Identification of Clinical and Behavioral Outcomes Predictive of FTLD-TDP Pathology

Frontotemporal Lobar Dementia (FTLD) is a neurogenerative disease often misdiagnosed as Alzheimer’s Disease (AD), resulting in poor treatment outcomes (Rascovsky et al., 2011). Multi-factorial approaches are increasingly being applied to yield more accurate and earlier diagnoses. These standard clinical outcomes include MRI imaging, biomarkers, and assessments of cognitive ability. While each of these outcomes are partially predictive of FTLD diagnosis, none alone carry enough power to differentiate FTLD patients from other dementias, including AD. One notable variable is TDP-43, a DNA-binding protein involved in regulating the FTLD risk gene UNC13A, suggested as one of the more effective biomarkers for early FTLD diagnosis. While it is understood that TDP-43 serves as a good diagnostic biomarker, it is less understood what unique clinical outcomes emerge as a consequence of FTLD-TDP pathology compared to other TDP-related diagnoses. To examine best clinical predictivity, exploratory analyses will be run to investigate outcome combinations that most accurately identify TDP-43 pathology. These variables include: CSF tau concentration, level of cognitive ability, and cerebral gray matter volume. Data was extracted from the National Alzheimer’s Coordinating Center (NACC). Inclusion criterion were completeness of the following items/scores: FTD diagnosis, T1 scan (gray matter volumes), Montreal Cognitive Assessment (MoCA), CSF tau, and TDP-43 pathology. Structural equation modeling (SEM) - specifically between FTLD-TDP patients compared to FTLD patients investigated the predictiveness of these variables. Data collection is still being conducted and results will be presented and discussed in full during the oral presentation. Overall, the results are expected to shed light on what combination of clinical outcomes are most related to FTLD-TDP pathology over other FTLD cases

Use of a regional wall motion score to enhance risk stratification of patients receiving an implantable cardioverter-defibrillator

AbstractObjectives. We postulated that preoperative assessment of both regional wall motion and left ventricular ejection fraction would serve as an accurate prognostic indicator of long-term cardiac mortality and functional outcome in patients treated with an implantable cardioverter-defibrillator.Background. Long-term cardiac mortality has remained high in patients receiving an implantable cardioverter-defibrillator. The ability to risk stratify patients before defibrillator implantation is becoming increasingly important from a medical and economic standpoint.Methods. The hypothesis was retrospectively tested in 74 patients who had received an implantable cardioverterdefibrillator. Left ventricular ejection fraction and regional wall motion score, derived from centerline chord motion analysis, were calculated for each patient from the preoperative right anterior oblique contrast ventriculogram. Wall motion score was the only significant independent predictor of long-term cardiac mortality and functional status by multivariate analysis because of its enhanced prognostic capability in patients with an ejection fraction in the critical range of 30% to 40%.Results. Patients with an ejection fraction >40% had a 3-year cardiac mortality rate of 0% compared with 25% for those with an ejection fraction of 30% to 40% and 48% for those with an ejection fraction <30% (p < 0.05). Similarly, 75% of patients with an ejection fraction >40% were in New York Heart Association functional class I or II during long-term follow-up compared with 59% of those with an ejection fraction 30% to 40% and 29% of those with an ejection fraction <30%. Among patients with an ejection fraction of 30% to 40%, those with a wall motion score >16% had a 3-year cardiac mortality rate of 0% compared with 71% of those with a wall motion score ≤ 16% (p = 0.002). In addition, 86% of patients with a wall motion score >16% were in functional class I or II during long-term follow-up compared with 13% of those with a wall motion score ≤16% (p = 0.001).Conclusions. Long-term cardiac mortality and functional outcome in patients receiving an implantable cardioverterdefibrillator can be predicted if the left ventricular ejection fraction and regional wall motion score are measured preoperatively

The Power of Play: A Pediatric Role in Enhancing Development in Young Children

Children need to develop a variety of skill sets to optimize their development and manage toxic stress. Research demonstrates that developmentally appropriate play with parents and peers is a singular opportunity to promote the social-emotional, cognitive, language, and self-regulation skills that build executive function and a prosocial brain. Furthermore, play supports the formation of the safe, stable, and nurturing relationships with all caregivers that children need to thrive

Identification of early changes in specific symptoms that predict longer-term response to atypical antipsychotics in the treatment of patients with schizophrenia

<p>Abstract</p> <p>Background</p> <p>To identify a simple decision tree using early symptom change to predict response to atypical antipsychotic therapy in patients with (Diagnostic and Statistical Manual, Fourth Edition, Text Revised) chronic schizophrenia.</p> <p>Methods</p> <p>Data were pooled from moderately to severely ill patients (n = 1494) from 6 randomized, double-blind trials (N = 2543). Response was defined as a ≥30% reduction in Positive and Negative Syndrome Scale (PANSS) Total score by Week 8 of treatment. Analyzed predictors were change in individual PANSS items at Weeks 1 and 2. A decision tree was constructed using classification and regression tree (CART) analysis to identify predictors that most effectively differentiated responders from non-responders.</p> <p>Results</p> <p>A 2-branch, 6-item decision tree was created, producing 3 distinct groups. First branch criterion was a 2-point score decrease in at least 2 of 5 PANSS positive items (Week 2). Second branch criterion was a 2-point score decrease in the PANSS excitement item (Week 2). "Likely responders" met the first branch criteria; "likely non-responders" did not meet first or second criterion; "not predictable" patients did not meet the first but did meet the second criterion. Using this approach, response to treatment could be predicted in most patients (92%) with high positive predictive value (79%) and high negative predictive value (75%). Predictive findings were confirmed through analysis of data from 2 independent trials.</p> <p>Conclusions</p> <p>Using a data-driven approach, we identified decision rules using early change in the scores of selected PANSS items to accurately predict longer-term treatment response or non-response to atypical antipsychotic therapy. This could lead to development of a simple quantitative evaluation tool to help guide early treatment decisions.</p> <p>Trial Registration</p> <p>This is a retrospective, non-intervention study in which pooled results from 6 previously published reports were analyzed; thus, clinical trial registration is not required.</p

An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment 1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease 3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines 4,5. We identified a whole blood 393 transcript signature for active TB in intermediate and high burden settings, correlating with radiological extent of disease and reverting to that of healthy controls following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and Type I IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN signature was also observed in whole blood of patients with Systemic Lupus Erythematosus (SLE), their complete modular signature differed from TB with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic

Novel Phosphorylation Sites in the S. cerevisiae Cdc13 Protein Reveal New Targets for Telomere Length Regulation

The S. cerevisiae Cdc13 is a multifunctional protein with key roles in regulation of telomerase, telomere end protection, and conventional telomere replication, all of which are cell cycle-regulated processes. Given that phosphorylation is a key mechanism for regulating protein function, we identified sites of phosphorylation using nano liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS). We also determined phosphorylation abundance on both wild type (WT) and a telomerase deficient form of Cdc13, encoded by the cdc13-2 allele, in both G1 phase cells, when telomerase is not active, and G2/M phase cells, when it is. We identified 21 sites of in vivo phosphorylation, of which only five had been reported previously. In contrast, phosphorylation of two in vitro targets of the ATM-like Tel1 kinase, S249 and S255, was not detected. This result helps resolve conflicting data on the importance of phosphorylation of these residues in telomerase recruitment. multiple residues showed differences in their cell cycle pattern of modification. For example, phosphorylation of S314 was significantly higher in the G2/M compared to the G1 phase and in WT versus mutant Cdc13, and a S314D mutation negatively affected telomere length. Our findings provide new targets in a key telomerase regulatory protein for modulation of telomere dynamics. [Image: see text

Generational status and duration of residence predict diabetes prevalence among Latinos: the California Men's Health Study

<p>Abstract</p> <p>Background</p> <p>Diabetes disproportionately affects Latinos. However, examining Latinos as one group obscures important intra-group differences. This study examined how generational status, duration of US residence, and language preference are associated with diabetes prevalence and to what extent these explain the higher prevalence among Latinos.</p> <p>Methods</p> <p>We determined nativity, duration of US residence, language preference, and diabetes prevalence among 11 817 Latino, 6109 black, and 52 184 white participants in the California Men's Health Study. We combined generational status and residence duration into a single migration status variable with levels: ≥ third generation; second generation; and immigrant living in the US for > 25, 16-25, 11-15, or ≤ 10 years. Language preference was defined as language in which the participant took the survey. Logistic regression models were specified to assess the associations of dependent variables with prevalent diabetes.</p> <p>Results</p> <p>Diabetes prevalence was 22%, 23%, and 11% among Latinos, blacks, and whites, respectively. In age-adjusted models, we observed a gradient of risk of diabetes by migration status among Latinos. Further adjustment for socioeconomic status, obesity and health behaviors only partially attenuated this gradient. Language preference was a weak predictor of prevalent diabetes in some models and not significant in others. In multivariate models, we found that odds of diabetes were higher among US-born Latinos than US-born blacks.</p> <p>Conclusion</p> <p>Generational status and residence duration were associated with diabetes prevalence among middle-aged Latino men in California. As the Latino population grows, the burden of diabetes-associated disease is likely to increase and demands public health attention.</p