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Objective: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks., Methods: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital., Inclusion Criteria: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures., Results: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome., Significance: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression., (© 2023 International League Against Epilepsy.)

Background: Continuous positive airway pressure (CPAP) has been a key treatment modality for Coronavirus Disease 2019 (COVID-19) worldwide. Globally, the demand for CPAP outstripped the supply during the pandemic. The LeVe CPAP System was developed to provide respiratory support for treatment of COVID-19 and tailored for use in low- and middle-income country (LMIC) settings. Prior to formal trial approval, received in November 2021, these devices were used in extremis to support critically unwell adult patients requiring non-invasive ventilatory support., Methods: This is a retrospective descriptive review of adult patients with COVID-19 pneumonitis, who were treated with advanced respiratory support (CPAP and/or high-flow nasal oxygen, HFNO) at Mengo Hospital, Uganda. Patients were treated with the LeVe CPAP System, Elisa CPAP and/or AIRVO™ HFNO. Treatment was escalated per standard local protocols for respiratory failure, and CPAP was the maximum respiratory support available. Data were collected on patient characteristics, length of time of treatment, clinical outcome, and any adverse events., Results: Overall 333 patients were identified as COVID-19 positive, 44 received CPAP ± HFNO of which 43 were included in the study. The median age was 58 years (range 28-91 years) and 58% were female. The median duration of advanced respiratory support was 7 days (range 1-18 days). Overall (all device) mortality was 49% and this was similar between those started on the LeVe CPAP System and those started non-LeVe CPAP System devices (50% vs 47%)., Conclusions: The LeVe CPAP system was the most used CPAP device during the pandemic, bringing the hospital's number of available HFNO/CPAP devices from two to 14. They were a critical resource for providing respiratory support to the sickest group of patients when no alternative devices were available. The devices appear to be safe and well-tolerated with no serious adverse events recorded. This study is unable to assess the efficacy of the LeVe CPAP System; therefore, formal comparative studies are required to inform further use., (© 2023. Japanese Society of Tropical Medicine.)

Purpose of Review: Clostridioides difficile infection (CDI) is the most common cause of healthcare-associated diarrhoea in western countries, being categorized as an urgent healthcare threat. Historically, researchers have relied on the use of in vivo animal models to study CDI pathogenesis; however, differences in physiology and disease prognosis compared with humans limit their suitability to model CDI. In vitro models are increasingly being used as an alternative as they offer excellent process control, and some are able to use human ex-vivo prokaryotic and/or eukaryotic cells., Recent Findings: Simulating the colonic environment in vitro is particularly challenging. Bacterial fermentation models have been used to evaluate novel therapeutics, explore the re-modelling of the gut microbiota, and simulate disease progression. However, they lack the scalability to become more widespread. Models that co-culture human and bacterial cells are of particular interest, but the different conditions required by each cell type make these models challenging to run. Recent advancements in model design have allowed for longer culture times with more representative bacterial populations., Summary: As in vitro models continue to evolve, they become more physiologically relevant, offering improved simulations of CDI, and extending their applicability., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Reorganization of the language network from typically left-lateralized frontotemporal regions to bilaterally distributed or right-lateralized networks occurs in anywhere from 25%-30% of patients with focal epilepsy. In patients who have been recently diagnosed with epilepsy, an important question remains as to whether it is the presence of seizures or the underlying epilepsy etiology that leads to atypical language representations. This question becomes even more interesting in pediatric samples, where the typical developmental processes of the language network may confer more variability and plasticity in the language network. We assessed a carefully selected cohort of children with recent-onset epilepsy to examine whether it is the effects of seizures or their underlying cause that leads to atypical language lateralization., Methods: We used functional magnetic resonance imaging (fMRI) to compare language laterality in children with recently diagnosed focal unaware epilepsy and age-matched controls. Age at epilepsy onset (age 4 to 6 years vs age 7 to 12 years) was also examined to determine if age at onset influenced laterality., Results: The majority of recent-onset patients and controls exhibited left-lateralized language. There was a significant interaction such that the relationship between epilepsy duration and laterality differed by age at onset. In children with onset after age 6, a longer duration of epilepsy was associated with less left-lateralized language dominance. In contrast, in children with onset between 4 and 6 years of age, a longer duration of epilepsy was not associated with less left language dominance., Significance: Our results demonstrate that although language remained largely left-lateralized in children recently diagnosed with epilepsy, the impact of seizure duration depended on age at onset, indicating that the timing of developmental and disease factors are important in determining language dominance., (© 2022 International League Against Epilepsy.)

Competing Interests: Declaration of Competing Interest Michael Nurok reported receiving stock options for his role as an adviser to Avant-Garde Health Inc. The other authors have nothing to disclose.

Objective: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome., Methods: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom., Results: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%., Significance: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Due to COVID-19 a live, in-person meeting was not possible for the American Epilepsy Society in 2020. An alternative, virtual event, the AES2020, was held instead. AES2020 was a great success with 4679 attendees from 70 countries. The educational content was outstanding and spanned the causes, treatments, and outcomes from epileptic encephalopathy to the iatrogenicity of epilepsy interventions to neurocognitive disabilities to the approach to neocortical epilepsies. New gene therapy approaches such as antisense oligonucleotide treatment for Dravet syndrome were introduced and neuromodulation devices were discussed. There were many other topics discussed in special interest groups and investigators' workshops. A highlight was having a Nobel prize winner speak about memory processing. Human intracranial electrophysiology contributes insights into memory processing and complements animal work. In a special COVID symposium, the impact of COVID on patients with epilepsy was reviewed. Telehealth has been expanded rapidly and may be well suited for some parts of epilepsy care. In summary, the epilepsy community was alive and engaged despite being limited to a virtual platform.

Objective: Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery., Methods: A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used., Results: Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm 3 (range: 1.87-591.73 cm 3 ). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset., Significance: Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomena generated by NO degradation by the blood or parenchyma., Competing Interests: The authors have declared that no competing interests exist.

Brain injury contributes more to death and disability globally than any other traumatic incident. 1 While the past decade has seen significant medical advances, laws and policies remain stumbling blocks to treatment and care. The quality of life of persons with severe brain injury often declines with unnecessary institutionalization and inadequate access to rehabilitation and assistive technologies. 62 This raises a host of rights violations that are hidden, given that persons with severe brain injury are generally invisible and marginalized. This article highlights the current neglect and experiences of persons with severe brain injury in the United States, analyzing the rights to life, health, benefit from scientific progress, education, freedom of expression, community, family, and equality., Competing Interests: Competing interests: None declared., (Copyright © 2020 Ezer, Wright, and Fins.)

Background: Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC)., Method: The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation., Results: There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores., Conclusion: Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications., (Copyright © 2019. Published by Elsevier Inc.)

Epilepsy affects 2.2 million adults in the USA, with 1 in 26 people developing epilepsy at some point in their lives. Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy as medial structures, and the hippocampus in particular, are prone to generating seizures. Selective anterior temporal resection (which removes the hippocampus) is the most effective intractable TLE treatment, but given the critical role of the mesial temporal lobe in memory functioning, resection can have negative effects on this crucial cognitive skill. To minimize the adverse impact of temporal lobe surgery on memory functioning, reliable pre-surgical guides are needed. Clinical functional magnetic resonance imaging (fMRI) provides reliable, noninvasive guidance of language functioning and plays a growing role in the pre-surgical evaluation for epilepsy patients; however, localization of memory function in children with epilepsy using fMRI has not been established. Aside from the lack of neuroimaging memory studies in children with TLE, studies of typical development are limited. This review will focus on the functional anatomy of memory systems throughout development, with a focus on TLE. TLE provides the ideal model from which to understand memory function and the limits of plasticity and compensation/reorganization throughout development.

Background: Continuous EEG studies demonstrate that neonates with seizures due to cerebral pathology, such as hypoxia ischemia, exhibit predominantly electrographic seizures (i.e. those only detected with EEG because they lack clinical features). Previous small case series demonstrate EEG changes and seizures during hyperammonemia associated with inborn errors of metabolism (IEM) but there are no reports utilizing continuous EEG in these conditions., Objective: To characterize seizures and evaluate the utility of continuous EEG recording during hyperammonemia due to inborn errors of metabolism., Methods: We retrospectively reviewed medical records and EEG tracings of neonates who presented with hyperammonemia due to inborn errors of metabolism who had continuous EEG and full medical records available for review, including follow up., Results: Eight neonates with hyperammonemia were studied, 7 had urea cycle defects: Argininosuccinate lyase deficiency [3], (ornithine transcarbamylase deficiency [3], carbomyl phosphate synthase deficiency [1] and one had an organic acidemia: Methylmalonic acidemia [1]. Most common presentations were lethargy and poor feeding at 12-72 h of life. The highest blood ammonia level was 874 μmol/L (median); range 823-1647 μmol/L (normal value <50 μmol/L in term neonates). Seven were treated with hemodialysis in addition to nitrogen scavengers. Seven neonates had seizures; six had only electrographic seizures. Seizures initially occurred within 24-36 h of clinical presentation, sometimes with normal ammonia and glutamine levels. Neonates with seizures all lacked state changes on EEG. Inter burst interval duration correlated with degree of hyperammonemia. Two cases with normal plasma ammonia but increasing interburst interval duration were proven to have stroke by MRI., Conclusions: Seizures occur frequently in neonates with hyperammonemia; most can be detected only with continuous EEG. Seizures may occur when ammonia and glutamine levels are normal. Interburst interval duration is associated with ammonia levels or cerebral dysfunction from other brain pathology. Continuous EEG can be a useful tool for managing infants with hyperammonemia and may be essential for seizure management especially for infants in deep metabolic coma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The relationship between language abilities and language lateralization in the developing brain is important for our understanding of the neural architecture of language development., Methods: We investigated 35 right-handed children and adolescents aged 7-16 years with a functional magnetic resonance imaging language paradigm and a comprehensive language and verbal memory examination., Results: We found that less lateralized language was significantly correlated with better language performance across areas of the brain and across different language tasks. Less lateralized language in the overall brain was associated with better in-scanner task accuracy on a semantic language decision task and out-of-scanner vocabulary and verbal fluency. Specifically, less lateralized frontal lobe language dominance was associated with better in-scanner task accuracy and out-of-scanner verbal fluency. Furthermore, less lateralized parietal language was associated with better out-of-scanner verbal memory across learning, short- and long-delay trials. In contrast, we did not find any relationship between temporal lobe language laterality and verbal performance., Conclusions: This study suggests that semantic language performance is better with some involvement of the nondominant hemisphere., (© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Studies on the victimization and abuse of seniors in Canada have largely ignored the influence of place-based variations in social bonds and socioeconomic characteristics. Using the 2014 General Social Survey (GSS) data on Canadians' safety, we examine neighborhood, social capital, and socioeconomic characteristics as predictors of the incidence of victimization among seniors and their satisfaction with personal safety from crime. Generally, seniors with poor neighborhood ties and social capital were more likely to have experienced victimization and have a lower satisfaction with personal safety. Seniors who viewed people in their neighborhood as unhelpful were more likely to have experienced some form of victimization and more likely to have a lower satisfaction with personal safety. Highly educated and high-income seniors were also more likely to have experienced some form of victimization. Paradoxically, such seniors were less likely to have lower satisfaction with personal safety. The results also show that place, defined as population centers (urban and rural) may have a significant influence on variations in victimization and satisfaction with personal safety. A significant proportion of the variance in victimization (38%) and satisfaction with personal safety (23%) are largely the result of differences in place of residence (urban and rural). Our findings suggest that there is the need to improve neighborhood social capital, reduce neighborhood disorder and improve the socioeconomic status of community-dwelling seniors in order to minimize their susceptibility to victimization as well as to improve their sense of safety from crime., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The number of older adults in Ghana is growing rapidly. Associated with this growth, is the rise in age-related chronic diseases such as cardiovascular and musculoskeletal conditions. However, there is limited knowledge in the Ghanaian context on the effect of chronic diseases on functional disabilities among older adults. In this study, we examine the association between chronic diseases, socioeconomic status, and functional disabilities. Data from 4107 Ghanaian older adults (persons aged 50 years and above) who participated in the World Health Organization's Global Ageing and Adult Health survey (SAGE-Wave 1) were used to fit random effect multivariate logistic and complementary log-log regression. Stroke was significantly associated with difficulty in performing both basic self-care functions and intermediate self-care functions. Hypertension and arthritis, on the other hand, were associated with basic self-care functional disability only. Socioeconomically vulnerable groups such as females, those with less education and low-incomes were more likely to have functional disabilities associated with basic self-care and intermediate self-care activities. In order to reduce functional disabilities among older persons in Ghana, efforts should be aimed at reducing chronic conditions as well as improving socioeconomic status., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose of Review: In this review, we examine one of the ironies of American health care-that we pay more for disease management than disease prevention. Instead of preventing type 2 diabetes (T2DM) by treating its precursor, obesity, we fail to provide sufficient insurance coverage for weight management only to fund the more costly burden of overt T2DM., Recent Findings: There is a vital need for expanded insurance coverage to help foster a weight-centric approach to T2DM management. This includes broader coverage of anti-diabetic medications with evidence of cardiovascular risk reduction and mortality benefit, anti-obesity pharmacotherapy, bariatric surgery, weight loss devices, endoscopic bariatric therapies, and lifestyle interventions for the treatment of obesity. The fundamental question to ask is why weight? Why wait to go after obesity until its end-stage sequelae cause intractable conditions? Instead of managing the complications of T2DM, consider preventing them by tackling obesity.

A survey of 146 pediatric care providers (PCPs) revealed that 75.3% were unaware that children with epilepsy were at risk of death, specifically from sudden unexpected (or unexplained) death in epilepsy (SUDEP). PCPs assume that the treating neurologist discusses these risks. Increasing PCPs' knowledge of SUDEP will help address the care gap related to informing families about SUDEP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

As the field of hospital medicine celebrates its twenty-first anniversary, we believe it is time to expand its mission to play an even greater role in medical education. Given hospitalists' proximity to students and clinical material, members of this growing cohort of physicians are uniquely positioned to teach normative reasoning, professionalism, communication, and medical ethics in real time to trainees on the wards. But, to do so, we must reimagine the role of the hospitalist in graduate and postgraduate medical education., (© 2017 American Medical Association. All Rights Reserved.)

Decisions about end-of-life care and participation in clinical research for patients with disorders of consciousness begin with diagnostic discernment. Accurately distinguishing between brain states clarifies clinicians' ethical obligations and responsibilities. Central to this effort is the obligation to provide neuropalliative care for patients in the minimally conscious state who can perceive pain and to restore functional communication through neuroprosthetics, drugs, and rehabilitation to patients with intact but underactivated neural networks. Efforts to bring scientific advances to patients with disorders of consciousness are reviewed, including the investigational use of deep brain stimulation in patients in the minimally conscious state. These efforts help to affirm the civil rights of a population long on the margins., (© 2016 American Medical Association. All Rights Reserved.)

Background: The purpose of this study was to test the hypothesis that a health and wellness coaching (HWC)-based intervention for fibromyalgia (FM) would result in sustained improvements in health and quality of life, and reductions in health care utilization., Methods: Nine female subjects meeting American College of Rheumatology criteria for a diagnosis of primary FM were studied. The HWC protocol had two components, which were delivered telephonically over a twelve-month period. First, each patient met individually with a coach during the 12 month study at the patient's preference of schedule and frequency (Range:22-32 × 45-min sessions). Coaches were health professionals trained in health and wellness coaching tasks, knowledge, and skills. Second, each patient participated in bimonthly (first six months) and monthly (second six months) group classes on self-coaching strategies during the 12 month study. Prior to the intervention, and after 6 months and 12 months of coaching, the Revised Fibromyalgia Impact Questionnaire (FIQR) was used to measure health and quality of life, and the Brief Pain Inventory-Short Form (BPI) was used to measure pain intensity and interference with function. Total and rheumatology-related health encounters were documented using electronic medical records. Data were analyzed using repeated measures ANOVA., Results: All nine patients finished the HWC protocol. FIQR scores improved by 35 % (P = 0.001). BPI scores decreased by 32 % overall (P = 0.006), 31 % for severity (P = 0.02), and 44 % for interference (P = 0.006). Health care utilization declined by 86 % (P = 0.006) for total and 78 % (P < 0.0001) for rheumatology-related encounters., Conclusion: The HWC program added to standard FM therapy produced clinically significant improvements in quality of life measures (FIQR), pain (BPI), and marked reductions in health care utilization. Such improvements do not typically occur spontaneously in FM patients, suggesting that HWC deserves further consideration as an intervention for FM.

While often confused by non-medical specialists, brain death and disorders of consciousness such as coma, vegetative state, and minimally conscious state are clearly distinct and unambiguously distinguishable. Moreover, biological models underpin each category uniquely and with increasing precision. In this Primer, we frame the distinctions across the different conditions, point to recent work that advances measurements able to identify their differences, and explain two inter-related paradoxes. The first paradox is the brain dead patient whose 'phenotype' betrays the ultimate futility and lack of sustainability of the state. The second paradox is that of patients who retain apparent higher levels of cognitive function but who may be misidentified as remaining in a vegetative state or one of the similar conditions formulated in the recently defined syndrome of cognitive motor dissociation. Building on emerging data and models underlying each of these brain states, we place recent controversies over the assessment of brain dead patients into a scientific and wider societal context. We conclude by placing brain death into a broader conceptual framework that takes account of emerging scientific knowledge about disorders of consciousness., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Mitochondrial dysfunction may play a central role in the pathologic process of Alzheimer's disease (AD), but there is still a scarcity of data that directly links the pathology of AD with the alteration of mitochondrial DNA. This study aimed to provide a comprehensive assessment of mtDNA rearrangement events in AD brain tissue., Patients and Methods: Postmortem frozen human brain cerebral cortex samples were obtained from the Banner Sun Health Research Institute Brain and Body Donation Program, Sun City, AZ. Mitochondria were isolated and direct sequence by using MiSeq®, and analyzed by relative software., Results: Three types of mitochondrial DNA (mtDNA) rearrangements have been seen in post mortem human brain tissue from patients with AD and age matched control. These observed rearrangements include a deletion, F-type rearrangement, and R-type rearrangement. We detected a high level of mtDNA rearrangement in brain tissue from cognitively normal subjects, as well as the patients with Alzheimer's disease (AD). The rate of rearrangements was calculated by dividing the number of positive rearrangements by the coverage depth. The rearrangement rate was significantly higher in AD brain tissue than in control brain tissue (17.9%versus 6.7%; p = 0.0052). Of specific types of rearrangement, deletions were markedly increased in AD (9.2% versus 2.3%; p = 0.0005)., Conclusions: Our data showed that failure of mitochondrial DNA in AD brain might be important etiology of AD pathology.

As improvements in neuroscience have enabled a better understanding of disorders of consciousness as well as methods to treat them, a hurdle that has become all too prevalent is the denial of coverage for treatment and rehabilitation services. In 2011, a settlement emerged from a Vermont District Court case, Jimmo v. Sebelius, which was brought to stop the use of an "improvement standard" that required tangible progress over an identifiable period of time for Medicare coverage of services. While the use of this standard can have deleterious effects on those with many chronic conditions, it is especially burdensome for those in the minimally conscious state (MCS), where improvements are unpredictable and often not manifested through repeatable overt behaviors. Though the focus of this paper is on the challenges of brain injury and the minimally conscious state, which an estimated 100,000 to 200,000 individuals suffer from in the United States, the post-Jimmo arguments presented can and should have a broad impact as envisioned by the plaintiffs who brought the case on behalf of multiple advocacy groups representing patients with a range of chronic care conditions., (© 2016 American Society of Law, Medicine & Ethics.)

The author suggests the creation of expert-generalists to help provide the additional cost-effective access to care necessitated by increased insurance coverage under the Affordable Care Act. Expert-generalists, a concept drawn from an extant Canadian model, would be a cohort of primary care physicians who obtain additional training in a subspecialty area, which would widen their practice portfolio and bring enhanced infrastructure to primary care settings. Expanding the reach of primary care into the realm of more advanced subspecialty practice could be a way to enhance both access to and quality of care in a cost-effective fashion, in part because the educational framework for additional training already exists. Trainees could opt for an extra year of training after traditional residency or return to training after years in practice. Properly trained, an expert-generalist would benefit both the quality of the patient experience and the bottom line by expertly triaging patients to determine who will truly benefit from specialty consultations, decreasing specialists' engagement with cases that do not require their higher-tier care. The author considers the merits of this proposal, as well as potential objections and implementation challenges. It is suggested that this model be adopted incrementally, using demonstration projects that could assess the impact of an expert-generalist initiative on the physician workforce and on patients' access to quality primary and specialty care.

Effectively developing professionalism requires a programmatic view on how medical ethics and humanities should be incorporated into an educational continuum that begins in premedical studies, stretches across medical school and residency, and is sustained throughout one's practice. The Project to Rebalance and Integrate Medical Education National Conference on Medical Ethics and Humanities in Medical Education (May 2012) invited representatives from the three major medical education and accreditation organizations to engage with an expert panel of nationally known medical educators in ethics, history, literature, and the visual arts. This article, based on the views of these representatives and their respondents, offers a future-tense account of how professionalism can be incorporated into medical education.The themes that are emphasized herein include the need to respond to four issues. The first theme highlights how ethics and humanities can provide a response to the dissonance that occurs in current health care delivery. The second theme focuses on how to facilitate preprofessional readiness for applicants through reform of the medical school admission process. The third theme emphasizes the importance of integrating ethics and humanities into the medical school administrative structure. The fourth theme underscores how outcomes-based assessment should reflect developmental milestones for professional attributes and conduct. The participants emphasized that ethics and humanities-based knowledge, skills, and conduct that promote professionalism should be taught with accountability, flexibility, and the premise that all these traits are essential to the formation of a modern professional physician.

Background: Families of critically ill patients often make difficult decisions related to end-of-life (EOL) care including the withdrawal of life-sustaining therapies., Objectives: This study explored patient and proxy decisions related to mechanical ventilator withdrawal in scenarios characterizing 3 distinct disease trajectories (cancer, stroke, and heart failure [HF]) with different prognoses. The relationship between patient directives, modification of directives, prognosis, trust, and EOL decisions were examined., Methods: This secondary analysis of data obtained in the "Contracts, Covenants, and Advance Care Planning" study included a sample of 110 subjects with 50 patient-proxy pairs. Patient and proxy agreement was assessed in response to questions regarding mechanical ventilator withdrawal while considering directives or modification of directives in 3 different scenarios., Results: Patient and proxy agreement ranged from 48% (n = 24 pairs) to 94% (n = 47 pairs). Agreement was lowest in HF (uncertain prognosis) when the directive indicated "do nothing" or "did not indicate any preference." Modified directives yielded 48% (n = 24 pairs) to 84% (n = 42 pairs) agreement. Changing directives from "do nothing" to "more hopeful" in HF (uncertain prognosis) had the highest agreement among modified scenarios. Despite wide variability in agreement, patients reported a high level of trust in their proxies' decisions., Discussion: This study highlighted differences in patient and proxy agreement about withdrawal of mechanical ventilation. Critical care nurses provide a key role in supporting EOL decisions. Encouraging ongoing communication about preferences and understanding the role of disease process and prognosis in decision making are paramount. Future research needs to explore factors that may improve patient and proxy agreement in EOL decisions and ways critical care nurses can support patients and proxies in these decisions, ultimately improving EOL care.

Given the high morbidity and mortality associated with metastatic melanoma, considerable attention has been paid to identifying potential therapies. Until recently, few therapies have been specifically approved for treating metastatic melanoma. In an attempt to increase clinical trial successes, many therapies are implementing biomarkers for patient stratification. This strategy narrows down the population in an effort to identify appropriate subpopulations that have increased efficacy or fewer safety concerns. However, the addition of a biomarker constitutes an additional risk to clinical development and may therefore increase the overall clinical trial risk. Here, we examine the clinical trial success rate for therapies targeting metastatic melanoma. In addition, we identify the impact that biomarkers have had on the clinical development of this disease.

The thalamic relay neurons, reticular thalamic nucleus, and neocortical pyramidal cells form a circuit that sustains oscillatory burst firing, and is regarded as the underlying mechanism of absence seizures. T-type calcium channels play a key role in this circuit. Here, we review the role of T-type calcium channel genes in the development of absence seizures, and emphasize gain or loss of function mutations, and other variations that alter both quantity and quality of transcripts, and methylation status of isoforms of T-type calcium channel proteins might be of equal importance in understanding the pathological mechanism of absence seizures.

Advances in functional imaging have provided noninvasive techniques to probe brain organization of multiple constructs including language and memory. Because of high overall rates of agreements with older techniques, including Wada testing and cortical stimulation mapping (CSM), some have proposed that those approaches should be largely abandoned because of their invasiveness, and replaced with noninvasive functional imaging methods. High overall agreement, however, is based largely on concordant language lateralization in series dominated by cases of typical cerebral dominance. Advocating a universal switch from Wada testing and cortical stimulation mapping to functional magnetic resonance imaging (fMRI) or magnetoencephalography (MEG) ignores the differences in specific expertise across epilepsy centers, many of which often have greater skill with one approach rather than the other, and that Wada, CSM, fMRI, and MEG protocols vary across institutions resulting in different outcomes and reliability. Specific patient characteristics also affect whether Wada or CSM might influence surgical management, making it difficult to accept broad recommendations against currently useful clinical tools. Although the development of noninvasive techniques has diminished the frequency of more invasive approaches, advocating their use to replace Wada testing and CSM across all epilepsy surgery programs without consideration of the different skills, protocols, and expertise at any given center site is ill-advised., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Although health care reform efforts are laudably directed at promoting quality and efficiency, added bureaucracy may have the unintended consequence of constraining physicians' creativity. This has the potential to undermine clinicians' freedom to reframe their thinking in response to unfolding biological knowledge, a defining feature of academic medicine. In this Perspective, the authors illustrate the confluence of creativity, context, and discovery through a historical example: the evolution of tuberculosis (TB) multidrug chemotherapy as espoused by Walsh McDermott and his colleagues during the 1940s and 1950s.Before the discovery of streptomycin in 1943, clinician-researchers aimed to identify a "magic bullet" that would rapidly eradicate tubercle bacilli from the body. In the years following the discovery of streptomycin, it became clear that the biology of TB did not conform to researchers' expectations. The recognition that treatment would neither be simple nor quick prompted further attempts to devise an optimal streptomycin regimen, which would enable the host's immune system to suppress infection and prevent the emergence of streptomycin-resistant strains. By the late 1950s, investigators clarified the limits of streptomycin's effectiveness, which led to combined chemotherapy. In so doing, they gained a better understanding of drug-bacilli-host interactions and shifted attention from the host to the drug-resistant microbe.The authors argue that this tale of discovery offers a latent lesson for academic medicine: As the health care system undergoes systemic restructuring, it is essential to preserve the freedom to reframe thinking and creatively solve translational problems in research and practice.

The timing and developmental factors underlying the establishment of language dominance are poorly understood. We investigated the degree of lateralization of traditional frontotemporal and modulatory prefrontal-cerebellar regions of the distributed language network in children (n = 57) ages 4 to 12--a critical period for language consolidation. We examined the relationship between the strength of language lateralization and neuropsychological measures and task performance. The fundamental language network is established by four with ongoing maturation of language functions as evidenced by strengthening of lateralization in the traditional frontotemporal language regions; temporal regions were strongly and consistently lateralized by age seven, while frontal regions had greater variability and were less strongly lateralized through age 10. In contrast, the modulatory prefrontal-cerebellar regions were the least strongly lateralized and degree of lateralization was not associated with age. Stronger core language skills were significantly correlated with greater right lateralization in the cerebellum., (Copyright © 2012 Wiley Periodicals, Inc.)

Insect neuropeptides control various biological processes including growth, development, homeostasis and reproduction. The calcitonin-like diuretic hormone (CT/DH) is one such neuropeptide that has been shown to affect salt and water transport by Malpighian tubules of several insects. With an increase in the number of sequenced insect genomes, CT/DHs have been predicted in several insect species, making it easier to characterize the gene encoding this hormone and determine its function in the species in question. This mini review summarizes the current knowledge on insect CT/DHs, focusing on mRNA and peptide structures, distribution patterns, physiological roles, and receptors in insects., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Child neurology has evolved from a primarily diagnostic to a therapeutic subspecialty. Despite well-documented manpower shortages, child neurology programs at major children's hospitals have expanded, and the optimal administrative structure for child neurology programs has not been clearly defined. The Division of Child Neurology at Children's National Medical Center in Washington, DC, is a part of the Center for Neuroscience and Behavioral Medicine. This center includes multiple medical, behavioral health, and surgical subspecialties, and fosters the development of child neurology. During the 10 years of its existence, the number of board-certified or eligible child neurologists within the center has tripled to over 30. Because of its success, the Division of Child Neurology was split into three free-standing divisions and two institutes. This unique structure has fostered the development of numerous multidisciplinary programs, and is fiscally sustainable. The strengths, limitations, and challenges of this structure in terms of child neurology are reviewed. This administrative structure has been successful and may act as a model for other programs., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Listening and reading comprehension of paragraph-length material are considered higher-order language skills fundamental to social and academic functioning. Using ecologically relevant language stimuli that were matched for difficulty according to developmental level, we analyze the effects of task, age, neuropsychological skills, and post-task performance on fMRI activation and hemispheric laterality. Areas of supramodal language processing are identified, with the most robust region being left-lateralized activation along the superior temporal sulcus. Functionally, this conjunction has a role in semantic and syntactic processing, leading us to refer to this conjunction as "comprehension cortex." Different from adults, supramodal areas for children include less extensive inferior frontal gyrus but more extensive right cerebellum and right temporal pole. Broader neuroanatomical pathways are recruited for reading, reflecting the more active processing and larger set of cognitive demands needed for reading compared to listening to stories. ROI analyses reveal that reading is a less lateralized language task than listening in inferior frontal and superior temporal areas, which likely reflects the difficulty of the task as children in this study are still developing their reading skills. For listening to stories, temporal activation is stable by age four with no correlations with age, neuropsychological skills or post-task performance. In contrast, frontal activation during listening to stories occurs more often in older children, and frontal activation is positively correlated with better performance on comprehension questions, suggesting that the activation of frontal networks may reflect greater integration and depth of story processing., (2010 Elsevier Inc. All rights reserved.)

This is a case report of a man with chronic hidradenitis suppurativa who developed reactive arthritis. He presented with swelling and pain in his larger joints, along with conjunctivitis involving his right eye. These symptoms coincided with a flare of the hidradenitis suppurativa. His clinical picture and laboratory findings were consistent with a diagnosis of reactive arthritis. He was initially treated with prednisone, and later with methotrexate, with improvement in his symptoms. This case report is a discussion of a rare cause of reactive arthritis. A review of the literature regarding this condition is also included.

This is a case report of a woman with multicentric reticulohistiocytosis with positive anticyclic citrullinated antibodies. This patient had been misdiagnosed with rheumatoid arthritis for many years. Recently, she presented with symmetric distal interphalangeal joint destruction and papules along her nail beds. Her clinical presentation, laboratory data, radiographic and histologic findings were all consistent with multicentric reticulohistiocytosis, not rheumatoid arthritis. This is the first case report of a patient with multicentric reticulohistiocytosis that tested positive for anticyclic citrullinated antibodies.

Characterization of brain-behavior relationships through functional magnetic imaging (fMRI) within typically or atypically developing populations poses methodological and interpretational challenges. We consider theoretical, methodological, and artifactual factors that influence characterization of developmental and adaptive changes in childhood. Findings from anatomical and physiological brain development studies are highlighted as they may influence functional imaging results. Then, we consider several patterns of functional activation within the context of developmental processes as well as neurologic disease. Hypotheses regarding the development of cognitive networks are proposed to account for the individual differences seen in normal and atypical development. We also identify potential sources of unwanted variability related to experimental design and task performance and suggest possible solutions to help minimize these effects. Lastly, a challenge for current studies is a lack of group and individual analysis methods that can be reliably applied to capture and quantify factors that contribute to variability introduced by developmental and disease processes. We review current methods and propose potential solutions.

fMR imaging is a versatile technology that allows for the noninvasive identification of sensory, motor,and cognitive functions that may be impaired by surgical resection. fMR imaging provides the capacity to probe several brain functions, and when results are uncertain, to repeat or modify them. There are some limitations, MR contraindications to scanning, motion, and cooperation among them. Yet for most patients fMR imaging provides a reliable way to lateralize language dominance and to guide localization of language functions. Memory paradigms lag behind language in practical application, but the impediments to its utility will likely be resolved in the near future.

The extent to which visual word perception engages speech codes (i.e., phonological recoding) remains a crucial question in understanding mechanisms of reading. In this study, we used functional magnetic resonance imaging techniques combined with behavioral response measures to examine neural responses to focused versus incidental phonological and semantic processing of written words. Three groups of subjects made simple button-pressing responses in either phonologically (rhyming-judgment) or semantically (category-judgment) focused tasks or both tasks with identical sets of visual stimuli. In the phonological tasks, subjects were given both words and pseudowords separated in different scan runs. The baseline task required feature search of scrambled letter strings created from the stimuli for the experimental conditions. The results showed that cortical regions associated with both semantic and phonological processes were strongly activated when the task required active processing of word meaning. However, when subjects were actively processing the speech sounds of the same set of written words, brain areas typically engaged in semantic processing became silent. In addition, subjects who performed both the rhyming and the semantic tasks showed diverse and significant bilateral activation in the prefrontal, temporal, and other brain regions. Taken together, the pattern of brain activity provides evidence of a neural basis supporting the theory that in normal word reading, phonological recoding is automatic and facilitates semantic processing of written words, while rapid comprehension of word meaning requires devoted attention. These results also raise questions about including multiple cognitive tasks in the same neuroimaging sessions.