The improving Medication Adherence in Adolescents and young adults following Liver Transplantation (iMALT) multisite trial: Design and trial implementation considerations.

BACKGROUND/AIMS: Medication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection. METHODS: Improving Medication Adherence in adolescent Liver Transplant is a randomized single-blind controlled multisite, multinational National Institutes of Health-funded trial involving 13 pediatric transplant centers in the United States and Canada. An innovative, objective adherence biomarker-the Medication Level Variability Index, which is the standard deviation of a series of medication blood levels for each patient, is used to identify non-adherent patients at risk for rejection. The index is computed using electronic health record information for all potentially eligible patients based on repeated reviews of the entire clinic's roster. Identified patients, after consent, are randomized to intervention versus control (treatment as usual) arms. The remote intervention is delivered for 2 years by trained interventionists who reside in various locations in the United States. The primary outcome is the incidence of biopsy-confirmed acute cellular rejection, as confirmed by a majority vote of three pathologists who are masked to the study allocation and clinical information. DISCUSSION: Improving Medication Adherence in adolescent Liver Transplant includes several innovative design elements. The use of a validated, objective adherence index to survey a large cohort of transplant recipients allows the teams to avoid bias inherent in both convenience sampling and referral-based recruitment and enroll only patients whose computed index indicates substantially increased risk of rejection. The remote intervention paradigm helps to engage patients who are by definition hard to engage. The use of an objective, masked medical (rather than behavioral) outcome measure reduces the likelihood of biases related to clinical information and ensures broad acceptance by the field. Finally, monitoring for potential adverse events related to increased medication exposure due to the adherence intervention acknowledges that a successful intervention (increasing adherence) could have detrimental side effects via increased exposure to and potential toxicity of the medication. Such monitoring is almost never attempted in clinical trials evaluating adherence interventions.

A pharmacokinetic model for amiodarone in infants developed from an opportunistic sampling trial and published literature data.

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants < 2 years old, so our analysis was restricted to this group. The final combined dataset consisted of 266 plasma drug concentrations in 45 subjects with a median (interquartile range) postnatal age of 40.1 (11.0-120.4) days and weight of 3.9 (3.1-5.1) kg. Since the median sampling time after the first dose was short (study: 95 h; literature: 72 h) relative to the terminal half-life estimated in adult PopPK studies, values of the deep compartment volume and flow were fixed to literature values. A 3-compartment model best described the data and was validated by visual predictive checks and non-parametric bootstrap analysis. The final model included body weight as a covariate on all volumes and on both inter-compartmental and elimination clearances. The empiric Bayesian estimates for clearance (CL), volume of distribution at steady state, and terminal half-life were 0.25 (90% CL 0.14-0.36) L/kg/h, 93 (68-174) L/kg, and 266 (197-477) h, respectively. These studies will provide useful information for future PopPK studies of amiodarone in infants and children that could improve dosage regimens.

Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates.

BACKGROUND: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. METHODS: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. RESULTS: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPlasma) was derived using (CONCDBS - 3.223)/0.51. The median bias and geometric mean ratio improved to -11% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (-11 to 50) and -8% (-34 to 11), respectively, when eCONCPlasma was used. CONCLUSIONS: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

Population Pharmacokinetics of Trimethoprim-Sulfamethoxazole in Infants and Children.

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/F) and volume of distribution (V/F). Both TMP and SMX CL/F increased with age. In addition, TMP and SMX CL/F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to <21 years and 0 to <6 years of age, respectively, and was optimal for bacteria with an MIC of up to 1 mg/liter.

Effectiveness of sanitizing products on controlling selected pathogen surrogates on retail deli slicers.

The objectives of this study were (i) to assess the efficacy of quaternary ammonium chloride-based wet foam (WF) and dry foam (DF) sanitizer systems (600 ppm) for reducing Listeria innocua (a nonpathogenic surrogate of Listeria monocytogenes) or a 100.0 µg/ml rifampin-resistant Salmonella Typhimurium LT2 (a nonpathogenic surrogate of Salmonella enterica serovar Typhimurium) on niche and transfer point areas of an unwashed retail deli slicer as compared with traditional chlorine (Cl(-)) treatment (200 ppm) and (ii) to compare sanitizer surface contact times (10 and 15 min) for pathogen surrogate control. Turkey frankfurter slurries inoculated with L. innocua or Salmonella Typhimurium were used to inoculate seven high-risk sites on a commercial slicer. After 30 min of bacterial attachment, slicers were dry wiped to remove excess food matter, followed by a randomly assigned sanitizer treatment. Surviving pathogen surrogate cells were enumerated on modified Oxford's agar not containing antimicrobic supplement (L. innocua) or on tryptic soy agar supplemented with 100 µg/ml rifampin (Salmonella Typhimurium LT2). Replicate-specific L. innocua and Salmonella Typhimurium reductions were calculated as log CFU per square centimeter of control minus log CFU per square centimeter of enumerated survivors for each site. For both organisms, all sanitizer treatments differed from each other, with Cl(-) producing the least reduction and WF the greatest reduction. A significant (P < 0.05) site-by-treatment interaction was observed. The results of the study indicate that quaternary ammonium chloride sanitizers (600 ppm) applied by both WF and DF were more effective at reducing L. innocua and Salmonella Typhimurium than a traditional Cl sanitizer (200 ppm) on unwashed slicer surfaces.

Safety and efficacy of sodium nitroprusside during prolonged infusion in pediatric patients.

OBJECTIVE: Sodium nitroprusside is a direct-acting vasodilator used to lower blood pressure in the operating room and ICU. The efficacy of sodium nitroprusside has been analyzed in few pediatric randomized trials. This study assesses the efficacy and safety of sodium nitroprusside following at least 12 hours of IV infusion in children. DESIGN: Randomized, double-blind withdrawal to placebo study. SETTING: ICUs. PATIENTS: Pediatric patients younger than 17 years. INTERVENTIONS: Following 12-24 hours of open-label sodium nitroprusside titration, a blinded infusion of sodium nitroprusside or placebo was administered (at the stable rate used at the end of the open-label phase) for up to 30 minutes. MEASUREMENTS AND MAIN RESULTS: The primary efficacy measure was whether control of mean arterial blood pressure was lost, that is, increased above ambient baseline for two consecutive minutes during the blinded phase. The proportion of patients who lost mean arterial blood pressure control in the placebo group (15/19; 79%) was significantly different than those in the sodium nitroprusside group (9/20; 45%) (p = 0.048). Three patients experienced rebound hypertension during the blinded phase, and all were in the placebo group. Serious adverse event rates were low (7/52; 13%), and in only one patient was the serious adverse event determined to be related to sodium nitroprusside by the site investigator. Fourteen patients (27%) had whole blood cyanide levels above 0.5 µg/mL, with high correlation (0.7) between infusion rate and cyanide levels, but there were few clinical signs of cyanide toxicity. CONCLUSIONS: Sodium nitroprusside is efficacious in maintaining mean arterial blood pressure control in children following a 12-hour infusion. Although a high proportion of patients were found to have elevated cyanide levels, toxicity was not observed.

Reproductive implications of exposure to Toxoplasma gondii and Neospora caninum in western grey kangaroos (Macropus fuliginosus ocydromus).

Australian marsupials are thought to be particularly vulnerable to pathologic impacts of Toxoplasma gondii, and they may be similarly affected by Neospora caninum. Pathology due to either organism could be expressed as reduced female reproductive performance. We studied adult female western grey kangaroos (Macropus fuliginosus ocydromus) from suburban Perth, Western Australia, between May 2006 and October 2008. We used indirect fluorescent antibody tests to look for evidence of exposure to T. gondii and N. caninum in M. fuliginosus ocydromus and tested the association between their reproductive performance and a positive test result. Although 20% of plasma samples collected from 102 female kangaroos were positive for T. gondii and 18% were positive for N. caninum, we found no association between positive results and reproductive performance. Further study will be required to clarify if, and under what circumstances, T. gondii and N. caninum are pathogenic to macropod marsupials.

Sodium nitroprusside is not associated with metabolic acidosis during intraoperative infusion in children.

BACKGROUND: Sodium nitroprusside (SNP) is a potent vasodilator that has been used to induce deliberate hypotension in children during surgery involving significant blood loss, including craniofacial and spinal fusion procedures. SNP metabolism liberates cyanide, which may cause interference with cellular energy metabolism, leading to metabolic acidosis and central nervous system injury. We performed a retrospective, case-control study to determine whether the short-term intra-operative use of SNP for deliberate hypotension is associated with metabolic acidosis in children undergoing surgical procedures for craniofacial or spinal anomalies. Cyanide and thiocyanate concentrations were also recorded in patients who received SNP. METHODS: Data from 166 children undergoing craniofacial and spinal fusion surgery between 2005 and 2010 at Lucile Packard Children's Hospital (LPCH) at Stanford were analyzed. Records from 60 patients who received SNP (SNP group) as part of a multicenter, randomized, double-blind study were compared with records from 106 eligible patients who had blood pressure reduction using anesthetic agents and did not receive SNP (control group). Metabolic acidosis was defined as serum bicarbonate (HCO3) < 18.5 mEq/L. Whole blood CN, plasma thiocyanate and urinary thiocyanate concentrations were measured in patients in the SNP group. Differences in metabolic acidosis rates between the SNP and control groups were assessed through a test of noninferiority in the rate for the SNP group with a noninferiority threshold of 0.2. A z-test was used to test the null hypothesis. The alternative hypothesis was that the difference in these rates was less than 0.2. The same noninferiority threshold of 0.2 was also used to perform separate, secondary tests for noninferiority in the proportion of patients with HCO3 levels below 18.5 mEq/L and the proportion of patients who required HCO3 administration. RESULTS: Fewer patients in the SNP group experienced metabolic acidosis compared to the control group (31.7% vs. 36.8%, respectively; p < .001). No whole blood CN levels above the lower limit of quantification were detected in any of the 51 patients with validated CN data. Plasma and urinary thiocyanate levels were also low. CONCLUSIONS: Our findings suggest that SNP, when used for short-term deliberate hypotension, does not cause an increased incidence of metabolic acidosis compared with the use of anesthetic agents alone. TRIAL REGISTRATION NUMBER: NCT00135668.

Essential components of transition to adult transplant services: the transplant coordinators' perspective.

CONTEXT: Medical and surgical advancements have resulted in improved long-term survival of pediatric liver transplant recipients. As pediatric patients approach school age and adolescence, transplant centers are challenged to facilitate the process of transitioning from pediatric to adult centers. OBJECTIVE: To describe pediatric and adult liver transplant coordinators' perspective regarding practice for transitioning patients to adult-oriented transplant centers. DESIGN: Descriptive SETTING: Pediatric and adult liver transplant coordinators associated with Studies of Pediatric Liver Transplantation. PARTICIPANTS: A total of 35 pediatric liver transplant coordinators and 24 adult liver transplant coordinators completed the survey. METHOD: Investigator-developed survey to identify current practice for transition process and actual transfer of a patient from pediatric to adult care. RESULTS: Transplant coordinators play an integral role in the transition process, and study results highlight what experienced coordinators believe are important considerations for a successful transition process. Results also highlight the importance of communication and partnership between the pediatric and adult programs.

Simulating greenhouse gas budgets of four California cropping systems under conventional and alternative management.

Despite the importance of agriculture in California's Central Valley, the potential of alternative management practices to reduce soil greenhouse gas (GHG) emissions has been poorly studied in California. This study aims at (1) calibrating and validating DAYCENT, an ecosystem model, for conventional and alternative cropping systems in California's Central Valley, (2) estimating CO2, N2O, and CH4 soil fluxes from these systems, and (3) quantifying the uncertainty around model predictions induced by variability in the input data. The alternative practices considered were cover cropping, organic practices, and conservation tillage. These practices were compared with conventional agricultural management. The crops considered were beans, corn, cotton, safflower, sunflower, tomato, and wheat. Four field sites, for which at least five years of measured data were available, were used to calibrate and validate the DAYCENT model. The model was able to predict 86-94% of the measured variation in crop yields and 69-87% of the measured variation in soil organic carbon (SOC) contents. A Monte Carlo analysis showed that the predicted variability of SOC contents, crop yields, and N2O fluxes was generally smaller than the measured variability of these parameters, in particular for N2O fluxes. Conservation tillage had the smallest potential to reduce GHG emissions among the alternative practices evaluated, with a significant reduction of the net soil GHG fluxes in two of the three sites of 336 +/- 47 and 550 +/- 123 kg CO2-eq x ha(-1) x yr(-1) (mean +/- SE). Cover cropping had a larger potential, with net soil GHG flux reductions of 752 +/- 10, 1072 +/- 272, and 2201 +/- 82 kg CO2-eq x ha(-1) x yr(-1). Organic practices had the greatest potential for soil GHG flux reduction, with 4577 +/- 272 kg CO2-eq x ha(-1) x yr(-1). Annual differences in weather or management conditions contributed more to the variance in annual GHG emissions than soil variability did. We concluded that the DAYCENT model was successful at predicting GHG emissions of different alternative management systems in California, but that a sound error analysis must accompany the predictions to understand the risks and potentials of GHG mitigation through adoption of alternative practices.

The genome of the domesticated apple (Malus × domestica Borkh.).

We report a high-quality draft genome sequence of the domesticated apple (Malus × domestica). We show that a relatively recent (>50 million years ago) genome-wide duplication (GWD) has resulted in the transition from nine ancestral chromosomes to 17 chromosomes in the Pyreae. Traces of older GWDs partly support the monophyly of the ancestral paleohexaploidy of eudicots. Phylogenetic reconstruction of Pyreae and the genus Malus, relative to major Rosaceae taxa, identified the progenitor of the cultivated apple as M. sieversii. Expansion of gene families reported to be involved in fruit development may explain formation of the pome, a Pyreae-specific false fruit that develops by proliferation of the basal part of the sepals, the receptacle. In apple, a subclade of MADS-box genes, normally involved in flower and fruit development, is expanded to include 15 members, as are other gene families involved in Rosaceae-specific metabolism, such as transport and assimilation of sorbitol.

Composition in distributional models of semantics.

Vector-based models of word meaning have become increasingly popular in cognitive science. The appeal of these models lies in their ability to represent meaning simply by using distributional information under the assumption that words occurring within similar contexts are semantically similar. Despite their widespread use, vector-based models are typically directed at representing words in isolation, and methods for constructing representations for phrases or sentences have received little attention in the literature. This is in marked contrast to experimental evidence (e.g., in sentential priming) suggesting that semantic similarity is more complex than simply a relation between isolated words. This article proposes a framework for representing the meaning of word combinations in vector space. Central to our approach is vector composition, which we operationalize in terms of additive and multiplicative functions. Under this framework, we introduce a wide range of composition models that we evaluate empirically on a phrase similarity task.

Identifying risk for attrition during treatment for depression.

BACKGROUND: Understanding patients' ambivalence about treatment persistence may be useful in tailoring retention interventions for individual patients with major depressive disorder. METHODS: Participants (n = 265) with major depressive disorder were enrolled into an 8-week trial with a selective serotonin reuptake inhibitor. At baseline and week 2, the participants were asked about their intent to return for the next visit, complete the study and continue in the study should they experience side effects or no improvement. Dropouts were defined as participants who discontinued attending clinic visits before completing the trial. RESULTS: Participants who at baseline reported an uncertain/negative intent to continue if they experienced side effects or no improvement dropped out at a significantly higher rate by weeks 6 and 8. Uncertain/negative intent at week 2 predicted attrition at all following visits. Dropouts without side effects were more likely to have reported an uncertain/negative intent to attend at both baseline and week 2, while dropouts who experienced side effects were more likely to have reported an uncertain/negative intent to attend only at baseline. Positive intent to continue was associated with greater symptom improvement in both dropouts and completers despite the possibility of lack of efficacy. CONCLUSIONS: Participants' pretreatment concerns about continuing antidepressant treatment in the presence of side effects signals challenges to the completion of a full 8-week acute phase treatment, even if the participant does not develop side effects. Individualized review of concerns and tailoring appropriate interventions may be necessary to reduce attrition.

Soil water content and soil disaggregation by disking affects PM10 emissions.

Row crop agriculture in California's San Joaquin Valley is a major contributor of particulate matter <10 microm in aerodynamic diameter (PM10). The California Air Resources Board uses fixed PM10 emission values for various tillage operations to monitor and design attainment strategies. However, fixed emission values do not reflect emissions produced by a single implement operating under different soil conditions. This 2-yr study evaluated how PM10 mass concentrations (microg L(-1)) from disking change as a function of gravimetric soil water content (GWC), number of sequential diskings (D1, D2, D3), and the soil's weighted mean ped diameter (WMPD). Results showed PM10 increased logarithmically as the soil dried from a GWC of 14 to 4%. Average PM10 values at the lower GWCs were six to eight times greater than at the higher GWCs. Number of diskings also increased PM10, especially in drier soil. Below a GWC of 7%, PM10 for D3 was about twice that for D1. Despite strong correlations between more disking and lower WMPD, a lower WMPD did not always result in an increase in PM10. This underscored the role soil water plays in reducing PM10 at high GWCs despite low WMPDs from multiple diskings. Three-way interactions between GWC, disking, and PM10 showed, on average, that the magnitude of PM10 produced by D1 was 1.3 to 1.6 times lower than by D3, despite having insignificantly different GWC. Therefore, a disking operation can yield two different PM10 values under similar GWCs if the amount of soil disaggregation is different. Our results show that inclusion of soil parameters in PM10 emission estimates is essential to describing agriculture's role in air quality violations and to assess the value of proposed mitigation measures, such as conservation tillage.

Rate of inpatient weight restoration predicts outcome in anorexia nervosa.

OBJECTIVE: To examine weight restoration parameters during inpatient treatment as predictors of outcome in anorexia nervosa (AN). METHOD: Adolescent and adult females admitted for inpatient eating disorder treatment were recruited for an ongoing longitudinal study. This analysis examined several weight restoration parameters as predictors of clinical deterioration after discharge among participants with AN. RESULTS: Rate of weight gain was the only restoration parameter that predicted year 1 outcome. Clinical deterioration occurred significantly less often among participants who gained >or=0.8 kg/week (12/41, 29%) than those below this threshold (20/38, 53%) (chi(2) = 4.37, df = 1, p = .037) and remained significant after adjustment for potential confounders. DISCUSSION: Weight gain rate during inpatient treatment for AN was a significant predictor of short-term clinical outcome after discharge. It is unclear whether weight gain rate exerts a causal effect or is rather a marker for readiness to tolerate weight restoration and engage in the recovery process.

Attention-deficit hyperactivity symptoms and disorder in eating disorder inpatients.

OBJECTIVE: The objective of this study was to determine the prevalence of attention-deficit hyperactivity disorder (ADHD) symptoms and a DSM-IV ADHD diagnosis in women admitted for treatment of an eating disorder. METHOD: One hundred eighty-nine inpatient women with an eating disorder were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and ADHD interview from the Multi-international Psychiatric Interview (MINI). RESULTS: Twenty-one percent of the sample reported at least six current ADHD symptoms, but the estimated prevalence rate for a diagnosis of ADHD in this population was only 5.8% (95% CI: 2.6%-9.5%). Most current ADHD inattentive symptoms appeared after childhood suggesting late-onset non-ADHD origins. Current inattention symptoms in those without a diagnosis of ADHD correlated with higher BMI (p < .0001), symptoms of bulimia nervosa and current level of depression symptoms (p = .025). DISCUSSION: Although current ADHD symptoms were commonly endorsed in this population, clinicians should carefully examine for childhood symptom-onset of ADHD.

Sequencing and assembly of highly heterozygous genome of Vitis vinifera L. cv Pinot Noir: problems and solutions.

A new approach to sequencing and assembling a highly heterozygous genome, that of grape, species Vitis vinifera cv Pinot Noir, is described. The combining of genome shotgun of paired reads produced by Sanger sequencing and sequencing by synthesis of unpaired reads was shown to be an efficient procedure for decoding a complex genome. About 2 million SNPs and more than a million heterozygous gaps have been identified in the 500 Mb genome of grape. More than 91% of the sequence assembled into 58,611 contigs is now anchored to the 19 linkage groups of V. vinifera.

A high quality draft consensus sequence of the genome of a heterozygous grapevine variety.

BACKGROUND: Worldwide, grapes and their derived products have a large market. The cultivated grape species Vitis vinifera has potential to become a model for fruit trees genetics. Like many plant species, it is highly heterozygous, which is an additional challenge to modern whole genome shotgun sequencing. In this paper a high quality draft genome sequence of a cultivated clone of V. vinifera Pinot Noir is presented. PRINCIPAL FINDINGS: We estimate the genome size of V. vinifera to be 504.6 Mb. Genomic sequences corresponding to 477.1 Mb were assembled in 2,093 metacontigs and 435.1 Mb were anchored to the 19 linkage groups (LGs). The number of predicted genes is 29,585, of which 96.1% were assigned to LGs. This assembly of the grape genome provides candidate genes implicated in traits relevant to grapevine cultivation, such as those influencing wine quality, via secondary metabolites, and those connected with the extreme susceptibility of grape to pathogens. Single nucleotide polymorphism (SNP) distribution was consistent with a diffuse haplotype structure across the genome. Of around 2,000,000 SNPs, 1,751,176 were mapped to chromosomes and one or more of them were identified in 86.7% of anchored genes. The relative age of grape duplicated genes was estimated and this made possible to reveal a relatively recent Vitis-specific large scale duplication event concerning at least 10 chromosomes (duplication not reported before). CONCLUSIONS: Sanger shotgun sequencing and highly efficient sequencing by synthesis (SBS), together with dedicated assembly programs, resolved a complex heterozygous genome. A consensus sequence of the genome and a set of mapped marker loci were generated. Homologous chromosomes of Pinot Noir differ by 11.2% of their DNA (hemizygous DNA plus chromosomal gaps). SNP markers are offered as a tool with the potential of introducing a new era in the molecular breeding of grape.

Clinical features of depression in outpatients with and without co-occurring general medical conditions in STAR*D: confirmatory analysis.

BACKGROUND: Concurrent medical comorbidity influences the accurate diagnosis and treatment of major depressive disorder (MDD). OBJECTIVE: The objective of this study was to validate previous findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study using a confirmation analysis in a previously unanalyzed cohort. DESIGN: Baseline cross-sectional case-control study of patients enrolling in a prospective randomized multistage treatment study of nonpsychotic MDD. SETTING: Fourteen regional U.S. centers representing 18 primary care and 23 psychiatric practices. PARTICIPANTS: 2541 outpatients with DSM-IV nonpsychotic MDD. MEASUREMENTS: Sociodemographic status, medical illness ratings, psychiatric status, quality of life, and DSM-IV depression symptom ratings. RESULTS: The prevalence of significant general medical comorbidity in this population was 50.0% (95% CI = 48.1% to 52.0%), consistent with findings reported for the first cohort. Concurrent significant medical comorbidity was associated with older age, lower income, unemployment, limited education, and longer duration of index depressive episode. The group with significant medical comorbidity reported higher rates of somatic symptoms, gastrointestinal symptoms, sympathetic arousal, and leaden paralysis. These results were generally consistent between the 2 cohorts from STAR*D. CONCLUSIONS: Major depressive disorder with concurrent general medical conditions is associated with a specific sociodemographic profile and pattern of depressive symptoms. This association has implications for diagnosis and clinical care.