Aflibercept Off-Target Effects in Diabetic Macular Edema: An In Silico Modeling Approach.

Intravitreal aflibercept injection (IAI) is a treatment for diabetic macular edema (DME), but its mechanism of action (MoA) has not been completely elucidated. Here, we aimed to explore IAI's MoA and its multi-target nature in DME pathophysiology with an in silico (computer simulation) disease model. We used the Therapeutic Performance Mapping System (Anaxomics Biotech property) to generate mathematical models based on the available scientific knowledge at the time of the study, describing the relationship between the modulation of vascular endothelial growth factor receptors (VEGFRs) by IAI and DME pathophysiological processes. We also undertook an enrichment analysis to explore the processes modulated by IAI, visualized the effectors' predicted protein activity, and specifically evaluated the role of VEGFR1 pathway inhibition on DME treatment. The models simulated the potential pathophysiology of DME and the likely IAI's MoA by inhibiting VEGFR1 and VEGFR2 signaling. The action of IAI through both signaling pathways modulated the identified pathophysiological processes associated with DME, with the strongest effects in angiogenesis, blood-retinal barrier alteration and permeability, and inflammation. VEGFR1 inhibition was essential to modulate inflammatory protein effectors. Given the role of VEGFR1 signaling on the modulation of inflammatory-related pathways, IAI may offer therapeutic advantages for DME through sustained VEGFR1 pathway inhibition.

A decision support system based on artificial intelligence and systems biology for the simulation of pancreatic cancer patient status.

Oncology treatments require continuous individual adjustment based on the measurement of multiple clinical parameters. Prediction tools exploiting the patterns present in the clinical data could be used to assist decision making and ease the burden associated to the interpretation of all these parameters. The goal of this study was to predict the evolution of patients with pancreatic cancer at their next visit using information routinely recorded in health records, providing a decision-support system for clinicians. We selected hematological variables as the visit's clinical outcomes, under the assumption that they can be predictive of the evolution of the patient. Multivariate models based on regression trees were generated to predict next-visit values for each of the clinical outcomes selected, based on the longitudinal clinical data as well as on molecular data sets streaming from in silico simulations of individual patient status at each visit. The models predict, with a mean prediction score (balanced accuracy) of 0.79, the evolution trends of eosinophils, leukocytes, monocytes, and platelets. Time span between visits and neutropenia were among the most common factors contributing to the predicted evolution. The inclusion of molecular variables from the systems-biology in silico simulations provided a molecular background for the observed variations in the selected outcome variables, mostly in relation to the regulation of hematopoiesis. In spite of its limitations, this study serves as a proof of concept for the application of next-visit prediction tools in real-world settings, even when available data sets are small.

Effects of reminiscence therapy on anxiety and depression during acute hospitalization in older patients: Controlled study.

BACKGROUND/OBJECTIVES: Hospitalization due to acute illness in older patients is often associated with anxiety or depressive symptoms. In these circumstances, given that pharmacologic treatment should be avoided to reduce interactions with ongoing medication regimes, psychotherapy techniques should be considered. The purpose of this study was to evaluate the effectiveness of group reminiscence therapy (RT) on the reduction of anxiety and depressive symptoms in acutely hospitalized older patients. METHODS: Controlled and prospective study conducted on the Acute Geriatric Unit of a university hospital. Patients included in the intervention group (RT Group) attended a group session focused on RT, whereas those included in the control group (UC) received usual hospital care. Exclusion criteria were severe cognitive impairment, impossibility to mobilize, and clinical/hemodynamic instability. The intervention was based on a multi-task daily group session of reminiscence activities. The severity of anxiety (Hamilton Anxiety Rating Scale, HAM-A), depressive symptoms (15-item Geriatric Depression Scale, GDS-15), loneliness (ESTE-II social loneliness scale), and fear of death (Collet-Lester scale) was assessed at admission and discharge in both groups. RESULTS: The intervention was effective in reducing the proportion of patients with anxiety and depressive symptoms during hospitalization. The proportion of patients with moderate-severe anxiety at discharge was 32.1% in the UC and 13.4% in the RT Group (p < 0.001), whereas the proportion of patients with depressive symptoms at discharge was 49.1% in the UC and 19.5% in the RT Group (p < 0.001). The intervention was independently associated with benefits on anxiety levels (RR 2.45, 95% CI 1.83-3.28) and depression (RR 3.71, 95% CI 2.22-6.19) at discharge. No differences were found in loneliness or fear of death. CONCLUSIONS: A group reminiscence activity reduces the proportion of patients with anxiety and depressive symptoms during hospitalization for an acute disease. Absolute changes in both anxiety and depression scores, even though significant, were relatively small.

Effectivity of Saffron Extract (Saffr'Activ) on Treatment for Children and Adolescents with Attention Deficit/Hyperactivity Disorder (ADHD): A Clinical Effectivity Study.

Attention Deficit/Hyperactivity Disorder is the most prevalent neurodevelopmental disorder worldwide. Choice treatment includes psychostimulants, but parents tend to be reluctant to administer them due to side effects, and alternatives are needed. Saffron extract is a natural stimulant that has been proven safe and effective for treating a variety of mental disorders. This study compares the efficacy of saffron and the usual treatment with methylphenidate, using objective and pen-and-paper tests. We performed a non-randomized clinical trial with two groups, methylphenidate (n = 27) and saffron (n = 36), in children and adolescents aged 7 to 17. Results show that the efficacy of saffron is comparable to that of methylphenidate. Saffron is more effective for treating hyperactivity symptoms, while methylphenidate is more effective for inattention symptoms.

Evaluation of the hospital care quality perceived by patients with immune-mediated inflammatory diseases from the pharmacy service. SACVINFA study.

WHAT IS KNOWN AND OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are a group of chronic and highly disabling diseases. The objective is to evaluate the satisfaction with the health care received by patients with the most prevalent IMIDs in Spain: inflammatory bowel disease (IBD), psoriasis (Ps) psoriatic arthritis (PsA), rheumatoid arthritis (RA) and spondyloarthropathies (SpAs), and to determine the factors that influence patient satisfaction. METHODS: This was an observational, cross-sectional, multicentre study in a real-world evidence context conducted in the Pharmacy Service in four hospital centres of the Community of Madrid that belong to the National Health System. The study included adult patients diagnosed with an IMID who had attended the Pharmacy Service at least three times. The patients were grouped according to the main IMID. Health care satisfaction was evaluated using the chronic patient experience assessment (IEXPAC) questionnaire. The responses to IEXPAC are grouped into three factors: productive interactions, new relational model and patient self-management, with a total score from 0 (worst) to 10 (best experience). Health-related quality of life (HRQoL) was also evaluated using the EQ-5D-5L questionnaire, and pharmacological adherence was evaluated through the Morisky-Green test. RESULTS AND DISCUSSION: A total of 578 patients were analysed (IBD = 25.3%; Ps = 19.7%; SpAs = 18.7%; RA = 18.5%; PsA = 17.8%). The mean age (SD) was 49.8 (12.3) years and 50.7% were male. The average score (SD) for the total IEXPAC sample was 6.6 (1.9). RA was the IMID with the lowest score, at 5.83 (2.0), significantly lower than the scores of Ps (SD) [7.01 (1.7); p = 0.003], IBD [6.83 (1, 9); p = 0.012] and SpAs [6.80 (1.6); p = 0.001]. Productive interactions (SD) [8.5 (1.8)] and patient self-management (SD) [7.3 (2.3)] were the factors with the highest scores, and the new relational model had the lowest score (SD) [3.2 (2.7)]. Male gender, a longer time interval between medication administrations and a higher HRQoL were correlated with better patient satisfaction. Current biological therapy (according to the Anatomical Chemical classification system) also had a significant influence; patients treated with tumour necrosis factor inhibitors and interleukin inhibitors showed greater satisfaction than those treated with selective immunosuppressants. WHAT IS NEW AND CONCLUSION: The IEXPAC results show high general satisfaction with care quality reported by patients with IMIDs treated in the Pharmacy Service. However, there are areas of improvement in care quality specially health professional-patient communication, such as increasing access to information, and promoting and facilitating relationships with patients in similar conditions.

A portable fan-based device for evaluating lung function in horses by the forced oscillation technique.

Objective. The assessment of lung mechanics in horses is nowadays based on invasive methods that may require sedation. The forced oscillation technique (FOT) allows the non-invasive assessment of respiratory mechanics during spontaneous breathing, but current devices are complex, cumbersome, expensive, and difficult to be applied in horses.Approach. We developed a portable FOT device based on a novel approach in which the pressure waveforms are generated by a servo-controlled ducted fan. This new approach allows the design of devices that are more sturdy, compact, and portable compared to already existing approaches. The prototype includes 1) a small microcontroller-based electronic board for controlling the fan and measuring flow and pressure and 2) an optimized data processing algorithm.Main results. This device provides a maximum error of 0.06 cmH2O·s/L and 0.15 cmH2O·s/L in measuring respiratory resistance and reactance duringin-vitrovalidation. A pilot study was also performed on three healthy horses and three horses with severe equine asthma (SEA) and it demonstrated good tolerability and feasibility of the new device. Total respiratory system resistance (Rrs) and reactance (Xrs) significantly differed (p< 0.05) between groups. At 5 Hz,Rrswas 0.66 ± 0.02 cmH2O·s/L and 0.94 ± 0.07 cmH2O·s/L in healthy and in SEA, respectively.Xrs0.38 ± 0.02 cmH2O·s/L and -0.27 ± 0.05 cmH2O·s/L.Significance. This novel approach for applying FOT allowed the development of a small, affordable, and portable device for the non-invasive evaluation of respiratory mechanics in spontaneously breathing horses, providing a useful new tool for improving veterinary respiratory medicine. Moreover, our results provide supporting evidence of the value of this novel approach for developing portable FOT devices also for applications in humans.

Bronchial angiogenesis in horses with severe asthma and its response to corticosteroids.

BACKGROUND: Severe asthma in horses is characterized by structural changes that thicken the lower airway wall, a change that is only partially reversible by current treatments. Increased vascularization contributes to the thickening of the bronchial wall in humans with asthma and is considered a potential new therapeutic target. OBJECTIVE: To determine the presence of angiogenesis in the bronchi of severely asthmatic horses, and if present, to evaluate its reversibility by treatment with corticosteroids. ANIMALS: Study 1: Bronchial samples from asthmatic horses in exacerbation (7), in remission (7), and aged-matched healthy horses. Study 2: Endobronchial biopsy samples from asthmatic horses in exacerbation (6) and healthy horses (6) before and after treatment with dexamethasone. METHODS: Blinded, randomized controlled study. Immunohistochemistry was performed using collagen IV as a marker for vascular basement membranes. Number of vessels, vascular area, and mean vessel size in the bronchial lamina propria were measured by histomorphometry. Reversibility of vascular changes in Study 2 was assessed after 2 weeks of treatment with dexamethasone. RESULTS: The number of vessels and vascular area were increased in the airway walls of asthmatic horses in exacerbation (P = .01 and P = .02, respectively) and in remission (P = .02 and P = .04, respectively) when compared to controls. In Study 2, the differences observed between groups disappeared after 2 weeks of treatment with corticosteroids because of the increased number of vessels in healthy horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Angiogenesis contributes to thickening of the airway wall in asthmatic horses and was not reversed by a 2-week treatment with corticosteroids.

Clustering Complex Chronic Patients: A Cross-Sectional Community Study From the General Practitioner's Perspective.

OBJECTIVE: Characterize subgroups of Complex Chronic Patients (CCPs) with cluster analysis from the general practitioner's perspective. STUDY DESIGN: Cross-sectional population-based study. SETTING: Three Primary Care urban centres for a reference population of 43,647 inhabitants over 14 years old in Sabadell, Catalonia, Spain. METHODS: Complexity is defined by the independent clinical judgment of general practitioners with the aid of complexity domains (both clinical and social). We used a Two-Step Cluster method to identify relevant subgroups of CCPs. RESULTS: Three relevant subgroups were identified. The first one was mainly managed by primary care professionals, and 63% of its CCPs belonged to the high-risk stratum of the Adjusted Morbidity Groups (GMA). The second subgroup included younger patients than the other two clusters, and showed the highest ratios of social deprivation and severe mental disease; 48% of its CCPs belonged to the high-risk stratum of the GMA. A third cluster included patients who belonged to the high-risk stratum of the GMA. Their age was similar to that of the patients in the first cluster, but they showed the highest values in the following areas: (i) risk of admission; (ii) proportion of advanced chronic disease and limited-life prognosis; (iii) functional loss and (iv) geriatric syndromes, along with special uncertainty in decision-making and clinical management. CONCLUSIONS: Characterization of CCPs shows clearly distinct profiles of needs, which provides an improved epidemiological picture by identifying clusters of patients who are likely to benefit from targeted interventions.

Pulmonary response of severely asthmatic horses after intra-articular administration of methylprednisolone.

BACKGROUND: Intra-articular (IA) administration of corticosteroids is performed routinely in equine practice. The lung function of severe asthmatic horses has recently been shown to be improved by IA triamcinolone acetonide (TA). We therefore hypothesised that IA methylprednisolone acetate (MPA), another commonly used corticosteroids, would also decrease the airway obstruction in severe asthmatic horses. OBJECTIVES: To compare the effects of intra-articular (IA) and intramuscular (IM) methylprednisolone acetate (MPA) administration on lung function and serum cortisol levels in horses with severe asthma. STUDY DESIGN: Randomised and controlled experiments on severe asthmatic research animals. METHODS: Severe asthmatic horses in exacerbation were administered 200 mg of MPA either intramuscularly (n = 6) or via intra-articular injections in the tarsocrural joints (n = 6; 100 mg/joint). Serum cortisol concentration and pulmonary function was measured for 8 days. RESULTS: A significant decrease in pulmonary resistance in the IA group (P = .003, mean diff 1.14) on day 1 in comparison with baseline was observed. A significant decrease from baseline was also observed on serum cortisol values in the IA group 6 hours after injection (P = .001, mean diff 44.5), and at day 1 (P = .003, mean diff 45.1). MAIN LIMITATIONS: Joint health was not evaluated in the current study and the physiological response of the severe asthmatic horses might deviate from that of the milder forms of asthma. CONCLUSIONS: MPA IA administration improves the lung function of severe asthmatic horses. However, this effect was mild and of a short duration.

IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study.

BACKGROUND: Patients with coronavirus disaese 2019 (COVID-19) can develop a cytokine release syndrome that eventually leads to acute respiratory distress syndrome requiring invasive mechanical ventilation (IMV). Because IL-6 is a relevant cytokine in acute respiratory distress syndrome, the blockade of its receptor with tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19. OBJECTIVE: We sought to determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ. METHODS: A retrospective observational study was performed in hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with preadministration and postadministration of TCZ. Multivariable logistic and linear regressions and survival analysis were performed depending on outcomes: need for IMV, evolution of arterial oxygen tension/fraction of inspired oxygen ratio, or mortality. RESULTS: One hundred forty-six patients were studied, predominantly males (66%); median age was 63 years. Forty-four patients (30%) required IMV, and 58 patients (40%) received treatment with TCZ. IL-6 levels greater than 30 pg/mL was the best predictor for IMV (odds ratio, 7.1; P < .001). Early administration of TCZ was associated with improvement in oxygenation (arterial oxygen tension/fraction of inspired oxygen ratio) in patients with high IL-6 (P = .048). Patients with high IL-6 not treated with TCZ showed high mortality (hazard ratio, 4.6; P = .003), as well as those with low IL-6 treated with TCZ (hazard ratio, 3.6; P = .016). No relevant serious adverse events were observed in TCZ-treated patients. CONCLUSIONS: Baseline IL-6 greater than 30 pg/mL predicts IMV requirement in patients with COVID-19 and contributes to establish an adequate indication for TCZ administration.

Randomized Comparative Trial of Acupuncture and Exercise Versus Uterine Ecbolics in the Treatment of Persistent Postbreeding Endometritis in Mares.

Although exercise and acupuncture are frequently used therapies to treat persistent postbreeding endometritis, their efficacy to date is unproven. The objective of this study was to determine if exercise and acupuncture are effective methods to reduce intrauterine fluid and compare the effectiveness of these treatments to the use of uterine ecbolics. Twelve mares susceptible to postbreeding endometritis were enrolled in the study with a randomized cross-over design using both positive and negative controls. During each estrous cycle, mares were randomized into one of six treatment groups, including stall rest (SR), oxytocin, cloprostenol, exercise, electroacupuncture, and oxytocin and exercise. Each mare was challenged with an insemination dose of 500 × 106 dead sperm at time 0 hours. Intrauterine fluid measurements were taken at 0, 4, 24, 48, 72, and 96 hours postbreeding. Associations between treatment efficacy and fluid clearance were investigated using a random-effects logistic regression model that controlled for positive uterine culture. Compared with the SR negative control, exercise was the most effective treatment and had 29.7 times increased odds of fluid clearance. The second most effective treatment was oxytocin alone, with 16.9 times increased odds of fluid clearance. This was followed by cloprostenol that had 10.6 greater odds of fluid clearance, and finally, the treatment that combined exercise with oxytocin had 8.4 times greater odds of fluid clearance. Results from this study confirm that exercise and exercise combined with oxytocin are effective methods to clear intrauterine fluid.

Girthiness: Retrospective Study of 37 Horses (2004-2016).

Girth aversion or girthiness is a nonspecific clinical sign anecdotally associated with multiple conditions in the horse (behavioral problems, gastric ulcers, back pain); however, studies have not been conducted to definitively correlate this clinical sign to specific pathologies. This retrospective study aims to describe the clinical signs and final diagnoses of 37 horses evaluated at the University of California, Davis with a presenting complaint of girthiness. Medical records of all horses presented to the veterinary hospital between 2004 and 2016 for girthiness were reviewed. Twelve horses were diagnosed with gastric ulceration, 10 with various orthopedic problems, 3 with ill-fitting saddles, 1 with reproductive tract neoplasia, and 10 with various diseases including liver abscessation, vena cava aneurism, sternum pain, and urinary tract infection. Identifying the exact cause of girthiness remains a challenge; however, gastric ulcers was a common finding; therefore, a clinical examination should be oriented to further investigate this condition because 92% of gastroscoped horses in this study were diagnosed with gastric ulcers.

Cost, Time, and Error Assessment During Preparation of Parenteral Nutrition: Multichamber Bags Versus Hospital-Compounded Bags.

BACKGROUND: Parenteral nutrition (PN) is associated with material and manpower costs and requires preparation time. The aim of this study was to evaluate the cost of PN using multichamber bags (MCBs) compared with hospital-compounded bags (COBs). The secondary aim of this study was to assess and compare preparation time and errors related to the production and preparation processes of PN bags. MATERIALS AND METHODS: A prospective, observational, cost-accounting study was conducted in 10 Spanish hospital pharmacy services. The cost assessments included components, raw materials, and hospital staff. Only PN bags with equivalent volume and nutrition value were included in the analyses. Assessment of errors related to PN was performed simultaneously with the cost and time comparison analyses. RESULTS: Among the 597 PN bags (295 MCBs, 302 COBs) evaluated, 392 PN bags (295 MCBs, 97 COBs) had an equivalent volume and nutrition value. The mean (standard deviation) total cost of the MCB was $62.11 ($12.34) per bag compared with $67.54 ($8.50) per bag for COBs, resulting in a significant cost savings of $5.71. On average, the time required to prepare an MCB was 38 minutes shorter (P < .001). Significantly fewer total number (percent) of errors was observed in the preparation of MCBs (3 [1.0%]) compared with COBs (15 [5.0%]); P < .01). CONCLUSION: The use of MCBs results in significant savings in cost and preparation time, which may have a beneficial effect on the economic burden associated with PN as well as a reduction in errors related to PN preparation.

Experience With the Use of Rituximab for the Treatment of Rheumatoid Arthritis in a Tertiary Hospital in Spain: RITAR Study.

BACKGROUND/OBJECTIVE: There is evidence supporting that there are no relevant clinical differences between dosing rituximab 1000 mg or 2000 mg per cycle in rheumatoid arthritis (RA) patients in clinical trials, and low-dose cycles seem to have a better safety profile. Our objective was to describe the pattern of use of rituximab in real-life practice conditions. METHODS: Rituximab for RA in clinical practice (RITAR) study is a retrospective cohort study from 2005 to 2015. Eligibility criteria were RA adults treated with rituximab for active articular disease. Response duration was the main outcome defined as months elapsed from the date of rituximab first infusion to the date of flare. A multivariable analysis was performed to determine the variables associated with response duration. RESULTS: A total of 114 patients and 409 cycles were described, 93.0% seropositive and 80.7% women. Rituximab was mainly used as second-line biological therapy. On demand retreatment was used in 94.6% of cases versus fixed 6 months retreatment in 5.4%. Median response duration to on demand rituximab cycles was 10 months (interquartile range, 7-13). Multivariable analysis showed that age older than 65 years, number of rituximab cycles, seropositivity, and first- or second-line therapy were associated with longer response duration. The dose administered at each cycle was not significantly associated with response duration. CONCLUSIONS: Our experience suggests that 1000 mg rituximab single infusion on demand is a reasonable schedule for long-term treatment of those patients with good response after the first cycles, especially in seropositive patients and when it is applied as a first- or second-line biological therapy.

Complex Care Needs in Multiple Chronic Conditions: Population Prevalence and Characterization in Primary Care. A Study Protocol.

BACKGROUND: Chronicity, and particularly complex care needs for people with chronic diseases is one of the main challenges of health systems. OBJECTIVE: To determine the population prevalence of people with chronic diseases and complex care needs and to characterize these needs considering features of health and social complexity in Primary Care. DESIGN: Cross-sectional population-based study. SCOPE: Patients who have one or more chronic health conditions from three Primary Care urban centres of a reference population of 43.647 inhabitants older than 14 years old. METHODOLOGY: Data will be obtained from the review of electronical medical records. Complexity will be defined by: 1) the independent clinical judgment of primary care physicians and nurses and 2) the aid of three complexity domains (clinical and social). Patients with advanced chronic disease and limited life prognosis will be also described. CONCLUSIONS: This research protocol intends to describe and analyse complex care needs from a primary care professional perspective in order to improve knowledge of complexity beyond multimorbidity and previous consumption of health resources. Knowing about health and social complexity with a more robust empirical basis could help for a better integration of social and health policies and a more proactive and differentiated care approach in this most vulnerable population.

Large-scale assessment of myxomatosis prevalence in European wild rabbits (Oryctolagus cuniculus) 60years after first outbreak in Spain.

Myxomatosis is a viral disease that affects European rabbits (Oryctolagus cuniculus) worldwide. In Spain, populations of wild rabbits drastically decreased in the 1950s after the first outbreak of myxomatosis. Since that first appearance, it seems to be an annual epizootic in Spain with periodic outbreaks, predominantly in summer and autumn. Taking into account rabbit population structure, abundance, and genetic lineage, this paper attempts to make a large-scale characterization of myxomatosis seroprevalence based on the immune status of 29 rabbit populations distributed throughout Spain, where O. cuniculus cuniculus and O. c. algirus, the two known rabbit subspecies, naturally inhabit. A total of 654 samples were collected between 2003 and 2009, and seroprevalence of antibodies against Myxoma virus (MYXV) was determined. Overall, our results revealed that 53% of the rabbit samples were positive to antibodies against MYXV. Newborn and juvenile rabbits were the most susceptible animals to the virus, with 19% and 16% seropositivity for newborn and juveniles, respectively, while adult rabbits were the most protected, with 65% of seropositive samples. This suggests that prevalence is negatively related to the proportion of newborn and juvenile rabbits in a population. Our results also showed that seroprevalence against MYXV tended to be higher in high-abundance populations. In contrast, no differences were detected in seroprevalence between rabbit subspecies. This study confirms that >60years since first outbreak, myxomatosis is an endemic disease in Spain. Based on the results, the establishment of a myxomatosis surveillance protocol is proposed.

Level of distress, somatisation and beliefs on health-disease in newly arrived immigrant patients attended in primary care centres in Catalonia and definition of professional competences for their most effective management: PROMISE Project.

BACKGROUND: Newly arrived immigrant patients who frequently use primary health care resources have difficulties in verbal communication. Also, they have a system of beliefs related to health and disease that makes difficult for health care professionals to comprehend their reasons for consultation, especially when consulting for somatic manifestations. Consequently, this is an important barrier to achieve optimum care to these groups. The current project has two main objectives: 1. To define the different stressors, the level of distress perceived, and its impact in terms of discomfort and somatisation affecting the main communities of immigrants in our area, and 2. To identify the characteristics of cross-cultural competence of primary health care professionals to best approach these reasons for consultation. METHODS/DESIGN: It will be a transversal, observational, multicentre, qualitative-quantitative study in a sample of 980 people from the five main non-European Union immigrant communities residing in Catalonia: Maghrebis, Sub-Saharans, Andean South Americans, Hindustanis, and Chinese. Sociodemographic data, level of distress, information on the different stressors and their somatic manifestations will be collected in specific questionnaires. Through a semi-structured interview and qualitative methodology, it will be studied the relation between somatic manifestations and particular beliefs of each group and how these are associated with the processes of disease and seeking for care. A qualitative methodology based on individual interviews centred on critical incidents, focal groups and in situ questionnaires will be used to study the cross-cultural competences of the professionals. DISCUSSION: It is expected a high level of chronic stress associated with the level of somatisations in the different non-European Union immigrant communities. The results will provide better knowledge of these populations and will improve the comprehension and the efficacy of the health care providers in prevention, communication, care management and management of resources.

Steep clines within a highly permeable genome across a hybrid zone between two subspecies of the European rabbit.

Maintenance of genetic distinction in the face of gene flow is an important aspect of the speciation process. Here, we provide a detailed spatial and genetic characterization of a hybrid zone between two subspecies of the European rabbit. We examined patterns of allele frequency change for 22 markers located on the autosomes, X-chromosome, Y-chromosome and mtDNA in 1078 individuals sampled across the hybrid zone. While some loci revealed extremely wide clines (w ≥ 300 km) relative to an estimated dispersal of 1.95-4.22 km/generation, others showed abrupt transitions (w ≈ 10 km), indicating localized genomic regions of strong selection against introgression. The subset of loci showing steep clines had largely coincident centers and stepped changes in allele frequency that did not co-localize with any physical barrier or ecotone, suggesting that the rabbit hybrid zone is a tension zone. The steepest clines were for X- and Y-chromosome markers. Our results are consistent with previous inference based on DNA sequence variation of individuals sampled in allopatry in suggesting that a large proportion of each genome has escaped the overall barrier to gene flow in the middle of the hybrid zone. These results imply an old history of hybridization and high effective gene flow and anticipate that isolation factors should often localize to small genomic regions.