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Relationship between Massachusetts Youth Screening Instrument-second version and psychiatric disorders in youths in welfare and juvenile justice institutions in Switzerland

Thu, 02/02/2017 - 3:44pm

BACKGROUND: There is growing evidence that it is important to have well-standardized procedures for identifying the mental health needs of youths in welfare and juvenile justice institutions. One of the most widely used tools for mental health screening in the juvenile justice system is the Massachusetts Youth Screening Instrument-second version (MAYSI-2). To contribute to the body of research examining the utility of the MAYSI-2 as a mental health screening tool; the first objective of the current study was to examine the relationship between the MAYSI-2 and the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL) in a sample of Swiss youths in welfare and juvenile justice institutions using a cross-sectional design. Secondly, as the sample was drawn from the French-, German- and Italian-speaking parts of Switzerland, the three languages were represented in the total sample and consequently differences between the language regions were analyzed as well. The third objective was to examine gender differences in this relationship.

METHODS: Participants were 297 boys and 149 girls (mean age = 16.2, SD = 2.5) recruited from 64 youth welfare and juvenile justice institutions in Switzerland. The MAYSI-2 was used to screen for mental health or behavioral problems that could require further evaluation. Psychiatric classification was based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime version (K-SADS-PL). Binomial logistic regression analysis was used to predict (cluster of) psychiatric disorders from MAYSI-2 scales.

RESULTS: The regression analyses revealed that the MAYSI-2 scales generally related well to their corresponding homotypic (cluster of) psychiatric disorders. For example, the alcohol/drug use scale identified the presence of any substance use disorder and the suicide ideation scale identified youths reporting suicide ideation or suicide attempts. Several MAYSI-2 scales were also related to heterotypic (cluster of) psychiatric disorders. For example, the MAYSI-2 scale alcohol/drug use, was positively related to any disruptive disorder. Furthermore, the results revealed gender differences in the relationship between the MAYSI-2 and K-SADS-PL (e.g., in the boys' subsample no MAYSI-2 scale was significantly related to any affective disorder; whereas, in the girls' subsample the MAYSI-2 scales depressed-anxious and somatic complaints were significantly related to any affective disorder).

CONCLUSIONS: Overall, The MAYSI-2 seems to serve well as a first-stage screen to identify service needs for youths in welfare and juvenile justice institutions in Switzerland. Its effectiveness to identify the presence of (cluster of) psychiatric disorders differs between genders.

Diagnostic Prevalence of Ankylosing Spondylitis Using Computerized Health Care Data, 1996 to 2009: Underrecognition in a US Health Care Setting

Thu, 02/02/2017 - 3:44pm

INTRODUCTION: Few studies have assessed the prevalence and features of axial spondyloarthritis (axSpA) and ankylosing spondylitis in diverse, population-based, community settings.

OBJECTIVES: We used computerized diagnoses to estimate the prevalence of axSpA and ankylosing spondylitis in Kaiser Permanente Northern California (KPNC).

METHODS: We identified persons aged 18 years or older with 1 or more International Classification of Diseases, Ninth Revision (ICD-9) diagnosis Code 720.X (ankylosing spondylitis and other inflammatory spondylopathies) in clinical encounter data from 1996 through 2009 to estimate the prevalence of axSpA and ankylosing spondylitis. We reviewed medical records to confirm the diagnosis in a random sample and estimated the positive predictive value of computerized data to identify confirmed cases using various case definitions.

RESULTS: In the computerized data, 5568 adults had diagnostic codes indicating axSpA. On the basis of our case-finding approach using a single physician diagnosis code for ICD-9 720.X, the point prevalence of these conditions, standardized to the 2000 US Census, was 2.26 per 1000 persons for axSpA and 1.07 per 1000 for ankylosing spondylitis. Less than half of suspected cases saw a rheumatologist. The most specific algorithm for confirmed ankylosing spondylitis required 2 or more computerized diagnoses assigned by a rheumatologist, with 67% sensitivity (95% confidence interval, 64%-69%) and 81% positive predictive value (95% confidence interval, 79%-83%).

CONCLUSIONS: Observed prevalence in the KPNC population, compared with national estimates for axSpA and ankylosing spondylitis, suggests there is substantial underrecognition of these conditions in routine clinical practice. However, use of computerized data is able to identify true cases of ankylosing spondylitis, facilitating population-based research.

Autophagy Activation by Transcription Factor EB (TFEB) in Striatum of HDQ175/Q7 Mice

Thu, 02/02/2017 - 3:44pm

BACKGROUND: Mutant huntingtin (mHTT) is encoded by the Huntington's disease (HD) gene and its accumulation in the brain contributes to HD pathogenesis. Reducing mHTT levels through activation of the autophagosome-lysosomal pathway may have therapeutic benefit. Transcription factor EB (TFEB) regulates lysosome biogenesis and autophagy.

OBJECTIVE: To examine if increasing TFEB protein levels in HD mouse striatum induces autophagy and influences mHTT levels.

METHODS: We introduced cDNA encoding TFEB with an HA tag (TFEB-HA) under the control of neuron specific synapsin 1 promoter into the striatum of 3 month old HDQ175/Q7 mice using adeno-associated virus AAV2/9. The levels of exogenous TFEB were analyzed using qPCR and Western blot. Proteins involved in autophagy, levels of huntingtin, and striatal-enriched proteins were examined using biochemical and/or immunohistochemical methods.

RESULTS: In HD mice expressing TFEB-HA, HA immunoreactivity distributed throughout the striatum in neuronal cell bodies and processes and preferentially in neuronal nuclei and overlapped with a loss of DARPP32 immunoreactivity. TFEB-HA mRNA and protein were detected in striatal lysates. There were increased levels of proteins involved with autophagosome/lysosome activity including LAMP-2A, LC3II, and cathepsin D and reduced levels of mutant HTT and the striatal enriched proteins DARPP32 and PDE10A. Compared to WT mice, HDQ175/Q7 mice had elevated levels of the ER stress protein GRP78/BiP and with TFEB-HA expression, increased levels of the astrocyte marker GFAP and pro-caspase 3.

CONCLUSION: These results suggest that TFEB expression in the striatum of HDQ175/Q7 mice stimulates autophagy and lysosome activity, and lowers mHTT, but may also increase a neuronal stress response.

Listening for Grace

Thu, 02/02/2017 - 3:44pm

Narrative essay which under the title "That's Our Saving Grace" was the Family Medicine Education Consortium (FMEC) Annual Prose Contest Winner for 2015.

Gene therapy approaches for the treatment of retinal disorders

Thu, 02/02/2017 - 3:44pm

There is an impelling need to develop effective therapeutic strategies for patients with retinal disorders. Gleaning from the large quantity of information gathered over the past two decades on the mechanisms governing degeneration of the retina, it is now possible to devise innovative therapies based on retinal gene transfer. Different gene-based approaches are under active investigation. They include strategies to correct the specific genetic defect in inherited retinal diseases, strategies to delay the onset of blindness independently of the disease-causing mutations, and strategies to reactivate residual cells at late stages of the diseases. In this review, we discuss the status of application of these technologies, outlining the future therapeutic potential for many forms of retinal blinding diseases.

ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics

Thu, 02/02/2017 - 3:43pm

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of-toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA-binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1-G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS.

Preserving Patient Privacy When Sharing Same-Disease Data

Thu, 02/02/2017 - 3:43pm

Medical and health data are often collected for studying a specific disease. For such same-disease microdata, a privacy disclosure occurs as long as an individual is known to be in the microdata. Individuals in same-disease microdata are thus subject to higher disclosure risk than those in microdata with different diseases. This important problem has been overlooked in data-privacy research and practice, and no prior study has addressed this problem. In this study, we analyze the disclosure risk for the individuals in same-disease microdata and propose a new metric that is appropriate for measuring disclosure risk in this situation. An efficient algorithm is designed and implemented for anonymizing same-disease data to minimize the disclosure risk while keeping data utility as good as possible. An experimental study was conducted on real patient and population data. Experimental results show that traditional reidentification risk measures underestimate the actual disclosure risk for the individuals in same-disease microdata and demonstrate that the proposed approach is very effective in reducing the actual risk for same-disease data. This study suggests that privacy protection policy and practice for sharing medical and health data should consider not only the individuals' identifying attributes but also the health and disease information contained in the data. It is recommended that data-sharing entities employ a statistical approach, instead of the HIPAA's Safe Harbor policy, when sharing same-disease microdata.

Distinct surveillance pathway for immunopathology during acute infection via autophagy and SR-BI

Thu, 02/02/2017 - 3:43pm

The mechanisms protecting from immunopathology during acute bacterial infections are incompletely known. We found that in response to apoptotic immune cells and live or dead Listeria monocytogenes scavenger receptor BI (SR-BI), an anti-atherogenic lipid exchange mediator, activated internalization mechanisms with characteristics of macropinocytosis and, assisted by Golgi fragmentation, initiated autophagic responses. This was supported by scavenger receptor-induced local increases in membrane cholesterol concentrations which generated lipid domains particularly in cell extensions and the Golgi. SR-BI was a key driver of beclin-1-dependent autophagy during acute bacterial infection of the liver and spleen. Autophagy regulated tissue infiltration of neutrophils, suppressed accumulation of Ly6C+ (inflammatory) macrophages, and prevented hepatocyte necrosis in the core of infectious foci. Perifocal levels of Ly6C+ macrophages and Ly6C- macrophages were unaffected, indicating predominant regulation of the focus core. SR-BI-triggered autophagy promoted co-elimination of apoptotic immune cells and dead bacteria but barely influenced bacterial sequestration and survival or inflammasome activation, thus exclusively counteracting damage inflicted by immune responses. Hence, SR-BI- and autophagy promote a surveillance pathway that partially responds to products of antimicrobial defenses and selectively prevents immunity-induced damage during acute infection. Our findings suggest that control of infection-associated immunopathology can be based on a unified defense operation.

The Zn-finger domain of MdmX suppresses cancer progression by promoting genome stability in p53-mutant cells

Thu, 02/02/2017 - 3:43pm

The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis. We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis in primary and tumor cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed tumors more rapidly than p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in cancers with compromised p53 function. By using orthotopic transplantation and lung colonization assays in mice we now establish a p53-independent anti-oncogenic role for MdmX in tumor progression. We also demonstrate that the roles of MdmX in genome stability and in proliferation are two distinct functions encoded by the separate MdmX protein domains. The central Zn-finger domain suppresses multipolar mitosis and chromosome loss, whereas the carboxy-terminal RING domain suppresses proliferation of p53-deficient cells. Furthermore, we determine that it is the maintenance of genome stability that underlies MdmX role in suppression of tumorigenesis in hyperploid p53 mutant tumors. Our results offer a rationale for the increased metastatic potential of p53 mutant human cancers with aberrant MdmX function and provide a caveat for the application of anti-MdmX treatment of tumors with compromised p53 activity.

A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119

Thu, 02/02/2017 - 3:43pm

The most widespread Plasmodium species, Plasmodium vivax, poses a significant public health threat. An effective vaccine is needed to reduce global malaria burden. Of the erythrocytic stage vaccine candidates, the 19 kDa fragment of the P. vivax Merozoite Surface Protein 1 (PvMSP119) is one of the most promising. Our group has previously defined several promiscuous T helper epitopes within the PvMSP1 protein, with features that allow them to bind multiple MHC class II alleles. We describe here a P. vivax recombinant modular chimera based on MSP1 (PvRMC-MSP1) that includes defined T cell epitopes genetically fused to PvMSP119. This vaccine candidate preserved structural elements of the native PvMSP119 and elicited cytophilic antibody responses, and CD4+ and CD8+ T cells capable of recognizing PvMSP119. Although CD8+ T cells that recognize blood stage antigens have been reported to control blood infection, CD8+ T cell responses induced by P. falciparum or P. vivax vaccine candidates based on MSP119 have not been reported. To our knowledge, this is the first time a protein based subunit vaccine has been able to induce CD8+ T cell against PvMSP119. The PvRMC-MSP1 protein was also recognized by naturally acquired antibodies from individuals living in malaria endemic areas with an antibody profile associated with protection from infection. These features make PvRMC-MSP1 a promising vaccine candidate.

Clinical Topic Review 2013 - Behavioral Health Screening Among MassHealth Children and Adolescents

Wed, 02/01/2017 - 10:28am

Results from the 2013 evaluation suggest that the Children’s Behavioral Health Initiative had a large impact on formal behavioral health screening and treatment utilization among children and adolescents enrolled in MassHealth.

Clinical Topic Review: Behavioral Health Screening for Children with Well Visits

Wed, 02/01/2017 - 10:28am

The first Clinical Topic Review was conducted in order to better understand how behavioral health screenings were occurring for children and adolescents during well visits prior to the implementation of a requirement that primary care providers perform behavioral health screening using a standardized behavioral health screening tool during every well child visit.

Evaluation of online and in-person motivational interviewing training for healthcare providers

Mon, 01/30/2017 - 12:28pm

INTRODUCTION: This study examines the outcomes of a 22-hr motivational interviewing (MI) course and compares online and in-person offerings of the course. It also evaluates clinicians' ability to accurately self-assess their MI skills.

METHOD: 34 clinicians participated in this study and completed MI workshops either in-person or online. Use of MI in an acting patient encounter was recorded early in the training and again following the training. Recordings of these encounters were coded using the Motivational Interviewing Treatment Integrity (MITI) 3.1 coding system. After each acting patient encounter clinicians also self-evaluated their use of MI.

RESULTS: Participants showed statistically significant improvement in MI skills measured by the MITI. There were no meaningful differences between the MI skills acquired by the participants in the online group compared with those who completed training in-person. There was little correlation between participants' self-assessment of MI skills and objective assessment.

DISCUSSION: It is feasible to complete MI training through synchronous online workshops. Participant self-assessment of MI skill does not appear to be a useful approach for assessing MI skill. The acquisition of MI skills by health professionals is possible via the Internet. Learning should be assessed using objective measures rather than relying on self-report.

Cellular perception and misperception: Internal models for decision-making shaped by evolutionary experience

Mon, 01/30/2017 - 11:01am

Cells live in dynamic environments that necessitate perpetual adaptation. Since cells have limited resources to monitor external inputs, they are required to maximize the information content of perceived signals. This challenge is not unique to microscopic life: Animals use senses to perceive inputs and adequately respond. Research showed that sensory-perception is actively shaped by learning and expectation allowing internal cognitive models to "fill in the blanks" in face of limited information. We propose that cells employ analogous strategies and use internal models shaped through the long process of evolutionary adaptation. Given this perspective, we postulate that cells are prone to "misperceptions," analogous to visual illusions, leading them to incorrectly decode patterns of inputs that lie outside of their evolutionary experience. Mapping cellular misperception can serve as a fundamental approach for dissecting regulatory networks and could be harnessed to modulate cell behavior, a potentially new avenue for therapy.

Crystal structure of the DNA binding domain of the transcription factor T-bet suggests simultaneous recognition of distant genome sites

Mon, 01/30/2017 - 11:01am

The transcription factor T-bet (Tbox protein expressed in T cells) is one of the master regulators of both the innate and adaptive immune responses. It plays a central role in T-cell lineage commitment, where it controls the TH1 response, and in gene regulation in plasma B-cells and dendritic cells. T-bet is a member of the Tbox family of transcription factors; however, T-bet coordinately regulates the expression of many more genes than other Tbox proteins. A central unresolved question is how T-bet is able to simultaneously recognize distant Tbox binding sites, which may be located thousands of base pairs away. We have determined the crystal structure of the Tbox DNA binding domain (DBD) of T-bet in complex with a palindromic DNA. The structure shows a quaternary structure in which the T-bet dimer has its DNA binding regions splayed far apart, making it impossible for a single dimer to bind both sites of the DNA palindrome. In contrast to most other Tbox proteins, a single T-bet DBD dimer binds simultaneously to identical half-sites on two independent DNA. A fluorescence-based assay confirms that T-bet dimers are able to bring two independent DNA molecules into close juxtaposition. Furthermore, chromosome conformation capture assays confirm that T-bet functions in the direct formation of chromatin loops in vitro and in vivo. The data are consistent with a looping/synapsing model for transcriptional regulation by T-bet in which a single dimer of the transcription factor can recognize and coalesce distinct genetic elements, either a promoter plus a distant regulatory element, or promoters on two different genes.

Mapping the 3D genome: Aiming for consilience

Mon, 01/30/2017 - 11:01am

The spatial organization of genomes is studied using microscopy- and chromosome conformation capture (3C)-based methods. The two types of methods produce data that are often consistent, but there are cases where they appear discordant. These cases provide opportunities to derive better models of chromatin folding, which can reconcile the datasets.

CTCF-mediated topological boundaries during development foster appropriate gene regulation

Mon, 01/30/2017 - 11:01am

The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation. Moreover, our data suggest that CTCF-dependent boundary function can be modulated by competing forces, such as the self-assembly of polycomb domains within the nucleus. Therefore, CTCF boundaries are not merely static structural components of the genome but instead are locally dynamic regulatory structures that control gene expression during development.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma

Mon, 01/30/2017 - 11:01am

RATIONALE: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease.

OBJECTIVES: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma.

METHODS: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays.

MEASUREMENTS AND MAIN RESULTS: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 x 10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene.

CONCLUSIONS: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups.

Clinical trial registered with (NCT00000575).

Linked Data for Cultural Heritage

Fri, 01/27/2017 - 4:22pm

This is a review of the book, Linked Data for Cultural Heritage, edited by Ed Jones and Michele Seikel. Published by American Library Association, 2016.

The Relevance of Ultrasound Imaging of Suspicious Axillary Lymph Nodes and Fine-needle Aspiration Biopsy in the Post-ACOSOG Z11 Era in Early Breast Cancer

Thu, 01/19/2017 - 12:58pm

RATIONALE AND OBJECTIVES: Evaluation of nodal involvement in early-stage breast cancers (T1 or T2) changed following the Z11 trial; however, not all patients meet the Z11 inclusion criteria. Hence, the relevance of ultrasound imaging of the axilla and fine-needle aspiration biopsy (FNA) in early-stage breast cancers was investigated.

MATERIALS AND METHODS: In this single-center, retrospective study, 758 subjects had pathology-verified breast cancer diagnosis over a 3-year period, of which 128 subjects with T1 or T2 breast tumors had abnormal axillary lymph nodes on ultrasound, had FNA, and proceeded to axillary surgery. Ultrasound images were reviewed and analyzed using multivariable logistic regression to identify the features predictive of positive FNA. Accuracy of FNA was quantified as the area under the receiver operating characteristic curve with axillary surgery as reference standard.

RESULTS: Of 128 subjects, 61 were positive on FNA and 65 were positive on axillary surgery. Sensitivity, specificity, positive predictive value, and negative predictive value of FNA were 52 of 65 (80%), 54 of 63 (85.7%), 52 of 61(85.2%), and 54 of 67 (80.5%), respectively. After adjusting for neoadjuvant chemotherapy between FNA and surgery, a positive FNA was associated with higher likelihood for positive axillary surgery (odds ratio: 22.7; 95% confidence interval [CI]: 7.2-71.3, P < .0001), and the accuracy of FNA was 0.801 (95% CI: 0.727-0.876). Among ultrasound imaging features, cortical thickness and abnormal hilum were predictive (P < .017) of positive FNA with accuracy of 0.817 (95% CI: 0.741-0.893).

CONCLUSIONS: Ultrasound imaging and FNA can play an important role in the management of early breast cancers even in the post-Z11 era. Higher weightage can be accorded to cortical thickness and hilum during ultrasound evaluation.