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BACKGROUND The potential of harnessing the plurality of available data in real time along with advanced data analytics towards the accurate prediction of influenza-like-illness (ILI) outbreaks has gained significant scientific interest. Different methodologies based on the use of machine learning techniques and traditional and alternative data sources such as ILI surveillance reports, weather reports, search engine queries, and social media, have been explored with the ultimate goal to be utilized in the development of electronic surveillance systems that could complement existing monitoring resources. OBJECTIVE The aim of the present study is to investigate for the first time the combined use of ILI surveillance data, weather data, and Twitter data, along with deep learning techniques towards the development of prediction models able to nowcast and forecast weekly ILI cases. METHODS The model’s input space consists of information related to weekly ILI surveillance, online social (e.g., Twitter) behavior, and weather conditions. For the design and development of the model, relevant data corresponding to the period 2010-2019 and focusing on the Greek population and weather have been collected. Long short term memory neural networks (LSTMs) are leveraged to efficiently handle the sequential and nonlinear nature of the multitude of collected data. The three data categories are firstly utilized separately for training three LSTM-based primary models. Subsequently, different transfer learning (TL) approaches are explored with the aim of creating various feature spaces combining the features extracted from the corresponding primary models’ LSTM layers in order for the latter to feed a dense layer. RESULTS The primary model which learns from weather data yields better forecast accuracy (root mean square error - RMSE = 0.144, pearson correlation coefficient - PCC= 0.801) than the model which is trained with ILI historical data (RMSE = 0.159, PCC= 0.794). The best performance is achieved by the TL-based model leveraging the combination of the three data categories (RMSE = 0.128, PCC = 0.822). CONCLUSIONS The superiority of the TL-based model which takes into account Twitter data, weather data, and ILI surveillance data reflects the potential of alternative public sources to enhance accurate and reliable prediction of the ILI spread.

Unhealthy dietary habits constitute a major risk factor for the onset of chronic diseases, such as cardiovascular diseases, cancer, diabetes and other conditions linked to obesity. Effective dietary changes are of paramount importance and can be promoted through empowering individuals with Nutrition Literacy (NL) and Food Literacy (FL) skills. This paper presents a novel serious game aiming at building NL and FL skills in adolescents and young adults. It is based on an innovative conceptual framework, incorporating a recipe ontology and a theory driven game design approach maximizing user attractiveness and promoting sustainable effective dietary changes. The ontological modeling of recipes offers game experience personalization while providing a realistic and diverse simulation environment. Modern game design techniques from three game genres (cooking, roguelike, puzzle) are employed along with a compelling plot for engagement purposes.

Cardiovascular Disease (CVD) is an important cause of disability and death among individuals with Diabetes Mellitus (DM). International clinical guidelines for the management of Type 2 DM (T2DM) are founded on primary and secondary prevention and favor the evaluation of CVD related risk factors towards appropriate treatment initiation. CVD risk prediction models can provide valuable tools for optimizing the frequency of medical visits and performing timely preventive and therapeutic interventions against CVD events. The integration of explainability modalities in these models can enhance human understanding on the reasoning process, maximize transparency and embellish trust towards the models’ adoption in clinical practice. The aim of the present study is to develop and evaluate an explainable personalized risk prediction model for the fatal or non-fatal CVD incidence in T2DM individuals. An explainable approach based on the eXtreme Gradient Boosting (XGBoost) and the Tree SHAP (SHapley Additive exPlanations) method is deployed for the calculation of the 5-year CVD risk and the generation of individual explanations on the model’s decisions. Data from the 5- year follow up of 560 patients with T2DM are used for development and evaluation purposes. The obtained results (AUC=71.13%) indicate the potential of the proposed approach to handle the unbalanced nature of the used dataset, while providing clinically meaningful insights about the ensemble model’s decision process.

The multi-proxy investigation of the deep-marine Kottafi Hill section (KHS), a part of the carbonate system of the Miocene Pakhna Formation, Cyprus, involved such proxies as calcareous nannofossil analysis, measurements of the oxygen and carbon isotope composition of the planktonic foraminifer Orbulina universa, and determination of the pollen and palynomorph contents, revealed the importance of these sedimentary sequences in the assessment of the impact of major global events during the middle Miocene on the regional scale. The KHS spans the 20.89–11.6 Ma time interval, during which eighteen OC-rich siltstone intercalated laminae have been deposited under warm and humid climate at 15.5–11.6 Ma. These layers can be possibly considered as the precursors of sapropelic layers mostly developed in the eastern Mediterranean Basin during Pliocene–Holocene. The global glacial events Mi3a–Mi5, traced by δ18O planktonic foraminifera records in the KHS, represent the stepwise cooling phase during the middle Miocene Climate Transition.

Objective To determine whether the time to achieve full oral feeding differed between infants with bronchopulmonary dysplasia (BPD) supported by nasal continuous positive airway pressure (nCPAP) compared with those supported by nCPAP and subsequently transferred to heated, humidified, high-flow nasal cannula oxygen (HHFNC). Design Two-cohort comparison. Setting Tertiary neonatal unit. Patients –72 infants, median gestational age 27 (range 24–32) weeks in the nCPAP group, and 44 infants, median gestational age 27 (range 24–31) weeks in the nCPAP/HHFNC group. Interventions Between 2011 and 2013, infants post extubation were supported by nCPAP and from 2013 infants were supported by nCPAP and then HHFNC. Main outcome measures The postnatal age at which oral feeds were first trialled and full oral feeds established. The length of respiratory support as either nCPAP or nCPAP/HHFNC and the total length of respiratory support and hospital stay were also determined. Subanalysis was undertaken of infants requiring respiratory support beyond 34 weeks postmenstrual age (PMA). Results The postnatal age at trial of first oral feeds was earlier in the nCPAP/HHFNC group (p=0.012), but infants were a shorter time on nCPAP compared with nCPAP/HHFNC (p=0.003). On subgroup analysis, the age to achieve full oral feeds was earlier in the nCPAP/HHFNC group (p Conclusions In infants with BPD who required respiratory support beyond 34 weeks PMA, use of nCPAP then HHFNC was associated with earlier establishment of full oral feeds. Consideration should be given to assessing stable BPD infants with regard to oral feeding while on CPAP.

Introduction: this study explored the differences on the level of medical care required by camp and non-camp resident patients during utilisation of the health services in Mae La refugee camp, Tak province, Thailand during the years 2006 and 2007. Methods: data were extracted from camp registers and the Health Information System used during the years 2006 and 2007 and statistical analysis was performed. Results: the analysis showed that during 2006 and 2007 non-camp resident patients, coming from Thailand as well as Myanmar, who sought care in the outpatient depart-ment (OPD) of the camp required at a significantly higher proportion admission to the inpatient department (IPD) or referral to the district hospital compared to camp resident patients. Although there was a statistically significant increased mortality of the non-camp resident patients admitted in the IPD compared to camp resident patients, there was no significant difference in mortality among these two groups when the re-ferrals to the district hospital were analysed. Conclusion: non-camp resident patients tended to need a more advanced level of medical care compared to camp resident patients. Provided that this it is further vali-dated, the above observed pattern might be potentially useful as an indirect indicator of unaddressed health needs of populations surrounding a refugee camp.

The estimation of long-term diabetes complications risk is essential in the process of medical decision making. Guidelines for the management of Type 2 Diabetes Mellitus (T2DM) advocate calculating the Cardiovascular Disease (CVD) risk to initiate appropriate treatment. The objective of this study is to investigate the use of sophisticated machine learning techniques toward the development of personalized models able to predict the risk of fatal or nonfatal CVD incidence in T2DM patients. The important challenge of handling the unbalanced nature of the available dataset is addressed by applying novel ensemble strategies. Hybrid Wavelet Neural Networks (HWNNs) and Self-Organizing Maps (SOMs) constitute the primary models for building ensembles following a subsampling approach. Different methods for combining the decisions of the primary models are applied and comparatively assessed. Data from the 5-year follow up of 560 patients with T2DM are used for development and evaluation purposes. The highest discrimination performance (Area Under the Curve (AUC): 71.48%) is achieved by taking into account both the HWNN- and SOM- based primary models’ outputs. The proposed method is superior to the Binomial Linear Regression (BLR) model justifying the need to apply more sophisticated techniques in order to produce reliable CVD risk scores.

Vilazodone is a novel antidepressant with a dual mechanism of action that combines selective serotonin reuptake inhibition and partial 5-hydroxytryptamine1A receptor agonism. Vilazodone is undergoing clinical development for the treatment of major depressive disorder and has demonstrated antidepressant efficacy. In addition, in a placebo-controlled, randomized study, vilazodone has been shown to be well tolerated with a low discontinuation rate due to adverse events. Importantly, in this study, the incidence of sexual dysfunction with vilazodone was similar to that of the placebo. A key feature of the vilazodone clinical development program is the identification and development of biomarkers that predict response to therapy. This article will review the pharmacology, efficacy and tolerability, and pharmacogenetic data of vilazodone for the treatment of major depressive disorder. Vilazodone may be the first antidepressant to provide targeted therapy to patients most likely to achieve a response, and to offer an individualized approach to therapy.

Quantitative analyses of calcareous nannofossils in the sediments of Pissouri South section on the island of Cyprus have produced a paleoceanographic record reflecting the paleoclimatic conditions during the Zanclean/Piacenzian transition. Pissouri South cyclical lithological alternations between organic-rich laminated layers and grey marls reflect the Earth’s orbital precession. According to the calcareous nannofossil biostratigraphy which has been performed, the studied section is correlated with MNN14/15 and MNN16 calcareous nannofossil biozones and is astronomically dated between 4.065 and 3.217 Ma. Intervals of increased organic carbon content, along with the positive values of Florisphaera profunda, Helicosphaera sellii, Discoaster spp. and the subsequent increase of stratification S-index, correspond to the sapropel deposition during periods of wetter climate and intense continental runoff, especially from the river Nile. These layers alternate with grey marly intervals, featured by the increased values of small placoliths of Reticulofenestra and Gephyrocapsa species, which are indicative of eutrophic conditions during intense surface-water mixing. Our data support the prevalence of a generally warm phase characterized by the absence of high-frequency climate variations in the southeastern Mediterranean during the Zanclean/Piacenzian (Early/Late Pliocene) transition.

Organic geochemical (alkenones) and micropaleontological (nannofossil) data from the Pissouri South section (PPS) in the island of Cyprus provided a detailed description of the paleoclimatic (sea surface temperature-SST) and paleoenvironmental conditions during the “warm Pliocene” (c. 4.1–3.25 Ma) in the Eastern Mediterranean. We found that the suite of sapropel events recorded in the studied interval took place under conditions of increased SST, enhanced water column stratification and development of a productive deep chlorophyll maximum (DCM), as witnessed by the dominance of Florisphaera profunda species. Such conditions are similar to those prevailing during Quaternary sapropel formation, triggered by freshwater discharges from the N. African margin due to insolation-driven intensification of the African monsoon. The absence of F. profunda in Pliocene sapropels from central Mediterranean records highlights the sensitive response of the eastern basin to freshwater perturbations. Comparisons between alkenone and calcareous nannofossil assemblage patterns infer Pseudoemiliania lacunosa as the main alkenone producer in sapropel layers; yet Reticulofenestra spp. contribution cannot be ruled out. The first Pliocene alkenone-SST record in the E. Mediterranean presented here documents the “warm Pliocene” period (~ 4.1–3.25 Ma) characterized by mean SST of c. 26 °C. Distinct SST minima at ~ 3.9 Ma, 3.58 Ma and between 3.34 and 3.31 Ma, correspond to the MIS Gi16, MIS MG12 and MIS M2 global cooling episodes, before the onset of the Northern Hemisphere glaciation. Our findings imply that the peak of the MIS M2 cooling in the Eastern Mediterranean may be up to ~ 40 kyrs older than the age attributed before to benthic stable oxygen isotopes records of this event.

This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT 1A receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT 1A autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID 50 ) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)- p -chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo . Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2–3-fold) the ID 50 of 8-OH-DPAT at 4 h, but not 24 h after administration. Subchronic administration (3 days) significantly increased the ID 50 value at 4 h (3–4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID 50 value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID 50 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT 1A autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties.

Vilazodone is a selective serotonin reuptake inhibitor and 5-HTPooled data from two 8-week, double-blind studies of vilazodone (n = 436) vs placebo (n = 433) and data from one 52-week, open-label study (n = 616, vilazodone only) were analyzed. Patients aged 18-70 with DSM-IV-TR-defined MDD received vilazodone or placebo (8-week studies only) once daily, with food, titrated to 40 mg/day over 2 weeks. Safety and tolerability assessments included adverse events (AEs), laboratory tests, vital signs, electrocardiograms, and weight.The most common AEs in all studies were diarrhea, nausea, and headache. Vilazodone-associated AEs in the two 8-week studies, defined as an incidence rate of ≥5% in the vilazodone group and at least twice that for placebo, were diarrhea (28.0% vs 9.2%), nausea (23.4% vs 5.1%), and insomnia (6.0% vs 2.1%), with the majority reported as mild to moderate and5% of those patients requiring concomitant (directed) treatment for these conditions. Discontinuation rates due to AEs were 7.1% (vilazodone) and 3.2% (placebo) in the 8-week studies and 20.7% in the 52-week study. Vilazodone had no clinically significant effects on vital signs, laboratory tests, or electrocardiograms.Vilazodone 40 mg/day was well tolerated during short- and long-term MDD treatment in these trials. Safety profiles associated with 8- and 52-week exposure were consistent.

We provide new evidence on sea surface temperature (SST) variations and paleoceanographic/paleoenvironmental changes over the past 1500 years for the north Aegean Sea (NE Mediterranean). The reconstructions are based on multiproxy analyses, obtained from the high resolution (decadal to multi-decadal) marine record M2 retrieved from the Athos basin. Reconstructed SSTs show an increase from ca. 850 to 950 AD and from ca. 1100 to 1300 AD. A cooling phase of almost 1.5 °C is observed from ca. 1600 AD to 1700 AD. This seems to have been the starting point of a continuous SST warming trend until the end of the reconstructed period, interrupted by two prominent cooling events at 1832 ± 15 AD and 1995 ± 1 AD. Application of an adaptive Kernel smoothing suggests that the current warming in the reconstructed SSTs of the north Aegean might be unprecedented in the context of the past 1500 years. Internal variability in atmospheric/oceanic circulations systems as well as external forcing as solar radiation and volcanic activity could have affected temperature variations in the north Aegean Sea over the past 1500 years. The marked temperature drop of approximately ∼2 °C at 1832 ± 15 yr AD could be related to the 1809 ΑD ‘unknown’ and the 1815 AD Tambora volcanic eruptions. Paleoenvironmental proxy-indices of the M2 record show enhanced riverine/continental inputs in the northern Aegean after ca. 1450 AD. The paleoclimatic evidence derived from the M2 record is combined with a socio-environmental study of the history of the north Aegean region. We show that the cultivation of temperature-sensitive crops, i.e. walnut, vine and olive, co-occurred with stable and warmer temperatures, while its end coincided with a significant episode of cooler temperatures. Periods of agricultural growth in Macedonia coincide with periods of warmer and more stable SSTs, but further exploration is required in order to identify the causal links behind the observed phenomena. The Black Death likely caused major changes in agricultural activity in the north Aegean region, as reflected in the pollen data from land sites of Macedonia and the M2 proxy-reconstructions. Finally, we conclude that the early modern peaks in mountain vegetation in the Rhodope and Macedonia highlands, visible also in the M2 record, were very likely climate-driven.

Vilazodone is a novel serotonin reuptake inhibitor and serotonin 1A receptor partial agonist approved for the treatment of major depressive disorder (MDD). This evaluation presents side-by-side efficacy data from two randomized, double-blind, placebo-controlled, short-term 8-week trials (referred to as randomized controlled trial [RCT]-1 [N = 410] and RCT-2 [N = 481]); efficacy data for demographic and clinical subgroups (derived from pooled RCT data); and effectiveness data from a 52-week, open-label, long-term study (N = 616). The objective is to summarize the efficacy profile of vilazodone at its approved dose of 40 mg/day.The main assessment in individual pivotal trials and pooled subgroup analyses was the change from baseline to end of treatment (EOT, 8 weeks) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Mixed-effects repeated-measures analyses were conducted in the placebo-controlled trials. Effectiveness analyses in the long-term study included mean MADRS score change over time.Vilazodone-treated patients in both short-term studies showed greater improvement from baseline to EOT in mean MADRS scores than placebo-treated patients (least-squares mean [LSM] treatment difference: -3.2 [p = 0.001], RCT-1; -2.5 [p = 0.009], RCT-2). Clinical Global Impressions-Improvement mean scores at EOT reflected greater improvement with vilazodone compared with placebo in both studies (LSM treatment difference: -0.4 [p = 0.001], RCT-1; -0.3 [p = 0.004], RCT-2). MADRS response rates were significantly greater among patients receiving vilazodone versus those receiving placebo (RCT-1: 40.4% versus 28.1%, respectively [p = 0.007]; RCT-2: 43.7% versus 30.3%, respectively [p = 0.002]). The greater efficacy of vilazodone versus placebo was consistent for the majority of demographic and MDD characteristic subgroups. In the long-term study, the mean MADRS score improved from 29.9 (baseline) to 11.4 (week 8), 8.2 (week 24), and 7.1 (week 52).Vilazodone 40 mg/day resulted in clinically meaningful, statistically significant improvement in MDD symptoms in two placebo-controlled, 8-week studies. Findings are supported by subgroup analysis and open-label, long-term effectiveness data.Randomized controlled trial 1: ClinicalTrials.gov identifier: NCT00285376, http://ClinicalTrials.gov/ct2/show/NCT00285376 ; randomized controlled trial 2: ClinicalTrials.gov identifier: NCT00683592, http://ClinicalTrials.gov/ct2/show/NCT00683592 ; open-label, long-term study: ClinicalTrials.gov identifier: NCT00644358, http://ClinicalTrials.gov/ct2/show/NCT00644358 .

During 2010, an outbreak of West Nile virus infection occurred in Greece. A total of 197 patients with neuroinvasive disease were reported, of whom 33 (17%) died. Advanced age and a history of heart disease were independently associated with death, emphasizing the need for prevention of this infection in persons with these risk factors.

Objective To evaluate the efficacy, and further establish the safety profile, of oral once-daily vilazodone, a potent and selective serotonin 1A receptor partial agonist and reuptake inhibitor, in the treatment of major depressive disorder (MDD). Method This phase 3, randomized, double-blind, placebo-controlled, 8-week study (conducted March 2008-February 2009) enrolled 481 adults with DSM-IV-TR-defined MDD. Patients received vilazodone (titrated to 40 mg/d) or placebo. The primary efficacy endpoint was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to end of treatment. Secondary efficacy measures included MADRS and 17-item Hamilton Depression Rating Scale (HDRS-17) response and change in HDRS-17, HDRS-21, Hamilton Anxiety Rating Scale (HARS), Clinical Global Impressions-Severity of Illness (CGI-S), and Clinical Global Impressions-Improvement (CGI-I) scores. The Changes in Sexual Functioning Questionnaire (CSFQ) was administered at baseline and week 8. Results Vilazodone-treated patients had significantly greater improvement (P = .009) according to the MADRS than placebo patients (intent-to-treat; least-squares mean changes: -13.3, -10.8). MADRS response rates were significantly higher with vilazodone than placebo (44% vs 30%, P = .002). Remission rates for vilazodone were not significantly different based on the MADRS (vilazodone, 27.3% vs placebo, 20.3%; P = .066) or HDRS-17 (vilazodone, 24.2% vs placebo, 17.7%; P = .088). Vilazodone-treated patients had significantly greater improvements from baseline in HDRS-17 (P = .026), HDRS-21 (P = .029), HARS (P = .037), CGI-S (P = .004), and CGI-I (P = .004) scores than placebo patients. Rates of discontinuation due to adverse events were 5.1% (vilazodone) and 1.7% (placebo). The most common adverse events (vilazodone vs placebo) were diarrhea (31% vs 11%), nausea (26% vs 6%), and headache (13% vs 10%). Treatment-related effects on sexual function as measured by the CSFQ were small and similar to placebo. Effects on weight were no different from placebo. Conclusions Vilazodone 40 mg/d was well tolerated and effective in adult patients with MDD. Trial registration clinicaltrials.gov Identifier: NCT00683592.

Objective: Clozapine is considered to be the most efficacious drug to treat schizophrenia, although it is underutilized, partially due to a side effect of agranulocytosis. This analysis of 74 candidate genes was designed to identify an association between sequence variants and clozapine-induced agranulocytosis (CIA). Method: Blood and medical history were collected for 33 CIA cases and 54 clozapine-treated controls enrolled between April 2002 and December 2003. Significant markers from 4 genes were then assessed in an independently collected case-control cohort (49 CIA cases, 78 controls). Results: Sequence variants in 5 genes were found to be associated with CIA in the first cohort: HLA-DQB1, HLA-C, DRD1, NTSR1, and CSF2RB. Sequence variants in HLA-DQB1 were also found to be associated with CIA in the second cohort. After refinement analyses of sequence variants in HLA-DQB1, a single SNP (single nucleotide polymorphism), 6672G>C, was found to be associated with risk for CIA; the odds of CIA are 16.9 times greater in patients who carry this marker compared to those who do not. Conclusions: A sequence variant (6672G>C) in HLA-DQB1 is associated with increased risk for CIA. This marker identifies a subset of patients with an exceptionally high risk of CIA, 1,175 higher than the overall clozapine-treated population under the current blood-monitoring system. Assessing risk for CIA by testing for this and other genetic variants yet to be determined may be clinically useful when deciding whether to begin or continue treatment with clozapine. J Clin Psychiatry 2011;72(4):458-463 (C) Copyright 2010 Physicians Postgraduate Press, Inc.

Symptoms of central nervous system (CNS) disorders include abnormalities in both physical and psychological domains. Many drugs indicated for the treatment of CNS disorders are fraught with side effects and/or poor efficacy which impact patients’ quality of life and drives non-compliance. Moreover, for many CNS drugs such as antidepressants and antipsychotics, it takes time to determine whether a particular drug is efficacious in an individual patient. To optimize drug treatment for each patient, prescribing physicians often need to raise or lower doses, switch drug classes, or prescribe additional drugs to mitigate side effects, often in a “trial and error” fashion. Pharmacogenetic (PGx) testing, particularly in the realm of CNS therapy, can reduce the unpredictability of this process. By determining a patient’s genetic profile, individual therapy parameters may be predicted pre-treatment for drug efficacy, optimal drug dose, and the risk of adverse drug reactions (ADRs). The intent of this review is to highlight the power of PGx testing to predict the likelihood of ADRs and efficacy during the treatment of the following CNS disorders: epilepsy, bipolar disorder, schizophrenia and depression.

We have determined the complete sequence of 951,695 bp from the class I region ofH2,the mouse major histocompatibility complex (Mhc) from strain 129/Sv (haplotypebc). The sequence contains 26 genes. The sequence spans from the last 50 kb of theH2-Tregion, including 2 class I genes and 3 class I pesudogenes, and includes theH2-Mregion up toGabbr1.A 500-kb stretch of theH2-Mregion contains 9 class I genes and 4 pseudogenes, which fall into two subfamilies,M1andM10, distinct from other mouse class I genes. ThisM1/M10class I gene-cluster is separated from the centromericH2-Tand the telomericH2-M4, -5 and-6class I genes by “nonclass I genes”. Comparison with the corresponding 853-kb region of the humanMhc,which includes theHLA-Aregion, shows a mosaic of conserved regions of orthologous nonclass I genes separated by regions of species-specific expansion of paralogousMhcclass I genes. The analysis of this mosaic structure illuminates the dynamic evolution of theMhcclass I region among mammals and provides evidence for the framework hypothesis.[Supplemental material is available online atwww.genome.org. The sequence data from this study have been submitted to GenBank under accession nos.AC005413,AC005665,AF532111–AF532117. A preliminary draft sequence was earlier submitted asAC002615and replaced this year by NT002615.]

Olfactory receptor (OR) genes represent approximately 1% of genomic coding sequence in mammals, and these genes are clustered on multiple chromosomes in both the mouse and human genomes. We have taken a comparative genomics approach to identify features that may be involved in the dynamic evolution of this gene family and in the transcriptional control that results in a single OR gene expressed per olfactory neuron. We sequenced approximately 350 kb of the murine P2 OR cluster and used synteny, gene linkage, and phylogenetic analysis to identify and sequence approximately 111 kb of an orthologous cluster in the human genome. In total, 18 mouse and 8 human OR genes were identified, including 7 orthologs that appear to be functional in both species. Noncoding homology is evident between orthologs and generally is confined within the transcriptional unit. We find no evidence for common regulatory features shared among paralogs, and promoter regions generally do not contain strong promoter motifs. We discuss these observations, as well as OR clustering, in the context of evolutionary expansion and transcriptional regulation of OR repertoires.

Η βιοστρωματογραφική ανάλυση με βάση τα ασβεστολιθικά ναννοπολιθώματα που διεξήχθη στην τομή Κοτάφι επέτρεψε τον προσδιορισμό βιοζωνών του Μειόκαινου, καθώς και το συσχετισμό με τη θερμή φάση του Κλιματικού Βέλτιστου του Μέσου Μειόκαινου (Middle Miocene Climate Optimum, MMCO). Η τομή Κοτάφι βρίσκεται στον οικισμό Αγροκηπιά (Λευκωσία, Κύπρος) και αποτελείται από θαλάσσια ιζήματα με έντονη κυκλικότητα του Σχηματισμού της Πάχνας. Η υψηλής ανάλυσηςδειγματοληψία που πραγματοποιήθηκε, περιλαμβάνει συνολικά 84 δείγματα. Τα πρώτα αποτελέσματα επέτρεψαν την αναγνώριση διαδοχικών συμβάντων του ασβεστολιθικού ναννοπλαγκτού. Η υψηλή αφθονία του είδους Discoaster druggii και η ανώτερη παρουσία (HO) του είδους Sphenolithus procerus παραπέμπουν στη βιοζώνη NN2 ενώ, η βάση της βιοζώνης ΝN3 αναγνωρίστηκε με τη κατώτερη παρουσία (LO) του είδους Sphenolithus belemnos. Επιπλέον, το όριο των βιοζωνών ΝN3-ΝΝ4 προσδιορίστηκε με βάση τη κατώτερη συχνή παρουσία (LCO) του είδους Sphenolithus heteromorphus. Η βιοζώνη NN4 χαρακτηρίζεται από την υψηλή αφθονία του είδους S. heteromorphus ενώ στα ανώτερα στρώματα της τομής, η πλήρης απουσία αυτού σε συνδυασμό με τη κατώτερη παρουσία (LO) του είδους Helicosphaera walbedorfensis σηματοδοτούν το κατώτερο όριο του διαστήματος παρακμής (PB) του S. heteromorphus. Η αφθονία των θερμών αντιπροσώπων Discoasterids, S. heteromorphus, S. moriformis και Helicosphaera carteri που καταγράφεται, πιθανόν να αντανακλά τη θερμή φάση του MMCO., Calcareous nannofossil biostratigraphy from Kotaphi Hill section allowed not only the biostratigraphic zonation of the Miocene units but also provided evidence for a distinct warm phase known as the Middle Miocene Climate Optimum (MMCO). Kotaphi Hill section is located in Agrokipia village (Nicosia region, Cyprus) and consists of cyclic marine deposits of the Pakhna Formation. High resolution sampling has been conducted and 84 samples were collected. Preliminary results indicated that several important calcareous nannofossil events can be consistently recognized along the studied section. High abundances of Discoaster druggii and Highest occurrence (HO) of Sphenolithus procerus suggest the presence of NN2 biozone while, LO of Sphenolithus belemnos has been used to recognize the base of biozone NN3. Upwards, Lowest Common Occurrence (LCO) of Sphenolithus heteromorphus marked the NN3-4 boundary-level. Biozone NN4 in Kotaphi Hill section is featured by high abundance of S. heteromorphus whereas total absence of the species together with the LO of Helicosphaera walbedorfensis mark the Paracme Beginning (PB) of S. heteromorphus interval. High abundance of warm indicators such as Discoasterids, S. heteromorphus, S. moriformis and Helicosphaera carteri observed in our material may partly reflect the warm phase of MMCO. Key words: Agrokipia village, Pakhna Formation, Cyprus, Sphenolithus heteromorphus, Middle Miocene Climate Optimum.

This study examined the effect of vilazodone, a combined serotonin (5-HT) reuptake inhibitor and 5-HT(1A) receptor partial agonist, paroxetine and fluoxetine on the sensitivity of 5-HT(1A) autoreceptors of serotonergic dorsal raphe nucleus neurons in rats. These effects were assessed by determining the intravenous dose of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) required to suppress the basal firing rate of these neurons by 50% (ID₅₀) in anesthetized rats using in vivo electrophysiology. 5-HT uptake inhibition was determined by the ability of the compounds to reverse (±)-p-chloroamphetamine (PCA)-induced rat hypothalamic 5-HT depletion ex vivo. Acute vilazodone administration (0.63 and 2.1 µmol/kg, s.c.), compared with vehicle, significantly increased (2-3-fold) the ID₅₀ of 8-OH-DPAT at 4 h, but not 24h after administration. Subchronic administration (3 days) significantly increased the ID₅₀ value at 4 h (3-4-fold) and at 24 h (~2-fold). In contrast, paroxetine and fluoxetine at doses that were supramaximal for 5-HT uptake inhibition did not significantly alter the ID₅₀ value of 8-OH-DPAT after acute or subchronic administration. Vilazodone antagonized the action of PCA 3.5 h and 5 h after a single dose (ID₅₀ 1.49 and 0.46 µmol/kg, s.c., respectively), but was inactive 18 h post-administration, corroborating the electrophysiological results at 24 h following acute administration. The results are consistent with the concept of rapid and, following repeated treatment, prolonged inhibition of 5-HT(1A) autoreceptors by vilazodone. This effect could occur by either direct interaction with, or desensitization of, these receptors, an effect which cannot be ascribed to vilazodone's 5-HT reuptake inhibiting properties.

In this manuscript, we summarise the experience of Greece during the post-pandemic influenza season 2010/11 from 04 October 2010 to 22 May 2011. The spread of the disease and its impact were monitored using multiple surveillance systems, such as sentinel surveillance, virological surveillance and all-cause mortality surveillance. We also focus on the characteristics of laboratory-confirmed severe influenza cases who required admission to an intensive care unit (ICU) (n=368), and/or with a fatal outcome (n=180). The influenza-like illness rate reported from sentinel surveillance started rising in early January 2011 and peaked between 31 January and 6 February 2011. The total number of ICU admissions was higher in the post-pandemic influenza season than during the pandemic period causing a lot of pressure on ICUs. The overall population mortality rate due to influenza A(H1N1)2009 was higher than during the pandemic period (15.9 vs 13.2 fatal cases per million, p=0.087). Our data suggest that the severity of clinical illness in the first post-pandemic influenza season was comparable or even higher than during the pandemic.

Between 18 May 2009 and 3 May 2010, a total of 149 fatal cases associated with pandemic influenza A (H1N1) were reported in Greece. Detailed case-based epidemiological information was available for the large majority of fatal cases. The time distribution follows an epidemic curve with a peak in the beginning of December 2009 and a second peak one month later. This is similar to that of laboratory confirmed cases and influenza-like illness cases from our sentinel surveillance system, with two weeks delay. The most commonly reported underlying conditions were chronic cardiovascular disease and immunosuppression, while the most frequently identified risk factor was obesity. These findings should be taken into consideration, when vaccination strategies are employed.

OBJECTIVE The efficacy and tolerability of vilazodone, a combined selective serotonin reuptake inhibitor and partial 5-hydroxytryptamine-1A (5-HT(1A)) receptor agonist, were evaluated in adult patients with major depressive disorder (MDD). METHOD This was a randomized, double-blind, placebo-controlled trial conducted from February 2006 to May 2007. Patients aged 18 through 65 years with MDD (DSM-IV criteria) and a baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) score of >or= 22 were randomly assigned to vilazodone or placebo for 8 weeks. Vilazodone was titrated from 10 mg to 40 mg once a day over 2 weeks. Efficacy was assessed by mean change from baseline to week 8 on the Montgomery-Asberg Depression Rating Scale (MADRS), HAM-D-17, and Hamilton Rating Scale for Anxiety. Response rates were determined at week 8 for the MADRS, HAM-D-17, and Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. Data were analyzed using a modified last-observation-carried-forward method in the intention-to-treat (ITT) sample. The Arizona Sexual Experience Scale (ASEX) was also measured at baseline and week 8. RESULTS Of 410 randomly assigned patients, 198 receiving vilazodone and 199 receiving placebo were included in the ITT population. The mean changes in MADRS and HAM-D-17 total scores from baseline to week 8 were significantly (p = .001 and p = .022, respectively) greater with vilazodone than with placebo. Significant (p < .05) improvements in MADRS and HAM-D-17 scores were noted at week 1, the earliest time point measured. Response rates were significantly higher with vilazodone than with placebo on the MADRS (p = .007), HAM-D-17 (p = .011), and CGI-I (p = .001). Treatment-emergent adverse events with vilazodone included diarrhea, nausea, and somnolence; most adverse events were of mild or moderate intensity. There were no clinically significant differences for either gender in ASEX scores at end of treatment. CONCLUSIONS Vilazodone is effective for the treatment of MDD in adults, with symptom relief starting at 1 week, and is well tolerated at a dose of 40 mg/day. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00285376.

Introduction The increasing prevalence of multiresistant Gram-negative strains in intensive care units (ICUs) has recently rekindled interest in colistin, a bactericidal antibiotic that was used in the 1960s for treatment of infections caused by Gram-negative bacilli. We conducted the present observational study to evaluate the efficacy of intravenous colistin in the treatment of critically ill patients with sepsis caused by Gram-negative bacilli resistant to all other antibiotics. Patients and method Critically ill patients with sepsis caused by Gram-negative bacilli resistant to all antibiotics with the exception of colistin were treated in the six-bed ICU of a trauma hospital. Diagnosis of infection was based on clinical data and isolation of bacteria, and the bacteria were tested with respect to their susceptibility to colistin. Clinical response to colistin was evaluated. Results Twenty-four patients (mean age 44.3 years, mean Acute Physiology and Chronic Health Evaluation II score 20.6) received 26 courses of colistin. Clinical response was observed for 73% of the treatments. Survival at 30 days was 57.7%. Deterioration in renal function was observed in 14.3% of 21 patients who were not already receiving renal replacement therapy, but in only one case did this deterioration have serious clinical consequences. Conclusion The lack of a control group in the present study does not allow any definite conclusions to be drawn regarding the clinical effectiveness of colistin. On the other hand, this drug has an acceptable safety profile and its use should be considered in severe infections with multiresistant Gram-negative bacilli.

The treatment of seriously mentally ill patients is complicated by variability in individual response to psychotropic drugs. Some patients remain treatment refractory even after two to three therapeutic modalities. Other patients experience adverse events that range from mild discomfort, to poor compliance, to life threatening. Genaissance Pharmaceuticals is actively engaged in a candidate gene-based haplotype (HAP Marker) approach to the pharmacogenetics of drug response and adverse events. In the present article, we review reasons why HAP Markers are more useful than single nucleotide polymorphisms (SNPs) for discovering genetic correlations to clinical response. In addition, we review our approach to HAP Marker discovery, which involves discovering SNPs in the functional regions of genes by sequencing, organizing these SNPs into HAP Markers for an index population of ethnically diverse individuals and calculating population frequencies for these HAP Markers. For clinical correlations, HAP Markers are defined and correlated to clinical data using the in-house DecoGen Informatics System. This approach has clear implications for the discovery of psychiatric disease-associated genes as well as for the development of safer, more efficacious psychiatric drugs.

Clozapine is a highly efficacious drug for the treatment of schizophrenia, but its use is limited, in part due to the side effect of agranulocytosis. In order to reduce the incidence of clozapine-induced agranulocytosis (CIA), patients are required to submit to a blood monitoring program. A genetic component to CIA is suggested by published associations in a number of genes. A genetic test assessing the risk of CIA might allow safer and more broad use of clozapine. We previously conducted a candidate gene-based case-control study to discover genes associated with CIA. Cases were patients with an ANC A replication analysis was performed on an independently collected cohort of 49 cases and 78 controls from Germany. Cases were patients who developed an ANC

During the last three decades, the area of expert systems has attracted enormous research interest, and a multitude of systems, tackling all kinds of applications, have been designed and implemented. An area where expert systems have been extensively applied is medical care; however, despite the very large number of systems implemented, no system for the special care required for wheelchair users with spinal injury has been developed. The purpose of this report is to present the design and implementation methodology of the DIMITRA expert system, an online consultation system under development for the special caring procedure of such patients. This system is considered to be of value for virtual healthcare in the home, because it is designed for remote access by carers and their patients.

Clozapine is a highly efficacious drug for the treatment of schizophrenia, but its use is limited, in part due to the side effect of agranulocytosis. In order to reduce the incidence of clozapine-induced agranulocytosis (CIA), patients are required to submit to a blood monitoring program. There is evidence that there is a genetic component to CIA, with previously published associations in a number of genes, including HLA-DQB1 (Dettling et. al., Arch Gen Psychiatry2001: 59, 93–94) and HLA-C (Dettling et. al., Pharmacogenetics2001: 11, 135–141). If a genetic test for CIA were developed, it is possible that clozapine could become a safer drug and more patients could benefit from its use. As a first step in developing such a test, we have conducted a case-control study to discover genetic markers associated with CIA. Cases were patients with an ANC5000 and ANC Characteristics of the Discovery Cases n=33 Controls n=54 Gender Male 17 33 Female 16 21 Ethnicity American Indian 4 4 Black or African American 1 2 White 28 48 Age Median (range) in years 36 (20–58) 35 (18–54) Nadir ANC Median (range) 237 (0–506) N/A Diagnosis Schizophrenia/Schizoaffective Disorder 32 53 Bipolar Disorder 1 1 Time to CIA Median (range) in months 2.2 (0.5–62.6) N/A Seventy-four candidate genes were sequenced in the exons, intron-exon boundaries, 5′ untranslated region and promoter region for each of the cases and controls. Single nucleotide polymorphisms and small insertion/deletions were scored and a haplotype analysis conducted, comparing the frequency of haplotypes in cases to those in controls using logistic regression with covariates of age, gender and race. Permutation tests were done within each gene and a genetic marker was considered significant with an adjusted p value