Cognitive training for children with ADHD: composite cognitive score outcome in a randomized controlled trial.

PURPOSE OF THE ARTICLE: Cognitive training for Attention Deficit/Hyperactivity Disorder (ADHD) has shown promising, although mixed results. In post-hoc analyses, we evaluate effects of cognitive training using a novel composite cognition score as the outcome for children attending at least 16 sessions of training, dose-response of training and associations between symptoms and cognitive functioning. MATERIALS AND METHODS: Children (age 6-13) with ADHD were randomized to intervention (n = 26) or control (n = 34). For the current analysis, we restricted the intervention group to children, who completed at least 16 sessions of cognitive training (n = 26) and examined a dose response within that group. RESULTS: Cognition improved significantly in the intervention, but not control group. Amount of the completed training sessions correlated significantly with the amount of cognitive improvement. CONCLUSION: Variations in dose and frequency of training may be an important source of the variance in previous studies.

Comparison of RNA content from hydrophobic interaction chromatography-isolated seminal plasma exosomes from intrauterine insemination (IUI) pregnancies.

Male factors account for roughly half of infertility cases, with most male infertility diagnosed as idiopathic. Researchers predicting intrauterine insemination success rates have identified multiple prognostic factors, including semen parameters and seminal fluid composition. Seminal plasma contains extracellular exosomes, which contain RNAs and proteins involved in spermatogenesis. The contents of seminal plasma exosomes may be an indicator of overall sperm quality or fertility potential; therefore, analysis of exosomes may provide a measure for sperm viability and fertilization potential. In our study, exosomes were isolated and purified from seminal plasma obtained from IUI treatments with known pregnancy outcomes. We used a unique method to isolate the exosomes which made use of the hydrophobic interaction chromatography method. RNASeq was performed on RNAs from the purified exosomes. This analysis revealed holistic trends, including increased expression associated with RNA originating from chromosomes 1, 10, 12, 16 and 21. Overall, total RNA was significantly decreased and rRNA was significantly increased in successful IUI attempts. Furthermore, we found specific mRNAs and lincRNAs associated with positive versus negative pregnancy outcomes. Our study isolated and purified seminal plasma exosomes without ultracentrifugation, and it provides further evidence for differences in seminal plasma exosome molecular contents associated with pregnancy status.

The Effects of General Anaesthesia and Light on Behavioural Rhythms and GABAA Receptor Subunit Expression in the Mouse SCN.

General anaesthesia (GA) is known to affect the circadian clock. However, the mechanisms that underlie GA-induced shifting of the clock are less well understood. Activation of γ-aminobutyric acid (GABA)-type A receptors (GABAAR) in the suprachiasmatic nucleus (SCN) can phase shift the clock and thus GABA and its receptors represent a putative pathway via which GA exerts its effect on the clock. Here, we investigated the concurrent effects of the inhalational anaesthetic, isoflurane, and light, on mouse behavioural locomotor rhythms and on α1, ß3, and γ2 GABAAR subunit expression in the SCN of the mouse brain. Behavioural phase shifts elicited by exposure of mice to four hours of GA (2% isoflurane) and light (400 lux) (n = 60) were determined by recording running wheel activity rhythms in constant conditions (DD). Full phase response curves for the effects of GA + light on behavioural rhythms show that phase shifts persist in anaesthetized mice exposed to light. Daily variation was detected in all three GABAAR subunits in LD 12:12. The γ2 subunit expression was significantly increased following GA in DD (compared to light alone) at times of large behavioural phase delays. We conclude that the phase shifting effect of light on the mouse clock is not blocked by GA administration, and that γ2 may potentially be involved in the phase shifting effect of GA on the clock. Further analysis of GABAAR subunit expression in the SCN will be necessary to confirm its role.

Comparative analysis of viral infection outcomes in human seminal fluid from prior viral epidemics and Sars-CoV-2 may offer trends for viral sexual transmissibility and long-term reproductive health implications.

BACKGROUND: Viral detection in seminal fluid indicates their potential for both sexual transmission and impairment of reproductive health. Review of the mechanistic entry, sexual transmission and viral impacts for patients during major recent viral outbreaks of Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome (SARS)-coronavirus (CoV), and SARS-coronavirus 2 (CoV-2) (the virus which causes COVID-19) provides a framework to discuss this potential. AIM: Comparative analysis of prior viral presence on seminal fluid against current (preliminary) findings for SARS-CoV-2 to predict biological implications of the novel coronavirus upon current sexual transmissibility, viral presence, and reproductive health. METHODOLOGY AND FINDINGS: Literature review was conducted using PubMed and Google Scholar databases. ZIKV and EBOV were found to be present in semen and to be sexually transmitted, leading the World Health Organization (WHO) to update their guidelines on prevention of the two viruses to include refraining from sexual contact. There are conflicting studies regarding the presence of SARS-CoV in male reproductive tissue, but it has been linked to testicular atrophy and orchitis. To date, two studies have detected SARS-CoV-2 RNA in semen, while seven studies have reported no positive detection. CONCLUSIONS: Though unlikely in the majority of cases, SARS-CoV-2 can potentially be present in seminal fluid, although there are no reports of sexual transmission to date. Prior epidemics raise significant concerns regarding the long-term reproductive health capacity for patients who are affected by entry of Sars-CoV-2 into the reproductive tract, therefore more study is needed to clarify the impacts to reproductive health.

This review describes the detection of viruses in seminal fluid and their sexual transmission, focusing on the major viral outbreaks of Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome (SARS)-coronavirus (CoV), and SARS-coronavirus 2 (CoV-2). ZIKV and EBOV were found to be present in semen and to be sexually transmitted, leading the World Health Organization (WHO) to update their guidelines on prevention of the two viruses to include refraining from sexual contact. There are conflicting studies regarding the presence of SARS-CoV in male reproductive tissue, but it has been linked to testicular atrophy and orchitis. To date, two studies have detected SARS-CoV-2 RNA in semen, while seven studies have reported no positive detection. More studies must be completed to accurately determine its risk of sexual transmission to ensure mitigation of further transmission and understand the long-term implications of SARS-CoV-2 on the reproductive health of recovered patients.

Risk factors for obsessive-compulsive symptoms. Follow-up of a community-based youth cohort.

Environmental factors are at least as important as genetic factors for the development of obsessive-compulsive symptoms (OCS), but the identification of such factors remain a research priority. Our study aimed to investigate the association between a broad scope of potential risk factors and OCS in a large community cohort of children and adolescents. We evaluated 1877 participants and their caregivers at baseline and after 3 years to assess various demographic, prenatal, perinatal, childhood adversity, and psychopathological factors. Mean age at baseline was 10.2 years (SD 1.9) and mean age at follow-up was 13.4 years (SD 1.9). Reports of OCS at baseline and follow-up were analyzed using latent variable models. At preliminary regression analysis, 15 parameters were significantly associated with higher OCS scores at follow-up. At subsequent regression analysis, we found that eight of these parameters remained significantly associated with higher follow-up OCS scores while being controlled by each other and by baseline OCS scores. The significant predictors of follow-up OCS were: lower socioeconomic status (p = 0.033); lower intelligence quotient (p = 0.013); lower age (p < 0.001); higher maternal stress level during pregnancy (p = 0.028); absence of breastfeeding (p = 0.017); parental baseline OCS (p = 0.038); youth baseline anxiety disorder (p = 0.023); and youth baseline OCS scores (p < 0.001). These findings may better inform clinicians and policymakers engaged in the mental health assessment and prevention in children and adolescents.

Family accommodation mediates the impact of childhood anxiety on functional impairment.

BACKGROUND: Anxiety disorders are the most common childhood-onset psychiatric disorders and are extensively associated with child functional impairment. Data suggest that family accommodation plays a role in the association between anxiety severity and functional impairment in children, but more empirical evidence is needed. METHODS: Participants were 425 clinically anxious children (ages 6-17 years), and their mothers. We first examined associations between child anxiety symptom severity, family accommodation, and child functional impairment. Next, we investigated the hypothesized mediation pathway linking anxiety severity to child impairment through increased family accommodation using structural equation modeling. We tested two models: one using parent ratings of their child's anxiety and the other using the child's self-ratings. Finally, we estimated the effect sizes of the mediation pathway in both models. RESULTS: Family accommodation was significantly correlated with all the study variables. Child functional impairment was significantly correlated with parent-rated and self-rated child anxiety severity. Both structural equation models provided excellent fit for the data and supported the theoretical model by which family accommodation significantly explains part of the association between anxiety symptoms and functional impairment. The indirect effect sizes indicate that family accommodation accounts for between a fifth and a half of the impairment associated with symptom severity. CONCLUSIONS: The data provide important empirical evidence that family accommodation mediates the association between child anxiety and functional impairment and accounts for up to 50 % of this association. These findings contribute to the growing understanding of the critical role of family accommodation and underscore the importance of assessing accommodation when evaluating and treating anxious children.

A rare case of pancreatic adenocarcinoma metastasized to the bladder.

Pancreatic cancer is usually detected in late stages due to lack of identifiable symptoms and rapid progression. It commonly metastasizes to the liver, lung, and peritoneum, but only rarely to the bladder. We present a 41-year-old female with a history of pancreatic adenocarcinoma, asthma, gastroesophageal reflux disease, uterine fibroids, and tobacco use who presented with hematuria, polyuria, and abdominal pain. The CT showed bilateral hydroureteronephrosis with a hyperdense region in the posterior wall of the bladder. Pathology revealed metastatic pancreatic adenocarcinoma to the bladder. This is the fourth reported case of pancreatic adenocarcinoma metastasizing to the bladder since 1953.

Implementation Evaluation of the Mother-Child Education Program Among Refugee and Other Vulnerable Communities in Lebanon.

Despite the knowledge that quality early childhood development programs, including those that target parental knowledge and behaviors, are essential for ameliorating the negative effects of early-life adversity, robust analyses of their implementation and impact in highly vulnerable settings are scarce. To address this knowledge gap, we conducted a pilot wait-list randomized controlled trial (RCT) to assess the impact and the process of implementing and evaluating the Mother-Child Education Program (MOCEP) among refugee families and one low-income community in Beirut, Lebanon. This paper focuses on the analysis of MOCEP's implementation (i.e., key enablers of and barriers to the application and evaluation of the program). Our analysis suggests that, despite multiple challenges, implementation and robust evaluations of early childhood parenting programs in fragile contexts are feasible and urgently needed. This study illustrates how implementation evaluations are a key component of RCTs and crucial to identifying strategies to optimize program uptake and maximize impact.

The functional changes of the circadian system organization in aging.

The circadian clock drives periodic oscillations at different levels of an organism from genes to behavior. This timing system is highly conserved across species from insects to mammals and human beings. The question of how the circadian clock is involved in the aging process continues to attract more attention. We aim to characterize the detrimental impact of aging on the circadian clock organization. We review studies on different components of the circadian clock at the central and periperal levels, and their changes in aged rodents and humans, and the fruit fly Drosophila. Intracellular signaling, cellular activity and intercellular coupling in the central pacemaker have been found to decline with advancing age. Evidence of degradation of the molecular clockwork reflected by clock gene expression in both central and peripheral oscillators due to aging is inadequate. The findings on age-associated molecular and functional changes of peripheral clocks are mixed. We conclude that aging can affect the circadian clock organization at various levels, and the impairment of the central network may be a fundamental mechanism of circadian disruption seen in aged species.

Development of the Molecular Circadian Clock and Its Light Sensitivity in Drosophila Melanogaster.

The importance of the circadian clock for the control of behavior and physiology is well established but how and when it develops is not fully understood. Here the initial expression pattern of the key clock gene period was recorded in Drosophila from embryos in vivo, using transgenic luciferase reporters. PERIOD expression in the presumptive central-clock dorsal neurons started to oscillate in the embryo in constant darkness. In behavioral experiments, a single 12-h light pulse given during the embryonic stage synchronized adult activity rhythms, implying the early development of entrainment mechanisms. These findings suggest that the central clock is functional already during embryogenesis. In contrast to central brain expression, PERIOD in the peripheral cells or their precursors increased during the embryonic stage and peaked during the pupal stage without showing circadian oscillations. Its rhythmic expression only initiated in the adult. We conclude that cyclic expression of PERIOD in the central-clock neurons starts in the embryo, presumably in the dorsal neurons or their precursors. It is not until shortly after eclosion when cyclic and synchronized expression of PERIOD in peripheral tissues commences throughout the animal.

The Performance of Higher Frequency Microwave Ablation in the Presence of Perfusion.

OBJECTIVE: In this paper, we investigate the impact of perfusion on the performance of microwave ablation across a large frequency range. METHODS: We designed multiple microwave ablation antennas to operate in liver tissue at discrete frequencies in the range 1.9-18 GHz. We performed electromagnetic simulations to calculate microwave power absorption patterns. Five-minute, 25 W ablation experiments were performed at each frequency in perfused and nonperfused ex vivo porcine livers, and thermal lesion dimensions were measured. RESULTS: The volume of greatest microwave power absorption shrinks by two orders of magnitude as the frequency is increased from 1.9 to 18 GHz. Mean thermal lesion volumes are consistent across the frequency range for a given perfusion state and are about three times smaller under active perfusion. Typical thermal lesion diameters (perpendicular to the antenna axis) were 24 mm and 16 mm for nonperfused and perfused ablations, respectively. No significant differences in axial ratio were observed among different frequency groups in active-perfusion experiments. CONCLUSION: Higher-frequency microwave ablation produces thermal lesions with volumes comparable to those achieved at lower frequencies, even in strongly perfused environments. SIGNIFICANCE: Higher-frequency microwave ablation is appealing because it allows for more flexibility in antenna design. A critical issue concerning the feasibility of higher frequency microwave ablation, considering its strong dependence on heat diffusion to grow thermal lesions, is its performance in strongly perfused environments. This paper shows that higher frequency microwave ablation achieves thermal lesions comparable to those from microwave ablation performed at conventional frequencies in both non- and strongly perfused environments.

Insect-inspired acoustic micro-sensors.

Micro-Electro Mechanical System (MEMS) microphones inspired by the remarkable phonotactic capability of Ormia ochracea offer the promise of microscale directional microphones with a greatly reduced need for post-processing of signals. Gravid O. ochracea females can locate their host cricket's 5 kHz mating calls to an accuracy of less than 2° despite having a distance of approximately 500 µm between the ears. MEMS devices base on the principles of operation of O. ochracea's hearing system have been well studied, however commercial implementation has proven challenging due to the system's reliance on carefully tailored ratios of stiffness and damping, which are difficult to realize in standard MEMS fabrication processes, necessitating a trade-off between wide-band operation and sensitivity. A survey of the variety of strategies that have been followed to address these inherent challenges is presented.

Clock gene expression and locomotor activity predict death in the last days of life in Drosophila melanogaster.

The importance of the circadian clock for the regulation of behaviour and physiology, and the molecular control of these rhythms by a set of clock genes are well defined. The circadian clock deteriorates with advancing age but the mechanism underlying is unclear. Here we recorded the expression of two key clock genes in young, middle-aged and old Drosophila using transgenic luciferase lines reporting period and timeless in vivo. We report a novel marker of imminent death in the expression of TIMELESS. In the days immediately preceding death TIMELESS expression increased to at least 150% of previous acrophase values (88.0% of n = 217) and lost circadian rhythmicity, which predicted death equally well in flies of different ages and under light and temperature cycles. We suggest this transient aberrant clock-gene expression is central to the mechanism of the disturbance in circadian behaviour before death (82.7% of n = 342). We also find that PERIOD expression in central-clock neurons remained robust with age, however PERIOD and TIMELESS in peripheral clocks showed a reduction in both expression level and rhythmicity. In conclusion, as flies age the molecular clock gradually declines at the peripheral level but continues to function at the central until days before death.

Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry.

Importance: Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective: To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants: The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. Exposures: Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]). Main Outcomes and Measures: Scores on the Yale Global Tic Severity Scale and adverse events. Results: The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Conclusions and Relevance: Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.

Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning.

BACKGROUND: Cardiosphere-derived cells (CDCs) confer cardioprotection in acute myocardial infarction by distinctive macrophage (Mϕ) polarization. Here we demonstrate that CDC-secreted exosomes (CDCexo) recapitulate the cardioprotective effects of CDC therapy known as cellular postconditioning. METHODS: Rats and pigs underwent myocardial infarction induced by ischemia/reperfusion before intracoronary infusion of CDCexo, inert fibroblast exosomes (Fbexo; control), or vehicle. Two days later, infarct size was quantified. Macrophages were isolated from cardiac tissue or bone marrow for downstream analyses. RNA sequencing was used to determine exosome content and alterations in gene expression profiles in Mϕ. RESULTS: Administration of CDCexo but not Fbexo after reperfusion reduces infarct size in rat and pig models of myocardial infarction. Furthermore, CDCexo reduce the number of CD68+ Mϕ within infarcted tissue and modify the polarization state of Mϕ so as to mimic that induced by CDCs. CDCexo are enriched in several miRNAs (including miR-146a, miR-181b, and miR-126) relative to Fbexo. Reverse pathway analysis of whole-transcriptome data from CDCexo-primed Mϕ implicated miR-181b as a significant (P=1.3x10-21) candidate mediator of CDC-induced Mϕ polarization, and PKCδ (protein kinase C δ) as a downstream target. Otherwise inert Fbexo loaded selectively with miR-181b alter Mϕ phenotype and confer cardioprotective efficacy in a rat model of myocardial infarction. Adoptive transfer of PKCδ-suppressed Mϕ recapitulates cardioprotection. CONCLUSIONS: Our data support the hypothesis that exosomal transfer of miR-181b from CDCs into Mϕ reduces PKCδ transcript levels and underlies the cardioprotective effects of CDCs administered after reperfusion.

The Concave Faces of the Great Pyramid: An Explanation.

A construction methodology proposed by the author in 2003 to explain how the Great Pyramid was built suggested that workers used the angled faces of the pyramid as surfaces on which to transport block and sledge assemblies. This methodology however would leave few material traces behind making it more difficult to conclusively prove. This article argues that the known concavity of the outer packing blocks of the Great Pyramid provides meangingful archaeological evidence to add weight to the author's proposed construction methodology.

Landscape Analysis of Adult Florida Panther Habitat.

Historically occurring throughout the southeastern United States, the Florida panther is now restricted to less than 5% of its historic range in one breeding population located in southern Florida. Using radio-telemetry data from 87 prime-aged (≥3 years old) adult panthers (35 males and 52 females) during the period 2004 through 2013 (28,720 radio-locations), we analyzed the characteristics of the occupied area and used those attributes in a random forest model to develop a predictive distribution map for resident breeding panthers in southern Florida. Using 10-fold cross validation, the model was 87.5 % accurate in predicting presence or absence of panthers in the 16,678 km2 study area. Analysis of variable importance indicated that the amount of forests and forest edge, hydrology, and human population density were the most important factors determining presence or absence of panthers. Sensitivity analysis showed that the presence of human populations, roads, and agriculture (other than pasture) had strong negative effects on the probability of panther presence. Forest cover and forest edge had strong positive effects. The median model-predicted probability of presence for panther home ranges was 0.81 (0.82 for females and 0.74 for males). The model identified 5579 km2 of suitable breeding habitat remaining in southern Florida; 1399 km2 (25%) of this habitat is in non-protected private ownership. Because there is less panther habitat remaining than previously thought, we recommend that all remaining breeding habitat in south Florida should be maintained, and the current panther range should be expanded into south-central Florida. This model should be useful for evaluating the impacts of future development projects, in prioritizing areas for panther conservation, and in evaluating the potential impacts of sea-level rise and changes in hydrology.

An Exploration of Decision-Making Processes on Infant Delivery Site from the Perspective of Pregnant Women, New Mothers, and Their Families in Northern Karnataka, India.

This study was conducted to explore the decision-making processes regarding sites for delivery of infants among women, their husbands, and mothers-in-law in a rural area of northern Karnataka state, south India. Qualitative semi-structured, individual in-depth interviews were conducted in 2010 among 110 pregnant women, new mothers, husbands and mothers-in-law. Interviews were conducted by trained local researchers in participants' languages and then translated into English. Decisions were made relationally, as family members weighed their collective attitudes and experiences towards a home, private or public delivery. Patterns of both concordance and discordance between women and their families' preferences for delivery site were present. The voice of pregnant women and new mothers was not always subordinate to that of other family members. Still, the involvement of husbands and mothers-in-law was important in decision-making, indicating the need to consider the influence of household gender and power dynamics. All respondent types also expressed shifts in social context and cultural attitudes towards increasing preference for hospital delivery. An appreciation of the interdependence of family members' roles in delivery site decision-making, and how they are influenced by the socio-cultural context, must be considered in frameworks used to guide the development of relevant interventions to improve the utilization and quality of maternal, neonatal and child health services.

Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.

Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model.