Personalising Social Ills: An Analysis of Race-based Genomics and Personalised Medicine.

The mapping and sequencing of the human genome at the turn of the new millennium marks a pivotal reassessment of genomic science in its potential to replace traditional "one-size-fits-all" medicine with a personalised approach. The use of racial proxies in the development of pharmacogenomic products risks conflating genetics with race under the guise of alleviating health disparities. This article argues that the current genomic approaches to realising personalised medicine do not deliver on the promise for optimised health for all and may result in irreversible harm, including psychological, social and medical harm, to racial minority groups. In light of recent epigenetic findings, the article provides a reconceptualisation of the genome and race, which is necessary to understand enduring racial disparities and the cumulative effects of racial discrimination. It then addresses the need for regulatory oversight of the approval of race-based pharmacogenomic products.

Hydrogel-Based Biosensors.

There is an increasing interest in sensing applications for a variety of analytes in aqueous environments, as conventional methods do not work reliably under humid conditions or they require complex equipment with experienced operators. Hydrogel sensors are easy to fabricate, are incredibly sensitive, and have broad dynamic ranges. Experiments on their robustness, reliability, and reusability have indicated the possible long-term applications of these systems in a variety of fields, including disease diagnosis, detection of pharmaceuticals, and in environmental testing. It is possible to produce hydrogels, which, upon sensing a specific analyte, can adsorb it onto their 3D-structure and can therefore be used to remove them from a given environment. High specificity can be obtained by using molecularly imprinted polymers. Typical detection principles involve optical methods including fluorescence and chemiluminescence, and volume changes in colloidal photonic crystals, as well as electrochemical methods. Here, we explore the current research utilizing hydrogel-based sensors in three main areas: (1) biomedical applications, (2) for detecting and quantifying pharmaceuticals of interest, and (3) detecting and quantifying environmental contaminants in aqueous environments.

Process Characterization of Polyvinyl Acetate Emulsions Applying Inline Photon Density Wave Spectroscopy at High Solid Contents.

The high solids semicontinuous emulsion polymerization of polyvinyl acetate using poly (vinyl alcohol-co-vinyl acetate) as protective colloid is investigated by optical spectroscopy. The suitability of Photon Density Wave (PDW) spectroscopy as inline Process Analytical Technology (PAT) for emulsion polymerization processes at high solid contents (>40% (w/w)) is studied and evaluated. Inline data on absorption and scattering in the dispersion is obtained in real-time. The radical polymerization of vinyl acetate to polyvinyl acetate using ascorbic acid and sodium persulfate as redox initiator system and poly (vinyl alcohol-co-vinyl acetate) as protective colloid is investigated. Starved-feed radical emulsion polymerization yielded particle sizes in the nanometer size regime. PDW spectroscopy is used to monitor the progress of polymerization by studying the absorption and scattering properties during the synthesis of dispersions with increasing monomer amount and correspondingly decreasing feed rate of protective colloid. Results are compared to particle sizes determined with offline dynamic light scattering (DLS) and static light scattering (SLS) during the synthesis.

A Rare Ocular Manifestation of Idiopathic Hypertrophic Cranial Pachymeningitis.

Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare form of thickening of the dura mater. There are limited reports on the ocular manifestation of IHCP and its treatment. Up to our knowledge, there is no report on bilateral superior ophthalmic veins (SOV) dilatation with IHCP and there are only a few reports on anterior scleritis with IHCP. We report a 62-year-old gentleman with underlying hypertension and chronic headache who presented with fever, headache, and unresolving both eyes redness as manifestations of bilateral anterior scleritis, anterior uveitis, secondary glaucoma, and multiple cranial nerve palsies. Magnetic resonance imaging of the brain showed global thickening and enhancement of the pachymeninges with bilateral SOV dilatations. The diagnosis of IHCP was made after ruling out infective and autoimmune causes. The patient was treated with oral prednisolone, oral azathioprine, topical timolol maleate, topical dexamethasone, and topical moxifloxacin. The patient was successfully treated and was stable throughout two years review. In conclusion, unresolved red eyes with headaches can be an early presentation of IHCP. Pathophysiology and treatment of the ocular manifestations and IHCP were discussed.

Investigating the reaction and substrate preference of indole-3-acetaldehyde dehydrogenase from the plant pathogen Pseudomonas syringae PtoDC3000.

Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae.

Physician Renewal of Chronically Prescribed Controlled Substances Based on Urine Drug Test Results.

Objective: The effect of specific urine drug testing (UDT) results on physician prescribing habits has not been well described. The primary objective was to report renewal rates of chronically prescribed controlled substances based on types of inconsistent UDT results. Methods: We conducted a retrospective chart review over a 5-month period comparing prescription renewals rates for patients with consistent versus inconsistent UDTs. Inconsistent UDTs were defined by prescribed drug not detected or the presence of heroin, cocaine, nonprescribed opioids, nonprescribed benzodiazepines, or marijuana. Results: Of the 474 UDTs reviewed, 214 (45.1%) were inconsistent. The most common findings among inconsistent UDTs, including overlapping results, were prescribed drug not detected (26.8%) and the presence of marijuana (20.7%), nonprescribed opioids (9.9%), and nonprescribed benzodiazepines (6.1%). In contrast, cocaine (5.5%) and heroin (0.4%) were less likely to be found on UDTs for this population. The relative risk (RR) of prescription renewal was 0.64 (95% CI 0.57-0.71) for inconsistent UDTs versus consistent UDTs. Within the inconsistent UDTs, the renewal rates when marijuana (79.6%) or nonprescribed opioids or benzodiazepines (63.6%) were present were much higher than when heroin or cocaine were present (0.0%; P < .001). Patients whose prescribed controlled substance was not detected had a 55.8% renewal rate. Conclusions: Prescription renewal rates were high when patient UDTs contained nonprescribed marijuana, opioids, and benzodiazepines, or when the prescribed drug was not detected. Prescription renewal rates were low when illicit drugs, such as heroin and cocaine, were detected.

Genetic and physical interactions between the organellar mechanosensitive ion channel homologs MSL1, MSL2, and MSL3 reveal a role for inter-organellar communication in plant development.

Plant development requires communication on many levels, including between cells and between organelles within a cell. For example, mitochondria and plastids have been proposed to be sensors of environmental stress and to coordinate their responses. Here we present evidence for communication between mitochondria and chloroplasts during leaf and root development, based on genetic and physical interactions between three Mechanosensitive channel of Small conductance-Like (MSL) proteins from Arabidopsis thaliana. MSL proteins are Arabidopsis homologs of the bacterial Mechanosensitive channel of Small conductance (MscS), which relieves cellular osmotic pressure to protect against lysis during hypoosmotic shock. MSL1 localizes to the inner mitochondrial membrane, while MSL2 and MSL3 localize to the inner plastid membrane and are required to maintain plastid osmotic homeostasis during normal growth and development. In this study, we characterized the phenotypic effect of a genetic lesion in MSL1, both in wild type and in msl2 msl3 mutant backgrounds. msl1 single mutants appear wild type for all phenotypes examined. The characteristic leaf rumpling in msl2 msl3 double mutants was exacerbated in the msl1 msl2 msl3 triple mutant. However, the introduction of the msl1 lesion into the msl2 msl3 mutant background suppressed other msl2 msl3 mutant phenotypes, including ectopic callus formation, accumulation of superoxide and hydrogen peroxide in the shoot apical meristem, decreased root length, and reduced number of lateral roots. All these phenotypes could be recovered by molecular complementation with a transgene containing a wild type version of MSL1. In yeast-based interaction studies, MSL1 interacted with itself, but not with MSL2 or MSL3. These results establish that the abnormalities observed in msl2 msl3 double mutants is partially dependent on the presence of functional MSL1 and suggest a possible role for communication between plastid and mitochondria in seedling development.

A topographical map approach to representing treatment efficacy: a focus on positive psychology interventions.

A recent meta-analysis by Bolier et al. indicated that positive psychology interventions have overall small to moderate effects on well-being, but results were quite heterogeneous across intervention trials. Such meta-analytic research helps condense information on the efficacy of a broad psychosocial intervention by averaging across many effects; however, such global averages may provide limited navigational guidance for selecting among specific interventions. Here, we introduce a novel method for displaying qualitative and quantitative information on the efficacy of interventions using a topographical map approach. As an initial prototype for demonstrating this method, we mapped 50 positive psychology interventions targeting well-being (as captured in the Bolier et al. [2013] meta-analysis, [Bolier, L., Haverman, M., Westerhof, G. J., Riper, H., Smit, F., & Bohlmeijer, E. (2013). Positive psychology interventions: A meta-analysis of randomized controlled studies. BMC Public Health, 13, 83]). Each intervention domain/subdomain was mapped according to its average effect size (indexed by vertical elevation), number of studies providing effect sizes (indexed by horizontal area), and therapist/client burden (indexed by shading). The geographical placement of intervention domains/subdomains was determined by their conceptual proximity, allowing viewers to gauge the general conceptual "direction" in which promising intervention effects can be found. The resulting graphical displays revealed several prominent features of the well-being intervention "landscape," such as more strongly and uniformly positive effects of future-focused interventions (including, goal-pursuit and optimism training) compared to past/present-focused ones.

Prevalence and Characteristics of Body Dysmorphic Disorder Among Patients in a Partial Hospital Program.

Body dysmorphic disorder (BDD) is a common disorder that is usually associated with impaired functioning and high levels of suicidality. The current study is the first to assess prevalence of BDD among patients in a partial hospital program and compare patients with and without BDD on demographic and clinical variables. Participants were 207 patients with a variety of Axis I diagnoses. Prevalence of current BDD was 7.2%, and a diagnosis of BDD did not predict worse treatment outcome in the program. Patients with current BDD were more likely to be female and younger and have more comorbid diagnoses than patients without current BDD. No other significant differences were found at baseline between patients with and without current BDD. Results indicate that BDD is relatively common among patients in partial hospital programs and that such programs may be as beneficial to patients with BDD as to other patients.

Examining the efficacy of d-cycloserine to augment therapeutic learning in depression.

Despite advances in individual and combined treatments for major depression, issues with non-response and partial-response remain relatively common, motivating the search for new treatment strategies. This study aims to develop one such novel treatment. In this proof-of-concept study, we are investigating whether the treatment enhancing effects of d-cycloserine (DCS) administration can be extended outside the extinction-learning paradigms where they have been primarily examined. Using uniform delivery of cognitive behavioral therapy (CBT) content via computer-administered interventions for depression, we are assessing the value of pre-session administrations of DCS for retention of therapeutic learning. Recall of this information is evaluated in conjunction with performance on standardized tests of memory recall with both emotional and non-emotional stimuli. Specifically, in a randomized, double-blind trial we will compare the benefits of two pre-session administrations of DCS augmentation to those achieved by similar administrations of modafinil or placebo. Because modafinil is associated with a number of discriminable effects in addition to cognitive enhancement (e.g., feelings of vigor, alertness, positive mood); whereas these effects would not be expected with DCS, we will assess drug context effects in relation to memory augmentation effects.

When Partial Hospitalization Fails: Risk Factors for Inpatient Hospitalization.

Partial hospitalization is an understudied bridge between outpatient and inpatient care. One of its primary functions is to prevent the need for inpatient hospitalization. We examined potential demographic and clinical risk factors for inpatient hospitalization for current partial hospital patients. We conducted separate multiple logistic regression analyses for patients referred from inpatient care and the community. For individuals referred from inpatient care, suicidal ideation and greater psychotic symptoms upon admission to the partial program were associated with acute inpatient re-hospitalization. For individuals referred from the community, suicidal ideation and worse relationship functioning upon partial hospital admission were significant risk factors for inpatient hospitalization. Number of previous inpatient hospitalizations and greater substance abuse were not associated with inpatient hospitalization in either sample. Implications at the provider and program level are discussed.

Predictors of Depression Treatment Response in an Intensive CBT Partial Hospital.

OBJECTIVE: Despite the effectiveness of cognitive behavioral therapy (CBT) for depression, a significant number of patients do not respond. Data examining predictors of treatment response in settings in which CBT is delivered naturalistically are lacking. METHOD: Treatment outcome data collected at a CBT-based partial hospital (n = 956) were used to examine predictors of two types of treatment response: (a) a reliable and clinically significant change in depressive symptoms and (b) a self-rating of "very much" or "much" improved. In multiple logistic regression models, we examined predictors of response in the total sample and separately for patients with a primary diagnosis of major depressive disorder (MDD) versus patients with other primary diagnoses. RESULTS: In the total sample, higher treatment outcome expectations and fewer past hospitalizations predicted clinically significant improvement in depression symptoms, and higher treatment expectations and ethnoracial minority background predicted global improvement. In patients with primary MDD, higher treatment outcome expectations and being referred from the community (vs. inpatient hospitalization) predicted better depression response, and higher treatment outcome expectations predicted global improvement. In patients with other primary diagnoses, higher treatment outcome expectations and fewer borderline personality disorder traits predicted depression reduction, and higher treatment outcome expectations, less relationship difficulty, and female gender predicted global improvement. CONCLUSIONS: Results are generally consistent with data from randomized controlled trials on longer term outpatient CBT. Interventions that increase treatment expectancy and modifications to better target men may enhance treatment outcome. Future research should include objective outcome measures and examine mechanisms underlying treatment response.

Haplotyping germline and cancer genomes with high-throughput linked-read sequencing.

Haplotyping of human chromosomes is a prerequisite for cataloguing the full repertoire of genetic variation. We present a microfluidics-based, linked-read sequencing technology that can phase and haplotype germline and cancer genomes using nanograms of input DNA. This high-throughput platform prepares barcoded libraries for short-read sequencing and computationally reconstructs long-range haplotype and structural variant information. We generate haplotype blocks in a nuclear trio that are concordant with expected inheritance patterns and phase a set of structural variants. We also resolve the structure of the EML4-ALK gene fusion in the NCI-H2228 cancer cell line using phased exome sequencing. Finally, we assign genetic aberrations to specific megabase-scale haplotypes generated from whole-genome sequencing of a primary colorectal adenocarcinoma. This approach resolves haplotype information using up to 100 times less genomic DNA than some methods and enables the accurate detection of structural variants.

The relationship between depression and generalized anxiety during intensive psychological and pharmacological treatment.

BACKGROUND: In the present study we examined the relationship between depressive symptoms and generalized anxiety symptoms during intensive cognitive-behavioral and pharmacological treatment. METHOD: Individuals (n = 157) with major depressive disorder (MDD; n = 83), generalized anxiety disorder (GAD; n = 29) and their combination (n = 45) who attended an intensive partial hospital treatment program, completed daily self-report measures of depression and generalized anxiety. Treatment included empirically-based cognitive-behavioral interventions in both individual and group format, as well as pharmacotherapy. RESULTS: Multilevel linear modeling indicated that for all diagnostic groups, changes in depressive symptoms led to changes in generalized anxiety symptoms to a greater extent than vice versa during treatment. Moreover, changes in depressive symptoms fully mediated changes in generalized anxiety symptoms, whereas changes in generalized anxiety symptoms only partially mediated the changes in depressive symptoms. LIMITATIONS: Partial hospital setting. CONCLUSIONS: Our results suggest that depressive symptoms may play a prominent role in the process of change in both MDD and GAD. This has implications for the classification of GAD as well as for choosing early treatment targets for individuals with comorbid MDD and GAD.

Helicobacter pylori Activates and Expands Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands.

BACKGROUND & AIMS: Helicobacter pylori infection is the main risk factor for gastric cancer. We characterized the interactions of H pylori with gastric epithelial progenitor and stem cells in humans and mice and investigated how these interactions contribute to H pylori-induced pathology. METHODS: We used quantitative confocal microscopy and 3-dimensional reconstruction of entire gastric glands to determine the localizations of H pylori in stomach tissues from humans and infected mice. Using lineage tracing to mark cells derived from leucine-rich repeat-containing G-protein coupled receptor 5-positive (Lgr5(+)) stem cells (Lgr5-eGFP-IRES-CreERT2/Rosa26-TdTomato mice) and in situ hybridization, we analyzed gastric stem cell responses to infection. Isogenic H pylori mutants were used to determine the role of specific virulence factors in stem cell activation and pathology. RESULTS: H pylori grow as distinct bacterial microcolonies deep in the stomach glands and interact directly with gastric progenitor and stem cells in tissues from mice and humans. These gland-associated bacteria activate stem cells, increasing the number of stem cells, accelerating Lgr5(+) stem cell proliferation, and up-regulating expression of stem cell-related genes. Mutant bacteria with defects in chemotaxis that are able to colonize the stomach surface but not the antral glands in mice do not activate stem cells. In addition, bacteria that are unable to inject the contact-dependent virulence factor CagA into the epithelium colonized stomach glands in mice, but did not activate stem cells or produce hyperplasia to the same extent as wild-type H pylori. CONCLUSIONS: H pylori colonize and manipulate the progenitor and stem cell compartments, which alters turnover kinetics and glandular hyperplasia. Bacterial ability to alter the stem cells has important implications for gastrointestinal stem cell biology and H pylori-induced gastric pathology.

Regulation of Helicobacter pylori Virulence Within the Context of Iron Deficiency.

Helicobacter pylori strains that harbor the oncoprotein CagA increase gastric cancer risk, and this risk is augmented under iron-deficient conditions. We demonstrate here that iron depletion induces coccoid morphology in strains lacking cagA. To evaluate the stability of augmented H. pylori virulence phenotypes stimulated by low-iron conditions, H. pylori isolated from iron-depleted conditions in vivo were serially passaged in vitro. Long-term passage decreased the ability of hypervirulent strains to translocate CagA or induce interleukin 8, indicating that hypervirulent phenotypes stimulated by low-level iron conditions are reversible. Therefore, rectifying iron deficiency may attenuate disease among H. pylori-infected persons with no response to antibiotics.

Psychometric properties of abbreviated and ultra-brief versions of the Penn State Worry Questionnaire.

The Penn State Worry Questionnaire (PSWQ) is a 16-item self-report measure considered the gold-standard assessment instrument for worry. Two abbreviated versions of the PSWQ have also been developed. An 8-item measure (PSWQ-A) was designed to address poor model fit of the full version with older adult samples, and a 3-item version (PSWQ-3) was developed in a clinical setting to avoid problems related to the reverse-scored items and to increase clinical utility. Preliminary examinations of the abbreviated forms have been promising, but additional psychometric evaluation is needed to confirm their reliability and validity. The current study compared psychometric properties of the 3 versions of the PSWQ in a heterogeneous clinical sample of 272 patients presenting for treatment in a partial hospital setting. Results suggested that scores for all 3 versions had good internal consistency; convergent validity with anxiety, stress, intolerance of uncertainty, negative problem orientation, and negative beliefs about worry; as well as adequate discriminant validity with depression, emotional lability, and substance abuse. On all 3 versions, individuals with generalized anxiety disorder (GAD) scored higher than those without the disorder, and across all participants, scores decreased from pre- to posttreatment. Finally, scores on the 3 versions showed similar levels of sensitivity and specificity as screening tools for GAD. Overall, the PSWQ-A and PSWQ-3 scores appear to be internally consistent and valid measures of worry that performed similarly to the full 16-item PSWQ. Given the strong psychometric properties of the shorter form scores, clinicians may prefer such forms, as they are quick to administer and easy to score in session.

Examining the latent structure of worry and generalized anxiety in a clinical sample.

Generalized anxiety disorder (GAD) is characterized by "pathological" worry, suggesting that GAD worriers differ qualitatively from non-GAD worriers. However, results from taxometric studies of worry in undergraduate and community samples have been mixed and to date, no studies have utilized clinical samples. The current study examined the latent structure of worry and GAD symptoms in a diagnostically heterogeneous clinical sample. Indicators were selected from the Penn State Worry Questionnaire-Abbreviated (n=1175) and the GAD-7 (n=638) and submitted to three taxometric procedures: MAXCOV, MAMBAC, and L-Mode. Results from all three procedures suggested that both worry and generalized anxiety are best conceptualized as dimensional constructs. Findings also indicated that ongoing conceptualization, assessment, and treatment of worry and GAD may be hampered by the application of a categorical framework.

Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans.

Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag+), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenesis, Mongolian gerbils were maintained on iron-depleted diets and infected with an oncogenic H. pylori cag+ strain. Iron depletion accelerated the development of H. pylori-induced premalignant and malignant lesions in a cagA-dependent manner. H. pylori strains harvested from iron-depleted gerbils or grown under iron-limiting conditions exhibited enhanced virulence and induction of inflammatory factors. Further, in a human population at high risk for gastric cancer, H. pylori strains isolated from patients with the lowest ferritin levels induced more robust proinflammatory responses compared with strains isolated from patients with the highest ferritin levels, irrespective of histologic status. These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer.

Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion.

Chemotaxis depends on a network of parallel pathways that coordinate cytoskeletal events to bias cell movement along a chemoattractant gradient. Using a forward genetic screen in Dictyostelium discoideum, we identified the Ste20 kinase KrsB, a homolog of tumor suppressors Hippo and MST1/2, as a negative regulator of cell spreading and substrate attachment. The excessive adhesion of krsB(-) cells reduced directional movement and prolonged the streaming phase of multicellular aggregation. These phenotypes depended on an intact kinase domain and phosphorylation of a conserved threonine (T176) within the activation loop. Chemoattractants triggered a rapid, transient autophosphorylation of T176 in a heterotrimeric G protein-dependent and PI3K- and TorC2-independent manner. The active phosphorylated form of KrsB acts to decrease adhesion to the substrate. Taken together these studies suggest that cycling between active and inactive forms of KrsB may provide the dynamic regulation of cell adhesion needed for proper cell migration and chemotaxis. KrsB interacts genetically with another D. discoideum Hippo/MST homolog, KrsA, but the two genes are not functionally redundant. These studies show that Hippo/MST proteins, like the tumor suppressor PTEN and oncogenes Ras and PI3K, play a key role in cell morphological events in addition to their role in regulating cell growth.