Reliable change in developmental outcomes of Brain Balance® participants stratified by baseline severity

The effects of comprehensive multimodal programs on developmental outcomes have not been well-studied. Emerging evidence suggests a possible role for the Brain Balance® (BB) program, a multimodal training program, in serving as a nonpharmacologic approach to addressing cognitive, attentional, and emotional issues in youth. In this analysis, we examined the effects of 3 months of participation in the BB program on the outcomes of children and adolescents with developmental difficulties (N = 4,041; aged 4–18 years; 69.7% male). Parent-rated scores on the Brain Balance–Multidomain Developmental Survey (BB-MDS) were used to assess six areas at baseline and post-program: (1) negative emotionality; (2) reading/writing difficulties; (3) hyperactive/disruptive behavior; (4) academic disengagement; (5) motor/coordination problems; and (6) social communication problems. To estimate change from pre- to post-program, we calculated effect size (Cohen’s d) and the Reliable Change Index (RCI) for groups stratified by baseline severity. There was a very large effect size for the moderate/high severity (d = 1.63) and extreme severity (d = 2.08) groups, and a large effect size for the mild severity group (d = 0.87). The average percentage of participants who observed reliable change over all BB-MDS domains was 60.1% (RCICTT) for extreme severity, 46.6% (RCICTT) for moderate/high severity, and 21.1% (RCICTT) for baseline mild severity. In additional assessments of primitive reflexes and sensory motor activity, students demonstrated significantly diminished primitive reflexes from pre- to post-participation and significant improvements in sensory motor skills including fine motor skills, gait and aerobic ability, proprioception, rhythm and timing, and eye-gaze stability. Overall, these results demonstrate improvements in primitive reflex integration and sensory motor skills, as well as statistically significant reliable change in emotionality, reading/writing, behavior, academic engagement, motor skills, and social communication in BB participants from pre- to post-program, with the probability and degree of change increasing as the participants’ baseline severity increases. These results contribute to the growing literature on the need for evidence-based nonpharmacologic approaches to addressing developmental issues. Future research with well-controlled designs, longitudinal follow-up, implementation across settings, and participant groups in which diagnoses are known, will help to more fully characterize the effects of the BB program

Complete atrial-specific knockout of sodium-calcium exchange eliminates sinoatrial node pacemaker activity.

The origin of sinoatrial node (SAN) pacemaker activity in the heart is controversial. The leading candidates are diastolic depolarization by "funny" current (If) through HCN4 channels (the "Membrane Clock" hypothesis), depolarization by cardiac Na-Ca exchange (NCX1) in response to intracellular Ca cycling (the "Calcium Clock" hypothesis), and a combination of the two ("Coupled Clock"). To address this controversy, we used Cre/loxP technology to generate atrial-specific NCX1 KO mice. NCX1 protein was undetectable in KO atrial tissue, including the SAN. Surface ECG and intracardiac electrograms showed no atrial depolarization and a slow junctional escape rhythm in KO that responded appropriately to β-adrenergic and muscarinic stimulation. Although KO atria were quiescent they could be stimulated by external pacing suggesting that electrical coupling between cells remained intact. Despite normal electrophysiological properties of If in isolated patch clamped KO SAN cells, pacemaker activity was absent. Recurring Ca sparks were present in all KO SAN cells, suggesting that Ca cycling persists but is uncoupled from the sarcolemma. We conclude that NCX1 is required for normal pacemaker activity in murine SAN

Sensitivity of a real-time PCR method for the detection of transgenes in a mixture of transgenic and non-transgenic seeds of papaya (\u3cem\u3eCarica papaya\u3c/em\u3e L.)

Background Genetically engineered (GE) ringspot virus-resistant papaya cultivars ‘Rainbow’ and ‘SunUp’ have been grown in Hawai’i for over 10 years. In Hawai’i, the introduction of GE papayas into regions where non-GE cultivars are grown and where feral non-GE papayas exist have been accompanied with concerns associated with transgene flow. Of particular concern is the possibility of transgenic seeds being found in non-GE papaya fruits via cross-pollination. Development of high-throughput methods to reliably detect the adventitious presence of such transgenic material would benefit both the scientific and regulatory communities. Results We assessed the accuracy of using conventional qualitative polymerase chain reaction (PCR) as well as real-time PCR-based assays to quantify the presence of transgenic DNA from bulk samples of non-GE papaya seeds. In this study, an optimized method of extracting high quality DNA from dry seeds of papaya was standardized. A reliable, sensitive real-time PCR method for detecting and quantifying viral coat protein (cp) transgenes in bulk seed samples utilizing the endogenous papain gene is presented. Quantification range was from 0.01 to 100 ng/μl of GE-papaya DNA template with a detection limit as low as 0.01% (10 pg). To test this system, we simulated transgene flow using known quantities of GE and non-GE DNA and determined that 0.038% (38 pg) GE papaya DNA could be detected using real-time PCR. We also validated this system by extracting DNA from known ratios of GE seeds to non-GE seeds of papaya followed by real-time PCR detection and observed a reliable detection limit of 0.4%. Conclusions This method for the quick and sensitive detection of transgenes in bulked papaya seed lots using conventional as well as real-time PCR-based methods will benefit numerous stakeholders. In particular, this method could be utilized to screen selected fruits from maternal non-GE papaya trees in Hawai’i for the presence of transgenic seed at typical regulatory threshold levels. Incorporation of subtle differences in primers and probes for variations in cp worldwide should allow this method to be utilized elsewhere when and if deregulation of transgenic papaya occurs

High Harvest Yield, High Expansion, and Phenotype Stability of CD146 Mesenchymal Stromal Cells from Whole Primitive Human Umbilical Cord Tissue

Human umbilical cord blood is an excellent primitive source of noncontroversial stem cells for treatment of hematologic disorders; meanwhile, new stem cell candidates in the umbilical cord (UC) tissue could provide therapeutic cells for nonhematologic disorders. We show novel in situ characterization to identify and localize a panel of some markers expressed by mesenchymal stromal cells (MSCs; CD44, CD105, CD73, CD90) and CD146 in the UC. We describe enzymatic isolation and purification methods of different UC cell populations that do not require manual separation of the vessels and stroma of the coiled, helical-like UC tissue. Unique quantitation of in situ cell frequency and stromal cell counts upon harvest illustrate the potential to obtain high numerical yields with these methods. UC stromal cells can differentiate to the osteogenic and chondrogenic lineages and, under specific culturing conditions, they exhibit high expandability with unique long-term stability of their phenotype. The remarkable stability of the phenotype represents a novel finding for human MSCs, from any source, and supports the use of these cells as highly accessible stromal cells for both basic studies and potentially therapeutic applications such as allogeneic clinical use for musculoskeletal disorders

Expression Levels of a Kinesin-13 Microtubule Depolymerase Modulates the Effectiveness of Anti-Microtubule Agents

Chemotherapeutic drugs often target the microtubule cytoskeleton as a means to disrupt cancer cell mitosis and proliferation. Anti-microtubule drugs inhibit microtubule dynamics, thereby triggering apoptosis when dividing cells activate the mitotic checkpoint. Microtubule dynamics are regulated by microtubule-associated proteins (MAPs); however, we lack a comprehensive understanding about how anti-microtubule agents functionally interact with MAPs. In this report, we test the hypothesis that the cellular levels of microtubule depolymerases, in this case kinesin-13 s, modulate the effectiveness of the microtubule disrupting drug colchicine.We used a combination of RNA interference (RNAi), high-throughput microscopy, and time-lapse video microscopy in Drosophila S2 cells to identify a specific MAP, kinesin-like protein 10A (KLP10A), that contributes to the efficacy of the anti-microtubule drug colchicine. KLP10A is an essential microtubule depolymerase throughout the cell cycle. We find that depletion of KLP10A in S2 cells confers resistance to colchicine-induced microtubule depolymerization to a much greater extent than depletion of several other destabilizing MAPs. Using image-based assays, we determined that control cells retained 58% (+/-2%SEM) of microtubule polymer when after treatment with 2 microM colchicine for 1 hour, while cells depleted of KLP10A by RNAi retained 74% (+/-1%SEM). Likewise, overexpression of KLP10A-GFP results in increased susceptibility to microtubule depolymerization by colchicine.Our results demonstrate that the efficacy of microtubule destabilization by a pharmacological agent is dependent upon the cellular expression of a microtubule depolymerase. These findings suggest that expression levels of Kif2A, the human kinesin-13 family member, may be an attractive biomarker to assess the effectiveness of anti-microtubule chemotherapies. Knowledge of how MAP expression levels affect the action of anti-microtubule drugs may prove useful for evaluating possible modes of cancer treatment

Correlation Of Terrestrial gamma flashes, Electric fields, and Lightning strikes (COTEL) in thunderstorms using networked balloon payloads developed by university and community college students

High energy gamma ray flashes from terrestrial sources have been observed by satellites for decades, but the actual mechanism, assumed to be thunderstorm lightning, has yet to be fully characterized. The goal of COTEL, funded by NASA through the University Student Instrument Project (USIP) program, is to correlate in time TGF events, lightning strikes, and electric fields inside of thunderstorms. This will be accomplished using a small network of balloon-borne payloads suspended in and around thunderstorm environments. The payloads will detect and timestamp gamma radiation bursts, lightning strikes, and the intensity of localized electric fields. While in flight, data collected by the payloads will be transmitted to a ground station in real-time and will be analyzed post-flight to investigate potential correlations between lightning, TGFs, and electric fields. The ground station system that will be used for COTEL was developed for the Eclipse 2017 ballooning project, and was used during flight operations on the day of the eclipse. The COTEL student team is in its second year of effort having spent the first year developing the basic balloon payloads and ground tracking system. Currently the team is focusing on prototype electric field and gamma radiation detectors. Testing and development of these systems will continue into 2018, and flight operations will take place during the spring 2018 Louisiana thunderstorm season. The poster will cover the student team effort in developing said system, an overview of the system architecture, balloon flight tests conducted to date, preliminary results from prototype detectors, and future plans

Neurocognitive markers of passive suicidal ideation in late-life depression

Objectives: (1) To delineate whether cognitive flexibility and inhibitory ability are neurocognitive markers of passive suicidal ideation (PSI), an early stage of suicide risk in depression and (2) to determine whether PSI is associated with volumetric differences in regions of the prefrontal cortex (PFC) in middle-aged and older adults with depression. Design: Cross-sectional study. Setting: University medical school. Participants: Forty community-dwelling middle-aged and older adults with depression from a larger study of depression and anxiety (NIMH R01 MH091342-05 PI: O\u27Hara). Measurements: Psychiatric measures were assessed for the presence of a DSM-5 depressive disorder and PSI. A neurocognitive battery assessed cognitive flexibility, inhibitory ability, as well as other neurocognitive domains. Results: The PSI group (n = 18) performed significantly worse on cognitive flexibility and inhibitory ability, but not on other neurocognitive tasks, compared to the group without PSI (n = 22). The group with PSI had larger left mid-frontal gyri (MFG) than the no-PSI group. There was no association between cognitive flexibility/inhibitory ability and left MFG volume. Conclusions: Findings implicate a neurocognitive signature of PSI: poorer cognitive flexibility and poor inhibitory ability not better accounted for by other domains of cognitive dysfunction and not associated with volumetric differences in the left MFG. This suggests that there are two specific but independent risk factors of PSI in middle- and older-aged adults

Challenges and opportunities for implementing integrated mental health care: a district level situation analysis from five low- and middle-income countries.

BACKGROUND: Little is known about how to tailor implementation of mental health services in low- and middle-income countries (LMICs) to the diverse settings encountered within and between countries. In this paper we compare the baseline context, challenges and opportunities in districts in five LMICs (Ethiopia, India, Nepal, South Africa and Uganda) participating in the PRogramme for Improving Mental health carE (PRIME). The purpose was to inform development and implementation of a comprehensive district plan to integrate mental health into primary care. METHODS: A situation analysis tool was developed for the study, drawing on existing tools and expert consensus. Cross-sectional information obtained was largely in the public domain in all five districts. RESULTS: The PRIME study districts face substantial contextual and health system challenges many of which are common across sites. Reliable information on existing treatment coverage for mental disorders was unavailable. Particularly in the low-income countries, many health service organisational requirements for mental health care were absent, including specialist mental health professionals to support the service and reliable supplies of medication. Across all sites, community mental health literacy was low and there were no models of multi-sectoral working or collaborations with traditional or religious healers. Nonetheless health system opportunities were apparent. In each district there was potential to apply existing models of care for tuberculosis and HIV or non-communicable disorders, which have established mechanisms for detection of drop-out from care, outreach and adherence support. The extensive networks of community-based health workers and volunteers in most districts provide further opportunities to expand mental health care. CONCLUSIONS: The low level of baseline health system preparedness across sites underlines that interventions at the levels of health care organisation, health facility and community will all be essential for sustainable delivery of quality mental health care integrated into primary care

Comparing the cost-per-QALYs gained and cost-per-DALYs averted literatures [version 2; referees: 3 approved]

Background: We examined the similarities and differences between studies using two common metrics used in cost-effectiveness analyses (CEAs): cost per quality-adjusted life year (QALY) gained and cost per disability-adjusted life year (DALY) averted. Methods: We used the Tufts Medical Center CEA Registry, which contains English-language cost-per-QALY gained studies, and the Global Cost-Effectiveness Analysis (GHCEA) Registry, which contains cost-per-DALY averted studies. We examined study characteristics, including intervention type, sponsor, country, and primary disease, and also compared the number of published CEAs to disease burden for major diseases and conditions across geographic regions. Results: We identified 6,438 cost-per-QALY and 543 cost-per-DALY studies published through 2016 and observed rapid growth for both literatures. Cost-per-QALY studies most often examined pharmaceuticals and interventions in high-income countries. Cost-per-DALY studies predominantly focused on infectious disease interventions and interventions in low and lower-middle income countries. We found that while diseases imposing a larger burden tend to receive more attention in the cost-effectiveness analysis literature, the number of publications for some diseases and conditions deviates from this pattern, suggesting “under-studied” conditions (e.g., neonatal disorders) and “over-studied” conditions (e.g., HIV and TB). Conclusions: The CEA literature has grown rapidly, with applications to diverse interventions and diseases.  The publication of fewer studies than expected for some diseases given their imposed burden suggests funding opportunities for future cost-effectiveness research