An open-source behavior controller for associative learning and memory (B-CALM).

Associative learning and memory, i.e., learning and remembering the associations between environmental stimuli, self-generated actions, and outcomes such as rewards or punishments, are critical for the well-being of animals. Hence, the neural mechanisms underlying these processes are extensively studied using behavioral tasks in laboratory animals. Traditionally, these tasks have been controlled using commercial hardware and software, which limits scalability and accessibility due to their cost. More recently, due to the revolution in microcontrollers or microcomputers, several general-purpose and open-source solutions have been advanced for controlling neuroscientific behavioral tasks. While these solutions have great strength due to their flexibility and general-purpose nature, for the same reasons, they suffer from some disadvantages including the need for considerable programming expertise, limited online visualization, or slower than optimal response latencies for any specific task. Here, to mitigate these concerns, we present an open-source behavior controller for associative learning and memory (B-CALM). B-CALM provides an integrated suite that can control a host of associative learning and memory behaviors. As proof of principle for its applicability, we show data from head-fixed mice learning Pavlovian conditioning, operant conditioning, discrimination learning, as well as a timing task and a choice task. These can be run directly from a user-friendly graphical user interface (GUI) written in MATLAB that controls many independently running Arduino Mega microcontrollers in parallel (one per behavior box). In sum, B-CALM will enable researchers to execute a wide variety of associative learning and memory tasks in a scalable, accurate, and user-friendly manner.

Early pregnancy loss medical management in clinical practice.

OBJECTIVES: This study aimed to review clinical practice outcomes of early pregnancy loss (EPL) medical management using mifepristone and misoprostol outside of a clinical trial setting. STUDY DESIGN: In this retrospective cohort study, we reviewed a deidentified database of patients who received mifepristone-misoprostol for EPL from May 2018 to May 2021 at our academic center-based clinic, which was a study site for a multicenter mifepristone-misoprostol EPL trial completed in March 2018. All patients received mifepristone 200 mg orally and misoprostol 800 mcg vaginally or buccally, with clinic follow-up typically scheduled within 1 week. The primary outcome was successful medical management, defined as management without the need for aspiration, and the secondary outcomes included additional interventions and indications, follow-up ultrasonography findings, and adverse events requiring treatment. RESULTS: We treated 90 patients with a median ultrasound-measured gestational size of 49 (range 30-80) days and median time from mifepristone to misoprostol of 24 (range 8-66) hours. Follow-up was completed in clinic by 80 (88.9%), completed remotely by five (5.6%), and not completed by five (5.6%) patients. Overall, 76 (95% CI 82.9%-96.0%) of 85 patients (89.4%) with follow-up were successfully managed without uterine aspiration. Eighty patients had initial follow-up ultrasonography interpreted as gestational sac expulsion; seven (8.8%) of these ultimately underwent aspiration, including one patient who had a previously undiagnosed cesarean scar ectopic pregnancy. Two patients had significant safety outcomes: one pelvic infection and one blood transfusion during aspiration in the patient with a cesarean scar ectopic pregnancy. CONCLUSIONS: Outside of a clinical trial setting, medical management of EPL with mifepristone and misoprostol remains effective and safe. IMPLICATIONS: Medical management of EPL with mifepristone and misoprostol is effective and safe outside of a clinical trial setting. A standardized protocol based on the best available clinical trial evidence can be used in clinical practice for the medical management of EPL.

Few-shot learning: temporal scaling in behavioral and dopaminergic learning.

How do we learn associations in the world (e.g., between cues and rewards)? Cue-reward associative learning is controlled in the brain by mesolimbic dopamine1-4. It is widely believed that dopamine drives such learning by conveying a reward prediction error (RPE) in accordance with temporal difference reinforcement learning (TDRL) algorithms5. TDRL implementations are "trial-based": learning progresses sequentially across individual cue-outcome experiences. Accordingly, a foundational assumption-often considered a mere truism-is that the more cue-reward pairings one experiences, the more one learns this association. Here, we disprove this assumption, thereby falsifying a foundational principle of trial-based learning algorithms. Specifically, when a group of head-fixed mice received ten times fewer experiences over the same total time as another, a single experience produced as much learning as ten experiences in the other group. This quantitative scaling also holds for mesolimbic dopaminergic learning, with the increase in learning rate being so high that the group with fewer experiences exhibits dopaminergic learning in as few as four cue-reward experiences and behavioral learning in nine. An algorithm implementing reward-triggered retrospective learning explains these findings. The temporal scaling and few-shot learning observed here fundamentally changes our understanding of the neural algorithms of associative learning.

Management of cesarean scar ectopic pregnancies at an academic referral center: A case series.

OBJECTIVES: To describe treatment and outcomes of patients with confirmed cesarean scar ectopic pregnancy (CSEP) at a tertiary referral center. STUDY DESIGN: We reviewed a deidentified family planning clinical database for patients seen by our subspecialty service for CSEP from January 2017 through December 2021 in this case series. We extracted referral information, final diagnosis, management, and outcome measures including estimated blood loss, secondary procedures, and treatment complications. RESULTS: Of 57 cases referred for suspected CSEPs, 23 (40%) had confirmed diagnoses; one additional case was diagnosed during clinic evaluation for early pregnancy loss. Most (n = 50 [88%]) referrals occurred in the last 2 years of the 5-year study period. Of 24 confirmed CSEP cases, eight were pregnancy losses at the time of diagnosis. Fourteen cases were ≤50 days gestation or gestational size (7 [50%] pregnancy losses) and 10 >50 days gestation (range 39-66 days). We treated all 14 patients ≤50 days primarily with suction aspiration under ultrasound guidance in an operating room with no complications and estimated blood loss of 14 ± 10 mL. Of the 10 patients>50 days (maximum 66 days), seven were managed with primary aspiration of which five were uncomplicated. We treated one patient (57 days) had primary intrauterine double-catheter balloon with immediate hemorrhage requiring uterine artery embolization followed by an uncomplicated suction aspiration. CONCLUSIONS: Patients with confirmed CSEPs at 50 days or less gestation or gestational size can likely be primarily treated with suction aspiration with low risk for significant adverse outcomes. Treatment success and complications are directly related to gestational age at treatment. IMPLICATIONS: Ultrasound-guided suction aspiration monotherapy should be considered for primary CSEP treatment up to 50 days and, with continued experience, may be reasonable beyond 50 days gestation. Invasive treatments or those that require multiple days and visits, such as methotrexate or balloon catheters, are not necessary for early CSEPs.

Mesolimbic dopamine release conveys causal associations.

Learning to predict rewards based on environmental cues is essential for survival. It is believed that animals learn to predict rewards by updating predictions whenever the outcome deviates from expectations, and that such reward prediction errors (RPEs) are signaled by the mesolimbic dopamine system-a key controller of learning. However, instead of learning prospective predictions from RPEs, animals can infer predictions by learning the retrospective cause of rewards. Hence, whether mesolimbic dopamine instead conveys a causal associative signal that sometimes resembles RPE remains unknown. We developed an algorithm for retrospective causal learning and found that mesolimbic dopamine release conveys causal associations but not RPE, thereby challenging the dominant theory of reward learning. Our results reshape the conceptual and biological framework for associative learning.

Predicted Effects and Cost-Effectiveness of Wheat Flour Fortification for Reducing Micronutrient Deficiencies, Maternal Anemia, and Neural Tube Defects in Yaoundé and Douala, Cameroon.

BACKGROUND: Policy makers aiming to reduce micronutrient deficiencies (MNDs) and their health effects must choose among alternative definitions of impact when evaluating cost-effectiveness. OBJECTIVE: Estimate the cost-effectiveness of a mandatory wheat flour fortification program for reducing cases of MNDs (iron, zinc, folate, vitamin B12), anemia and neural tube defects (NTDs) averted, and disability-adjusted life years (DALYs) averted in urban Cameroon. METHODS: A 13-year predictive model was developed, including a 3-year start-up period and 10 years of program activity. Costs were estimated using historical program budgets. Effects were calculated based on observed changes in prevalence of MND and anemia 1 year postfortification and predicted reductions in NTDs based on NTD burden and wheat flour intake. Total DALYs averted were estimated for anemia and NTDs. RESULTS: The program cost ∼$2.4 million over 13 years and averted an estimated ∼95 000 cases of maternal anemia and ∼83 500 cases of iron deficiency among children after 1 year. Cost/case-year averted for MNDs ranged from $0.50 for low plasma folate to $3.30 for iron deficiency and was $2.20 for maternal anemia. The program was predicted to avert 1600 cases of NTDs over 10 years at ∼$1500 per case averted. Estimated cost/DALY averted was $50 for NTDs and $115 for anemia. CONCLUSIONS: In Cameroon, cost-effectiveness of wheat flour fortification varied by the measure of impact employed, but was classified as "very cost-effective" for all outcomes using World Health Organization criteria. Policy makers and their advisors must determine how best to use information on program costs and benefits to inform their decisions.

Postoperative Opioid Prescribing and Consumption after Hysterectomy: A Prospective Cohort Study.

STUDY OBJECTIVE: To examine opioid prescribing and consumption patterns after hysterectomy and identify factors associated with postoperative opioid consumption. DESIGN: Prospective cohort study. SETTING: Single university medical center. PATIENTS: Women undergoing hysterectomy for benign, nonobstetric indications. INTERVENTIONS: Participant preoperative and surgical characteristics were obtained through chart review and patient report of baseline pain score. During the third postoperative week, participants completed a telephone interview, including a direct count of remaining opioid pills and assessment of satisfaction with pain management. We assessed factors associated with opioid consumption in oral morphine equivalents (OME) using a linear regression model. MEASUREMENTS AND MAIN RESULTS: Of the 129 participants, 113 (88%) completed the postoperative survey after hysterectomy: 16 vaginal, 43 robotic-assisted, 42 conventional laparoscopic, and 12 abdominal hysterectomies. The median amount of opioid prescribed was 150 OME (interquartile range [IQR] 113-200), while the median amount consumed was 75 (IQR 10-135), reflecting an average consumption of about 50% of the prescription. Opioid prescription size was associated with consumption; for every additional oral morphine equivalent prescribed, on average, an additional 0.5 was consumed (p <.001). If the indication for hysterectomy was related to pain, participants consumed 25.3 additional OME (p = .04). The amount of opioid prescribed was inversely correlated with pain management satisfaction; every additional point on a 1 through 5 Likert scale of increasing satisfaction was associated with 44 fewer OME prescribed (standard error 9 OME, p <.001). For the 1464 total unused pills among the 104 participants with leftover opioids, only 20% reported an Food and Drug Administration -compliant opioid disposal plan. CONCLUSION: Gynecologic surgeons can respond to the opioid epidemic by reducing excess opioid pills after hysterectomy by providing both the smallest effective prescription size and concrete resources for safe opioid disposal. These actions may contribute to a reduction in opioid use disorder cases or overdose deaths.

Palladium-catalyzed α,ß-dehydrogenation of acyclic ester equivalents promoted by a novel electron deficient phosphinooxazoline ligand.

A unique example of Pd-catalyzed decarboxylative dehydrogenation of fully substituted N-acyl allyl enol carbonates is enabled by a new electron deficient phosphinooxazoline (PHOX) ligand. The reaction proceeds from the Z-enol carbonate to provide dehydrogenation products exclusively in high E/Z selectivity, while the E-enol carbonate provides the α-allylation product with only minor dehydrogenation. The reaction proceeds with a broad scope of (Z)-enol carbonates derived from N-acyl indoles to furnish acyclic formal α,ß-unsaturated ester equivalents.

Survey of risk factors for osteoporosis and osteoprotective behaviors among patients with epilepsy.

The prevalence of risk factors for osteoporosis in persons with epilepsy, patients' awareness of their risk, and their engagement in osteoprotective behaviors were assessed in this study. Two hundred and sixty patients with epilepsy (F=51.5%, average age=42) completed a survey tool. Of 106 patients with a dual energy X-ray absorptiometry (DXA) result, 52% had low bone mineral density, and 11% had osteoporosis. The results suggest that the majority of patients with epilepsy do not engage in bone-protective behaviors. Those who have undergone a DXA scan may be more likely to take calcium and vitamin D supplementation compared with those who did not undergo a DXA scan, but they do not engage in other osteoprotective behaviors. Many patients did not accurately report their DXA results, indicating that better patient education is warranted.

Mechanical loading causes detectable changes in morphometric measures of trabecular structure in human cancellous bone.

The relationships between mechanical loads and bone microstructure are of interest to those who seek to predict bone mechanical properties from microstructure or to predict how organization of bone microstructure is driven by mechanical loads. While strains and displacements in the material are inherently responsible for mechanically caused changes in the appearance of the microstructure, it is the morphometric measures of microstructural organization that are often available for assessment of bone quality. Therefore, an understanding of how strain history is reflected in morphometric measures of bone microstructure has practical implications in that it may provide clinically measurable indices of mechanical history in bone and improve interpretation of bone mechanical properties from microstructural information. The objective of the current study was to examine changes in morphometric measures of cancellous bone microstructure in response to varying levels of continuum level strains. The experimental approach included stereologic analysis of microcomputed tomography (µCT) images of human cancellous bone samples obtained at sequentially increasing levels of strain in a custom-made loading apparatus mounted in a µCT scanner. We found that the degree of anisotropy (DA) decreased from baseline to failure and from failure to postfailure. DA partially recovered from postfailure levels upon unloading; however, the final DA was less than at failure and less than at baseline. We also found that average trabecular thickness (Tb.Th.Av) increased with displacements at postfailure and did not recover when unloaded. Average trabecular number decreased when the specimens were unloaded. In addition, the heterogeneity of Tb.Th as measured by intra-specimen standard deviation (Tb.Th.SD) increased and that of trabecular number (Tb.N.SD) decreased with displacements at postfailure. Furthermore, the intraspecimen coefficient of variation of trabecular number decreased at postfailure displacements but did not recover upon unloading. Finally, the coefficient of variation of trabecular separation at unload was less than that at baseline. These measures can be developed into image-based indices to estimate strain history, damage, and residual mechanical properties where direct analysis of stresses and strains, such as through finite element modeling, may not be feasible. It remains to be determined how wide a time interval can be used to estimate strain history before remodeling becomes an overriding effect on the trabecular architecture.

Off-label gabapentin masking ictal triphasic waves: case analysis of neuropsychiatric and electrographic correlates.

Antiepileptic drugs (AEDs) are frequently used off-label for the treatment of psychiatric, pain, and other neurological disorders. Off-label AED use may confound the diagnosis for acute neuropsychiatric changes associated with delirium by fortuitously treating, or partially treating, underlying seizure disorders while masking ictal electrographic patterns on EEGs. Standard video/EEG monitoring includes weaning from AEDs to maximize ictal activity and better determine seizure focus. We report a case of off-label gabapentin use masking ictal electrographic activity, the neuropsychiatric and electrographic consequences of discontinuing gabapentin, and the therapeutic response when gabapentin was re-initiated and titrated to a total daily dose greater than that at time of admission. Weaning from AEDs with concurrent video/EEG monitoring is an important diagnostic tool in these complex cases.

Lacosamide-induced second-degree atrioventricular block in a patient with partial epilepsy.

Dose-dependent PR interval prolongation has been reported in preclinical studies of lacosamide (LCM), a recently U.S. Food and Drug Administration (FDA)-approved antiepileptic drug (AED). Here we report a case of second-degree atrioventricular block (AV) block caused by the addition of LCM to other AEDs known to prolong the PR interval, resulting in hypotension and bradycardia, with consequent seizure exacerbation. The patient recovered completely after withdrawal of LCM. This case demonstrates the need for caution and interval cardiac testing when adding LCM to other AEDs known to prolong the PR interval.

Atypical Rasmussen's encephalitis treated with temporal lobectomy.

Rasmussen's encephalitis is characterized by seizures, progressive neurological deterioration and chronic inflammation of the brain. It typically presents in childhood and requires anatomic or functional hemispherectomy for seizure control. Here, we report an adult woman who presented with new onset, medically refractory seizures that were not progressive. The patient underwent a right anterior temporal lobectomy. The pathologic samples were consistent with Rasmussen's encephalitis. The patient remained seizure free until her last follow-up at 2 years. This is an example of unique adult onset Rasmussen's encephalitis, suggesting that this encephalitis represents a wide spectrum of presentations rather than a specific disease.

Focal chronic inflammatory epileptic encephalopathy in a patient with malformations of cortical development, with a review of the spectrum of chronic inflammatory epileptic encephalopathy.

PURPOSE: Chronic cellular inflammation closely associated with epilepsy without an active infection is a hallmark of Rasmussen encephalitis (RE). RE has typical and defining features lacking in other rare epilepsy patients who also have neocortical lymphocytes without an identifiable cause. A patient with malformations of cortical development had an abrupt change in frequency and epileptic focus after 22 years of a stable seizure disorder. Functional neurosurgery yielded a specimen showing a mixed cellular meningoencephalitis in the absence of a demonstrable infection. METHODS: Historical, neurologic, electroencephalographic, pathologic, and literature data were correlated. RESULTS: There was a subarachnoid mixed infiltrate including evidence of dendritic cells in our patient and also cytotoxic T lymphocytes adjacent to karyolytic neurons that corresponded to cells previously demonstrated to damage neurons in RE. Literature review disclosed 42 other cases similar to RE but with heterogeneous findings. The course was more protracted and often more benign than in RE. The inflammation that would have markedly decreased or disappeared in RE over that period was generally still well represented. CONCLUSIONS: Our patient has heterogeneous features similar to, yet with differences from, RE. Literature review of chronic cellular inflammatory epileptic encephalopathy cases also similar to RE discloses important differences that may reflect idiosyncratic reactions and pace of the disease rather than a different disease. Comorbidity factors, genetic population traits, and secondary effects of the seizure disorder may lead to an expansion of the initial site of damage by an autoimmune reaction. These cases might best be grouped, probably along with RE, as secondary autoimmune diseases.