Improved motor skills in autistic children after three weeks of neurologic music therapy via telehealth: a pilot study

Background: Many autistic children experience motor skill deficits which can impact other areas of functioning, and research on therapeutic interventions for motor skills in autism is in a preliminary stage. Music-based therapies have been used extensively to address motor skills in non-autistic populations. Though a handful of studies exist on the effects of music-based therapies for movement in autistic children, none have investigated the possibility of administering sessions via telehealth. This mixed-methods pilot study investigated whether nine Neurologic Music Therapy (NMT)® sessions via telehealth would improve motor and attention skills in autistic children. Methods: Five autistic children between five and 10 years of age participated in the study, with support from their caregivers. Motor skills were assessed using the Bruininks-Oseretsky Test of Motor Proficiency second edition, short form (BOT-2 SF), and a selective attention and sustained attention task were taken from the Test of Everyday Attention for Children, Second Edition (TEA-Ch2). Caregivers and the two neurologic music therapists involved in the study provided qualitative input about the perceived effectiveness of telehealth NMT for the children involved. Their responses were analyzed using qualitative content analysis. Caregivers also filled out a Sensory Profile 2 assessment prior to the onset of sessions so that each child’s sensory profile could be compared to their motor and attention results. Results: Statistically significant improvements in motor skills were observed between pre-test assessment and a two-week follow-up assessment. Results from attention test scores were not significant. Caregivers and neurologic music therapists generally perceived sessions positively and noted the importance of having caregivers actively involved. When compared with individual progress on the BOT-2 SF assessment, sensory profile results revealed that children with fewer sensory sensitivities tended to improve the most on motor skills. The improvements in motor skills and positive caregiver and therapist views of telehealth indicate that NMT motor interventions administered via telehealth are a promising avenue of therapeutic support for movement skill development in autistic children

Alzheimer\u27s Therapeutics Targeting Amyloid Beta 1-42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors is Displaced by Drug Candidates That Improve Cognitive Deficits

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer\u27s disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer\u27s disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer\u27s therapeutics

Intensive versus less-intensive antileukemic therapy in older adults with acute myeloid leukemia: A systematic review.

To compare the effectiveness and safety of intensive antileukemic therapy to less-intensive therapy in older adults with acute myeloid leukemia (AML) and intermediate or adverse cytogenetics, we searched the literature in Medline, Embase, and CENTRAL to identify relevant studies through July 2020. We reported the pooled hazard ratios (HRs), risk ratios (RRs), mean difference (MD) and their 95% confidence intervals (CIs) using random-effects meta-analyses and the certainty of evidence using the GRADE approach. Two randomized trials enrolling 529 patients and 23 observational studies enrolling 7296 patients proved eligible. The most common intensive interventions included cytarabine-based intensive chemotherapy, combination of cytarabine and anthracycline, or daunorubicin/idarubicin, and cytarabine plus idarubicin. The most common less-intensive therapies included low-dose cytarabine alone, or combined with clofarabine, azacitidine, and hypomethylating agent-based chemotherapy. Low certainty evidence suggests that patients who receive intensive versus less-intensive therapy may experience longer survival (HR 0.87; 95% CI, 0.76-0.99), a higher probability of receiving allogeneic hematopoietic stem cell transplantation (RR 6.14; 95% CI, 4.03-9.35), fewer episodes of pneumonia (RR, 0.25; 95% CI, 0.06-0.98), but a greater number of severe, treatment-emergent adverse events (RR, 1.34; 95% CI, 1.03-1.75), and a longer duration of intensive care unit hospitalization (MD, 6.84 days longer; 95% CI, 3.44 days longer to 10.24 days longer, very low certainty evidence). Low certainty evidence due to confounding in observational studies suggest superior overall survival without substantial treatment-emergent adverse effect of intensive antileukemic therapy over less-intensive therapy in older adults with AML who are candidates for intensive antileukemic therapy

Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics

Development and implementation of a mobile device-based pediatric electronic decision support tool as part of a national practice standardization project

OBJECTIVE: Implementing evidence-based practices requires a multi-faceted approach. Electronic clinical decision support (ECDS) tools may encourage evidence-based practice adoption. However, data regarding the role of mobile ECDS tools in pediatrics is scant. Our objective is to describe the development, distribution, and usage patterns of a smartphone-based ECDS tool within a national practice standardization project. MATERIALS AND METHODS: We developed a smartphone-based ECDS tool for use in the American Academy of Pediatrics, Value in Inpatient Pediatrics Network project entitled Reducing Excessive Variation in the Infant Sepsis Evaluation (REVISE). The mobile application (app), PedsGuide, was developed using evidence-based recommendations created by an interdisciplinary panel. App workflow and content were aligned with clinical benchmarks; app interface was adjusted after usability heuristic review. Usage patterns were measured using Google Analytics. RESULTS: Overall, 3805 users across the United States downloaded PedsGuide from December 1, 2016, to July 31, 2017, leading to 14 256 use sessions (average 3.75 sessions per user). Users engaged in 60 442 screen views, including 37 424 (61.8%) screen views that displayed content related to the REVISE clinical practice benchmarks, including hospital admission appropriateness (26.8%), length of hospitalization (14.6%), and diagnostic testing recommendations (17.0%). Median user touch depth was 5 [IQR 5]. DISCUSSION: We observed rapid dissemination and in-depth engagement with PedsGuide, demonstrating feasibility for using smartphone-based ECDS tools within national practice improvement projects. CONCLUSIONS: ECDS tools may prove valuable in future national practice standardization initiatives. Work should next focus on developing robust analytics to determine ECDS tools\u27 impact on medical decision making, clinical practice, and health outcomes

Correlation of brain concentration of compounds with behavioral efficacy and estimated receptor occupancy at sigma-2/PGRMC1 receptor.

<p>CT0093 and CT0109 were dosed subcutaneously in mice by continuous osmotic minipumps infusions at the doses indicated. CT01344 and CT01346 were dosed by once daily oral gavage. Twenty four hours after the last dose, animals were euthanized and drug concentration in the brain was measured. Ki  =  binding affinity of compound at the sigma-2/PGRMC1 receptor. Measured efficacy: statistically significant improvement (+), or no significant improvement (-) seen in behavioral tests. Estimated % receptor occupancy was calculated according to the formula (concentration/Ki)/[(concentration/Ki) + 1)], where Ki is determine by radioligand competition binding.</p><p>Correlation of brain concentration of compounds with behavioral efficacy and estimated receptor occupancy at sigma-2/PGRMC1 receptor.</p

Characterization of human Abeta 1–42 oligomers isolated from patient frozen, unfixed 1 gram brain samples by non-denaturing Western blot, MALDI-TOF and ELISA.

<p><b>A</b>, Non-denaturing Western blots of immunoprecipitated Alzheimer's patient hippocampal samples demonstrates heterogeneous populations of oligomer assemblies. 6E10 antibody labeling of western blots from four different AD patients (lanes 1–4) detects major bands ≥250 kDa, and multiple discrete bands between 50–75 kDa. In contrast, APP antibody detects a faint band at 125 kDa (lane 5). Significant amounts of monomeric Abeta 1–42 were not observed in any individual. MALDI-TOF analysis of immune-precipitated human brain samples demonstrates heterogeneous populations of oligomer assemblies, both between individual Alzheimer's patients (<b>B, D</b>) and between age-matched histologically normal individuals (<b>C, E</b>). Significant amounts of monomeric Abeta 1–42 were not observed in any individual. Albumin was added to samples as an internal size control (arrow in <b>B–E</b>).</p

Small molecule Abeta binding antagonists prevent Abeta 1–42 oligomer-induced synaptic regression in cultured neurons.

<p><b>A</b>, Abeta oligomers bound to a subset of neurites (red) reduces synaptophysin-immunoreactive synaptic puncta (green). <b>B</b>, Treatment with sigma-2/PGRMC1 antagonists reduces oligomer binding and restores normal immunoreactivity for the synaptic marker. <b>C</b>, Oligomers induce an average 18%±2 s.e.m. loss in the number of immunoreactive puncta per micron length of neurite (red bar) compared to vehicle-treated cultures (blue bar). Treatment of cultures with sigma-2/PGRMC1 antagonists (closed bars) restores synaptophysin immunoreactivity to normal, but has no effect when antagonists are dosed alone (open bars). *p = 0.05, Student's paired t-test.</p

Potency of compounds in membrane trafficking assay.

<p>Prevention: compound added 1 hr prior to Abeta oligomers. Treatment: compound added 1 hr after Abeta oligomers. N =  number of experimental repeats (four replicate wells per experiment). n.d.  =  not determined.</p><p>Potency of compounds in membrane trafficking assay.</p