Is diabetes a risk factor for a severe clinical presentation of dengue?--review and meta-analysis.

BACKGROUND: The mean age of acute dengue has undergone a shift towards older ages. This fact points towards the relevance of assessing the influence of age-related comorbidities, such as diabetes, on the clinical presentation of dengue episodes. Identification of factors associated with a severe presentation is of high relevance, because timely treatment is the most important intervention to avert complications and death. This review summarizes and evaluates the published evidence on the association between diabetes and the risk of a severe clinical presentation of dengue. METHODOLOGY/FINDINGS: A systematic literature review was conducted using the MEDLINE database to access any relevant association between dengue and diabetes. Five case-control studies (4 hospital-based, 1 population-based) compared the prevalence of diabetes (self-reported or abstracted from medical records) of persons with dengue (acute or past; controls) and patients with severe clinical manifestations. All except one study were conducted before 2009 and all studies collected information towards WHO 1997 classification system. The reported odds ratios were formally summarized by random-effects meta-analyses. A diagnosis of diabetes was associated with an increased risk for a severe clinical presentation of dengue (OR 1.75; 95% CI: 1.08-2.84, p = 0.022). CONCLUSIONS/SIGNIFICANCE: Large prospective studies that systematically and objectively obtain relevant signs and symptoms of dengue fever episodes as well as of hyperglycemia in the past, and at the time of dengue diagnosis, are needed to properly address the effect of diabetes on the clinical presentation of an acute dengue fever episode. The currently available epidemiological evidence is very limited and only suggestive. The increasing global prevalence of both dengue and diabetes justifies further studies. At this point, confirmation of dengue infection as early as possible in diabetes patients with fever if living in dengue endemic regions seems justified. The presence of this co-morbidity may warrant closer observation for glycemic control and adapted fluid management to diminish the risk for a severe clinical presentation of dengue.

Population pharmacokinetic study to evaluate dosing strategies of imipenem in neonates and infants

Objective: Imipenem is a broad spectrum antibiotic used to treat severe infections in critically ill patients. Imipenem pharmacokinetics (PK) was evaluated in a cohort of neonates treated in the Neonatal Intensive Care Unit of the Lausanne University Hospital. The objective of our study was to identify key demographic and clinical factors influencing imipenem exposure in this population. Method: PK data from neonates and infants with at least one imipenem concentration measured between 2002 and 2013 were analyzed applying population PK modeling methods. Measurement of plasma concentrations were performed upon the decision of the physician within the frame of a therapeutic drug monitoring (TDM) programme. Effects of demographic (sex, body weight, gestational age, postnatal age) and clinical factors (serum creatinine as a measure of kidney function; co-administration of furosemide, spironolactone, hydrochlorothiazide, vancomycin, metronidazole and erythromycin) on imipenem PK were explored. Model-based simulations were performed (with a median creatinine value of 46 μmol/l) to compare various dosing regimens with respect to their ability to maintain drug levels above predefined minimum inhibitory concentrations (MIC) for at least 40 % of the dosing interval. Results: A total of 144 plasma samples was collected in 68 neonates and infants, predominantly preterm newborns, with median gestational age of 27 weeks (24 - 41 weeks) and postnatal age of 21 days (2 - 153 days). A two-compartment model best characterized imipenem disposition. Actual body weight exhibited the greatest impact on PK parameters, followed by age (gestational age and postnatal age) and serum creatinine on clearance. They explain 19%, 9%, 14% and 9% of the interindividual variability in clearance respectively. Model-based simulations suggested that 15 mg/kg every 12 hours maintain drug concentrations over a MIC of 2 mg/l for at least 40% of the dosing interval during the first days of life, whereas neonates older than 14 days of life required a dose of 20 mg/kg every 12 hours. Conclusion: Dosing strategies based on body weight and post-natal age are recommended for imipenem in all critically ill neonates and infants. Most current guidelines seem adequate for newborns and TDM should be restricted to some particular clinical situations.

COMPASS identifies T-cell subsets correlated with clinical outcomes.

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software.

Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori.

Helicobacter pylori is an important human pathogen associated with serious gastric diseases. Owing to its medical importance and close relationship with its human host, understanding genomic patterns of global and local adaptation in H. pylori may be of particular significance for both clinical and evolutionary studies. Here we present the first such whole genome analysis of 60 globally distributed strains, from which we inferred worldwide population structure and demographic history and shed light on interesting global and local events of positive selection, with particular emphasis on the evolution of San-associated lineages. Our results indicate a more ancient origin for the association of humans and H. pylori than previously thought. We identify several important perspectives for future clinical research on candidate selected regions that include both previously characterized genes (e.g., transcription elongation factor NusA and tumor necrosis factor alpha-inducing protein Tipα) and hitherto unknown functional genes.

Serum 25-hydroxyvitamin D level and kidney function decline in a Swiss general adult population.

Molecular evidence suggests that levels of vitamin D are associated with kidney function loss. Still, population-based studies are limited and few have considered the potential confounding effect of baseline kidney function. This study evaluated the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline, and incidence of CKD and albuminuria. Baseline (2003-2006) and 5.5-year follow-up data from a Swiss adult general population were used to evaluate the association of serum 25-hydroxyvitamin D with change in eGFR, rapid eGFR decline (annual loss >3 ml/min per 1.73 m(2)), and incidence of CKD and albuminuria. Serum 25-hydroxyvitamin D was measured at baseline using liquid chromatography-tandem mass spectrometry. eGFR and albuminuria were collected at baseline and follow-up. Multivariate linear and logistic regression models were used considering potential confounding factors. Among the 4280 people included in the analysis, the mean±SD annual eGFR change was -0.57±1.78 ml/min per 1.73 m(2), and 287 (6.7%) participants presented rapid eGFR decline. Before adjustment for baseline eGFR, baseline 25-hydroxyvitamin D level was associated with both mean annual eGFR change and risk of rapid eGFR decline, independently of baseline albuminuria. Once adjusted for baseline eGFR, associations were no longer significant. For every 10 ng/ml higher baseline 25-hydroxyvitamin D, the adjusted mean annual eGFR change was -0.005 ml/min per 1.73 m(2) (95% confidence interval, -0.063 to 0.053; P=0.87) and the risk of rapid eGFR decline was null (odds ratio, 0.93; 95% confidence interval, 0.79 to 1.08; P=0.33). Baseline 25-hydroxyvitamin D level was not associated with incidence of CKD or albuminuria. The association of 25-hydroxyvitamin D with eGFR decline is confounded by baseline eGFR. Sufficient 25-hydroxyvitamin D levels do not seem to protect from eGFR decline independently from baseline eGFR.

Sociodemographic Factors and Clinical Conditions Associated to Hospitalization in Influenza A (H1N1) 2009 Virus Infected Patients in Spain, 2009-2010

The emergence and pandemic spread of a new strain of influenza A (H1N1) virus in 2009 resulted in a serious alarm in clinical and public health services all over the world. One distinguishing feature of this new influenza pandemic was the different profile of hospitalized patients compared to those from traditional seasonal influenza infections. Our goal was to analyze sociodemographic and clinical factors associated to hospitalization following infection by influenza A(H1N1) virus. We report the results of a Spanish nationwide study with laboratory confirmed infection by the new pandemic virus in a case-control design based on hospitalized patients. The main risk factors for hospitalization of influenza A (H1N1) 2009 were determined to be obesity (BMI≥40, with an odds-ratio [OR] 14.27), hematological neoplasia (OR 10.71), chronic heart disease, COPD (OR 5.16) and neurological disease, among the clinical conditions, whereas low education level and some ethnic backgrounds (Gypsies and Amerinds) were the sociodemographic variables found associated to hospitalization. The presence of any clinical condition of moderate risk almost triples the risk of hospitalization (OR 2.88) and high risk conditions raise this value markedly (OR 6.43). The risk of hospitalization increased proportionally when for two (OR 2.08) or for three or more (OR 4.86) risk factors were simultaneously present in the same patient. These findings should be considered when a new influenza virus appears in the human population.

Type 1 diabetes mellitus in people with pharmacoresistant epilepsy: Prevalence and clinical characteristics.

BACKGROUND: There have been inconsistent reports on the potential association between diabetes mellitus and epilepsy. METHODS: We examined a consecutive cohort of 2016 people with pharmacoresistant epilepsy admitted to a tertiary medical centre. RESULTS: We identified 20 individuals with type 1 diabetes mellitus (T1DM); a point prevalence of 9.9 (95% CI: 6.4, 15.3) cases per 1000 individuals. This represents a more than two-fold increase relative to published prevalence estimates of T1DM in the general population. The onset of T1DM preceded that of epilepsy in 80% of individuals, by a median of 1.5 years. Individuals with T1DM were significantly more likely to have cryptogenic/unknown epilepsy relative to those with type 2 diabetes mellitus or without diabetes (85% versus 35% and 49%, p=0.045). All individuals with T1DM had focal epilepsy, the majority of which were temporal lobe in origin, although there was no evidence that this proportion was any different from those without T1DM (p>0.999). CONCLUSIONS: The prevalence of T1DM appears to be increased in people with pharmacoresistant epilepsy and is associated with cryptogenic/unknown epilepsy. These findings may have pathophysiological implications, especially in the context of anti-glutamic acid decarboxylase antibodies.

Cognitive anatomy of the temporal lobe: Effect of personality in population with mild cognitive impairment & Functional specialization for memory systems in healthy individuals.

Résumé: L'impact de la maladie d'Alzheimer (MA) est dévastateur pour la vie quotidienne de la personne affectée, avec perte progressive de la mémoire et d'autres facultés cognitives jusqu'à la démence. Il n'existe toujours pas de traitement contre cette maladie et il y a aussi une grande incertitude sur le diagnostic des premiers stades de la MA. La signature anatomique de la MA, en particulier l'atrophie du lobe temporal moyen (LTM) mesurée avec la neuroimagerie, peut être utilisée comme un biomarqueur précoce, in vivo, des premiers stades de la MA. Toutefois, malgré le rôle évident du LMT dans les processus de la mémoire, nous savons que les modèles anatomiques prédictifs de la MA basés seulement sur des mesures d'atrophie du LTM n'expliquent pas tous les cas cliniques. Au cours de ma thèse, j'ai conduit trois projets pour comprendre l'anatomie et le fonctionnement du LMT dans (1) les processus de la maladie et dans (2) les processus de mémoire ainsi que (3) ceux de l'apprentissage. Je me suis intéressée à une population avec déficit cognitif léger (« Mild Cognitive Impairment », MCI), à risque pour la MA. Le but du premier projet était de tester l'hypothèse que des facteurs, autres que ceux cognitifs, tels que les traits de personnalité peuvent expliquer les différences interindividuelles dans le LTM. De plus, la diversité phénotypique des manifestations précliniques de la MA provient aussi d'une connaissance limitée des processus de mémoire et d'apprentissage dans le cerveau sain. L'objectif du deuxième projet porte sur l'investigation des sous-régions du LTM, et plus particulièrement de leur contribution dans différentes composantes de la mémoire de reconnaissance chez le sujet sain. Pour étudier cela, j'ai utilisé une nouvelle méthode multivariée ainsi que l'IRM à haute résolution pour tester la contribution de ces sous-régions dans les processus de familiarité (« ou Know ») et de remémoration (ou « Recollection »). Finalement, l'objectif du troisième projet était de tester la contribution du LTM en tant que système de mémoire dans l'apprentissage et l'interaction dynamique entre différents systèmes de mémoire durant l'apprentissage. Les résultats du premier projet montrent que, en plus du déficit cognitif observé dans une population avec MCI, les traits de personnalité peuvent expliquer les différences interindividuelles du LTM ; notamment avec une plus grande contribution du neuroticisme liée à une vulnérabilité au stress et à la dépression. Mon étude a permis d'identifier un pattern d'anormalité anatomique dans le LTM associé à la personnalité avec des mesures de volume et de diffusion moyenne du tissu. Ce pattern est caractérisé par une asymétrie droite-gauche du LTM et un gradient antéro-postérieur dans le LTM. J'ai interprété ce résultat par des propriétés tissulaires et neurochimiques différemment sensibles au stress. Les résultats de mon deuxième projet ont contribué au débat actuel sur la contribution des sous-régions du LTM dans les processus de familiarité et de remémoration. Utilisant une nouvelle méthode multivariée, les résultats supportent premièrement une dissociation des sous-régions associées aux différentes composantes de la mémoire. L'hippocampe est le plus associé à la mémoire de type remémoration et le cortex parahippocampique, à la mémoire de type familiarité. Deuxièmement, l'activation correspondant à la trace mnésique pour chaque type de mémoire est caractérisée par une distribution spatiale distincte. La représentation neuronale spécifique, « sparse-distributed», associée à la mémoire de remémoration dans l'hippocampe serait la meilleure manière d'encoder rapidement des souvenirs détaillés sans interférer les souvenirs précédemment stockés. Dans mon troisième projet, j'ai mis en place une tâche d'apprentissage en IRM fonctionnelle pour étudier les processus d'apprentissage d'associations probabilistes basé sur le feedback/récompense. Cette étude m'a permis de mettre en évidence le rôle du LTM dans l'apprentissage et l'interaction entre différents systèmes de mémoire comme la mémoire procédurale, perceptuelle ou d'amorçage et la mémoire de travail. Nous avons trouvé des activations dans le LTM correspondant à un processus de mémoire épisodique; les ganglions de la base (GB), à la mémoire procédurale et la récompense; le cortex occipito-temporal (OT), à la mémoire de représentation perceptive ou l'amorçage et le cortex préfrontal, à la mémoire de travail. Nous avons également observé que ces régions peuvent interagir; le type de relation entre le LTM et les GB a été interprété comme une compétition, ce qui a déjà été reporté dans des études récentes. De plus, avec un modèle dynamique causal, j'ai démontré l'existence d'une connectivité effective entre des régions. Elle se caractérise par une influence causale de type « top-down » venant de régions corticales associées avec des processus de plus haut niveau venant du cortex préfrontal sur des régions corticales plus primaires comme le OT cortex. Cette influence diminue au cours du de l'apprentissage; cela pourrait correspondre à un mécanisme de diminution de l'erreur de prédiction. Mon interprétation est que cela est à l'origine de la connaissance sémantique. J'ai également montré que les choix du sujet et l'activation cérébrale associée sont influencés par les traits de personnalité et des états affectifs négatifs. Les résultats de cette thèse m'ont amenée à proposer (1) un modèle expliquant les mécanismes possibles liés à l'influence de la personnalité sur le LTM dans une population avec MCI, (2) une dissociation des sous-régions du LTM dans différents types de mémoire et une représentation neuronale spécifique à ces régions. Cela pourrait être une piste pour résoudre les débats actuels sur la mémoire de reconnaissance. Finalement, (3) le LTM est aussi un système de mémoire impliqué dans l'apprentissage et qui peut interagir avec les GB par une compétition. Nous avons aussi mis en évidence une interaction dynamique de type « top -down » et « bottom-up » entre le cortex préfrontal et le cortex OT. En conclusion, les résultats peuvent donner des indices afin de mieux comprendre certains dysfonctionnements de la mémoire liés à l'âge et la maladie d'Alzheimer ainsi qu'à améliorer le développement de traitement. Abstract: The impact of Alzheimer's disease is devastating for the daily life of the affected patients, with progressive loss of memory and other cognitive skills until dementia. We still lack disease modifying treatment and there is also a great amount of uncertainty regarding the accuracy of diagnostic classification in the early stages of AD. The anatomical signature of AD, in particular the medial temporal lobe (MTL) atrophy measured with neuroimaging, can be used as an early in vivo biomarker in early stages of AD. However, despite the evident role of MTL in memory, we know that the derived predictive anatomical model based only on measures of brain atrophy in MTL does not explain all clinical cases. Throughout my thesis, I have conducted three projects to understand the anatomy and the functioning of MTL on (1) disease's progression, (2) memory process and (3) learning process. I was interested in a population with mild cognitive impairment (MCI), at risk for AD. The objective of the first project was to test the hypothesis that factors, other than the cognitive ones, such as the personality traits, can explain inter-individual differences in the MTL. Moreover, the phenotypic diversity in the manifestations of preclinical AD arises also from the limited knowledge of memory and learning processes in healthy brain. The objective of the second project concerns the investigation of sub-regions of the MTL, and more particularly their contributions in the different components of recognition memory in healthy subjects. To study that, I have used a new multivariate method as well as MRI at high resolution to test the contribution of those sub-regions in the processes of familiarity and recollection. Finally, the objective of the third project was to test the contribution of the MTL as a memory system in learning and the dynamic interaction between memory systems during learning. The results of the first project show that, beyond cognitive state of impairment observed in the population with MCI, the personality traits can explain the inter-individual differences in the MTL; notably with a higher contribution of neuroticism linked to proneness to stress and depression. My study has allowed identifying a pattern of anatomical abnormality in the MTL related to personality with measures of volume and mean diffusion of the tissue. That pattern is characterized by right-left asymmetry in MTL and an anterior to posterior gradient within MTL. I have interpreted that result by tissue and neurochemical properties differently sensitive to stress. Results of my second project have contributed to the actual debate on the contribution of MTL sub-regions in the processes of familiarity and recollection. Using a new multivariate method, the results support firstly a dissociation of the subregions associated with different memory components. The hippocampus was mostly associated with recollection and the surrounding parahippocampal cortex, with familiarity type of memory. Secondly, the activation corresponding to the mensic trace for each type of memory is characterized by a distinct spatial distribution. The specific neuronal representation, "sparse-distributed", associated with recollection in the hippocampus would be the best way to rapidly encode detailed memories without overwriting previously stored memories. In the third project, I have created a learning task with functional MRI to sudy the processes of learning of probabilistic associations based on feedback/reward. That study allowed me to highlight the role of the MTL in learning and the interaction between different memory systems such as the procedural memory, the perceptual memory or priming and the working memory. We have found activations in the MTL corresponding to a process of episodic memory; the basal ganglia (BG), to a procedural memory and reward; the occipito-temporal (OT) cortex, to a perceptive memory or priming and the prefrontal cortex, to working memory. We have also observed that those regions can interact; the relation type between the MTL and the BG has been interpreted as a competition. In addition, with a dynamic causal model, I have demonstrated a "top-down" influence from cortical regions associated with high level cortical area such as the prefrontal cortex on lower level cortical regions such as the OT cortex. That influence decreases during learning; that could correspond to a mechanism linked to a diminution of prediction error. My interpretation is that this is at the origin of the semantic knowledge. I have also shown that the subject's choice and the associated brain activation are influenced by personality traits and negative affects. Overall results of this thesis have brought me to propose (1) a model explaining the possible mechanism linked to the influence of personality on the MTL in a population with MCI, (2) a dissociation of MTL sub-regions in different memory types and a neuronal representation specific to each region. This could be a cue to resolve the actual debates on recognition memory. Finally, (3) the MTL is also a system involved in learning and that can interact with the BG by a competition. We have also shown a dynamic interaction of « top -down » and « bottom-up » types between the pre-frontal cortex and the OT cortex. In conclusion, the results could give cues to better understand some memory dysfunctions in aging and Alzheimer's disease and to improve development of treatment.

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.Genet Med 17 8, 651-659.

Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort.

BACKGROUND: High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. OBJECTIVE: Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. METHODS: Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPARα, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM(®)). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. RESULTS: The cytochrome P450 (CYP) 2D6 phenotype explained 52 % of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28 % higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26 % with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response. CONCLUSIONS: Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment.

Home Blood Pressure Measurement – Epidemiology and Clinical Application

Verenpaineen kotimittaus − epidemiologia ja kliininen käyttö Kohonnutta verenpainetta, maailmanlaajuisesti merkittävintä ennenaikaiselle kuolemalle altistavaa riskitekijää, ei voida tunnistaa tai hoitaa ilman tarkkoja ja käytännöllisiä verenpaineen mittausmenetelmiä. Verenpaineen kotimittaus on saavuttanut suuren suosion potilaiden keskuudessa. Lääkärit eivät ole kuitenkaan vielä täysin hyväksyneet verenpaineen kotimittausta, sillä riittävä todistusaineisto sen toimivuudesta ja eduista on puuttunut. Tämän tutkimuksen tarkoituksena oli osoittaa, että kotona mitattu verenpaine (kotipaine) on perinteistä vastaanotolla mitattua verenpainetta (vastaanottopaine) tarkempi, ja että se on tehokas myös kliinisessä käytössä. Tutkimme kotipaineen käyttöä verenpainetaudin diagnosoinnissa ja hoidossa. Lisäksi tarkastelimme kotipaineen yhteyttä verenpainetaudin aiheuttamiin kohde-elinvaurioihin. Ensimmäinen aineisto, joka oli edustava otos Suomen aikuisväestöstä, koostui 2 120 45–74-vuotiaasta tutkimushenkilöstä. Tutkittavat mittasivat kotipainettaan viikon ajan ja osallistuivat terveystarkastukseen, johon sisältyi kliinisen tutkimuksen ja haastattelun lisäksi sydänfilmin otto ja vastaanottopaineen mittaus. 758 tutkittavalle suoritettiin lisäksi kaulavaltimon seinämän intima-mediakerroksen paksuuden (valtimonkovettumataudin mittari) mittaus ja 237:lle valtimon pulssiaallon nopeuden (valtimojäykkyyden mittari) mittaus. Toisessa aineistossa, joka koostui 98 verenpainetautia sairastavasta potilaasta, hoitoa ohjattiin satunnaistamisesta riippuen joko ambulatorisen eli vuorokausirekisteröinnillä mitatun verenpaineen tai kotipaineen perusteella. Vastaanottopaine oli kotipainetta merkittävästi korkeampi (systolisen/diastolisen paineen keskiarvoero oli 8/3 mmHg) ja yksimielisyys verenpainetaudin diagnoosissa kahden menetelmän välillä oli korkeintaan kohtalainen (75 %). 593 tutkittavasta, joilla oli kohonnut verenpaine vastaanotolla, 38 %:lla oli normaali verenpaine kotona eli ns. valkotakkiverenpaine. Verenpainetauti voidaan siis ylidiagnosoida joka kolmannella potilaalla seulontatilanteessa. Valkotakkiverenpaine oli yhteydessä lievästi kohonneeseen verenpaineeseen, matalaan painoindeksiin ja tupakoimattomuuteen, muttei psykiatriseen sairastavuuteen. Valkotakkiverenpaine ei kuitenkaan vaikuttaisi olevan täysin vaaraton ilmiö ja voi ennustaa tulevaa verenpainetautia, sillä siitä kärsivien sydän- ja verisuonitautien riskitekijäprofiili oli normaalipaineisten ja todellisten verenpainetautisten riskitekijäprofiilien välissä. Kotipaineella oli vastaanottopainetta vahvempi yhteys verenpainetaudin aiheuttamiin kohde-elinvaurioihin (intima-mediakerroksen paksuus, pulssiaallon nopeus ja sydänfilmistä todettu vasemman kammion suureneminen). Kotipaine oli tehokas verenpainetaudin hoidon ohjaaja, sillä kotipaineeseen ja ambulatoriseen paineeseen, jota on pidetty verenpainemittauksen ”kultaisena standardina”, perustuva lääkehoidon ohjaus johti yhtä hyvään verenpaineen hallintaan. Tämän ja aikaisempien tutkimusten tulosten pohjalta voidaan todeta, että verenpaineen kotimittaus on selkeä parannus perinteiseen vastaanotolla tapahtuvaan verenpainemittaukseen verrattuna. Verenpaineen kotimittaus on käytännöllinen, tarkka ja laajasti saatavilla oleva menetelmä, josta voi tulla jopa ensisijainen vaihtoehto verenpainetautia diagnosoitaessa ja hoitaessa. Verenpaineen mittauskäytäntöön tarvitaan muutos, sillä näyttöön perustuvan lääketieteen perusteella vaikuttaa, että vastaanotolla tapahtuvaa verenpainemittausta tulisi käyttää vain seulontatarkoitukseen.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in france and characterization of biochemical and clinical features.

PURPOSE: To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report 6 novel mutations, to characterize the biochemical features of a recurrent novel mutation, and to study the clinical features of adRP patients. DESIGN: Retrospective clinical and molecular genetic study. METHODS: Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging, and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot. RESULTS: We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1-0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families. CONCLUSIONS: The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0%-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases, which could be underdiagnosed.

Pharmacogenetic and clinical study on adverse effects induced by psychotropic drugs

Second-generation antipsychotics (SGAs) have become the first-line antipsychotic treatment for psychotic disorders due to their better overall tolerance compared to classical antipsychotics. However, metabolic side effects such as weight gain are frequently described during treatment with SGAs and/or other psychotropic drugs including some antidepressants and mood stabilizers, which may also result in poor adherence to treatment. The aim of this work was to investigate different methods to predict common side effects, in particular weight gain during treatment with weight gain inducing psychotropic drugs. Firstly, clinical data were used to determine the potential predictive power of a one month weight gain on weight increase after three and 12 months of treatment (n=351 patients). A fast and strong weight gain of >5% after a period of one month (>5%WG) was found to be the best predictor for an important weight gain at three (>15%) and 12 months (>20%). Similar analyses in an independent cohort of psychiatric adolescents (n=42), showed that a comparable >4% weight gain at one month is the best predictor for an important weight gain at three months (>15%). Secondly, we aimed to determine whether an extensive analysis of genes could be used, in addition to clinical factors, to predict patients at risk for >5%WG or for type 2 diabetes (T2D). Adding genetic markers to clinical variables to predict >5%WG increased significantly the area under the curve (AUC) of the analysis (AUCfinai:0.92, AUCdmicai:0.75, pcO.OOOl, n=248). Conversely, genetic risk scores were found to be associated with T2D (OR: 2.5, p=0.03, n=285) but without a significant increase of AUC'when compared to the prediction based to clinical factors alone. Finally, therapeutic drug monitoring was used to predict extrapyramidal symptoms during risperidone treatment (n=150). Active moiety (sum of risperidone and of its active metabolite 9- hydroxyrisperidone plasma concentrations) of >40 ng/ml should be targeted only in case of insufficient response. These results highlight different approaches for personalizing psychotropic treatments in order to reduce related side effects. Further research is needed, in particular on the identification of genetic markers, to improve the implementation of these results into clinical practice. Résumé Les antipsychotiques atypiques (APA) sont devenus le traitement antipsychotique de première intention pour le traitement des psychoses, grâce à un profil d'effets secondaires plus favorables comparé aux antipsychotiques typiques. Néanmoins, d'autres effets indésirables d'ordre métabolique (ex. prise pondérale) sont observés sous APA, stabilisateurs de l'humeur et/ou certains antidépresseurs, pouvant aussi limiter l'adhérence au traitement. L'objectif de ce travail est d'explorer différentes méthodes permettant de prédire des effets secondaires courants, en particulier la prise de poids durant un traitement avec des psychotropes pouvant induire un tel effet. Dans une première partie, des données cliniques ont été évaluées pour leurs potentiels prédictifs d'une prise de poids à un mois sur une prise de poids à trois et 12 mois de traitement (n=351 patients). Une prise de poids rapide et forte >5% à un mois (PP>5%) s'est avérée être le meilleur prédicteur pour une prise pondérale importante à trois (>15%) et 12 (>20%) mois de traitement. Des analyses similaires dans une cohorte pédiatrique (n=42) ont indiqué une prise de poids >4% à un mois comme le meilleur prédicteur pour une prise pondérale importante (>15%) à trois mois de traitement. Dans une deuxième partie, des marqueurs génétiques, en complément aux données cliniques, ont été analysés pour leur contribution potentielle à la prédiction d'une PP>5% et au dépistage du diabète de type 2 (DT2). L'ajout de variants génétiques aux données cliniques afin de prédire une PP>5% a augmenté significativement l'aire sous la courbe (ASC) de l'analyse (ASCflnai:0.92, ASCC|inique:0.75, p<0.0001, n=248). Concernant le DT2, un score génétique est associé au DT2 (OR: 2.5, p=0.03, n=285), néanmoins aucune augmentation significative de l'ASC n'a été observée par rapport à l'analyse avec les données cliniques seules. Finalement, des mesures de concentrations plasmatiques de médicaments ont été utilisées pour prédire la survenue de symptômes extrapyramidaux sous rispéridone (n=150). Cette analyse nous a permis d'établir qu'une concentration plasmatique de rispéridone associée à son métabolite actif >40 ng/ml ne devrait être recherchée qu'en cas de réponse clinique insuffisante. Ces différents résultats soulignent différentes approches pour personnaliser la prescription de psychotropes afin de réduire la survenue d'effets secondaires. Des études supplémentaires sont néanmoins nécessaires, en particulier sur l'identification de marqueurs génétiques, afin d'améliorer l'implémentation de ces résultats en pratique clinique. Résumé large publique Les antipsychotiques atypiques et autres traitements psychotropes sont couramment utilisés pour traiter les symptômes liés à la schizophrénie et aux troubles de l'humeur. Comme pour tout médicament, des effets secondaires sont observés. L'objectif de ce travail est d'explorer différentes méthodes qui permettraient de prédire la survenue de certains effets indésirables, en particulier une prise de poids et la survenue d'un diabète. Dans une première partie, nous avons évalué l'effet d'une prise de poids précoce sur une prise de poids au long terme sous traitement psychotrope. Les analyses ont mis en évidence dans une population psychiatrique qu'une prise de poids à un mois >5% par rapport au poids initial permettait de prédire une prise pondérale importante après trois (>15%) et 12 (>20%) mois de traitement. Un résultat semblable a. été observé dans un autre groupe de patients exclusivement pédiatriques. Dans une deuxième partie, nous avons évalué la contribution potentielle de marqueurs génétiques à la prédiction d'une prise pondérale de >5% après un mois de traitement ainsi que dans la survenue d'un diabète de type 2. Pour la prise de poids, la combinaison des données génétiques aux données cliniques a permis d'augmenter de 17% la précision de la prédiction, en passant de 70% à 87%. Concernant la survenue d'un diabète, les données génétiques n'ont pas amélioré la prédiction. Finalement, nous avons analysé la relation possible entre les concentrations sanguines d'un antipsychotique atypique couramment utilisé, la rispéridone, et la survenue d'effets secondaires (ici les tremblements). Il est ressorti de cette étude qu'une concentration plasmatique du médicament supérieure à 40 ng/ml ne devrait être dépassée qu'en cas de réponse thérapeutique insuffisante, au risque de voir augmenter la survenue d'effets secondaires du type tremblements. Ces résultats démontrent la possibilité de prédire avec une bonne précision la survenue de certains effets secondaires. Cependant, en particulier dans le domaine de la génétique, d'autres études sont nécessaires afin de confirmer les résultats obtenus dans nos analyses. Une fois cette étape franchie, il serait possible d'utiliser ces outils dans la pratique clinique. A terme, cela pourrait permettre au prescripteur de sélectionner les traitements les mieux adaptés aux profils spécifiques de chaque patient.