Measurements of the diffuse Galactic synchrotron spectral index and curvature from MeerKLASS pilot data

21cm intensity mapping experiments are bringing an influx of high spectral resolution observational data in the $\sim100$ MHz $- 1$ GHz regime. We use pilot $971-1075$ MHz data from MeerKAT in single-dish mode, recently used to test the calibration and data reduction scheme of the upcoming MeerKLASS survey, to probe the spectral index of diffuse synchrotron emission below 1 GHz within $145^{\circ} < \alpha < 180^{\circ}$, $-1^{\circ} < \delta < 8^{\circ}$. Through comparisons with data from the OVRO Long Wavelength Array and the Maipu and MU surveys, we find an average spectral index of $-2.75 < \beta < -2.71$ between 45 and 1055 MHz. By fitting for spectral curvature with a spectral index of the form $\beta + c \, {\rm{ln}}(\nu / 73~{\rm MHz})$, we measure $\beta = -2.55 \pm 0.13$ and $c = -0.12 \pm 0.05$ within our target field. Our results are in good agreement (within $1\sigma$) with existing measurements from experiments such as ARCADE2 and EDGES. These results show the calibration accuracy of current data and demonstrate that MeerKLASS will also be capable of achieving a secondary science goal of probing the interstellar medium.Comment: 17 pages, 13 figures, accepted for publication in MNRAS. Updated to match published paper (additional references and acknowledgements

Stromal Cells Are Critical Targets in the Regulation of Mammary Ductal Morphogenesis by Parathyroid Hormone-Related Protein

AbstractParathyroid hormone-related protein (PTHrP) was originally identified as the tumor product responsible for humoral hypercalcemia of malignancy. It is now known that PTHrP is produced by many normal tissues in which it appears to play a role as a developmental regulatory molecule. PTHrP is a normal product of mammary epithelial cells, and recent experiments in our laboratory have demonstrated that overexpression or underexpression of PTHrP in the murine mammary gland leads to severe disruptions in its development. The nature of these phenotypes suggests that PTHrP acts to modulate branching growth during mammary development by regulating mammary stromal cell function. We now demonstrate that throughout mammary development, during periods of active ductal-branching morphogenesis, PTHrP is produced by epithelial cells, whereas the PTH/PTHrP receptor is expressed on stromal cells. In addition, we show that mammary stromal cells in culture contain specific binding sites for amino terminal PTHrP and respond with an increase in intracellular cAMP. Finally, we demonstrate that the mammary mesenchyme must express the PTH/PTHrP receptor in order to support mammary epithelial cell morphogenesis. These results demonstrate that PTHrP and the PTH/PTHrP receptor represent an epithelial/mesenchymal signaling circuit that is necessary for mammary morphogenesis and that stromal cells are a critical target for PTHrP's action in the mammary gland

Neuropsychological characterization of aggressive behavior in children and adolescents with cd/odd and effects of single doses of medications: The protocol of the matrics_wp6-1 study

Aggressive behaviors and disruptive/conduct disorders are some of the commonest reasons for referral to youth mental health services; nevertheless, the efficacy of therapeutic interventions in real-world clinical practice remains unclear. In order to define more appropriate targets for innovative pharmacological therapies for disruptive/conduct disorders, the European Commission within the Seventh Framework Programme (FP7) funded the MATRICS project (Multidisciplinary Approaches to Translational Research in Conduct Syndromes) to identify neural, genetic, and molecular factors underpinning the pathogenesis of aggression/antisocial behavior in preclinical models and clinical samples. Within the program, a multicentre case-control study, followed by a single-blind, placebo-controlled, cross-over, randomized acute single-dose medication challenge, was conducted at two Italian sites. Aggressive children and adolescents with conduct disorder (CD) or oppositional defiant disorder (ODD) were compared to the same age (10–17 y) typically developing controls (TDC) on a neuropsychological tasks battery that included both “cold” (e.g., inhibitory control, decision making) and “hot” executive functions (e.g., moral judgment, emotion processing, risk assessment). Selected autonomic measures (heart rate variability, skin conductance, salivary cortisol) were recorded before/during/after neuropsychological testing sessions. The acute response to different drugs (methylphenidate/atomoxetine, risperidone/aripiprazole, or placebo) was also examined in the ODD/CD cohort in order to identify potential neuropsychological/physiological mechanisms underlying aggression. The paper describes the protocol of the clinical MATRICS WP6-1 study, its rationale, the specific outcome measures, and their implications for a precision medicine approach

Persistence of Protective Immunity to Malaria Induced by DNA Priming and Poxvirus Boosting: Characterization of Effector and Memory CD8+-T-Cell Populations

The persistence of immunity to malaria induced in mice by a heterologous DNA priming and poxvirus boosting regimen was characterized. Mice were immunized by priming with DNA vaccine plasmids encoding the Plasmodium yoelii circumsporozoite protein (PyCSP) and murine granulocyte-macrophage colony-stimulating factor and boosting with recombinant vaccinia encoding PyCSP. BALB/c mice immunized with either high-dose (100 µg of p PyCSP plus 30 µg of pGM-CSF) or low-dose (1 µg of p PyCSP plus 1 µg of pGM-CSF DNA) priming were protected against challenge with 50 P. yoelii sporozoites. Protection 2 weeks after immunization was 70 to 100%, persisted at this level for at least 20 weeks, and declined to 30 to 40% by 28 weeks. Eight of eight mice protected at 20 weeks were still protected when rechallenged at 40 weeks. The antigen (Ag)-specific effector CD8+-T-cell population present 2 weeks after boosting had ex vivo Ag-specific cytolytic activity, expressed both gamma interferon (IFN-{gamma}) and tumor necrosis factor alpha, and constituted 12 to 20% of splenic CD8+ T cells. In contrast, the memory CD8+-Ag-specific-cell population at 28 weeks lacked cytolytic activity and constituted only 6% of splenic CD8+ T cells, but at the single-cell level it produced significantly higher levels of IFN-{gamma} than the effectors. High levels of Ag- or parasite-specific antibodies present 2 weeks after boosting had declined three- to sevenfold by 28 weeks. Low-dose priming was similarly immunogenic and as protective as high-dose priming against a 50-, but not a 250-, sporozoite challenge. These results demonstrate that a heterologous priming and boosting vaccination can provide lasting protection against malaria in this model system

Mapping Cosmic Dawn and Reionization: Challenges and Synergies

Cosmic dawn and the Epoch of Reionization (EoR) are among the least explored observational eras in cosmology: a time at which the first galaxies and supermassive black holes formed and reionized the cold, neutral Universe of the post-recombination era. With current instruments, only a handful of the brightest galaxies and quasars from that time are detectable as individual objects, due to their extreme distances. Fortunately, a multitude of multi-wavelength intensity mapping measurements, ranging from the redshifted 21 cm background in the radio to the unresolved X-ray background, contain a plethora of synergistic information about this elusive era. The coming decade will likely see direct detections of inhomogenous reionization with CMB and 21 cm observations, and a slew of other probes covering overlapping areas and complementary physical processes will provide crucial additional information and cross-validation. To maximize scientific discovery and return on investment, coordinated survey planning and joint data analysis should be a high priority, closely coupled to computational models and theoretical predictions.Comment: 5 pages, 1 figure, submitted to the Astro2020 Decadal Survey Science White Paper cal

Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis

Background: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. Methods: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. Findings: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). We did not find sufficient data for the 26-week and 52-week timepoints. Interpretation: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. Funding: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre

Comparative efficacy and tolerability of pharmacological interventions for attention-deficit/hyperactivity disorder in children, adolescents and adults: protocol for a systematic review and network meta-analysis

Introduction Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. Methods and analysis We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. Ethics and dissemination No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences

Computerized cognitive training in attention-deficit/hyperactivity disorder (ADHD): a meta-analysis of randomized controlled trials with blinded and objective outcomes

This meta-analysis investigated the effects of computerized cognitive training (CCT) on clinical, neuropsychological and academic outcomes in individuals with attention-deficit/hyperactivity disorder (ADHD). The authors searched PubMed, Ovid, and Web of Science until 19th January 2022 for parallel-arm randomized controlled trials (RCTs) using CCT in individuals with ADHD. Random-effects meta-analyses pooled standardized mean differences (SMD) between CCT and comparator arms. RCT quality was assessed with the Cochrane Risk of Bias 2.0 tool (PROSPERO: CRD42021229279). Thirty-six RCTs were meta-analysed, 17 of which evaluated working memory training (WMT). Analysis of outcomes measured immediately post-treatment and judged to be “probably blinded” (PBLIND; trial n = 14) showed no effect on ADHD total (SMD = 0.12, 95%CI[−0.01 to −0.25]) or hyperactivity/impulsivity symptoms (SMD = 0.12, 95%[−0.03 to−0.28]). These findings remained when analyses were restricted to trials (n: 5–13) with children/adolescents, low medication exposure, semi-active controls, or WMT or multiple process training. There was a small improvement in inattention symptoms (SMD = 0.17, 95%CI[0.02–0.31]), which remained when trials were restricted to semi-active controls (SMD = 0.20, 95%CI[0.04–0.37]), and doubled in size when assessed in the intervention delivery setting (n = 5, SMD = 0.40, 95%CI[0.09–0.71]), suggesting a setting-specific effect. CCT improved WM (verbal: n = 15, SMD = 0.38, 95%CI[0.24–0.53]; visual-spatial: n = 9, SMD = 0.49, 95%CI[0.31–0.67]), but not other neuropsychological (e.g., attention, inhibition) or academic outcomes (e.g., reading, arithmetic; analysed n: 5–15). Longer-term improvement (at ~6-months) in verbal WM, reading comprehension, and ratings of executive functions were observed but relevant trials were limited in number (n: 5–7). There was no evidence that multi-process training was superior to working memory training. In sum, CCT led to shorter-term improvements in WM, with some evidence that verbal WM effects persisted in the longer-term. Clinical effects were limited to small, setting specific, short-term effects on inattention symptoms