecuente es la segunda porción duodenal cercana a la cabeza pancreática, por lo cual puede ser confundido con neoplasias pancreáticas quísticas. Material y Método: Presentamos un paciente con diagnóstico de sospecha radiológica, mediante ecoendoscopia y punción aspiración con aguja fina (PAAF), de neoplasia mucinosa de páncreas que fue intervenido, encontrándose un endurecimiento de la cabeza pancreática y un divertículo duodenal yuxtavateriano, realizándose extirpación en bloque ante la sospecha de malignidad. Resultado: El posoperatorio del paciente fue favorable y el resultado anatomopatológico del tejido pancreático informó de tejido pancreático sin anomalías y divertículo duodenal. Discusión: El diagnóstico diferencial preoperatorio del divertículo duodenal con la neoplasia mucinosa quística de páncreas es muy complejo, ya que la punción del líquido del interior del divertículo puede ser similar al de un proceso neoplásico mucinoso pancreático. Ante la sospecha diagnóstica y la presencia de clínica está indicado realizar laparotomía exploradora, para obtener un diagnóstico de certeza.

Objective: The duodenal diverticulum presents with a frequency of 1 to 23% according to radiological series and autopsies. The most frequent localization is the second duodenal portion near the pancreatic head so it may be confused with cystic pancreatic neoplasms. Material and Method: We present a patient with diagnosis of radiological suspicion by means of echoendoscopy and fine needle aspiration biopsy (FNAB) of a mucinous neoplasm of the pancreas that was intervened, being a hardening of the pancreatic head and a duodenal juxtavaterian diverticulum, being performed a block removal on suspicion of malignancy. Result: The patient's postoperative period was favorable and the anatomopathological result of the pancreatic tissue was of pancreatic tissue without anomalies and duodenal diverticulum. Discussion: The preoperative differential diagnosis of duodenal diverticulum with mucinous cystic neoplasia of the pancreas is very complex, since the puncture of the fluid inside the diverticulum may be similar to that of a neoplastic process of the pancreatic mucin. Before the suspected diagnosis and the presence of clinic is indicated to perform exploratory laparotomy, to obtain a diagnosis of certainty.

Multivariate symbolic dynamics for analysis of respiratory-cardiovascular interactions.

In this work, a nonlinear method to study multivariate interactions, called multivariate symbolic dynamics (MSD), was introduced. The usefulness of this technique was studied on respiratory-cardiovascular data from young women with vasovagal syncope (VVS) and from healthy subjects. The study included 16 female patients diagnosed with VVS and 24 age-matched healthy subjects (12 women). All subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5 min of supine position and 18 to 28 min of 70° orthostatic phase. The MSD parameters were dynamically obtained for 5-min windows shifted by 1 min during HUT test. In supine position there were no considerable differences. During orthostatic phase, parameters from MSD showed a highly significantly (p=0.00005) increased occurrence of impaired respiratory-cardiovascular interactions in female patients susceptible to vasovagal syncope. This study provided promising results for a new multivariate method to investigate respiratory-cardiovascular interactions.

Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is a remarkable form of brain plasticity through which new neurons are generated throughout life. Despite its important roles in cognition and emotion and its modulation in various preclinical disease models, the functional importance of adult hippocampal neurogenesis in human health has not been revealed because of a lack of tools for monitoring adult neurogenesis in vivo. Therefore, we performed an unbiased proteomics screen to identify novel proteins expressed during neuronal differentiation using a human neural stem cell model, and we identified the proteoglycan Glypican-2 (Gpc2) as a putative secreted marker of immature neurons. Exogenous Gpc2 binds to FGF2 and inhibits FGF2-induced neural progenitor cell proliferation. Gpc2 is enriched in neurogenic regions of the adult brain. Its expression is increased by physiological stimuli that increase hippocampal neurogenesis and decreased in transgenic models in which neurogenesis is selectively ablated. Changes in neurogenesis also result in changes in Gpc2 protein level in cerebrospinal fluid (CSF). Gpc2 is detectable in adult human CSF, and first pilot experiments with a longitudinal cohort indicate a decrease over time. Thus, Gpc2 may serve as a potential marker to monitor adult neurogenesis in both animal and human physiology and disease, warranting future studies.

Allelopathic Activity of Extracts from Different Brazilian Peanut (Arachis hypogaea L.) Cultivars on Lettuce (Lactuca sativa) and Weed Plants.

Peanut (Arachis hypogaea L.) is the fourth most consumed oleaginous plant in the world, producing seeds with high contents of lipids, proteins, vitamins, and carbohydrates. Biological activities of different extracts of this species have already been evaluated by many researchers, including antioxidant, antitumoral, and antibacterial. In this work, the allelopathic activity of extracts from different Brazilian peanut cultivars against lettuce (Lactuca sativa) and two weed plants (Commelina benghalensis and Ipomoea nil) was studied. Aerial parts, roots, seeds, and seed coats were used for the preparation of crude extracts. Seed extract partitioning was performed with n-hexane, dichloromethane, ethyl acetate, n-butanol, and aqueous residue. Germination and growth of hypocotyls and rootlets were evaluated after one and five days of incubation with plant extracts, respectively. Crude seed extract and its dichloromethanic partition displayed highest allelopathic activity. These results contribute for the study of new potential natural herbicides.

Dose-response relationship of temozolomide, determined by the Pig-a, comet, and micronucleus assay.

Temozolomide (TMZ), a monofunctional alkylating agent, was selected as a model compound to determine its quantitative genotoxic dose-response relationship in different tissues (blood, liver, and jejunum) and endpoints [Pig-a-, comet-, and micronucleus assay (MNT)] in male rats. TMZ was administered p.o. over 5 consecutive days (day 1-5), followed by a treatment-free period of 50 days (day 6-56) and a final administration prior to necropsy (day 57-59). TMZ showed a dose-dependent increase in DNA damage in all interrogated endpoints. A statistically significant increase in Pig-a mutant phenotypes was observed on day 44 starting at 7.5 mg/kg/day for mutant reticulocytes (for RETCD59-) and at 3.75 mg/kg/day for mutant red blood cells (RBCCD59-), respectively. In addition, a statistically significant increase in cytogenetic damage, as measured by micronucleated reticulocytes, was observed starting at 3.75 mg/kg/day on day 3 and 1.5 mg/kg/day on day 59. DNA strand breaks, as detected by the comet assay, showed a dose-dependent and statistically significant increase in liver, blood, and jejunum starting at doses of 3.75, 3.75, and 7.5 mg/kg/day, respectively. The dose-response relationships of the Pig-a, MNT, and comet data were analyzed for possible points of departure (PoD) using the benchmark-dose (BMD) software PROAST with different critical effect sizes (CES) (BMD0.1, BMD0.5, BMD1, and BMD1SD). Overall, PoD values show a high concordance between different tissues and endpoints, underlining the suitability of this experimental design to explore quantitative dose-response relationships in a variety of different tissues and endpoints, while minimizing animal use.

Increased dietary protein in the second trimester of gestation increases live weight gain and carcass composition in weaner calves to 6 months of age.

Genetically similar nulliparous Polled Hereford heifers from a closed pedigree herd were used to evaluate the effects of dietary protein during the first and second trimester of gestation upon foetal, placental and postnatal growth. Heifers were randomly allocated into two groups at 35 days after artificial insemination (35 days post conception (dpc)) to a single bull and fed high (15.7% CP) or low (5.9% CP) protein in the first trimester (T1). At 90 dpc, half of each nutritional treatment group changed to a high- or low-protein diet for the second trimester until 180 dpc (T2). High protein intake in the second trimester increased birth weight in females (P=0.05), but there was no effect of treatment upon birth weight when taken over both sexes. Biparietal diameter was significantly increased by high protein in the second trimester with the effect being greater in the female (P=0.02), but also significant overall (P=0.05). Placental weight was positively correlated with birth weight, fibroblast volume and relative blood vessel volume (P<0.05). Placental fibroblast density was increased and trophoblast volume decreased in the high-protein first trimester treatment group (P<0.05). There was a trend for placental weight to be increased by high protein in the second trimester (P=0.06). Calves from heifers fed the high-protein treatment in the second trimester weighed significantly more on all occasions preweaning (at 1 month (P=0.0004), 2 months (P=0.006), 3 months (P=0.002), 4 months (P=0.01), 5 months (P=0.03), 6 months (P=0.001)), and grew at a faster rate over the 6-month period. By 6 months of age, the calves from heifers fed high nutrition in the second trimester weighed 33 kg heavier than those fed the low diet in the second trimester. These results suggest that dietary protein in early pregnancy alters the development of the bovine placenta and calf growth to weaning.

Men and women should be separately investigated in studies of orthostatic challenge due to different gender-related dynamics of autonomic response.

In studies of autonomic regulation during orthostatic challenges only a few nonlinear methods have been considered without investigating the effect of gender in young controls. Especially, the temporal development of the autonomic regulation has not yet been explicitly analyzed using short-term segments in supine position, transition and orthostatic phase (OP). In this study, nonlinear analysis of cardiovascular and respiratory time series was performed to investigate how nonlinear indices are dynamically changing with respect to gender during orthostatic challenges. The analysis was carried out using shifted short-term segments throughout a head-up tilt test in 24 healthy subjects, 12 men (26 ± 4 years) and 12 age-matched women (26 ± 5 years), at supine position and during OP at 70°. The nonlinear methods demonstrated statistical differences in the autonomic regulation between males and females. Orthostatic stress caused significantly decreased heart rate variability due to increased sympathetic activity mainly in men, already at the beginning and during the complete OP, revealed by (a) increased occurrence of specific word types with constant fluctuations as pW111 from symbolic dynamics, (b) augmented fractal correlation properties by the short-term index alpha1 from detrended fluctuation analysis, (c) increased slope indices (21ati and 31ati) from auto-transinformation and (d) augmented time irreversibility indices demonstrating more temporal asymmetries and nonlinear dynamics in men than in women. After tilt-up, both men and women increased their sympathetic activity but in a different way. Time-dependent gender differences during orthostatic challenge were shown directly between men and women or indirectly comparing baseline and different temporal stages of OP. The proposed dynamical study of autonomic regulation has the advantage of screening the fluctuations of the sympathetic and vagal activities that can be quantified by the temporal behavior of nonlinear indices. The findings in this paper strongly suggest the need for gender separation in studies of the dynamics of autonomic regulation during orthostatic challenge.

Orthostatic stress causes immediately increased blood pressure variability in women with vasovagal syncope.

The cardiovascular and respiratory autonomic nervous regulation has been studied mainly by hemodynamic responses during different physical stressors. In this study, dynamics of autonomic response to an orthostatic challenge was investigated by hemodynamic variables and by diverse linear and nonlinear indices calculated from time series of beat-to-beat intervals (BBI), respiratory cycle duration (RESP), systolic (SYS) and diastolic (DIA) blood pressure. This study included 16 young female patients (SYN) with vasovagal syncope and 12 age-matched female controls (CON). The subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5min of baseline (BL, supine position) and 18min of 70° orthostatic phase (OP). To increase the time resolution of the analysis the time series were segmented in five-minute overlapping windows with a shift of 1min. Hemodynamic parameters did not show any statistical differences between SYN and CON. Time domain linear analysis revealed increased respiratory frequency and increased blood pressure variability (BPV) in patients during OP meaning increased sympathetic activity and vagal withdrawal. Frequency domain analysis confirmed a predominance of sympathetic tone by steadily increased values of low over high frequency power in BBI and of low frequency power in SYS and DIA in patients during OP. The nonlinear analysis by symbolic dynamics seemed to be highly suitable for differentiation of SYN and CON in the early beginning of OP, i.e., 5min after tilt-up. In particular the index SYS_plvar3 showed less patterns of low variability in patients reflecting a steadily increase in both BPV and sympathetic activity. The proposed dynamical analysis could lead to a better understanding of the temporal underlying mechanisms in healthy subjects and patients under orthostatic stress.

Delta space plot analysis of cardiovascular coupling in vasovagal syncope during orthostatic challenge.

In this work, a graphical method to study cardiovascular coupling, called delta space plot analysis (DSPA), was introduced. The graphical representation is susceptible to be parameterized in shape and orientation. The usefulness of this technique was studied on cardiovascular data from patients with vasovagal syncope (VVS) and from controls. The study included 15 female patients diagnosed with VVS and 11 age-matched healthy female subjects. All subjects were enrolled in a head-up tilt (HUT) test, breathing normally, including 5 minutes of supine position (baseline) and 18 minutes of 70° orthostatic phase. The DSPA parameters were obtained at different times during the HUT test, i.e., at baseline, early (first 5 min) and late (10-15 min) orthostatic phases. In baseline there were no considerable differences between female controls and female patients. During the late orthostatic phase, parameters from DSPA showed highly significantly (p=0.000003) reduced cardiovascular coupling in patients. Findings indicated a loss of control on cardiovascular coupling in female patients susceptible to vasovagal syncope during orthostatic challenge. In addition, this study provided promising results for a new graphical method to investigate cardiovascular coupling.

Self-reported quality care for knee osteoarthritis: comparisons across Denmark, Norway, Portugal and the UK.

OBJECTIVES: To assess and compare patient perceived quality of osteoarthritis (OA) management in primary healthcare in Denmark, Norway, Portugal and the UK. METHODS: Participants consulting with clinical signs and symptoms of knee OA were identified in 30 general practices and invited to complete a cross-sectional survey including quality indicators (QI) for OA care. A QI was considered as eligible if the participant had checked 'Yes' or 'No', and as achieved if the participant had checked 'Yes' to the indicator. The median percentage (with IQR and range) of eligible QIs achieved by country was determined and compared in negative binominal regression analysis. Achievement of individual QIs by country was determined and compared using logistic regression analyses. RESULTS: A total of 354 participants self-reported QI achievement. The median percentage of eligible QIs achieved (checked 'Yes') was 48% (IQR 28%, 64%; range 0-100%) for the total sample with relatively similar medians across three of four countries. Achievement rates on individual QIs showed a large variation ranging from 11% (referral to services for losing weight) to 67% (information about the importance of exercise) with significant differences in achievement rates between the countries. CONCLUSIONS: The results indicated a potential for improvement in OA care in all four countries, but for somewhat different aspects of OA care. By exploring these differences and comparing healthcare services, ideas may be generated on how the quality might be improved across nations. Larger studies are needed to confirm and further explore the findings.