A shift in the mechanisms controlling hippocampal engram formation during brain maturation.

The ability to form precise, episodic memories develops with age, with young children only able to form gist-like memories that lack precision. The cellular and molecular events in the developing hippocampus that underlie the emergence of precise, episodic-like memory are unclear. In mice, the absence of a competitive neuronal engram allocation process in the immature hippocampus precluded the formation of sparse engrams and precise memories until the fourth postnatal week, when inhibitory circuits in the hippocampus mature. This age-dependent shift in precision of episodic-like memories involved the functional maturation of parvalbumin-expressing interneurons in subfield CA1 through assembly of extracellular perineuronal nets, which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.

Development, Acceptability, and Feasibility of a Digital Module for Coping with COVID-19 Distress: Pragmatic Retrospective Study.

Background: The coronavirus disease 2019 (COVID-19) pandemic and the measures to help contain it have taken a significant toll on mental health. Blended care psychotherapy combining provider-led care with digital tools can help alleviate this toll. This study describes the development of digital activities designed to teach cognitive-behavioral skills for coping with COVID-19 distress, and evaluates initial acceptability and feasibility data. Materials and Methods: Using a pragmatic retrospective cohort design, data from 664 U.S.-based individuals enrolled in blended care psychotherapy were analyzed. Descriptive analyses summarized acceptability for the digital activities. Ordinal logistic regression analyses were conducted on a subsample (n = 162) to explore the association between clients' attitudes toward the digital lesson and reported practice of skills in the exercise. Results: The majority of clients completed the assigned digital lesson and exercise. Clients reported finding the lesson valuable and relevant for coping with COVID-19 distress, and they intended to apply the skills to their lives. Higher agreement with these attitude questions was associated with a significantly greater number of skills practiced on the digital exercise. Discussion: Clients who were assigned a cognitive-behaviorally oriented digital lesson and/or exercise within a blended care model largely engaged with the materials and found them valuable. Clients with more positive attitudes about the digital lesson reported using more coping skills. Conclusions: Digital modules that teach specific skills for coping with COVID-19 can be integrated into treatment and minimize provider burden. Future study should investigate the clinical impact of these digital activities on psychiatric symptoms and personalizing the content.

The role of neuronal excitability, allocation to an engram and memory linking in the behavioral generation of a false memory in mice.

Memory is a constructive, not reproductive, process that is prone to errors. Errors in memory, though, may originate from normally adaptive memory processes. At the extreme of memory distortion is falsely "remembering" an event that did not occur. False memories are well-studied in cognitive psychology, but have received relatively less attention in neuroscience. Here, we took advantage of mechanistic insights into how neurons are allocated or recruited into an engram (memory trace) to generate a false memory in mice using only behavioral manipulations. At the time of an event, neurons compete for allocation to an engram supporting the memory for this event; neurons with higher excitability win this competition (Han et al., 2007). Even after the event, these allocated "engram neurons" remain temporarily (~6 h) more excitable than neighboring neurons. Should a similar event occur in this 6 h period of heightened engram neuron excitability, an overlapping population of neurons will be co-allocated to this second engram, which serves to functionally link the two memories (Rashid et al., 2016). Here, we applied this principle of co-allocation and found that mice develop a false fear memory to a neutral stimulus if exposed to this stimulus shortly (3 h), but not a longer time (24 h), after cued fear conditioning. Similar to co-allocation, the generation of this false memory depended on the post-training excitability of engram neurons such that these neurons remained more excitable during exposure to the neutral stimulus at 3 h but not 24 h. Optogenetically silencing engram neurons 3 h after cued fear conditioning impaired formation of a false fear memory to the neutral stimulus, while optogenetically activating engram neurons 24 h after cued fear conditioning created a false fear memory. These results suggest that some false memories may originate from normally adaptive mnemonic processes such as neuronal excitability-dependent allocation and memory linking.

A time-dependent role for the transcription factor CREB in neuronal allocation to an engram underlying a fear memory revealed using a novel in vivo optogenetic tool to modulate CREB function.

The internal representation of an experience is thought to be encoded by long-lasting physical changes to the brain ("engrams") . Previously, we and others showed within the lateral amygdala (LA), a region critical for auditory conditioned fear, eligible neurons compete against one other for allocation to an engram. Neurons with relatively higher function of the transcription factor CREB were more likely to be allocated to the engram. In these studies, though, CREB function was artificially increased for several days before training. Precisely when increased CREB function is important for allocation remains an unanswered question. Here, we took advantage of a novel optogenetic tool (opto-DN-CREB) to gain spatial and temporal control of CREB function in freely behaving mice. We found increasing CREB function in a small, random population of LA principal neurons in the minutes, but not 24 h, before training was sufficient to enhance memory, likely because these neurons were preferentially allocated to the underlying engram. However, similarly increasing CREB activity in a small population of random LA neurons immediately after training disrupted subsequent memory retrieval, likely by disrupting the precise spatial and temporal patterns of offline post-training neuronal activity and/or function required for consolidation. These findings reveal the importance of the timing of CREB activity in regulating allocation and subsequent memory retrieval, and further, highlight the potential of optogenetic approaches to control protein function with temporal specificity in behaving animals.

Prevalence and Economic Burden of Epilepsy in the Institutionalized Medicare Fee-for-Service Population.

BACKGROUND: Based on data from 2003 to 2007, the prevalence of epilepsy was significantly higher in the institutionalized elderly population than in the noninstitutionalized population, but the recent prevalence and economic impact of epilepsy specifically in the institutionalized Medicare population have not been reported. OBJECTIVES: To estimate the prevalence and economic burden of epilepsy and inpatient utilization rates among institutionalized Medicare beneficiaries and to provide a 10-year projection of their population size and the associated costs. METHODS: We performed a cross-sectional analysis of the institutionalized Medicare population with and without epilepsy using Medicare 5% sample claims data from 2013 and 2014. The identification of epilepsy required ≥1 qualifying claims with an epilepsy diagnosis, or ≥2 qualifying claims ≥30 days apart with a diagnosis of convulsion, in 2014. Institutionalized status was identified by having ≥6 consecutive months of nursing facility claims in 2013 or 2014. Inpatient admissions and 30-day readmissions, average allowed costs, and risk-adjusted incremental costs of epilepsy were calculated and compared between the institutionalized population of Medicare beneficiaries with and without epilepsy. The 2015 Medicare 100% and 5% sample data and inputs from other external sources were used to project the 10-year trends in the size and cost of the institutionalized Medicare population with epilepsy. RESULTS: The prevalence of epilepsy in 2014 was 11.1% in the institutionalized Medicare population. The institutionalized population with epilepsy had significantly higher per-patient per-month (PPPM) costs ($3479 vs $2381, respectively; P <.001), inpatient admissions per 1000 beneficiaries (1105 vs 697, respectively; P <.001), and 30-day readmissions per 1000 beneficiaries (287 vs 145, respectively; P <.001) versus the institutionalized population without epilepsy. The risk-adjusted incremental cost of epilepsy for the institutionalized population was $507.33 PPPM. Based on our model, between 2017 and 2027 an 18% increase in size and a 72% increase in cost are projected for the institutionalized Medicare beneficiaries with epilepsy. CONCLUSION: The high cost and inpatient resource utilization, as well as the projected growth of the institutionalized Medicare population with epilepsy highlight the need for further investigation of care management opportunities to reduce the cost burden associated with this condition.

The cost impact to Medicare of shifting treatment of worsening heart failure from inpatient to outpatient management settings.

PURPOSE: The aim of this study was to quantify the potential cost savings to Medicare of shifting the site of treatment for worsening heart failure (HF) from inpatient to outpatient (OP) settings for a subset of worsening HF episodes among the Medicare fee-for-service (FFS) population. MATERIALS AND METHODS: A cross-sectional analysis of a random 5% sample of 2014 FFS Medicare beneficiaries was conducted. Incidence and cost of worsening HF episodes in both inpatient and OP settings were identified. These results were used to calculate cost savings associated with shifting a proportion of worsening HF episodes from the inpatient to OP settings. RESULTS: A total of 151,908 HF beneficiaries were identified. The estimated annual cost for the treatment of worsening HF across both inpatient and OP settings ranged from US$9.3 billion to US$17.0 billion or 2.4%-4.3% of total Medicare FFS spend. The cost saving associated with shifting worsening HF treatment from inpatient hospital setting to OP settings was US$667.5 million or 0.17% of total Medicare spend when 10% of HF admissions were targeted and 60% of targeted HF admissions were successfully shifted. The cost savings increased to US$2.098 billion or 0.53% of total Medicare spend when 20% of HF admissions were targeted and 90% of targeted HF admissions were successfully shifted. CONCLUSION: Treatment options that can shift costly hospital admissions for worsening HF treatment to less expensive OP settings potentially lead to significant cost savings to Medicare. Pursuit of OP therapy options for treating worsening HF might be considered a viable alternative.

The Prevalence and Payer Costs of Potentially Avoidable Emergent Care Visits for Suspected Amniotic Membrane Rupture in Pregnant Women.

BACKGROUND: Concern over amniotic fluid leakage is common among pregnant women. Uncertainty about prelabor rupture of amniotic membranes (PROM) can lead women to present to emergency departments or to labor and delivery units for medical evaluation. Many of such visits do not result in delivery, yet they carry significant, and potentially unnecessary, healthcare expenditures. OBJECTIVE: To estimate the prevalence and payer cost of potentially avoidable visits by pregnant women to an emergent care facility (including emergency departments, labor and delivery units, or observation units) for suspected PROM. METHODS: This study included 2 processes-an electronic medical records chart review and a commercial health insurance claims data analysis. The medical chart review included 843 scheduled and 1250 unscheduled pregnancy-related visits at Robert Wood Johnson University Hospital between January 4 and June 30, 2017, which was conducted to determine the rates of visits by pregnant women with suspected PROM and their results (ie, hospital admission or discharge). In addition, we performed a retrospective analysis of medical claims data from the Truven Health MarketScan Commercial Database to measure population-level incidence rates and the costs of pregnancy-related emergent care visits for suspected PROM. RESULTS: Of the 1250 unscheduled visits reviewed, 663 did not result in delivery; of these, 68 had a primary complaint of suspected PROM, and 55 (81%) of them were discharged with PROM ruled out. Of all scheduled and unscheduled nondelivery visits (N = 1069), 5.1% (N = 55) were associated with suspected PROM but were discharged home with PROM ruled out. In the commercial claims analysis, the average rate of emergent care visits by pregnant women was 436.69 per 1000 deliveries, with an estimated average cost of $1428 per visit (in 2018 dollars), or $0.58 per member per month. Applying the rates from our chart review to the claims data, we estimated that commercial insurers pay, on average, for approximately 22.47 facility visits per 1000 deliveries for suspected and ruled-out PROM. CONCLUSIONS: Our findings suggest that for most PROM cases that do not result in delivery, PROM is ruled out and patients are sent home. Reducing the number of PROM-related visits to emergent care facilities that result in ruled-out PROM could reduce healthcare costs and help patients and providers avoid these inconvenient visits.

Utility values associated with advanced or metastatic non-small cell lung cancer: data needs for economic modeling.

INTRODUCTION: Cost-effectiveness analyses often inform healthcare reimbursement decisions. The preferred measure of effectiveness is the quality adjusted life year (QALY) gained, where the quality of life adjustment is measured in terms of utility. Areas covered: We assessed the availability and variation of utility values for health states associated with advanced or metastatic non-small cell lung cancer (NSCLC) to identify values appropriate for cost-effectiveness models assessing alternative treatments. Our systematic search of six electronic databases (January 2000 to August 2015) found the current literature to be sparse in terms of utility values associated with NSCLC, identifying 27 studies. Utility values were most frequently reported over time and by treatment type, and less frequently by disease response, stage of disease, adverse events or disease comorbidities. Expert commentary: In response to rising healthcare costs, payers increasingly consider the cost-effectiveness of novel treatments in reimbursement decisions, especially in oncology. As the number of therapies available to treat NSCLC increases, cost-effectiveness analyses will play a key role in reimbursement decisions in this area. Quantifying the relationship between health and quality of life for NSCLC patients via utility values is an important component of assessing the cost effectiveness of novel treatments.