Effect of Best Practice Alert (BPA) on Post-Discharge Opioid Prescribing After Minimally Invasive Hysterectomy: A Quality Improvement Study.

Purpose: The aim of this study was to describe the effectiveness of an electronic health record best practice alert (BPA) in decreasing gynecologic post-discharge opioid prescribing following benign minimally invasive hysterectomy. Patients and Methods: The BPA triggered for opioid orders >15 tablets. Prescribers' options included (1) decrease to 15 ≤ tablets; (2) remove the order/utilize a defaulted order set; or (3) override the alert. Results: 332 patients were included. The BPA triggered 29 times. The following actions were taken among 16 patients for whom the BPA triggered: "override the alert" (n=13); "cancel the alert" (n=2); and 'remove the opioid order set' (n=1). 12/16 patients had discharge prescriptions: one patient received 20 tablets; two received 10 tablets; and nine received 15 tablets. Top reasons for over prescribing included concerns for pain control and lack of alternatives. Conclusion: Implementing a post-discharge opioid prescribing BPA aligned opioid prescribing following benign minimally invasive hysterectomy with guideline recommendations.

A neural mechanism for learning from delayed postingestive feedback.

Animals learn the value of foods based on their postingestive effects and thereby develop aversions to foods that are toxic1-6 and preferences to those that are nutritious7-14. However, it remains unclear how the brain is able to assign credit to flavors experienced during a meal with postingestive feedback signals that can arise after a substantial delay. Here, we reveal an unexpected role for postingestive reactivation of neural flavor representations in this temporal credit assignment process. To begin, we leverage the fact that mice learn to associate novel15-18, but not familiar, flavors with delayed gastric malaise signals to investigate how the brain represents flavors that support aversive postingestive learning. Surveying cellular resolution brainwide activation patterns reveals that a network of amygdala regions is unique in being preferentially activated by novel flavors across every stage of the learning process: the initial meal, delayed malaise, and memory retrieval. By combining high-density recordings in the amygdala with optogenetic stimulation of genetically defined hindbrain malaise cells, we find that postingestive malaise signals potently and specifically reactivate amygdalar novel flavor representations from a recent meal. The degree of malaise-driven reactivation of individual neurons predicts strengthening of flavor responses upon memory retrieval, leading to stabilization of the population-level representation of the recently consumed flavor. In contrast, meals without postingestive consequences degrade neural flavor representations as flavors become familiar and safe. Thus, our findings demonstrate that interoceptive reactivation of amygdalar flavor representations provides a neural mechanism to resolve the temporal credit assignment problem inherent to postingestive learning.

A neural substrate of sex-dependent modulation of motivation.

While there is emerging evidence of sex differences in decision-making behavior, the neural substrates that underlie such differences remain largely unknown. Here we demonstrate that in mice performing a value-based decision-making task, while choices are similar between the sexes, motivation to engage in the task is modulated by action value more strongly in females than in males. Inhibition of activity in anterior cingulate cortex (ACC) neurons that project to the dorsomedial striatum (DMS) preferentially disrupts this relationship between value and motivation in females, without affecting choice in either sex. In line with these effects, in females compared to males, ACC-DMS neurons have stronger representations of negative outcomes and more neurons are active when the value of the chosen option is low. By contrast, the representation of each choice is similar between the sexes. Thus, we identify a neural substrate that contributes to sex-specific modulation of motivation by value.

Neuroscience: Secretin excites the thirst circuit.

Peptides secreted by internal organs and by neurons in the brain are major regulators of eating and drinking. New work shows that the peptide hormone secretin influences drinking by adjusting the excitability of neurons in the brain's thirst circuit.

Opponent control of behavior by dorsomedial striatal pathways depends on task demands and internal state.

A classic view of the striatum holds that activity in direct and indirect pathways oppositely modulates motor output. Whether this involves direct control of movement, or reflects a cognitive process underlying movement, remains unresolved. Here we find that strong, opponent control of behavior by the two pathways of the dorsomedial striatum depends on the cognitive requirements of a task. Furthermore, a latent state model (a hidden Markov model with generalized linear model observations) reveals that-even within a single task-the contribution of the two pathways to behavior is state dependent. Specifically, the two pathways have large contributions in one of two states associated with a strategy of evidence accumulation, compared to a state associated with a strategy of repeating previous choices. Thus, both the demands imposed by a task, as well as the internal state of mice when performing a task, determine whether dorsomedial striatum pathways provide strong and opponent control of behavior.

Duration of postictal impaired awareness after bilateral tonic-clonic seizures: EEG and patient characteristics.

OBJECTIVE: Ictal and postictal phenomena that may impact the duration of postictal impaired awareness have not been well studied. Postictal unresponsiveness invariably occurs following bilateral tonic-clonic seizures (BTCS). Bilateral tonic-clonic seizures are a major risk factor for sudden unexpected death in epilepsy (SUDEP). We quantify the effects of seizure characteristics on postictal recovery of awareness following BTCS. Factors include: the total seizure duration, the duration of the tonic phase of a BTCS, presence of postictal generalized EEG suppression (PGES), duration of postictal tonic electromyographic discharge, peri-ictal respiratory dysfunction, patient age, duration of epilepsy, and gender. METHODS: Fifty-eight patients admitted to the epilepsy monitoring unit with BTCS were studied. Forty-one had unilateral onset temporal seizures. The remainder had bitemporal onsets, extratemporal onsets, undetermined onsets, or were generalized at onset. Following the first BTCS, time to initial recovery of awareness and its possible association with patient and seizure characteristics as well as peri-ictal respiratory dysfunction were evaluated. The presence or absence of postictal agitation was noted. RESULTS: The severity of respiratory dysfunction and seizure characteristics were not associated with time to initial recovery of awareness. A shorter time to recovery of awareness was significantly associated with a younger age (p = 0.007). Postictal agitation was more common in males (p = 0.023). SIGNIFICANCE: Focal seizures may impair awareness by active inhibition of subcortical arousal mechanisms. Focal seizures progressing to bilateral tonic-clonic seizures (BTCS) result in further widespread cerebral dysfunction impacting postictal awareness. MRI studies show accelerated brain aging in patients with temporal lobe epilepsy. Our findings suggest that patient age, as a surrogate marker for the lifetime burden of seizures, results in a progressive worsening in time to recovery after BTCS by an increasing negative impact on networks involved in arousal.

Effect of Replacing Vendor QTc Alerts with a Custom QTc Risk Alert in Inpatients.

OBJECTIVE: The aim of the study is to implement a customized QTc interval clinical decision support (CDS) alert strategy in our electronic health record for hospitalized patients and aimed at providers with the following objectives: minimize QTc prolongation, minimize exposure to QTc prolonging medications, and decrease overall QTc-related alerts. A strategy that was based on the validated QTc risk scoring tool and replacing medication knowledge vendor alerts with custom QTc prolongation alerts was implemented. METHODS: This is a retrospective quasi-experimental study with a pre-intervention period (August 2019 to October 2019) and post-intervention period (December 2019 to February 2020). The custom alert was implemented in November 2019. RESULTS: In the pre-implementation group, 361 (19.3%) patients developed QTc prolongation, and in the post-implementation group, 357 (19.6%) patients developed QTc prolongation (OR: 1.02, 95% CI: 0.87-1.20, p = 0.81). The odds ratio of an action taken post-implementation compared with pre-implementation was 18.90 (95% CI: 14.03-25.47, p <0. 001). There was also a decrease in total orders for QTc prolonging medications from 7,921 (5.5%) to 7,566 (5.3%) with an odds ratio of 0.96 (95% CI: 0.93-0.99, p = 0.01). CONCLUSION: We were able to decrease patient exposure to QTc prolonging medications while not increasing the rate of QTc prolongation as well as improving alert action rate. Additionally, there was a decrease in QTc prolonging medication orders which illustrates the benefit of using a validated risk score with a customized CDS approach compared with a traditional vendor-based strategy. Further research is needed to confirm if an approach implemented at our organization can reduce QTc prolongation rates.

Incorporating preauthorization into antimicrobial stewardship pharmacist workflow reduces Clostridioides difficile and gastrointestinal panel testing.

OBJECTIVE: To evaluate whether incorporating mandatory prior authorization for Clostridioides difficile testing into antimicrobial stewardship pharmacist workflow could reduce testing in patients with alternative etiologies for diarrhea. DESIGN: Single center, quasi-experimental before-and-after study. SETTING: Tertiary-care, academic medical center in Ann Arbor, Michigan. PATIENTS: Adult and pediatric patients admitted between September 11, 2019 and December 10, 2019 were included if they had an order placed for 1 of the following: (1) C. difficile enzyme immunoassay (EIA) in patients hospitalized >72 hours and received laxatives, oral contrast, or initiated tube feeds within the prior 48 hours, (2) repeat molecular multiplex gastrointestinal pathogen panel (GIPAN) testing, or (3) GIPAN testing in patients hospitalized >72 hours. INTERVENTION: A best-practice alert prompting prior authorization by the antimicrobial stewardship program (ASP) for EIA or GIPAN testing was implemented. Approval required the provider to page the ASP pharmacist and discuss rationale for testing. The provider could not proceed with the order if ASP approval was not obtained. RESULTS: An average of 2.5 requests per day were received over the 3-month intervention period. The weekly rate of EIA and GIPAN orders per 1,000 patient days decreased significantly from 6.05 ± 0.94 to 4.87 ± 0.78 (IRR, 0.72; 95% CI, 0.56-0.93; P = .010) and from 1.72 ± 0.37 to 0.89 ± 0.29 (IRR, 0.53; 95% CI, 0.37-0.77; P = .001), respectively. CONCLUSIONS: We identified an efficient, effective C. difficile and GIPAN diagnostic stewardship approval model.

Layers of signals that regulate appetite.

All meals come to an end. This is because eating and drinking generate feedback signals that communicate to the brain what and how much has been consumed. Here we review our current understanding of how these feedback signals regulate appetite. We first describe classic studies that surgically manipulated the gastrointestinal tract and measured the effects on behavior. We then highlight recent experiments that have used in vivo neural recordings to directly observe how ingestion modulates circuit dynamics in the brain. A general theme emerging from this work is that eating and drinking generate layers of feedback signals, arising sequentially from different tissues in the body, that converge on individual neurons in the forebrain to regulate hunger and thirst.

Use of Capture-Recapture Analysis to Assess Reporting Completeness of Births to Hepatitis B-Positive Women in New York City, 2013-2014.

OBJECTIVES: The New York City (NYC) Department of Health and Mental Hygiene (DOHMH) depends on reporting by health care facilities and laboratories for disease surveillance. Our objective was to evaluate the completeness of DOHMH surveillance to identify births to hepatitis B virus (HBV)-positive women to prevent perinatal transmission. METHODS: We identified infants born to HBV-positive women by matching mothers of all infants born in NYC during May 1, 2013-May 1, 2014, identified from the Citywide Immunization Registry (CIR) to persons with HBV-positive laboratory reports in the Electronic Laboratory Reporting (ELR) system. We then matched infants born to mothers identified in the CIR/ELR match to infants born to HBV-positive women from the DOHMH perinatal HBV surveillance database. We performed capture-recapture analysis to evaluate completeness of DOHMH case identification. We compared the proportion of infants born to HBV-positive mothers reported to DOHMH with the proportion of infants identified only through the CIR/ELR match for receipt of postexposure prophylaxis (PEP) and completion of the HBV vaccination series and post-vaccination serology testing. RESULTS: Of 1662 infants identified from the CIR/ELR match and 1554 infants in the DOHMH database, 1493 infants matched. Of 169 infants only in the CIR/ELR data set, 55 were born to HBV-positive women residing in NYC. Sixty-one infants were only in the DOHMH database. An estimated 2 infants were not identified by either method. The CIR/ELR match increased infant identification by 3.5%, from 1554 to 1609 infants. The proportion of infants who received PEP was significantly higher among infants whose mothers were reported to DOHMH (vs not reported to DOHMH). PRACTICAL IMPLICATIONS: Use of the CIR/ELR match may further improve DOHMH identification of infants born to HBV-positive women and receipt of infant PEP.

A gut-to-brain signal of fluid osmolarity controls thirst satiation.

Satiation is the process by which eating and drinking reduce appetite. For thirst, oropharyngeal cues have a critical role in driving satiation by reporting to the brain the volume of fluid that has been ingested1-12. By contrast, the mechanisms that relay the osmolarity of ingested fluids remain poorly understood. Here we show that the water and salt content of the gastrointestinal tract are precisely measured and then rapidly communicated to the brain to control drinking behaviour in mice. We demonstrate that this osmosensory signal is necessary and sufficient for satiation during normal drinking, involves the vagus nerve and is transmitted to key forebrain neurons that control thirst and vasopressin secretion. Using microendoscopic imaging, we show that individual neurons compute homeostatic need by integrating this gastrointestinal osmosensory information with oropharyngeal and blood-borne signals. These findings reveal how the fluid homeostasis system monitors the osmolarity of ingested fluids to dynamically control drinking behaviour.

The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement.

The brain transforms the need for water into the desire to drink, but how this transformation is performed remains unknown. Here we describe the motivational mechanism by which the forebrain thirst circuit drives drinking. We show that thirst-promoting subfornical organ neurons are negatively reinforcing and that this negative-valence signal is transmitted along projections to the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO). We then identify molecularly defined cell types within the OVLT and MnPO that are activated by fluid imbalance and show that stimulation of these neurons is sufficient to drive drinking, cardiovascular responses, and negative reinforcement. Finally, we demonstrate that the thirst signal exits these regions through at least three parallel pathways and show that these projections dissociate the cardiovascular and behavioral responses to fluid imbalance. These findings reveal a distributed thirst circuit that motivates drinking by the common mechanism of drive reduction.

Neural circuits underlying thirst and fluid homeostasis.

Thirst motivates animals to find and consume water. More than 40 years ago, a set of interconnected brain structures known as the lamina terminalis was shown to govern thirst. However, owing to the anatomical complexity of these brain regions, the structure and dynamics of their underlying neural circuitry have remained obscure. Recently, the emergence of new tools for neural recording and manipulation has reinvigorated the study of this circuit and prompted re-examination of longstanding questions about the neural origins of thirst. Here, we review these advances, discuss what they teach us about the control of drinking behaviour and outline the key questions that remain unanswered.

Thirst.

Our bodies are mostly water, and this water is constantly being lost through evaporative and other means. Thus the evolution of robust mechanisms for finding and consuming water has been critical for the survival of most animals. In this Primer, we discuss how the brain monitors the water content of the body and then transforms that physical information into the motivation to drink.

Warm-Sensitive Neurons that Control Body Temperature.

Thermoregulation is one of the most vital functions of the brain, but how temperature information is converted into homeostatic responses remains unknown. Here, we use an unbiased approach for activity-dependent RNA sequencing to identify warm-sensitive neurons (WSNs) within the preoptic hypothalamus that orchestrate the homeostatic response to heat. We show that these WSNs are molecularly defined by co-expression of the neuropeptides BDNF and PACAP. Optical recordings in awake, behaving mice reveal that these neurons are selectively activated by environmental warmth. Optogenetic excitation of WSNs triggers rapid hypothermia, mediated by reciprocal changes in heat production and loss, as well as dramatic cold-seeking behavior. Projection-specific manipulations demonstrate that these distinct effectors are controlled by anatomically segregated pathways. These findings reveal a molecularly defined cell type that coordinates the diverse behavioral and autonomic responses to heat. Identification of these warm-sensitive cells provides genetic access to the core neural circuit regulating the body temperature of mammals. PAPERCLIP.

Thirst neurons anticipate the homeostatic consequences of eating and drinking.

Thirst motivates animals to drink in order to maintain fluid balance. Thirst has conventionally been viewed as a homeostatic response to changes in blood volume or tonicity. However, most drinking behaviour is regulated too rapidly to be controlled by blood composition directly, and instead seems to anticipate homeostatic imbalances before they arise. How this is achieved remains unknown. Here we reveal an unexpected role for the subfornical organ (SFO) in the anticipatory regulation of thirst in mice. By monitoring deep-brain calcium dynamics, we show that thirst-promoting SFO neurons respond to inputs from the oral cavity during eating and drinking and then integrate these inputs with information about the composition of the blood. This integration allows SFO neurons to predict how ongoing food and water consumption will alter fluid balance in the future and then to adjust behaviour pre-emptively. Complementary optogenetic manipulations show that this anticipatory modulation is necessary for drinking in several contexts. These findings provide a neural mechanism to explain longstanding behavioural observations, including the prevalence of drinking during meals, the rapid satiation of thirst, and the fact that oral cooling is thirst-quenching.

Hunger neurons drive feeding through a sustained, positive reinforcement signal.

The neural mechanisms underlying hunger are poorly understood. AgRP neurons are activated by energy deficit and promote voracious food consumption, suggesting these cells may supply the fundamental hunger drive that motivates feeding. However recent in vivo recording experiments revealed that AgRP neurons are inhibited within seconds by the sensory detection of food, raising the question of how these cells can promote feeding at all. Here we resolve this paradox by showing that brief optogenetic stimulation of AgRP neurons before food availability promotes intense appetitive and consummatory behaviors that persist for tens of minutes in the absence of continued AgRP neuron activation. We show that these sustained behavioral responses are mediated by a long-lasting potentiation of the rewarding properties of food and that AgRP neuron activity is positively reinforcing. These findings reveal that hunger neurons drive feeding by transmitting a positive valence signal that triggers a stable transition between behavioral states.

Increased appropriateness of customized alert acknowledgement reasons for overridden medication alerts in a computerized provider order entry system.

OBJECTIVE: Computerized provider order entry systems commonly contain alerting mechanisms for patient allergies, incorrect doses, or drug-drug interactions when ordering medications. Providers have the option to override (bypass) these alerts and continue with the order unchanged. This study examines the effect of customizing medication alert override options on the appropriateness of override selection related to patient allergies, drug dosing, and drug-drug interactions when ordering medications in an electronic medical record. MATERIALS AND METHODS: In this prospective, randomized crossover study, providers were randomized into cohorts that required a reason for overriding a medication alert from a customized or non-customized list of override reasons and/or by free-text entry. The primary outcome was to compare override responses that appropriately correlate with the alert type between the customized and non-customized configurations. The appropriateness of a subset of free-text responses that represented an affirmative and active acknowledgement of the alert without further explanation was classified as "indeterminate." Results were analyzed in three different ways by classifying indeterminate answers as either appropriate, inappropriate, or excluded entirely. Secondary outcomes included the appropriateness of override reasons when comparing cohorts and individual providers, reason selection based on order within the override list, and the determination of the frequency of free-text use, nonsensical responses, and multiple selection responses. RESULTS: Twenty-two clinicians were randomized into 2 cohorts and a total of 1829 alerts with a required response were generated during the study period. The customized configuration had a higher rate of appropriateness when compared to the non-customized configuration regardless of how indeterminate responses were classified (p<0.001). When comparing cohorts, appropriateness was significantly higher in the customized configuration regardless of the classification of indeterminate responses (p<0.001) with one exception: when indeterminate responses were considered inappropriate for the cohort of providers that were first exposed to the non-customized list (p=0.103). Free-text use was higher in the customized configuration overall (p<0.001), and there was no difference in nonsensical response between configurations (p=0.39). CONCLUSION: There is a benefit realized by using a customized list for medication override reasons. Poor application design or configuration can negatively affect provider behavior when responding to important medication alerts.