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Breathing (or respiration) is an unconscious and complex motor behavior which neuronal drive emerges from the brainstem. In simplistic terms, respiratory motor activity comprises two phases, inspiration (uptake of oxygen, O2) and expiration (release of carbon dioxide, CO2). Breathing is not rigid, but instead highly adaptable to external and internal physiological demands of the organism. The neurons that generate, monitor, and adjust breathing patterns locate to two major brainstem structures, the pons and medulla oblongata. Extensive research over the last three decades has begun to identify the developmental origins of most brainstem neurons that control different aspects of breathing. This research has also elucidated the transcriptional control that secures the specification of brainstem respiratory neurons. In this review, we aim to summarize our current knowledge on the transcriptional regulation that operates during the specification of respiratory neurons, and we will highlight the cell lineages that contribute to the central respiratory circuit. Lastly, we will discuss on genetic disturbances altering transcription factor regulation and their impact in hypoventilation disorders in humans.

The transcriptional programs of nuclei in the muscle syncytium were assumed to be homogenous except at the neuromuscular and myotendinous junctions. Here, using single-nucleus transcriptomics, the authors reveal a previously unrecognized diversity and dynamics of myonuclear transcriptional programs.

The mature cerebellum controls motor skill precision and participates in other sophisticated brain functions that include learning, cognition, and speech. Different types of GABAergic and glutamatergic cerebellar neurons originate in temporal order from two progenitor niches, the ventricular zone and rhombic lip, which express the transcription factors Ptf1a and Atoh1, respectively. However, the molecular machinery required to specify the distinct neuronal types emanating from these progenitor zones is still unclear. Here, we uncover the transcription factor Olig3 as a major determinant in generating the earliest neuronal derivatives emanating from both progenitor zones in mice. In the rhombic lip, Olig3 regulates progenitor cell proliferation. In the ventricular zone, Olig3 safeguards Purkinje cell specification by curtailing the expression of Pax2, a transcription factor that suppresses the Purkinje cell differentiation program. Our work thus defines Olig3 as a key factor in early cerebellar development.

Racial disparities affect multiple dimensions of epilepsy care including epilepsy surgery. This study aims to further explore these disparities by determining the utilization of invasive neuromodulation devices according to race and ethnicity in a multicenter study of patients living with focal drug-resistant epilepsy (DRE). We performed a post hoc analysis of the Human Epilepsy Project 2 (HEP2) data. HEP2 is a prospective study of patients living with focal DRE involving 10 sites distributed across the United States. There were no statistical differences in the racial distribution of the study population compared to the US population using census data except for patients reporting more than one race. Of 154 patients enrolled in HEP2, 55 (36%) underwent invasive neuromodulation for DRE management at some point in the course of their epilepsy. Of those, 36 (71%) were patients who identified as White. Patients were significantly less likely to have a device if they identified solely as Black/African American than if they did not (odds ratio = .21, 95% confidence interval = .05-.96, p = .03). Invasive neuromodulation for management of DRE is underutilized in the Black/African American population, indicating a new facet of racial disparities in epilepsy care., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1., Methods: Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics., Results: Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities., Significance: This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population., (© 2023 International League Against Epilepsy.)

Brown marmorated stink bug, Halyomorpha halys (Stål) (Hemiptera: Pentatomidae), is a generalist pest that causes serious injury to a variety of crops around the world. After the first detection in the USA, H. halys became a serious threat to growers resulting in significant crop damage. Understanding the effect of temperature on H. halys development will help to achieve successful control by predicting the phenological timing of the pest. Here, life table parameters (survival, development, reproduction, and daily mortality) of H. halys were evaluated for New Jersey and Oregon populations in the US. Parameters were determined from field-collected and laboratory-reared individuals. The results indicated that New Jersey populations had higher levels of egg-laying than Oregon populations and exhibited higher and earlier fecundity peaks. Survival levels were similar between populations. Linear and nonlinear fit were used to estimate the minimum (14.3 °C), optimal (27.8 °C), and maximum (35.9 °C) temperatures where development of H. halys can take place. An age-specific fecundity peak (M x = 36.63) was recorded at 936 degree days for New Jersey populations, while maximum fecundity (M x = 11.85) occurred at 1145 degree days in Oregon. No oviposition was recorded at the lowest (15 °C) or highest (35 °C) trialed temperatures. Developmental periods increased at temperatures above 30 °C, indicating that such higher temperatures are suboptimal for H. halys development. Altogether the most optimal temperatures for population increase ( r m ) ranged from 25 to 30 °C. Survival rates of H. halys at suboptimal low temperatures of 8 °C (i.e., 61%) is comparable to previous reports. The present paper provides additional data and context from a range of experimental conditions and populations. Such temperature-related H. halys life table parameters can be used to provide determine the risk to susceptible crops.

Importance: The COVID-19 pandemic has claimed nearly 6 million lives globally as of February 2022. While pandemic control efforts, including contact tracing, have traditionally been the purview of state and local health departments, the COVID-19 pandemic outpaced health department capacity, necessitating actions by private health systems to investigate and control outbreaks, mitigate transmission, and support patients and communities., Objective: To investigate the process of designing and implementing a volunteer-staffed contact tracing program at a large academic health system from April 2020 to May 2021, including program structure, lessons learned through implementation, results of case investigation and contact tracing efforts, and reflections on how constrained resources may be best allocated in the current pandemic or future public health emergencies., Design, Setting, and Participants: This case series study was conducted among patients at the University of Pennsylvania Health System and in partnership with the Philadelphia Department of Public Health. Patients who tested positive for COVID-19 were contacted to counsel them regarding safe isolation practices, identify and support quarantine of their close contacts, and provide resources, such as food and medicine, needed during isolation or quarantine., Results: Of 5470 individuals who tested positive for COVID-19 and received calls from a volunteer, 2982 individuals (54.5%; median [range] age, 42 [18-97] years; 1628 [59.4%] women among 2741 cases with sex data) were interviewed; among 2683 cases with race data, there were 110 Asian individuals (3.9%), 1476 Black individuals (52.7%), and 817 White individuals (29.2%), and among 2667 cases with ethnicity data, there were 366 Hispanic individuals (13.1%) and 2301 individuals who were not Hispanic (82.6%). Most individuals lived in a household with 2 to 5 people (2125 of 2904 individuals with household data [71.6%]). Of 3222 unique contacts, 1780 close contacts (55.2%; median [range] age, 40 [18-97] years; 866 [55.3%] women among 1565 contacts with sex data) were interviewed; among 1523 contacts with race data, there were 69 Asian individuals (4.2%), 705 Black individuals (43.2%), and 573 White individuals (35.1%), and among 1514 contacts with ethnicity data, there were 202 Hispanic individuals (12.8%) and 1312 individuals (83.4%) who were not Hispanic. Most contacts lived in a household with 2 to 5 people (1123 of 1418 individuals with household data [79.2%]). Of 3324 cases and contacts who completed a questionnaire on unmet social needs, 907 (27.3%) experienced material hardships that would make it difficult for them to isolate or quarantine safely. Such hardship was significantly less common among White compared with Black participants (odds ratio, 0.20; 95% CI, 0.16-0.25)., Conclusions and Relevance: These findings demonstrate the feasibility and challenges of implementing a case investigation and contact tracing program at an academic health system. In addition to successfully engaging most assigned COVID-19 cases and close contacts, contact tracers shared health information and material resources to support isolation and quarantine, thus filling local public health system gaps and supporting local pandemic control.

Background: Clinicians need to be able to assess the quality of the available information to aid clinical decision-making. The internet has become an important source of health information for consumers and their families., Objective: This study aimed to rate the quality of websites with psychosis-related information (to provide clinicians with a basis for recommending material to guide clinical decision-making with consumers and their families), using a validated instrument as well as a purpose-developed checklist, and consider improvement in quality over a 4-year period., Methods: Two measures of website quality were used: the DISCERN scale and the Psychosis Website Quality Checklist (PWQC). Terms related to psychosis, including "psychotic," "psychosis," "schizophrenia," "delusion," and "hallucination," were entered into Google, and the first 25 results were analyzed. In total, 6 raters with varying health professional backgrounds were used to evaluate the websites across two time points: January-March 2014 and January-March 2018., Results: Of the 25 websites rated, only the 6 highest ranked websites achieved a DISCERN score, indicating that they were of "good" quality (51-62 out of a possible 75), while the mean score of the websites (mean 43.96, SD 12.08) indicated an overall "fair" quality. The PWQC revealed that websites scored highly on "availability and usability" (mean 16.82, SD 3.96) but poorly on "credibility" (mean 20.99, SD 6.68), "currency" (mean 5.16, SD 2.62), and "breadth and accuracy" (mean 77.87, SD 23.20). Most sites lacked information about early intervention, recreational drug use and suicide risk, with little change in content over time. Stating an editorial or review process on the website (found in 56% of websites) was significantly associated with a higher quality score on both scales (the DISCERN scale, P=.002; the PWQC, P=.006)., Conclusions: The information on the internet available for clinicians to recommend to people affected by psychosis tended to be of "fair" quality. While higher-quality websites exist, it is generally not easy way to assess this on face value. Evidence of an editorial or review process was one indicator of website quality. While sites generally provided basic clinical information, most lacked material addressing weighing up risks and benefits of medication and alternatives, the role of coercive treatment and other more contentious issues. Insufficient emphasis is placed on detailed information on early intervention and importance of lifestyle modifications or how families and friends can contribute. These are likely to be the very answers that consumers and carers are seeking and this gap contributes to unmet needs among this group. We suggest that clinicians should be aware of what is available and where there are gaps., (©Kay Wilhelm, Tonelle Handley, Catherine McHugh, David Lowenstein, Kristy Arrold. Originally published in JMIR Formative Research (https://formative.jmir.org), 15.04.2022.)

Importance: Posttraumatic epilepsy (PTE) is a recognized sequela of traumatic brain injury (TBI), but the long-term outcomes associated with PTE independent of injury severity are not precisely known., Objective: To determine the incidence, risk factors, and association with functional outcomes and self-reported somatic, cognitive, and psychological concerns of self-reported PTE in a large, prospectively collected TBI cohort., Design, Setting, and Participants: This multicenter, prospective cohort study was conducted as part of the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study and identified patients presenting with TBI to 1 of 18 participating level 1 US trauma centers from February 2014 to July 2018. Patients with TBI, extracranial orthopedic injuries (orthopedic controls), and individuals without reported injuries (eg, friends and family of participants; hereafter friend controls) were prospectively followed for 12 months. Data were analyzed from January 2020 to April 2021., Exposure: Demographic, imaging, and clinical information was collected according to TBI Common Data Elements. Incidence of self-reported PTE was assessed using the National Institute of Neurological Disorders and Stroke Epilepsy Screening Questionnaire (NINDS-ESQ)., Main Outcomes and Measures: Primary outcomes included Glasgow Outcome Scale Extended, Rivermead Cognitive Metric (RCM; derived from the Rivermead Post Concussion Symptoms Questionnaire), and the Brief Symptom Inventory-18 (BSI)., Results: Of 3296 participants identified as part of the study, 3044 met inclusion criteria, and 1885 participants (mean [SD] age, 41.3 [17.1] years; 1241 [65.8%] men and 644 [34.2%] women) had follow-up information at 12 months, including 1493 patients with TBI; 182 orthopedic controls, 210 uninjured friend controls; 41 patients with TBI (2.8%) and no controls had positive screening results for PTE. Compared with a negative screening result for PTE, having a positive screening result for PTE was associated with presenting Glasgow Coma Scale score (8.1 [4.8] vs.13.5 [3.3]; P < .001) as well as with anomalous acute head imaging findings (risk ratio, 6.42 [95% CI, 2.71-15.22]). After controlling for age, initial Glasgow Coma Scale score, and imaging findings, compared with patients with TBI and without PTE, patients with TBI and with positive PTE screening results had significantly lower Glasgow Outcome Scale Extended scores (mean [SD], 6.1 [1.7] vs 4.7 [1.5]; P < .001), higher BSI scores (mean [SD], 50.2 [10.7] vs 58.6 [10.8]; P = .02), and higher RCM scores (mean [SD], 3.1 [2.6] vs 5.3 [1.9]; P = .002) at 12 months., Conclusions and Relevance: In this cohort study, the incidence of self-reported PTE after TBI was found to be 2.8% and was independently associated with unfavorable outcomes. These findings highlight the need for effective antiepileptogenic therapies after TBI.

Epilepsy is a heterogeneous condition with disparate etiologies and phenotypic and genotypic characteristics. Clinical and research aspects are accordingly varied, ranging from epidemiological to molecular, spanning clinical trials and outcomes, gene and drug discovery, imaging, electroencephalography, pathology, epilepsy surgery, digital technologies, and numerous others. Epilepsy data are collected in the terabytes and petabytes, pushing the limits of current capabilities. Modern computing firepower and advances in machine and deep learning, pioneered in other diseases, open up exciting possibilities for epilepsy too. However, without carefully designed approaches to acquiring, standardizing, curating, and making available such data, there is a risk of failure. Thus, careful construction of relevant ontologies, with intimate stakeholder inputs, provides the requisite scaffolding for more ambitious big data undertakings, such as an epilepsy data commons. In this review, we assess the clinical and research epilepsy landscapes in the big data arena, current challenges, and future directions, and make the case for a systematic approach to epilepsy big data., (© 2020 International League Against Epilepsy.)

This study aimed to assess drug-drug interaction alert interfaces and to examine the relationship between compliance with human factors principles and user-preferences of alerts. Three reviewers independently evaluated drug-drug interaction alert interfaces in seven electronic systems using the Instrument-for-Evaluating-Human-Factors-Principles-in-Medication-Related-Decision-Support-Alerts (I-MeDeSA). Fifty-three doctors and pharmacists completed a survey to rate the alert interfaces from best to worst and reported on liked and disliked features. Human factors compliance and user-preferences of alerts were compared. Statistical analysis revealed no significant association between I-MeDeSA scores and user-preferences. However, the strengths and weaknesses of drug-drug interaction alerts from users' perspectives were in-line with the human factors constructs evaluated by the I-MeDeSA. I-MeDeSA in its current form, is unable to identify alerts that are preferred by the users. The design principles assessed by I-MeDeSA appear to be sound, but its arbitrary allocation of points to each human factors construct may not reflect the relative importance that the end-users place on different aspects of alert design.

Objective: Examine the association of duration of therapeutic coma (TC) with seizure recurrence, morbidity, and mortality in refractory status epilepticus (RSE). Define an optimal window for TC that provides sustained seizure control and minimizes complications., Methods: Retrospective, observational cohort study involving patients who presented with RSE to the University of Alabama at Birmingham or the University of California at San Francisco from 2010 to 2016. Relationship of duration of TC with primary and secondary outcomes was evaluated using two-sample t tests, simple linear regression, and chi-square tests. Multivariable linear and logistic regression models were used to identify independent predictors. Predictive ability of TC for seizure recurrence was quantified using a receiver-operating characteristic curve. Youden index was used to determine an optimal cutoff value., Results: Multivariable analysis of clinical and treatment characteristics of 182 patients who were treated predominantly with propofol as anesthetic agent showed that longer duration of the first trial of TC (27.2 vs 15.6 hours) was independently associated with a higher chance of seizure recurrence following the first weaning attempt (P = 0.038) but not with poor functional neurologic outcome upon discharge, in-hospital complications, or mortality. Furthermore, higher doses of anesthetic utilized during the first trial of TC were independently associated with fewer in-hospital complications (P = 0.003) and associated with a shorter duration of mechanical ventilation and total length of stay. Duration of TC was identified as an independent predictor of seizure recurrence with an optimal cutoff point at 35 hours., Significance: This study suggests that a shorter duration yet deeper TC as treatment for RSE may be more effective and safer than the currently recommended TC duration of 24-48 hours. Prospective and randomized trials should be conducted to validate these assertions., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: Recently, attention has shifted to improving the design of computerized alerts via the incorporation of human factors design principles. The Instrument for Evaluating Human Factors Principles in Medication-Related Decision Support Alerts (I-MeDeSA) is a tool developed in the United States to guide improvements to alert design and facilitate selection of electronic systems with superior design. In this study, we aimed to determine the reliability, ease of use and usefulness of I-MeDeSA for assessing drug-drug interaction (DDI) alerts in an Australian context., Methods: Using the I-MeDeSA, three reviewers independently evaluated DDI alert interfaces of seven electronic systems used in Australia. Inter-rater reliability was assessed and reviewers met to discuss difficulties in using I-MeDeSA and the tool's usefulness., Results: Inter-rater reliability was high (Krippendorff's alpha = 0.76), however, ambiguous wording and the inclusion of conditional items impacted ease of use. A number of items were not relevant to Australian implementations and as a result, most systems achieved an I-MeDeSA score of less than 50%., Conclusions: The I-MeDeSA proved to be reliable, but item wording and structure made application difficult. Future studies should investigate potential modifications to the I-MeDeSA to improve ease of use and increase applicability to a variety of system configurations.

Background: There is currently no formal method for predicting the range expected in an individual's seizure counts. Having access to such a prediction would be of benefit for developing more efficient clinical trials, but also for improving clinical care in the outpatient setting., Methods: Using three independently collected patient diary datasets, we explored the predictability of seizure frequency. Three independent seizure diary databases were explored: SeizureTracker ( n = 3016), Human Epilepsy Project ( n = 93), and NeuroVista ( n = 15). First, the relationship between mean and standard deviation in seizure frequency was assessed. Using that relationship, a prediction for the range of possible seizure frequencies was compared with a traditional prediction scheme commonly used in clinical trials. A validation dataset was obtained from a separate data export of SeizureTracker to further verify the predictions., Results: A consistent mathematical relationship was observed across datasets. The logarithm of the average seizure count was linearly related to the logarithm of the standard deviation with a high correlation ( R 2 > 0.83). The three datasets showed high predictive accuracy for this log-log relationship of 94%, compared with a predictive accuracy of 77% for a traditional prediction scheme. The independent validation set showed that the log-log predicted 94% of the correct ranges while the RR50 predicted 77%., Conclusion: Reliably predicting seizure frequency variability is straightforward based on knowledge of mean seizure frequency, across several datasets. With further study, this may help to increase the power of RCTs, and guide clinical practice.