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Jurriaan M Peters,1 Danielle A Becker,2 Sunita N Misra,3 Enrique Carrazana,3,4 Adrian L Rabinowicz3 1Department of Neurology, Harvard Medical School and Boston Children’s Hospital, Boston, MA, USA; 2Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA; 3Neurelis, Inc, San Diego, CA, USA; 4Department of Family Medicine and Community Health, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USACorrespondence: Jurriaan M Peters, Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital and Harvard Medical School, 300 Longwood Ave, FE9, Boston, MA, 02115, USA, Tel +1 617-355-7970, Fax +1 617-730-4850, Email jurriaan.peters@childrens.harvard.eduAbstract: In the US, 3 rescue treatment options are approved for patients with seizure clusters (ie, acute repetitive seizures), which are intermittent increases of seizure activity. This narrative PubMed review of these 3 treatments examines newer intranasal options that are well suited for adolescent and adult patients who may desire a transition from rectal treatment. Diazepam rectal gel is indicated for patients ≥ 2 years, diazepam nasal spray for those ≥ 6 years, and midazolam nasal spray for those ≥ 12 years. Approvals for diazepam rectal gel and midazolam nasal spray were based on safety and efficacy comparisons with placebo. Approval for diazepam nasal spray was based on results from long-term safety and tolerability studies in addition to its comparable bioavailability to diazepam rectal gel, while also showing less interpatient variability. The safety profiles of diazepam rectal gel and nasal spray are similar, and the medications share safety, warning, and precaution labeling. Thus, patients ≥ 6 years could be introduced to intranasal diazepam, allowing for continuity of familiar treatment while improving access and comfort. Intranasal midazolam also has a well-characterized safety profile. A proxy for effectiveness is the number of seizure clusters that were treated with a single dose, and these differed in separate, noncomparative studies. The safety and effectiveness of diazepam nasal spray have been examined in multiple subpopulations, whereas patient/caregiver experiences with both approved intranasal formulations have been characterized. Users may prefer nasal administration because it is noninvasive and effective, and provides social advantages, comfort, ease of use, and less variability compared with rectal gel. Nasal sprays are portable and convenient for use in the community (school, work, travel), and self-administration was reported in one study, with patients as young as 11 years old self-administering diazepam nasal spray. These newer, intranasal rescue treatments for seizure clusters provide an alternative to the rectal route.Plain Language Summary: Some people with epilepsy may have seizure clusters, which are often defined as 2 or more seizures in a day that are not part of their normal seizure pattern. Rescue treatments approved in the United States are diazepam rectal gel, diazepam nasal spray, and midazolam nasal spray. These rescue drugs can help stop seizure clusters at home, school, or work. Diazepam rectal gel is for adults and children ages 2 years or older. To give a rectal dose, the caregiver must pull down the patient’s underwear. Spraying nasal treatment into the nose may be less embarrassing. Because some patients may want to switch their treatment, we looked for articles about how to use these treatments and summarized what we found. Diazepam nasal spray is for patients ages 6 years or older and midazolam nasal spray is for patients 12 years or older. Diazepam rectal gel and nasal spray use the same drug, and dosing is based on patient age and weight. Midazolam nasal spray uses a different drug, and everyone uses the same dose. Some drugs may be more likely than others to need a second dose for a seizure. Patients and caregivers (care partners) felt that diazepam nasal spray was easier to use than rectal gel. They were also more comfortable using diazepam nasal spray in public. Patients as young as 11 years have used diazepam nasal spray by themselves. In all, patients may prefer nasal treatment and now have options to change from rectal treatment of seizure clusters.Keywords: nasal spray, rectal gel, diazepam, midazolam, epilepsy, switch

Adrian L Rabinowicz,1 Edward Faught,2 David F Cook,1 Enrique Carrazana1,3 1Clinical Development & Medical Affairs, Neurelis, Inc., San Diego, CA, USA; 2Emory Epilepsy Program, Emory University School of Medicine, Atlanta, GA, USA; 3John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USACorrespondence: Edward Faught, Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive, NE, Atlanta, GA, 30329, USA, Tel +1 404 778-3444, Email rfaught@emory.eduPurpose: People with epilepsy may experience seizure clusters despite a stable regimen of antiseizure medications. Such clusters have the potential to last ≥ 24 hours, typically occur in the community setting, and may progress to medical emergencies, such as status epilepticus, if untreated. Thus, long-acting rescue therapy for seizure clusters is needed that can be administered by nonmedical individuals outside a hospital. Benzodiazepines are the foundation of rescue therapy for seizure clusters. The approved outpatient treatments (ie, diazepam, midazolam) have differing profiles that may affect multiple aspects of health-care utilization. The current labeling of these medications allows for a second dose if needed to control the cluster. Although no head-to-head studies directly comparing rescue treatments have been conducted, differences between studies with generally similar designs may provide context for the potential importance of second doses of rescue therapy on health-care utilization.Methods: For this analysis, large, long-term, open-label studies of approved seizure-cluster treatments designed for use by nonmedical caregivers were reviewed, and the percentage of seizure clusters for which a second dose was used or that were not controlled at 6, 12, and 24 hours was examined. Available data on hospitalizations were also collected.Results: The 3 identified studies meeting the inclusion criteria were for use of diazepam rectal gel, intranasal midazolam, and diazepam nasal spray. Across these studies, the use of a second dose ranged from < 40% at 6 hours to < 13% at 24 hours. Hospitalizations and serious treatment-emergent adverse events were reported variably across these studies.Conclusion: These results demonstrate the importance of second doses of rescue therapy for seizure clusters for optimizing health-care utilization. Need for second doses should be included as one component. In turn, when second doses are needed, they have the potential to curtail emergency department use and hospitalization and to prevent further seizure clusters.Keywords: diazepam, midazolam, nasal, rectal, acute repetitive seizures, twenty-four hours

Oxcarbazepine is a second-generation antiepileptic drug (AED) with proven efficacy in managing partial epileptic seizures, with or without secondary generalization, in adults and children. The overlap between the underlying pathophysiologic mechanisms of some epilepsy models and neuropathic pain models supports the rationale for using certain AEDs in the treatment of neuropathic pain. Several AEDs have reportedly produced analgesia in a range of neuropathic pains, including painful diabetic neuropathy (PDN) and post-herpetic neuralgia. Increasing evidence suggests that oxcarbazepine can provide significant analgesia in several neuropathic pain conditions, including trigeminal neuralgia and PDN, and is also may be effective in treating neuropathic pain refractory to other AEDs, such as carbamazepine and gabapentin. The analgesic effects of oxcarbazepine, and its generally improved safety and tolerability profile compared with other standard AEDs, suggests that oxcarbazepine will be an important addition to the neuropathic pain armamentarium. The rationale and evidence to support the efficacy of oxcarbazepine are presented here. [ABSTRACT FROM AUTHOR]

Background: Benzodiazepines are used in first-line rescue therapy as immediate-use seizure medication for the treatment of seizure clusters and prolonged seizures. Their use varies across clinical practices and conditions, and they can be used promptly when indicated. Clinical studies have demonstrated seizure termination within 2 min when diazepam nasal spray is used to treat seizure clusters within 5 min, but the response when treating longer duration seizures in a cluster remains to be characterized., Objective: To describe and assess timing and dosing of diazepam nasal spray in the subset of prolonged seizures within seizure clusters in a larger dataset of all treated seizure clusters collected during a long-term safety study of diazepam nasal spray., Methods: Using timing data recorded in seizure diaries, this post hoc analysis and associated sensitivity analyses focused on prolonged seizures treated 5 to 15 min after the seizure start. Measures included time to treatment administration and time to seizure termination. Second-dose data were used as a proxy for effectiveness., Results: In this group of seizure clusters treated 5 to 15 min after seizure start, median time drug administration was 6 min after seizure start, median time from drug administration to seizure termination was 7 min, and median overall seizure duration was 15 min. Sensitivity analyses by age, epilepsy type, and high seizure frequency confirmed this pattern. Use of a second dose occurred in 9.3 % of episodes, with the majority of second doses administered ≤ 4 h after the first dose. Safety results from the overall study showed 82.2 % of patients had ≥ 1 treatment-emergent adverse event (TEAE) irrespective of relationship to treatment, during a mean participation of ∼ 1.5 years. In addition, 30.7 % patients had a serious TEAE, and 18.4 % had TEAEs deemed at least possibly related to the study drug, none of which were serious. No events of cardiorespiratory depression were reported., Conclusions: Although immediate use of diazepam nasal spray (within 5 min) resulted in quicker seizure termination, a treatment delay of 5 to 15 min still produced rapid termination of the seizure cluster with high first-dose effectiveness and an overall acceptable safety profile. These findings suggest that diazepam nasal spray maintains effectiveness in prolonged seizures within a cluster with delayed treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr Jarrar is an advisor for Neurelis, Inc. Dr Stern is a consultant for Eisai; Jazz; Neurelis, Inc.; SK Life Science; and UCB. Dr Becker is a consultant/speaker for Neurelis, Inc; SK Life Science; and Jazz Pharmaceuticals. Dr Davis is a consultant to Neurelis, Inc. Dr Rabinowicz is an employee of and has received stock options from Neurelis, Inc. Dr Carrazana is an employee of and has received stock and stock options from Neurelis, Inc.]., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The burden of epilepsy is complex and consists of elements directly related to acute seizures as well as those associated with living with a chronic neurologic disorder. The purpose of this systematic review was to characterize short-term burdens of seizures and to explore the potential value of acute treatments to mitigate these burdens apart from reducing the risk of status epilepticus., Recent Findings: A systematic literature search was conducted using PubMed to identify articles published from January 1, 2017, to June 22, 2023, that described short-term burdens and acute treatments of seizures. Primary outcomes included those related to short-term burdens of seizures and the benefits of acute treatments to reduce short-term burdens. Of the 1332 articles identified through PubMed and 17 through other sources, 27 had relevant outcomes and were included in the qualitative synthesis. Seizure emergencies negatively affected short-term quality of life and the ability to conduct normal daily living activities and were associated with physical (injury) and financial (emergency transport, hospitalization) burdens. The use of acute treatment was associated with a rapid return (≤ 1 h) to normal function/self for both patients and caregivers and potentially lower healthcare utilization and costs. Seizure action plans may improve knowledge and comfort with seizure care, empowering patients and caregivers. The short-term burden of seizures can create a substantial negative impact on patients and caregivers. Acute treatments may reduce the short-term burdens of seizures in addition to their well-described role to reduce seizure activity and the risk for status epilepticus., (© 2024. The Author(s).)

Abstract: INTRODUCTION: Nurses have a central role in educating patients and families about treatment options and how to integrate them into action plans for neurologic conditions. In recent years, a growing number of intranasal formulations have become available as rescue therapy for neurologic conditions or symptoms including migraine, opioid overdose, and seizures. Rescue therapies do not replace maintenance medications or emergency care but are designed to enable rapid treatment of urgent or disabling conditions in community settings. Yet, discussion of rescue therapies for neurologic conditions remains limited in nursing literature. CONTENT: Intranasal formulations are specifically formulated for delivery and absorption in the nose and have several characteristics that are well suited as rescue therapies for neurologic conditions. Intranasal formulations include triptans for migraine, naloxone and nalmefene for opioid overdose, and benzodiazepines for seizure clusters in patients with epilepsy. Therapeutic attributes discussed here include ease of use in community settings by nonmedical professionals, relatively rapid onset of action, and favorable safety profile and patient experience. This information is critical for nurses to make informed decisions about rescue therapy options, incorporate these into plans of care, and educate patients, care partners, and other healthcare providers. CONCLUSION: Rescue therapies are increasingly important in the care of people with neurologic conditions. Various formulations are available and continue to evolve, offering easy and quick ways for nurses, patients, and nonmedical care partners to administer critical rescue medications. For nurses overseeing medication management, the attributes of intranasal rescue therapies should be considered in the context of providing patients with the right care at the right time., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Gomez-Lopez-Hernandez syndrome (GLHS), also known as cerebello-trigeminal-dermal dysplasia, is a neurocutaneous disorder typically presenting in childhood. GLHS is characterized by rhombencephalosynapsis (RES) and partial alopecia, with or without trigeminal anesthesia. We describe a rare case of GLHS in a paucisymptomatic adult who presented with new-onset seizure-like activity. Magnetic resonance imaging revealed partial midline fusion of the cerebellar hemispheres, incomplete development of vermis, and slight medialization of the dentate nuclei: all consistent with the diagnosis of RES. Radiographic evidence combined with partial alopecia, truncal ataxia, and muscular hypotonia are suggestive GLHS diagnosis. Our report not only highlights the importance of maintaining GLHS on the differential for new-onset seizure-like activity, but also demonstrates how patients with GLHS may be minimally symptomatic and diagnosed in adulthood., Lay Summary: The Gomez-Lopez-Hernandez syndrome (GLHS), or cerebellotrigeminal-dermal dysplasia, is a rare condition that affects both the nervous system and the skin. It involves abnormal development of the brain, partial alopecia [thinning of hair], and loss of sensation in the face. One specific brain malformation, called rhombencephalosynapsis (RES), results from abnormal formation of the cerebellum and is seen in GHLS.Both RES and GLHS present early in childhood, and cases presenting later in life are exceptionally rare. Here we describe a young adult with RES and GLHS whose normal development and mild clumsiness eluded recognition by doctors until early adulthood when she presented with a single seizure., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The diagnosis of epilepsy is associated with loss of predictability, which invariably results in the fear of when and if future seizures will occur. For a subset of patients with epilepsy (PWE), there may be a pathological persistent fear of seizure occurrence, resulting in limitations to daily activities through avoidant behaviors. Paradoxically, the research of anticipatory anxiety of seizures (AAS; also referred to as seizure phobia) has been practically nonexistent and, not surprisingly, this condition remains underrecognized by clinicians. The available data are derived from three small case series of patients followed in tertiary epilepsy centers. In this study, we review the available data on the reported clinical manifestations of AAS in PWE, and of the potential role of variables associated with it, such as personal and family psychosocial and psychiatric history and epilepsy-related variables. In addition, we review the need for the creation of screening tools to identify patients at risk of AAS and discuss potential treatment strategies, which could be considered as part of the comprehensive management for PWE., (© 2024 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Neurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited., Methods: We conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded., Results: Seizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray., Conclusion: These results suggest that diazepam nasal spray can be effectively administered at any time of day., Competing Interests: KL has received research support from National Institute of Neurological Disorders and Stroke; National Institutes of Health; Xenon; SK Life Science; Cerevel; Longboard; T3D; Athira; Takeda; UCB; NovoNordisk; Ipsen; Avanir; Ra Pharma; Sanofi; Novartis; Praxis; Annovis; Merck; NeuroDerm; Acadia; Biogen; Idorsia; Eisai; Axsome; Engage; LivaNova; Neurelis, Inc.; Sage; Jazz; NLS Pharmaceutics; Cyclerion; and Takeda. JW has served as an advisor or consultant for CombiMatrix; Eisai; GW Pharmaceuticals; Lundbeck; Neurelis, Inc.; NeuroPace; Supernus Pharmaceuticals; and Upsher-Smith Laboratories. He has served as a speaker or a member of a speakers bureau for Cyberonics; Eisai; Lundbeck; Mallinckrodt; Neurelis, Inc.; Supernus Pharmaceuticals; and Upsher-Smith Laboratories and has received grants for clinical research from Acorda Therapeutics; GW Pharmaceuticals; Insys Therapeutics; Lundbeck; Mallinckrodt; Neurelis, Inc.; NeuroPace; Upsher-Smith Laboratories; and Zogenix. DC and EC are employees of and have received stock and stock options from Neurelis, Inc. AR is an employee of and has received stock options from Neurelis, Inc. The authors retained full control of content of this manuscript and the decision to submit it for publication. The authors declare that this study received funding from Neurelis, Inc. The funder was involved in study design and collection and analysis of data., (Copyright © 2024 Liow, Wheless, Cook, Rabinowicz and Carrazana.)

Objective: Seizure clusters require prompt medical treatment to minimize possible progression to status epilepticus, increased health care use, and disruptions to daily life. Isolated seizures may exhibit cyclical patterns, including circadian and longer rhythms. However, little is known about the cyclical patterns in seizure clusters. This post hoc analysis of data from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray modeled the periodicity of treated seizure clusters., Methods: Mixed-effects cosinor analysis evaluated circadian rhythmicity, and single component cosinors using 12 and 24 h were used to calculate cosinor parameters (e.g., midline statistic of rhythm, wave ampitude, and acrophase [peak]). Analysis was completed for the full cohort and a consistent cohort of participants with two or more seizure clusters in each of four, 3-month periods. The influence of epilepsy type on cosinor parameters was also analyzed., Results: Seizure-cluster events plotted across 24 h showed a bimodal distribution with acrophases (peaks) at ~06:30 and ~18:30. A 12-h plot showed a single peak at ~06:30. Cosinor analyses of the full and consistent cohort aligned, with acrophases for both models predicting peak seizure activity at ~23:30 on a 24-h scale and ~07:30 on a 12-h scale. The consistent cohort was associated with increases in baseline and peak seizure-cluster activity. Analysis by epilepsy type identified distinct trends. Seizure clusters in the focal epilepsy group peaked in the evening (acrophase 19:19), whereas events in the generalized epilepsy group peaked in the morning (acrophase 04:46). Together they compose the bimodal clustering observed over 24 h., Significance: This analysis of seizure clusters treated with diazepam nasal spray demonstrated that seizure clusters occur cyclically in 12- and 24-h time frames similar to that reported with isolated seizures. Further elucidation of these patterns may provide important information for patient care, ranging from improved patient-centered outcomes to seizure-cluster prediction., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Alzheimer disease (AD), the most common neurodegenerative disorder in the United States, disproportionately burdens minority populations., Objective: To explore barriers to AD clinical trial participation by Asian and Native Hawaiian patients diagnosed with AD or mild cognitive impairment., Method: We surveyed 187 patients with a Mini-Mental State Examination score ≥14 between January 2022 and June 2022. The score cutoff for clinical trial eligibility was set by the institution. Individuals also completed a 15-question telephone survey that assessed demographics, barriers to clinical trial participation, and clinical trial improvement methods., Results: Forty-nine patients responded, with a response rate of 26%. Asian and Native Hawaiian patients were less likely than White patients to participate in AD trials. The main barrier to participation was a lack of information about AD trials. Providing additional information regarding AD trials to patients and family members were listed as the top two reasons patients would consider participating in a clinical trial., Conclusion: Insufficient information about AD clinical trials is the primary barrier to participation among Asian and Native Hawaiian patients, followed by difficulty coordinating transportation and, in the case of Asians, the time required for clinical trials. Increased outreach, education, and assistance with logistics in these populations should be pursued to improve rates of participation in clinical trials., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction The recommendations on return to exercise post-traumatic brain injury (TBI) remain debatable. As recent as 10 years ago, the conventional recovery modality for a mild TBI was to reduce neurostimulating activity and encourage rest until the symptoms subsided. However, emerging literature has challenged this notion, stating that returning to exercise early in the course of mild TBI recovery may be beneficial to the recovery timeline. This study surveys Hawaii's diverse population to identify trends in exercise and recovery for TBI patients to shape recommendations on return to exercise. Methods A single-center retrospective chart review of the patients with mild-to-moderate TBI was selected from a patient database at an outpatient neurology clinic between January 2020 and January 2022. The variables collected include demographics, the etiology of injury, and symptoms at diagnosis. Self-generated phone surveys were completed to evaluate exercise patterns post-TBI. Results The patients who recovered within two years displayed similar exercise patterns to the patients who took more than two years to recover. Exercise frequency, intensity, and duration did not differ significantly (p=0.75, p=0.51, and p=0.80, respectively; n=100). Hiking and walking were more common in the long recovery (LR) group (p=0.02), likely reflecting advanced age compared to the short recovery (SR) group (50 versus 39 years, p<0.01). Additionally, no correlation exists between exercise intensity and worsening symptoms (p=0.920), suggesting that the patients exhibit exercise patterns suitable for sub-symptomatic recovery. Conclusion Return to exercise does not appear to be a predictor for mild-to-moderate TBI recovery. The patients appear to self-regulate an exercise regimen that will not exacerbate their symptoms or recovery time; thus, it may be suitable to recommend return to exercise as tolerated. These, and other findings in the literature, suggest that patients should be encouraged to return to exercise shortly after a mild TBI so long as the exercise does not exacerbate their symptoms., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Weldon et al.)

Objective: Rescue benzodiazepine medication can be used to treat seizure clusters, which are intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. The NeuroPace RNS® System is a device that detects abnormal electrographic activity through intracranial electrodes and administers electrical stimulation to control seizures. Reductions in electrographic activity over days to weeks have been associated with the longer-term efficacy of daily antiseizure medications (ASMs). In this pilot study, electrographic activity over hours to days was examined to assess the impact of a single dose of a proven rescue therapy (diazepam nasal spray) with a rapid onset of action., Methods: Adult volunteers (>18 years old) with clinically indicated RNS (stable settings and ASM usage) received a weight-based dose of diazepam nasal spray in the absence of a clinical seizure. Descriptive statistics for a number of detections and a sum of durations of detections at 10-min, hourly, and 24-h intervals during the 7-day (predose) baseline period were calculated. Post-dose detections at each time interval were compared with the respective baseline-detection intervals using a 1 SD threshold. The number of long episodes that occurred after dosing also were compared with the baseline., Results: Five participants were enrolled, and four completed the study; the excluded participant had recurrent seizures during the study. There were no consistent changes (difference >1 SD) in detections between post-dose and mean baseline values. Although variability was high (1 SD was often near or exceeded the mean), three participants showed possible trends for reductions in one or more electrographic variables following treatment., Significance: RNS-assessed electrographic detections and durations were not shown to be sensitive measures of short-term effects associated with a single dose of rescue medication in this small group of participants. The variability of detections may have masked a measurable drug effect., Plain Language Summary: Rescue drugs are used to treat seizure clusters. Responsive neurostimulation (RNS) devices detect and record epilepsy brain waves and then send a pulse to help stop seizures. This pilot study looked at whether one dose of a rescue treatment changes brain activity detected by RNS. There was a very wide range of detections, which made it difficult to see if or how the drug changed brain activity. New studies should look at other types of brain activity, multiple doses, and larger patient groups., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Some patients with epilepsy experience seizure clusters, which may be defined as 2 or more seizures occurring within 24 hours. Left untreated, seizure clusters increase the risk for physical injury and may progress to status epilepticus, irreversible neurologic injury, and death. Rescue therapy is based on benzodiazepine treatment. Prompt, appropriate use should be specified in patients' individualized seizure action plans. Most seizure clusters occur outside the hospital setting. The ideal rescue therapy allows for easy and quick administration by a nonmedical person, which may minimize the need for intervention by emergency medical personnel or transportation to the hospital. In the 2 decades before the approval of 2 intranasal benzodiazepines in 2019 and 2020, rectal diazepam was the only route of administration approved by the US Food and Drug Administration specifically for seizure clusters. Each of the approved intranasal formulations has a unique profile. Both offer a convenient and socially acceptable route of administration. Recognition of seizure clusters and timing of proper administration are key to successful use of rescue therapy. Pharmacists' counseling plays an important role in reinforcing when and how to appropriately administer rescue therapies and the importance of consistently using rescue treatment when indicated to promote effective management. This review includes resources for pharmacists, patients, and caregivers; reviews currently available treatments; and discusses seizure action plans that support effective treatment of seizure clusters., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Gidal is a consultant for Aquestive, Eisai Inc., Greenwich, and SK Life Science; is a member of the End Point Review Committee for Sunovion Pharmaceuticals Inc; and has a grant/contract with UCB Inc. Dr. Welty has nothing to disclose. Dr. Cokley is on the speakers bureau for UCB Inc. Dr. Farrell has nothing to disclose. Ms. Shafer has been a consultant for Neurelis, Inc. and for the Epilepsy Foundation. Dr. Rabinowicz is an employee of and has received stock options from Neurelis, Inc. Dr. Carrazana is an employee of and has received stock and stock options from Neurelis, Inc.

Introduction: Although prompt treatment of status epilepticus is standard of care, the effect of timing of rescue therapy administration for seizure clusters in epilepsy remains unknown. Seizure clusters are a rare but clinically important condition, and benzodiazepines are the cornerstone rescue therapy for seizure clusters in epilepsy. We characterized temporal patterns from a large dataset of treated seizure clusters in the safety study of diazepam nasal spray., Methods: This post hoc analysis used timing data of treated seizure clusters recorded by care partners and patients in seizure diaries during a 1-year safety study. Data analysis used time from seizure start to administration of diazepam., Results: From 4466 observations, 3225 had data meeting criteria for analysis. Overall, median times from seizure start to dose administration, dose administration to seizure termination, and total seizure duration were 2, 3, and 7 min, respectively. In seizure clusters treated in < 5 min (median 1.0 min), median time from dose to seizure termination was 2.0 min, and median total seizure duration was 4.0 min. Among seizure clusters treated in ≥ 5 min (median 10.0 min), median time to seizure termination was 10.0 min, and median total seizure duration was 23.0 min. Previously published safety results reported that over a mean participation of 1.5 years, 82.2% of patients had ≥ 1 treatment-emergent adverse events (TEAEs) irrespective of relationship to treatment, including 30.7% with serious TEAEs; 18.4% had TEAEs deemed at least possibly related to the study drug, none of which were serious. There were no events of cardiorespiratory depression., Conclusion: Echoing the importance of early use of benzodiazepines in status epilepticus, the findings from this exploratory analysis of patients with refractory epilepsy and frequent seizure clusters identify a potential benefit of early diazepam nasal spray treatment leading to faster seizure resolution within the seizure cluster. Trial Registration Information: ClinicalTrials.gov identifier NCT02721069 ( https://clinicaltrials.gov/ct2/show/NCT02721069 )., (© 2024. The Author(s).)

Patients with epilepsy may experience seizure clusters, which are described by the US Food and Drug Administration (FDA) as intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. Untreated seizure clusters may increase the risk for status epilepticus, as well as decrease quality of life and increase burden on patients and care partners. Benzodiazepine therapies are the mainstay for acute treatment of seizure clusters and are often administered by nonmedical care partners outside a healthcare facility. Three rescue therapies are currently FDA-approved for this indication, with diazepam rectal gel being the first in 1997, for patients aged ≥  2 years. Limitations of rectal administration (e.g., positioning and disrobing the patient, which may affect ease of use and social acceptability; interpatient variation in bioavailability) led to the investigation of the potential for nasal administration as an alternative. Midazolam nasal spray (MDS) was approved by the FDA in 2019 for patients aged ≥  12 years and diazepam nasal spray (DNS) in 2020 for patients aged ≥  6 years; these two intranasal therapies have differences in their formulations [e.g., organic solvents (MDS) vs. Intravail and vitamin E for absorption and solubility (DNS)], effectiveness (e.g., proportion of seizure clusters requiring only one dose), and safety profiles. In clinical studies, the proportion of seizure clusters for which only one dose of medication was used varied between the three approved rescue therapies with the highest single-dose rate for any time period for DNS; however, although studies for all three preparations enrolled patients with highly intractable epilepsy, inclusion and exclusion criteria varied, so the three cannot be directly compared. Treatments that have been used off-label for seizure clusters in the USA include midazolam for injection as an intranasal spray (indicated for sedation/anxiolysis/amnesia and anesthesia) and tablet forms of clonazepam (indicated for treatment for seizure disorders) and lorazepam (indicated for anxiety). In the European Union, buccal and intranasal midazolam are used for treating the indication of prolonged, acute convulsive seizures and rectal diazepam solution for the indication of epileptic and febrile convulsions; duration of effectiveness for these medications for the treatment of seizure clusters has not been established. This paper examines the literature context for understanding seizure clusters and their treatment and provides effectiveness, safety, and administration details for the three FDA-approved rescue therapies. Additionally, other medications that are used for rescue therapy in the USA and globally are discussed. Finally, the potential benefits of seizure action plans and candidates for their use are addressed. This paper is intended to provide details about the unique characteristics of rescue therapies for seizure clusters to help clarify appropriate treatment for individual patients., (© 2024. The Author(s).)

Importance: The prompt effective treatment of acute agitation among patients with schizophrenia or bipolar disorder can alleviate distressing symptoms for the patient and decrease the risk of escalation to aggression and the potential for serious harm to the patient, health care providers, and others., Observations: A commonly used approach for the management of acute agitation has been the intramuscular administration of antipsychotic medications and/or benzodiazepines. However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film. Two formulations of intranasal olanzapine for acute agitation are in development., Conclusions and Relevance: Intranasal formulations offer the potential for favorable pharmacokinetics and onset of action combined with ease of delivery obviating the need for injections and are thus consistent with patient-centered factors such as preference and self-administration. In this review, alternative methods of medication delivery are discussed, with an emphasis on the potential for intranasal administration to treat acute agitation in adult patients with schizophrenia or bipolar disorder., Prim Care Companion CNS Disord 2024;26(1):23nr03596 ., Author affiliations are listed at the end of this article., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Cerebral cavernous malformations (CCMs) are vascular lesions characterized by a porous endothelium. The lack of a sufficient endothelial barrier can result in microbleeds and frank intracerebral hemorrhage. A primary mechanism for lesion development is a sequence variant in at least 1 of the 3 CCM genes ( CCM1 , CCM2 , and CCM3 ), which influence various signaling pathways that lead to the CCM phenotype. A common downstream process associated with CCM gene loss of function involves overactivation of RhoA and its effector Rho-associated kinase (ROCK). In this study, we review RhoA/ROCK-related mechanisms involved in CCM pathophysiology as potential therapeutic targets. Literature searches were conducted in PubMed using combinations of search terms related to RhoA/ROCK and CCMs. In endothelial cells, CCM1, CCM2, and CCM3 proteins normally associate to form the CCM protein complex, which regulates the functions of a wide variety of protein targets (e.g., MAP3K3, SMURF1, SOK-1, and ICAP-1) that directly or indirectly increase RhoA/ROCK activity. Loss of CCM complex function and increased RhoA/ROCK activity can lead to the formation of stress fibers that contribute to endothelial junction instability. Other RhoA/ROCK-mediated pathophysiologic outcomes include a shift to a senescence-associated secretory phenotype (primarily mediated by ROCK2), which is characterized by endothelial cell migration, cell cycle arrest, extracellular matrix degradation, leukocyte chemotaxis, and inflammation. ROCK represents a potential therapeutic target, and direct (fasudil, NRL-1049) and indirect (statins) ROCK inhibitors have demonstrated various levels of efficacy in reducing lesion burden in preclinical models of CCM. Current (atorvastatin) and planned (NRL-1049) clinical studies will determine the efficacy of ROCK inhibitors for CCM in humans, for which no US Food and Drug Administration-approved or EU-approved pharmacologic treatment exists., Competing Interests: C. Ayata serves on the scientific advisory board of Neurelis, Inc.; receives research support from the NINDS, the American Heart Association, and the Leducq Foundation; reports sponsored research agreements with Takeda Pharmaceuticals, Praxis Precision Medicines, and Neurelis, Inc.; and other research support from Hovid Berhad. H. Kim is a consultant for Recursion Pharmaceuticals; serves on the DSMB for Neurelis, Inc.; and receives research support from the NINDS. L. Morrison is a consultant for Neurelis, Inc. J.K. Liao is a consultant for Esperion. J. Gutierrez and M. Lopez-Toledano are employees of and have received stock options from Neurelis, Inc. E. Carrazana is an employee of and has received stock and stock options from Neurelis, Inc. A.L. Rabinowicz is an employee of and has received stock options from Neurelis, Inc. I.A. Awad is a consultant to Neurelis, Inc.; is chairman (unpaid) of the scientific advisory board for the Alliance to Cure Cavernous Malformation; and receives research support from the NINDS. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

For acute treatment of seizure clusters in patients with epilepsy, intranasal administration of acute seizure therapies has been shown to provide accessibility and ease of use to care partners as well as the potential for self-administration by patients. Diazepam nasal spray (Valtoco®) was approved by the US Food and Drug Administration for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Self-administration consistent with the prescribing information is feasible and was reported by a subgroup of patients (n = 27 of 163) in a long-term phase 3 safety study. Data regarding self-administration among these patients with seizure clusters are examined here to explore the safety profiles and measures of effectiveness, as well as the quality of life of those who self-treated. In addition, this focused look at patients who self-administered diazepam nasal spray may offer some insights into the characteristics of patients who may be appropriate for self-administration., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Misra was an employee of Neurelis, Inc., at the time of the development of this manuscript and has received stock options from Neurelis, Inc. Dr Sperling has received compensation for speaking at continuing medical education programs from Medscape, Projects for Knowledge, International Medical Press, and UCB Pharma. He has consulted for Medtronic; Neurelis, Inc.; and Johnson & Johnson. He has received research support from Eisai; Medtronic; Neurelis, Inc.; SK Life Science; Takeda; Xenon; Cerevel; UCB Pharma; Janssen; and Engage Pharmaceuticals. He receives royalties from Oxford University Press and Cambridge University Press. Dr Rao has served as a consultant for NeuroPace, Inc., manufacturer of the RNS® System. Dr Peters has served as a speaker and consultant for Neurelis, Inc.; SK Life Science; and Jazz Pharmaceuticals. Dr Penovich has served on speakers bureaus for Jazz Pharmaceuticals; Neurelis, Inc.; and UCB Pharma, and is an advisor to LVIS Corporation and Neurelis, Inc. Dr Wheless has served as an advisor or consultant for CombiMatrix; Eisai Inc.; GW Pharmaceuticals; Lundbeck, Inc.; Neurelis, Inc.; NeuroPace, Inc.; Supernus Pharmaceuticals, Inc.; and Upsher-Smith Laboratories, Inc. Dr. Wheless has served as a speaker or a member of a speakers bureau for: Cyberonics, Inc.; Eisai Inc.; Lundbeck, Inc.; Mallinckrodt; Neurelis, Inc.; Supernus Pharmaceuticals, Inc.; Upsher-Smith Laboratories, Inc., and has received grants for clinical research from Acorda Therapeutics; GW Pharmaceuticals; and INSYS. Dr Hogan has received research support from UCB Pharmaceuticals, Neurelis, Inc; and Biogen Inc, and is an advisor for Neurelis, Inc. Dr Davis is a consultant to Neurelis, Inc. Dr Carrazana is an employee of and received stock and stock options from Neurelis, Inc. Dr Rabinowicz is an employee of and has received stock options from Neurelis, Inc., (© 2024 The Authors. Published by Elsevier Inc.)

Epilepsy is a common pediatric neurological condition, affecting approximately 470,000 children in the USA and having a prevalence of 0.9% in the global population of approximately 2.6 billion children. Epilepsy is associated with disruptions in several areas of a child's life, including medical burden, quality of life, cognitive outcomes, and higher risk of mortality. Additionally, some pediatric patients may experience acute seizure emergencies such as seizure clusters (also called acute repetitive seizures), which are intermittent increases in seizure activity that differ from the patient's usual seizure pattern and may occur despite daily antiseizure drug administration. Seizure clusters increase a patient's risk for status epilepticus and emergency room visits. Benzodiazepines are the main category of drugs used as acute seizure therapies for seizure clusters. This narrative review provides a practical discussion of care for pediatric patients with epilepsy and seizure clusters exploring such topics as details about the US Food and Drug Administration-approved acute seizure therapies, safety and ease of use of these medications, benefits of seizure action plans to help ensure optimal treatment, and considerations for transitioning a pediatric patient with acute seizure therapy to adult healthcare management., (© 2023. The Author(s).)

Aim: To identify current perceptions of aducanumab among patients with Alzheimer's disease (AD) and their caregivers., Methods: A total of 352 caregivers of AD patients seen at Hawaii's largest multidisciplinary neuroscience center between January 01, 2019, and June 21, 2021, were surveyed by telephone to understand patient and caregiver knowledge, familiarity, and hesitancy toward aducanumab., Results: Thirty-seven percent of caregivers were familiar with aducanumab. Caregivers who were spouses of their respective patients with AD (p=0.0023) had increased odds of familiarity. Additional predictors of aducanumab familiarity included patients with higher mini-mental state examination scores (p=0.0076) and those who received mental stimulation (p=0.007). Conversely, caregivers who identified as native Hawaiian and other Pacific Islanders (NHPI) (p=0.044) or the patient's child (p=0.010) were predictors of decreased familiarity. Only 33% of caregivers familiar with aducanumab believed it to be safe and 56% reported "side effects" as their top concern. Thirty percent of caregivers were moderately ready or very ready to use aducanumab if given the opportunity., Conclusion:  Most caregivers of Hawaii AD patients were unfamiliar with aducanumab. Furthermore, those familiar were hesitant to trial the medication. Improved education and awareness of AD therapies are important, so families and caregivers of AD patients can make more informed decisions regarding AD treatment., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Goo et al.)

Potential airborne human pathogens (PAHPs) may be a relevant component of the air microbiome in built environments. Despite that PAHPs can cause infections, particularly in immunosuppressed patients at medical centers, they are scarcely considered in standards of indoor air quality (IAQ) worldwide. Here, we reviewed the current information on microbial aerosols (bacteria, fungal and viruses) and PAHPs in different types of built environments (e.g., medical center, industrial and non-industrial), including the main factors involved in their dispersion, the methodologies used in their study and their associated biological risks. Our analysis identified the human occupancy and ventilation systems as the primary sources of dispersal of microbial aerosols indoors. We also observed temperature and relative humidity as relevant physicochemical factors regulating the dispersion and viability of some PAHPs. Our analysis revealed that some PAHPs can survive and coexist in different environments while other PAHPs are limited or specific for an environment. In relation to the methodologies (conventional or molecular) the nature of PAHPs and sampling type are pivotal. In this context, indoors air-borne viruses are the less studies because their small size, environmental lability, and absence of efficient sampling techniques and universal molecular markers for their study. Finally, it is noteworthy that PAHPs are not commonly considered and included in IAQ standards worldwide, and when they are included, the total abundance is the single parameter considered and biological risks is excluded. Therefore, we propose a revision, design and establishment of public health policies, regulations and IAQ standards, considering the interactions of diverse factors, such as nature of PAHPs, human occupancy and type of built environments where they develop., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Currently, there are limited accessible and cost-effective biomarkers for preclinical Alzheimer's disease (AD) patients. However, the apolipoprotein E (ApoE) polymorphic alleles can predict if someone is at high (e4), neutral (e3), or low (e2) genetic risk for developing AD. This study analyzed electroencephalogram (EEG) reports from individuals with various ApoE genotypes, aiming to identify EEG changes and patterns that could potentially serve as predictive markers for preclinical AD progression., Methods: Participants aged 64-78 were selected from the patient database at an outpatient neurology clinic. Genotype studies were performed to determine ApoE status, followed by EEG analysis to identify any apparent trends. A case-control design was used, categorizing participants into cases (e2e3, e2e4, e3e4, e4e4) and controls (e3e3). EEG recordings were compared between the groups to identify potential differences in EEG characteristics, including abnormal temporal slowing, frequency, and ApoE genotype association., Results: Among 43 participants, 49% demonstrated evidence of abnormal temporal slowing on EEG. Of these, 48% displayed focal left temporal slowing, and 52% displayed bilateral temporal slowing. The right-sided temporal slowing was not observed. Among participants with abnormal slowing, 95% exhibited theta frequency (4-8 Hz) slowing, while only 4.8% displayed delta frequency (0-4 Hz) slowing. Among participants with the ApoE4 allele, 61.5% demonstrated evidence of abnormal slowing, compared to 43.3% without it. Furthermore, the presence of an ApoE4 allele was associated with a significantly higher proportion of males (54%) compared to those without it (13%) (p=0.009)., Conclusions: Although we did not find a statistically significant difference in temporal EEG slowing among different ApoE genotypes, our findings suggest a potential association between temporal slowing on EEG and the presence of an ApoE4 allele in individuals with preclinical AD. These observations highlight the need for further exploration into the potential influence of the ApoE4 allele on EEG findings and the utility of EEG as a complementary diagnostic tool for AD. Longitudinal studies with large sample sizes are needed to establish the precise relationship between EEG patterns, ApoE genotypes, and AD progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kim et al.)

Epilepsy is a common neurological disorder in the United States, affecting approximately 1.2% of the population. Some people with epilepsy may experience seizure clusters, which are acute repetitive seizures that differ from the person's usual seizure pattern. Seizure clusters are unpredictable, are emotionally burdensome to patients and caregivers (including care partners), and require prompt treatment to prevent progression to serious outcomes, including status epilepticus and associated morbidity (e.g., lacerations, fractures due to falls) and mortality. Rescue medications for community use can be administered to terminate a seizure cluster, and benzodiazepines are the cornerstone of rescue treatment. Despite the effectiveness of benzodiazepines and the importance of a rapid treatment approach, as many as 80% of adult patients do not use rescue medication to treat seizure clusters. This narrative review provides an update on rescue medications used for treatment of seizure clusters, with an emphasis on clinical development and study programs for diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Results from long-term clinical trials have shown that treatments for seizure clusters are effective. Intranasal benzodiazepines provide ease of use and patient and caregiver satisfaction in pediatric and adult patients. Adverse events attributed to acute rescue treatments have been characterized as mild to moderate, and no reports of respiratory depression have been attributed to treatment in long-term safety studies. The implementation of an acute seizure action plan to facilitate optimal use of rescue medications provides an opportunity for improved management of seizure clusters, allowing those affected to resume normal daily activities more quickly., (© 2023. The Author(s).)

Lake Villarrica, one of Chile's main freshwater water bodies, was recently declared a nutrient-saturated lake due to increased phosphorus (P) and nitrogen (N) levels. Although a decontamination plan based on environmental parameters is being established, it does not consider microbial parameters. Here, we conducted high-throughput DNA sequencing and quantitative polymerase chain reaction (qPCR) analyses to reveal the structure and functional properties of bacterial communities in surface sediments collected from sites with contrasting anthropogenic pressures in Lake Villarrica. Alpha diversity revealed an elevated bacterial richness and diversity in the more anthropogenized sediments. The phylum Proteobacteria, Bacteroidetes, Acidobacteria, and Actinobacteria dominated the community. The principal coordinate analysis (PCoA) and redundancy analysis (RDA) showed significant differences in bacterial communities of sampling sites. Predicted functional analysis showed that N cycling functions (e.g., nitrification and denitrification) were significant. The microbial co-occurrence networks analysis suggested Chitinophagaceae, Caldilineaceae, Planctomycetaceae, and Phycisphaerae families as keystone taxa. Bacterial functional genes related to P (phoC, phoD, and phoX) and N (nifH and nosZ) cycling were detected in all samples by qPCR. In addition, an RDA related to N and P cycling revealed that physicochemical properties and functional genes were positively correlated with several nitrite-oxidizing, ammonia-oxidizing, and N-fixing bacterial genera. Finally, denitrifying gene (nosZ) was the most significant factor influencing the topological characteristics of co-occurrence networks and bacterial interactions. Our results represent one of a few approaches to elucidate the structure and role of bacterial communities in Chilean lake sediments, which might be helpful in conservation and decontamination plans., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: There is an expanding body of literature implicating heart disease and stroke as risk factors for Alzheimer's disease (AD). Hawaii is one of the six majority-minority states in the United States and has significant racial health disparities. The Native-Hawaiians/Pacific-Islander (NHPI) population is well-known as a high-risk group for a variety of disease conditions., Objective: We explored the association of cardiovascular disease with AD development based on the Hawaii Medicare data, focusing on racial disparities., Methods: We utilized nine years of Hawaii Medicare data to identify subjects who developed heart failure (HF), ischemic heart disease (IHD), atrial fibrillation (AF), acute myocardial infarction (AMI), stroke, and progressed to AD, using multistate models. Propensity score-matched controls without cardiovascular disease were identified to compare the risk of AD after heart disease and stroke. Racial/Ethnic differences in progression to AD were evaluated, accounting for other risk factors., Results: We found increased risks of AD for AF, HF, IHD, and stroke. Socioeconomic (SE) status was found to be critical to AD risk. Among the low SE group, increased AD risks were found in NHPIs compared to Asians for all conditions selected and compared to whites for HF, IHD, and stroke. Interestingly, these observations were found reversed in the higher SE group, showing reduced AD risks for NHPIs compared to whites for AF, HF, and IHD, and to Asians for HF and IHD., Conclusions: NHPIs with poor SE status seems to be mostly disadvantaged by the heart/stroke and AD association compared to corresponding whites and Asians., Competing Interests: The authors have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)