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Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome. We enrolled adults (aged 16–34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711. The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: −4·58 s [–8·54 to −0·62], p=0·024; d −0·27 [–0·72 to −0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [–0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups. EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training. Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

This volume contains the proceedings of the AMS Special Session on Celebrating M. M. Rao's Many Mathematical Contributions as he Turns 90 Years Old, held from November 9-10, 2019, at the University of California, Riverside, California.The articles show the effectiveness of abstract analysis for solving fundamental problems of stochastic theory, specifically the use of functional analytic methods for elucidating stochastic processes and their applications. The volume also includes a biography of M. M. Rao and the list of his publications.

We are interested in characterising pairs S, T of F-linear subspaces in a field extension L/F such that the linear span ST of the set of products of elements of S and of elements of T has small dimension. Our central result is a linear analogue of Vosper's Theorem, which gives the structure of vector spaces S, T in a prime extension L of a finite field F for which \\begin{linenomath}$$ \\dim_FST =\\dim_F S+\\dim_F T-1, $$\\end{linenomath} when dim FS, dim FT ⩾ 2 and dim FST ⩽ [L : F] − 2.

Purpose The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). Materials and Methods In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy ( n  = 10) or Roux-en-Y gastric bypass ( n  = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. Results Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. Conclusions Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity).

Background There is a scarce number of studies on the cost of agitation and containment interventions and their results are still inconclusive. We aimed to calculate the economic consequences of agitation events in an in-patient psychiatric facility providing care for an urban catchment area. Methods A mixed approach combining secondary analysis of clinical databases, surveys and expert knowledge was used to model the 2013 direct costs of agitation and containment events for adult inpatients with mental disorders in an area of 640,572 adult inhabitants in South Barcelona (Spain). To calculate costs, a seven-step methodology with novel definition of agitation was used along with a staff survey, a database of containment events, and data on aggressive incidents. A micro-costing analysis of specific containment interventions was used to estimate both prevalence and direct costs from the healthcare provider perspective, by means of a mixed approach with a probabilistic model evaluated on real data. Due to the complex interaction of the multivariate covariances, a sensitivity analysis was conducted to have empirical bounds of variability. Results During 2013, 918 patients were admitted to the Acute Inpatient Unit. Of these, 52.8% were men, with a mean age of 44.6 years (SD = 15.5), 74.4% were compulsory admissions, 40.1% were diagnosed with schizophrenia or non-affective psychosis, with a mean length of stay of 24.6 days (SD = 16.9). The annual estimate of total agitation events was 508. The cost of containment interventions ranges from 282€ at the lowest level of agitation to 822€ when verbal containment plus seclusion and restraint have to be used. The annual total cost of agitation was 280,535€, representing 6.87% of the total costs of acute hospitalisation in the local area. Conclusions Agitation events are frequent and costly. Strategies to reduce their number and severity should be implemented to reduce costs to the Health System and alleviate patient suffering.

The areas of Ramsey theory and random graphs have been closely linked ever since Erdos's famous proof in 1947 that the \"diagonal\" Ramsey numbers $R(k)$ grow exponentially in $k$. In the early 1990s, the triangle-free process was introduced as a model which might potentially provide good lower bounds for the \"off-diagonal\" Ramsey numbers $R(3,k)$. In this model, edges of $K_n$ are introduced one-by-one at random and added to the graph if they do not create a triangle; the resulting final (random) graph is denoted $G_n,\\triangle $. In 2009, Bohman succeeded in following this process for a positive fraction of its duration, and thus obtained a second proof of Kim's celebrated result that $R(3,k) = \\Theta \\big ( k^2 / \\log k \\big )$. In this paper the authors improve the results of both Bohman and Kim and follow the triangle-free process all the way to its asymptotic end.

Arterial hypertension is a chronic medical condition associated with an elevated blood pressure. Chronic arterial hypertension initiates a series of events, which are known to collectively initiate arterial wall thickening. However, the correlation between macrostructural mechanical loading, microstructural cellular changes, and macrostructural adaptation remains unclear. Here, we present a microstructurally motivated computational model for chronic arterial hypertension through smooth muscle cell growth. To model growth, we adopt a classical concept based on the multiplicative decomposition of the deformation gradient into an elastic part and a growth part. Motivated by clinical observations, we assume that the driving force for growth is the stretch sensed by the smooth muscle cells. We embed our model into a finite element framework, where growth is stored locally as an internal variable. First, to demonstrate the features of our model, we investigate the effects of hypertensive growth in a real human carotid artery. Our results agree nicely with experimental data reported in the literature both qualitatively and quantitatively.

Background:The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression.Methods:We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis.Results:The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression.Conclusions:The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders.

In this work the mechanical response of the carotid arterial wall is studied. Some limitations of previous models of the arterial wall are overcomed and variability of the fitting problem is reduced. We review some experimental data from the literature and provide a constitutive model to characterize such data. A strain energy function is introduced including the behavior of cross-links between the main collagen fibers. With this function we are able to fit experimental data including information about the microstructure that previous models were not able to do. To demonstrate the applicability of the proposed model a patient-specific carotid artery geometry is reconstructed and simulated in a finite element framework, providing a microstructural description of the arterial wall. Our results qualitatively and quantitatively describe the experimental findings given in the literature fitting macroscopic mechanical tests and improving the features of previously developed models.

Lactococcus lactis is a Gram-positive (endotoxin-free) food-grade bacteria exploited as alternative to Escherichia coli for recombinant protein production. We have explored here for the first time the ability of this platform as producer of complex, self-assembling protein materials. Biophysical properties, cell penetrability and in vivo biodistribution upon systemic administration of tumor-targeted protein nanoparticles produced in L. lactis have been compared with the equivalent material produced in E. coli. Protein nanoparticles have been efficiently produced in L. lactis, showing the desired size, internalization properties and biodistribution. In vitro and in vivo data confirm the potential and robustness of the production platform, pointing out L. lactis as a fascinating cell factory for the biofabrication of protein materials intended for therapeutic applications.