Increased Reliability of Visually-Evoked Activity in Area V1 of the MECP2-Duplication Mouse Model of Autism.

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared with controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form of syndromic autism.SIGNIFICANCE STATEMENT Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in primary visual cortex of the animal model for MECP2-duplication syndrome, a high-penetrance single-gene cause of autism. Visual-evoked activity was abnormally decoupled from endogenous activity in mutant mice, suggesting in line with the influential "hypo-priors" theory of autism that sensory priors embedded in endogenous activity may have less influence on perception in autism.

Effectiveness of non-pharmaceutical interventions related to social distancing on respiratory viral infectious disease outcomes: A rapid evidence-based review and meta-analysis.

OBJECTIVES: Non-pharmaceutical interventions (e.g. quarantine and isolation) are used to mitigate and control viral infectious disease, but their effectiveness has not been well studied. For COVID-19, disease control efforts will rely on non-pharmaceutical interventions until pharmaceutical interventions become widely available, while non-pharmaceutical interventions will be of continued importance thereafter. METHODS: This rapid evidence-based review provides both qualitative and quantitative analyses of the effectiveness of social distancing non-pharmaceutical interventions on disease outcomes. Literature was retrieved from MEDLINE, Google Scholar, and pre-print databases (BioRxiv.org, MedRxiv.org, and Wellcome Open Research). RESULTS: Twenty-eight studies met inclusion criteria (n = 28). Early, sustained, and combined application of various non-pharmaceutical interventions could mitigate and control primary outbreaks and prevent more severe secondary or tertiary outbreaks. The strategic use of non-pharmaceutical interventions decreased incidence, transmission, and/or mortality across all interventions examined. The pooled attack rates for no non-pharmaceutical intervention, single non-pharmaceutical interventions, and multiple non-pharmaceutical interventions were 42% (95% confidence interval = 30% - 55%), 29% (95% confidence interval = 23% - 36%), and 22% (95% confidence interval = 16% - 29%), respectively. CONCLUSION: Implementation of multiple non-pharmaceutical interventions at key decision points for public health could effectively facilitate disease mitigation and suppression until pharmaceutical interventions become available. Dynamics around R 0 values, the susceptibility of certain high-risk patient groups to infection, and the probability of asymptomatic cases spreading disease should be considered.

Variations in breast cancer surgical treatment and timing: determinants and disparities.

PURPOSE: To describe clinical and non-clinical factors associated with receipt of breast conserving surgery (BCS) versus mastectomy and time to surgical intervention. METHODS: Cross-sectional retrospective study of January 1, 2012 through March 31, 2018 data from the IBM MarketScan Commercial Claims and Encounter and Medicare Supplemental Databases. Area Health Resource Files provided non-clinical characteristics and sociodemographic data. Eligibility: Female sex, claim(s) with ICD-9-CM or ICD-10-CM diagnosis of non-metastatic invasive breast cancer, > 6 months of continuous insurance pre- and post-diagnosis, evidence of BCS or mastectomy following initial ICD9/10 code diagnosis. Logistic and quantile multivariable regression models assessed the association between clinical and non-clinical factors and the outcome of BCS and time to surgery, respectively. RESULTS: A total of 53,060 women were included in the study. Compared to mastectomy, BCS was significantly associated with older age (ORs: 1.54 to 2.99, 95% CIs 1.45 to 3.38; ps < .0001) and higher community density of medical genetics (OR: 5.88, 95% CIs 1.38 to 25.00; p = 0.02) or obstetrics and gynecology (OR: 1.13, 95% CI 1.02 to 1.25; p = .02) physicians. Shorter time-to-BCS was associated with living in the South (-2.96, 95% CI -4.39 to -1.33; p < .0001). Longer time-to-BCS was associated with residence in more urban (4.18, 95% CI 0.08 to 8.29; p = 0. 05), educated (9.02, 95% CI 0.13 to 17.91; p = 0.05), or plastic-surgeon-dense (4.62, 95% CI 0.50 to 8.73; p = 0.03) communities. CONCLUSIONS: Clinical and non-clinical factors are associated with adoption of BCS and time to treatment, suggesting opportunities to ensure equitable and timely care.

A Narrative Review of Emerging Therapeutics for COVID-19.

The novel severe acute respiratory syndrome coronavirus 2, the causal agent of coronavirus disease 2019 (COVID-19), quickly spread around the world, resulting in the most aggressive pandemic experienced in more than 100 years. Research on targeted therapies and vaccines has been initiated on an unprecedented scale and speed but will take months and even years to come to fruition. Meanwhile, the efficacy of emerging therapeutics for use in treating COVID-19 is feverishly being investigated to identify the best available treatment options for dealing with the current wave of disease. This review of publications with a "treatment" tag through June 29, 2020 in the National Library of Medicine's LitCovid literature hub, provides frontline clinicians with a pragmatic summary of the current state of the rapidly evolving evidence supporting emerging candidate therapeutics for COVID-19. Two main categories of pharmaceutical therapeutics are showing promise: those with antiviral activity directly addressing infection and those that counteract the inflammatory cytokine storm induced by severe disease. Preliminary results suggest that other approaches such as convalescent plasma therapy and lung radiation therapy may have some efficacy. The current clinical evidence for potential treatments is preliminary-often small retrospective series or early results of randomized trials-and the science is evolving rapidly. The long-term results from large, well-designed randomized controlled trials will provide definitive evidence for therapeutic effectiveness and are likely months away. The trial landscape for promising therapies is described.

Long-lasting synaptic potentiation induced by depolarization under conditions that eliminate detectable Ca2+ signals.

Activity-dependent alterations of synaptic transmission important for learning and memory are often induced by Ca(2+) signals generated by depolarization. While it is widely assumed that Ca(2+) is the essential transducer of depolarization into cellular plasticity, little effort has been made to test whether Ca(2+)-independent responses to depolarization might also induce memory-like alterations. It was recently discovered that peripheral axons of nociceptive sensory neurons in Aplysia display long-lasting hyperexcitability triggered by conditioning depolarization in the absence of Ca(2+) entry (using nominally Ca(2+)-free solutions containing EGTA, "0Ca/EGTA") or the absence of detectable Ca(2+) transients (adding BAPTA-AM, "0Ca/EGTA/BAPTA-AM"). The current study reports that depolarization of central ganglia to approximately 0 mV for 2 min in these same solutions induced hyperexcitability lasting >1 h in sensory neuron processes near their synapses onto motor neurons. Furthermore, conditioning depolarization in these solutions produced a 2.5-fold increase in excitatory postsynaptic potential (EPSP) amplitude 1-3 h afterward despite a drop in motor neuron input resistance. Depolarization in 0 Ca/EGTA produced long-term potentiation (LTP) of the EPSP lasting > or = 1 days without changing postsynaptic input resistance. When re-exposed to extracellular Ca(2+) during synaptic tests, prior exposure to 0Ca/EGTA or to 0Ca/EGTA/BAPTA-AM decreased sensory neuron survival. However, differential effects on neuronal health are unlikely to explain the observed potentiation because conditioning depolarization in these solutions did not alter survival rates. These findings suggest that unrecognized Ca(2+)-independent signals can transduce depolarization into long-lasting synaptic potentiation, perhaps contributing to persistent synaptic alterations following large, sustained depolarizations that occur during learning, neural injury, or seizures.

Reinforcement in an in vitro analog of appetitive classical conditioning of feeding behavior in Aplysia: blockade by a dopamine antagonist.

In a recently developed in vitro analog of appetitive classical conditioning of feeding in Aplysia, the unconditioned stimulus (US) was electrical stimulation of the esophageal nerve (En). This nerve is rich in dopamine (DA)-containing processes, which suggests that DA mediates reinforcement during appetitive conditioning. To test this possibility, methylergonovine was used to antagonize DA receptors. Methylergonovine (1 nM) blocked the pairing-specific increase in fictive feeding that is usually induced by in vitro classical conditioning. The present results and previous observation that methylergonovine also blocks the effects of contingent reinforcement in an in vitro analog of appetitive operant conditioning suggest that DA mediates reinforcement for appetitive associative conditioning of feeding in Aplysia.

Operant reward learning in Aplysia: neuronal correlates and mechanisms.

Operant conditioning is a form of associative learning through which an animal learns about the consequences of its behavior. Here, we report an appetitive operant conditioning procedure in Aplysia that induces long-term memory. Biophysical changes that accompanied the memory were found in an identified neuron (cell B51) that is considered critical for the expression of behavior that was rewarded. Similar cellular changes in B51 were produced by contingent reinforcement of B51 with dopamine in a single-cell analog of the operant procedure. These findings allow for the detailed analysis of the cellular and molecular processes underlying operant conditioning.