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Background: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy., Methods: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR -mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed., Results: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents., Conclusions: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR -mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.)., (Copyright © 2023 Massachusetts Medical Society.)

The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling. SIGNIFICANCE STATEMENT: Nuclear receptors (NRs) are ligand-regulated transcription factors that are critical regulators of myriad physiological processes. NRs serve as receptors for an array of drugs, and in this review, we provide an update on recent research into the roles of these drug targets., (U.S. Government work not protected by U.S. copyright.)

Secondary prevention is a major priority for those living with stroke and may be improved through the use of mobile Health (mHealth) interventions. While evidence for the effectiveness of mHealth interventions for secondary prevention of stroke is growing, little attention has been given to the translation of these interventions into real-world use. In this review, we aimed to provide an update on the effectiveness of mHealth interventions for secondary prevention of stroke, and investigate their translation into real-world use. Four electronic databases and the gray literature were searched for randomized controlled trials of mHealth interventions for secondary prevention of stroke published between 2010 and 2023. Qualitative and mixed-methods evaluations of the trials were also included. Data were extracted regarding study design, population, mHealth technology involved, the intervention, and outcomes. Principal researchers from these trials were also contacted to obtain further translational information. From 1151 records, 13 randomized controlled trials and 4 evaluations were identified; sample sizes varied widely (median, 56; range, 24-4298). Short message service messages (9/13) and smartphone applications (6/13) were the main technologies used to deliver interventions. Primary outcomes of feasibility of the intervention were achieved in 4 trials, and primary outcomes of changes in risk factors, lifestyle behaviors, and adherence to medication improved in 6 trials. Only 1 trial had a hard end point (ie, stroke recurrence) as a primary outcome, and no significant differences were observed between groups. There was evidence for only 1 intervention being successfully translated into real-world use. Further evidence is required on the clinical effectiveness of mHealth interventions for preventing recurrent stroke, and the associated delivery costs and cost-effectiveness, before adoption into real-world settings., Competing Interests: Disclosures Prof Cadilhac reports grants paid to her institution unrelated to this review from Moleac, Boehringer Ingelheim, and Medtronic. The other authors report no conflicts.

Background: COVID-19 (COronaVIrus Disease-19) control measure stringency, including testing, has been among the highest globally in China. Psychosocial impact on pandemic workers in Shanghai and their pandemic-related attitudes were investigated., Methods: Participants in this cross-sectional study were health care providers (HCPs) and other pandemic workers. A Mandarin online survey was administered between April and June 2022 during the omicron-wave lockdown. The Perceived Stress Scale and Maslach Burnout Inventory were administered., Results: Eight hundred eighty-seven workers participated, of which 691 (77.9%) were HCPs. They were working 6.25 ± 1.24 days per week for 9.77 ± 4.28 hours per day. Most participants were burned out, with 143 (16.1%) moderately and 98 (11.0%) seriously. The Perceived Stress Scale score was 26.85 ± 9.92 of 56, with 353 participants (39.8%) having elevated stress. Many workers perceived benefits: cohesive relationships (n = 581 [65.5%]), resilience (n = 693 [78.1%]), and honor (n = 747 [84.2%]). In adjusted analyses, those perceiving benefits showed significantly less burnout (odds ratio, 0.573; 95% confidence interval, 0.411 to 0.799), among other correlates., Conclusions: Pandemic work, including among non-HCPs, is highly stressful, but some can derive benefits., Competing Interests: Conflict of interest: None declared., (Copyright © 2023 American College of Occupational and Environmental Medicine.)

Purpose: To evaluate the relationship between body mass index (BMI) and glaucoma progression., Design: Multicohort observational study., Methods: This study combined a retrospective longitudinal analysis of suspect and early manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study., Results: In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (β 0.04 dB/year/SD95% CI [0.005, 0.069]; P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (β -0.048/SD 95% CI [-0.056, 0.96]; P < .001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI [0.84, 0.98]; P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD; 95% CI [0.91, 0.98]; P = .002). Body mass index was also positively correlated with intraocular pressure (β 0.11/SD; 95% CI [0.06, 0.15]; P < .001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (β -0.007/SD; 95% CI [-0.01, -0.001]; P = .023)., Conclusions: Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Real-world evidence is limited on whether antihypertensive medications help avert major adverse cardiovascular events (MACE) after stroke without increasing the risk of falls. We investigated the association of adherence to antihypertensive medications on the incidence of MACE and falls requiring hospitalization after stroke., Methods: A retrospective cohort study of adults who were newly dispensed antihypertensive medications after an acute stroke (Australian Stroke Clinical Registry 2012-2016; Queensland and Victoria). Pharmaceutical dispensing records were used to determine medication adherence according to the proportion of days covered in the first 6 months poststroke. Outcomes between 6 and 18 months postdischarge included: (i) MACE, a composite outcome of all-cause death, recurrent stroke or acute coronary syndrome; and (ii) falls requiring hospitalization. Estimates were derived using Cox models, adjusted for >30 confounders using inverse probability treatment weights., Results: Among 4076 eligible participants (median age 68 years; 37% women), 55% had a proportion of days covered ≥80% within 6 months postdischarge. In the subsequent 12 months, 360 (9%) participants experienced a MACE and 337 (8%) experienced a fall requiring hospitalization. After achieving balance between groups, participants with a proportion of days covered ≥80% had a reduced risk of MACE (hazard ratio: 0.68; 95% CI: 0.54-0.84) and falls requiring hospitalization (subdistribution hazard ratio: 0.78; 95% CI: 0.62-0.98) than those with a proportion of days covered <80%., Conclusions: High adherence to antihypertensive medications within 6 months poststroke was associated with reduced risks of both MACE and falls requiring hospitalization. Patients should be encouraged to adhere to their antihypertensive medications to maximize poststroke outcomes.

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear., Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial)., Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4])., Setting: 94 hospitals in 10 countries (86% U.S. participants)., Participants: Adults hospitalized with COVID-19., Intervention: SOC., Measurements: 28-day mortality and recovery., Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages., Limitation: Unmeasured confounding., Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas., Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Background: Expanding specialty palliative care within complex health systems involves consideration of patients' unmet needs, clinicians' perceptions of palliative care, and the availability of palliative care resources. Prior to this quality improvement (QI) project, palliative care services in our health system primarily served oncology patients., Intervention: We undertook a prospective strategic planning process that included executive sponsorship and engagement of institutional leaders and clinicians to help define which palliative care services were most needed by the health system., Measures: We interviewed and surveyed a broad range of clinicians including physicians, nurse practitioners, and social workers., Outcomes: The two most prominent themes that emerged from the stakeholder engagement process were clinicians' wish for specialty-aligned interprofessional palliative care teams and for expansion of nononcology palliative care access., Conclusion: Careful needs assessment and stakeholder engagement can result in goal-directed and data-driven expansion of palliative care services within tertiary health care systems., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma., Methods: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed., Results: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group., Conclusions: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.)., (Copyright © 2022 Massachusetts Medical Society.)

We describe an educational intervention for neurology residents aimed at developing feedback skills. An objective structured clinical examination case was designed to simulate the provision of feedback to a medical student. After the simulated case session, residents received structured, individualized feedback on their performance and then participated in a group discussion about feedback methods. Survey data were collected from the standardized medical student regarding residents' performance and from residents for assessments of their performance and of the Objective Structured Clinical Examination case. This article aims to describe this educational intervention and to demonstrate the feasibility of this approach for feedback skills development., (© 2022 American Academy of Neurology.)

Background and Objectives: To investigate the long-term effect of permanent demyelination on axonal attrition by examining an association between intereye asymmetry of the multifocal visual evoked potential (mfVEP) latency delay and subsequent thinning of retinal ganglion cell axons in patients with a long-standing history of unilateral optic neuritis (ON)., Methods: Only patients with a significant degree of chronic demyelination (intereye latency asymmetry >5 ms) were included in this study. The level of optic nerve demyelination was estimated at baseline by the latency delay of mfVEP, while the degree of axonal loss was assessed by thinning of the retinal nerve fiber layer (RNFL) thickness between baseline and follow-up visits. Low-contrast visual acuity (LCVA) was also evaluated at baseline and follow-up. Patients were examined twice with an average interval of 6.1 ± 1.4 years., Results: From 85 examined patients with multiple sclerosis, 28 satisfied inclusion criteria. Latency of the mfVEP was delayed, and RNFL thickness was reduced in ON eyes compared with fellow eyes at both visits. There was significant correlation between latency asymmetry and baseline or follow-up intereye RNFL thickness asymmetry. Intereye asymmetry of LCVA at baseline correlated with baseline latency asymmetry of mfVEP and baseline asymmetry of RNFL thickness. Latency of the mfVEP in ON eyes improved slightly during the follow-up period, whereas latency of the fellow eye remained stable. By contrast, RNFL thickness significantly declined in both ON and fellow eyes during the follow-up period. The rate of RNFL thinning in ON eyes, however, was more than 2 times faster compared with the fellow eyes ( p < 0.001). Furthermore, baseline latency asymmetry significantly correlated with the rate of RNFL thinning in ON eyes during the follow-up ( p < 0.001), explaining almost half of the variability of temporal RNFL progression. For each millisecond of latency delay (i.e., ∼0.5 mm of demyelination along the optic nerve), temporal RNFL thickness was annually reduced by 0.05%., Discussion: Our study provides clear in vivo evidence that chronic demyelination significantly accelerates axonal loss. However, because this process is slow and its effect is mild, long-term monitoring is required to establish and confidently measure the neurodegenerative consequences of demyelination., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patient outcomes are poor for aggressive B-cell non-Hodgkin's lymphomas not responding to or progressing within 12 months after first-line therapy. Tisagenlecleucel is an anti-CD19 chimeric antigen receptor T-cell therapy approved for diffuse large B-cell lymphoma after at least two treatment lines., Methods: We conducted an international phase 3 trial involving patients with aggressive lymphoma that was refractory to or progressing within 12 months after first-line therapy. Patients were randomly assigned to receive tisagenlecleucel with optional bridging therapy (tisagenlecleucel group) or salvage chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT) (standard-care group). The primary end point was event-free survival, defined as the time from randomization to stable or progressive disease at or after the week 12 assessment or death. Crossover to receive tisagenlecleucel was allowed if a defined event occurred at or after the week 12 assessment. Other end points included response and safety., Results: A total of 322 patients underwent randomization. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs. 16.9%), as was the percentage with an International Prognostic Index score (range, 0 to 5, with higher scores indicating a worse prognosis) of 2 or higher (65.4% vs. 57.5%). A total of 95.7% of the patients in the tisagenlecleucel group received tisagenlecleucel; 32.5% of the patients in the standard-care group received autologous HSCT. The median time from leukapheresis to tisagenlecleucel infusion was 52 days. A total of 25.9% of the patients in the tisagenlecleucel group had lymphoma progression at week 6, as compared with 13.8% of those in the standard-care group. The median event-free survival in both groups was 3.0 months (hazard ratio for event or death in the tisagenlecleucel group, 1.07; 95% confidence interval, 0.82 to 1.40; P = 0.61). A response occurred in 46.3% of the patients in the tisagenlecleucel group and in 42.5% in the standard-care group. Ten patients in the tisagenlecleucel group and 13 in the standard-care group died from adverse events., Conclusions: Tisagenlecleucel was not superior to standard salvage therapy in this trial. Additional studies are needed to assess which patients may obtain the most benefit from each approach. (Funded by Novartis; BELINDA ClinicalTrials.gov number, NCT03570892.)., (Copyright © 2021 Massachusetts Medical Society.)

Background There are multiple tools available to visualize the retinal and choroidal vasculature of the posterior globe. However, there are currently no reliable in vivo imaging techniques that can visualize the entire retrobulbar course of the retinal and ciliary vessels. Purpose To identify and characterize the central retinal artery (CRA) using cone-beam CT (CBCT) images obtained as part of diagnostic cerebral angiography. Materials and Methods In this retrospective study, patients with catheter DSA performed between October 2019 and October 2020 were included if CBCT angiography included the orbit in the field of view. The CBCT angiography data sets were postprocessed with a small field-of-view volume centered in the posterior globe to a maximum resolution of 0.2 mm. The following were evaluated: CRA origin, CRA course, CRA point of penetration into the optic nerve sheath, bifurcation of the CRA at the papilla, visualization of anatomic variants, and visualization of the central retinal vein. Descriptive statistical analysis was performed. Results Twenty-one patients with 24 visualized orbits were included in the analysis (mean age, 55 years ± 15; 14 women). Indications for angiography were as follows: diagnostic angiography ( n = 8), aneurysm treatment ( n = 6), or other ( n = 7). The CRA was identified in all orbits; the origin, course, point of penetration of the CRA into the optic nerve sheath, and termination in the papilla were visualized in all orbits. The average length of the intraneural segment was 10.6 mm (range, 7-18 mm). The central retinal vein was identified in six of 24 orbits. Conclusion Cone-beam CT, performed during diagnostic angiography, consistently demonstrated the in vivo central retinal artery, demonstrating excellent potential for multiple diagnostic and therapeutic applications. © RSNA, 2021 Online supplemental material is available for this article.

Introduction: The impact of booster training on pediatric resuscitation skills is not well understood. Rapid cycle deliberate practice (RCDP) to supplement pediatric advanced life support (PALS) training is beginning to be used to improve resuscitation skills. We tested the impact of booster RCDP training performed at 9 months after initial RCDP training on pediatric resuscitation skills of pediatric residents., Objective: This study evaluated the impact of a 9-month RCDP booster training on PALS skills compared with usual practice debriefing (plus/delta) after an initial RCDP training session for PALS-certified pediatric interns., Methods: All pediatric interns at a single institution were invited to a 45-minute RCDP training session after their initial PALS certification. The PALS performance score and times for key events were recorded for participants immediately before and after the RCDP training as well as 6, 9, and 12 months after the RCDP training. Learners were randomized to an RCDP intervention and usual practice (plus/delta) group. The intervention group received booster RCDP training after their 9-month assessment., Results: Twenty eight of 30 residents participated in the initial training with 22 completing randomization at 9 months. There was no significant difference in 12-month PALS median performance scores after the booster training between the intervention and usual practice groups (83% vs. 94%, P = 0.31). There was significant improvement in PALS performance score from 51 ± 27% pre-initial RCDP assessment to 93 ± 5% post-initial RCDP training (P < 0.001). There were significant improvements in individual skills from pre- to post-initial RCDP testing, including time to verbalize pulseless, start compressions, and attach defibrillation pads (P < 0.001)., Conclusions: Rapid cycle deliberate practice booster training versus plus/delta training at 9-month post-initial RCDP training did not alter 12-month performance. However, RCDP is effective at improving PALS performance skills, and this effect is maintained at 6, 9, and 12 months. Our study supports the importance of supplemental resuscitation training in addition to the traditional PALS course., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Society for Simulation in Healthcare.)

The activity of local anesthetics (LAs) has been attributed to the inhibition of ion channels, causing anesthesia. However, there is a growing body of research showing that LAs act on a wide range of receptors and channel proteins far beyond simple analgesia. The current concept of ligand recognition may no longer explain the multitude of protein targets influenced by LAs. We hypothesize that LAs can cause anesthesia without directly binding to the receptor proteins just by changing the physical properties of the lipid bilayer surrounding these proteins and ion channels based on LAs' amphiphilicity. It is possible that LAs act in one of the following ways: They 1) dissolve raft-like membrane microdomains, 2) impede nerve impulse propagation by lowering the lipid phase transition temperature, or 3) modulate the lateral pressure profile of the lipid bilayer. This could also explain the numerous additional effects of LAs besides anesthesia. Furthermore, the concepts of membrane-mediated activity and binding to ion channels do not have to exclude each other. If we were to consider LA as the middle part of a continuum between unspecific membrane-mediated activity on one end and highly specific ligand binding on the other end, we could describe LA as the link between the unspecific action of general anesthetics and toxins with their highly specific receptor binding. This comprehensive membrane-mediated model offers a fresh perspective to clinical and pharmaceutical research and therapeutic applications of local anesthetics. SIGNIFICANCE STATEMENT: Local anesthetics, according to the World Health Organization, belong to the most important drugs available to mankind. Their rediscovery as therapeutics and not only anesthetics marks a milestone in global pain therapy. The membrane-mediated mechanism of action proposed in this review can explain their puzzling variety of target proteins and their thus far inexplicable therapeutic effects. The new concept presented here places LAs on a continuum of structures and molecular mechanisms in between small general anesthetics and the more complex molecular toxins., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

[Figure: see text].

Objective: To investigate the association between disease-modifying therapies (DMTs) and the rate of progressive retinal ganglion cell (RGC) and nerve fiber loss in MS., Methods: One hundred five relapsing-remitting patients with MS were followed annually for a median of 4.0 years using optical coherence tomography. Twenty-five healthy subjects were also included as normal controls. The rates of global peripapillary retinal nerve fiber layer (pRNFL), temporal RNFL (tRNFL), and ganglion cell inner plexiform layer (GCIPL) thinning were analyzed according to DMT type using a linear mixed-effects model. Optic radiation lesion volume was measured on brain MRI and included as a covariate to minimize the effects of retrograde transsynaptic degeneration., Results: The annual rates of RNFL and GCIPL thinning were higher in patients treated with "platform" therapies (interferon-β and glatiramer acetate) compared with DMTs of higher clinical efficacy (including fingolimod, dimethyl fumarate, natalizumab, alemtuzumab, rituximab, and ocrelizumab) (difference = -0.22 μm/y, p = 0.02 for pRNFL; difference = -0.34 μm/y, p = 0.009 for tRNFL; and difference = -0.16 μm/y, p = 0.005 for GCIPL). Based on an analysis of individual treatments (interferon-β, glatiramer acetate, fingolimod, and natalizumab), interferon-β was associated with inferior RGC preservation, relative to the other drugs. No effect difference was found between glatiramer acetate, fingolimod, and natalizumab., Conclusions: Progressive loss of RGCs in patients with MS is more pronounced in patients treated with interferon-β than other DMTs. This finding may have implications for DMT selection in MS., Classification of Evidence: This study provides Class IV evidence that for patients with MS, treatment with interferon-β compared with other DMTs leads to a more pronounced rate of retinal ganglion cell loss., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To assess whether angiotensin II-stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers, and angiotensin I receptor blockers) convey a lower risk of incident dementia compared to angiotensin II-inhibiting antihypertensives (angiotensin-converting enzyme inhibitors, β-blockers, and nondihydropyridine calcium channel blockers), in accordance with the "angiotensin hypothesis.", Methods: We performed Cox regression analyses of incident dementia (or mortality as competing risk) during 6-8 years of follow-up in a population sample of 1,909 community-dwelling individuals (54% women) without dementia, aged 70-78 (mean 74.5 ± 2.5) years., Results: After a median of 6.7 years of follow-up, dementia status was available for 1,870 (98%) and mortality for 1,904 (>99%) participants. Dementia incidence was 5.6% (27/480) in angiotensin II-stimulating, 8.2% (59/721) in angiotensin II-inhibiting, and 6.9% (46/669) in both antihypertensive type users. Adjusted for dementia risk factors including blood pressure and medical history, angiotensin II-stimulating antihypertensive users had a 45% lower incident dementia rate (hazard ratio [HR], 0.55; 95% CI, 0.34-0.89) without excess mortality (HR, 0.86; 95% CI, 0.64-1.16), and individuals using both types had a nonsignificant 20% lower dementia rate (HR, 0.80; 95% CI,0.53-1.20) without excess mortality (HR, 0.97; 95% CI, 0.76-1.24), compared to angiotensin II-inhibiting antihypertensive users. Results were consistent for subgroups based on diabetes and stroke history, but may be specific for individuals without a history of cardiovascular disease., Conclusions: Users of angiotensin II-stimulating antihypertensives had lower dementia rates compared to angiotensin II-inhibiting antihypertensive users, supporting the angiotensin hypothesis. Confounding by indication must be examined further, although subanalyses suggest this did not influence results. If replicated, dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Rationale: Brain arteriovenous malformations (AVMs) are abnormal tangles of vessels where arteries and veins directly connect without intervening capillary nets, increasing the risk of intracerebral hemorrhage and stroke. Current treatments are highly invasive and often not feasible. Thus, effective noninvasive treatments are needed. We previously showed that AVM-brain endothelial cells (BECs) secreted higher VEGF (vascular endothelial growth factor) and lower TSP-1 (thrombospondin-1) levels than control BEC; and that microRNA-18a (miR-18a) normalized AVM-BEC function and phenotype, although its mechanism remained unclear., Objective: To elucidate the mechanism of action and potential clinical application of miR-18a as an effective noninvasive treatment to selectively restore the phenotype and functionality of AVM vasculature., Methods and Results: The molecular pathways affected by miR-18a in patient-derived BECs and AVM-BECs were determined by Western blot, RT-qPCR (quantitative reverse transcription polymerase chain reaction), ELISA, co-IP, immunostaining, knockdown and overexpression studies, flow cytometry, and luciferase reporter assays. miR-18a was shown to increase TSP-1 and decrease VEGF by reducing PAI-1 (plasminogen activator inhibitor-1/SERPINE1) levels. Furthermore, miR-18a decreased the expression of BMP4 (bone morphogenetic protein 4) and HIF-1α (hypoxia-inducible factor 1α), blocking the BMP4/ALK (activin-like kinase) 2/ALK1/ALK5 and Notch signaling pathways. As determined by Boyden chamber assays, miR-18a also reduced the abnormal AVM-BEC invasiveness, which correlated with a decrease in MMP2 (matrix metalloproteinase 2), MMP9, and ADAM10 (ADAM metallopeptidase domain 10) levels. In vivo pharmacokinetic studies showed that miR-18a reaches the brain following intravenous and intranasal administration. Intranasal co-delivery of miR-18a and NEO100, a good manufacturing practices-quality form of perillyl alcohol, improved the pharmacokinetic profile of miR-18a in the brain without affecting its pharmacological properties. Ultra-high-resolution computed tomography angiography and immunostaining studies in an Mgp - /- AVM mouse model showed that miR-18a decreased abnormal cerebral vasculature and restored the functionality of the bone marrow, lungs, spleen, and liver., Conclusions: miR-18a may have significant clinical value in preventing, reducing, and potentially reversing AVM.

Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data., Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity., Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis., Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity., Classification of Evidence: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined., Methods: We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group., Results: The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups., Conclusions: A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.)., (Copyright © 2020 Massachusetts Medical Society.)

The COVID-19 pandemic is causing world-wide social dislocation, operational and economic dysfunction, and high rates of morbidity and mortality. Medical practices are responding by developing, disseminating, and implementing unprecedented changes in health care delivery. Telemedicine has rapidly moved to the frontline of clinical practice due to the need for prevention and mitigation strategies; these have been encouraged, facilitated, and enabled by changes in government rules and regulations and payer-driven reimbursement policies. We describe our neurology department's situational transformation from in-person outpatient visits to a largely virtual neurology practice in response to the COVID-19 pandemic. Two key factors enabled our rapid deployment of virtual encounters in neurology and its subspecialties. The first was a well-established robust information technology infrastructure supporting virtual urgent care services at our institution; this connected physicians directly to patients using both the physician's and the patient's own mobile devices. The second is the concept of one patient, one chart, facilitated by a suite of interconnected electronic medical record (EMR) applications on several different device types. We present our experience with conducting general teleneurology encounters using secure synchronous audio and video connections integrated with an EMR. This report also details how we perform virtual neurologic examinations that are clinically meaningful and how we document, code, and bill for these virtual services. Many of these processes can be used by other neurology providers, regardless of their specific practice model. We then discuss potential roles for teleneurology after the COVID-19 global pandemic has been contained., (© 2020 American Academy of Neurology.)

Objective: To outline changes made to a neurology residency program in response to coronavirus disease 2019 (COVID-19)., Methods: In early March 2020, the first cases of COVID-19 were announced in the United States. New York City quickly became the epicenter of a global pandemic, and our training program needed to rapidly adapt to the increasing number of inpatient cases while being mindful of protecting providers and continuing education. Many of these changes unfolded over days, including removing residents from outpatient services, minimizing the number of residents on inpatient services, deploying residents to medicine services and medical intensive care units, converting continuity clinic patient visits to virtual options, transforming didactics to online platforms only, and maintaining connectedness in an era of social distancing. We have been able to accomplish this through daily virtual meetings among leadership, faculty, and residents., Results: Over time, our program has successfully rolled out initiatives to service the growing number of COVID-related inpatients while maintaining neurologic care for those in need and continuing our neurologic education curriculum., Conclusion: It has been necessary and feasible for our residency training program to undergo rapid structural changes to adapt to a medical crisis. The key ingredients in doing this successfully have been flexibility and teamwork. We suspect that many of the implemented changes will persist long after the COVID-19 crisis has passed and will change the approach to neurologic and medical training., (© 2020 American Academy of Neurology.)

Objective: Polygenic risk scores (PRSs) are used to quantify the cumulative effects of a number of genetic variants, which may individually have a very small effect on susceptibility to a disease; we used PRSs to better understand the genetic contribution to common epilepsy and its subtypes., Methods: We first replicated previous single associations using 373 unrelated patients. We then calculated PRSs in the same French Canadian patients with epilepsy divided into 7 epilepsy subtypes and population-based controls. We fitted a logistic mixed model to calculate the variance explained by the PRS using pseudo-R 2 statistics., Results: We show that the PRS explains more of the variance in idiopathic generalized epilepsy than in patients with nonacquired focal epilepsy. We also demonstrate that the variance explained is different within each epilepsy subtype., Conclusions: Globally, we support the notion that PRSs provide a reliable measure to rightfully estimate the contribution of genetic factors to the pathophysiologic mechanism of epilepsies, but further studies are needed on PRSs before they can be used clinically., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To examine the effect of chronic demyelination in the optic nerve of patients with MS on progressive loss of retinal ganglion cell (RGC) axons., Methods: Progressive retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography, was longitudinally examined in 51 patients with MS with a history of unilateral optic neuritis (ON) and 25 normal controls. Patients were examined annually with a median of 4-year follow-up. Pairwise intereye comparison was performed between ON and fellow non-ON (NON) eyes of patients with MS using the linear mixed-effects model and survival analysis. The latency asymmetry of multifocal visual evoked potential (mfVEP) was used to determine the level of demyelination in the optic nerve., Results: Although both ON and NON eyes demonstrate significantly faster loss of RGC axons compared with normal subjects, ON eyes with severe chronic demyelination show accelerated thinning in the RNFL in the temporal sector of the optic disc (temporal RNFL [tRNFL]) compared with fellow eyes (evidenced by both the linear mixed-effects model and survival analysis). Furthermore, progressive tRNFL thinning is associated with the degree of optic nerve demyelination and reflects the topography of pathology in the optic nerve. More rapid axonal loss in ON eyes is also functionally evidenced by mfVEP amplitude reduction, which correlates with the level of optic nerve demyelination., Conclusions: Although the effect of demyelination on axonal survival has been demonstrated in experimental studies, our results provide first clinically meaningful evidence that chronic demyelination is associated with progressive axonal loss in human MS., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background Acute kidney injury (AKI) remains a concern in hospitalized children undergoing CT with intravenous iodinated contrast material (ICM). Adult studies have shown frequencies of AKI after CT with intravenous ICM to be similar to propensity score-matched ICM-unexposed patient groups; similar data in pediatric patients are lacking. Purpose To evaluate the association between intravenous ICM exposure and AKI in hospitalized pediatric patients with stable kidney function undergoing contrast material-enhanced CT by comparing with a propensity score-matched ICM-unexposed patient sample undergoing abdominal US. Materials and Methods In this retrospective observational study, hospitalized patients aged 18 years or younger with stable kidney function and available serum creatinine (SCr) measurement before and after imaging who underwent CT with intravenous ICM or abdominal US (control group) between January 2009 and November 2018 were identified. The 1:1 propensity score matching was performed by using 23 covariates, stratified by estimated glomerular filtration rate (eGFR) before imaging (≥60 mL/min/1.73 m 2 or <60 mL/min/1.73 m 2 ). AKI was defined by using Acute Kidney Injury Network SCr-related criteria. Multivariable logistic regression was performed to identify risk factors for AKI after imaging, including the effects of eGFR and intravenous ICM exposure before imaging. Results A total of 1850 unique patients were included in the propensity score-matched sample (925 exposed to ICM [mean age ± standard deviation, 8 years ± 6; 484 female patients]; 925 unexposed to ICM [mean age, 7 years ± 6; 484 female patients]). Frequency of AKI with eGFR greater than or equal to 60 mL/min/1.73 m 2 was 2.2% (20 of 889) for CT and US (odds ratio [OR]: 0.98; 95% confidence interval [CI]: 0.52, 1.86; adjusted P = .95) and with eGFR less than 60 mL/min/1.73 m 2 was 5.6% (two of 36) and 11.1% (four of 36) for CT and US, respectively (OR: 0.75; 95% CI: 0.11, 5.00; adjusted P = .76). Significant multivariable predictors of AKI included eGFR before imaging (OR: 0.99; 95% CI: 0.98, 0.995; P = .001), body mass index (OR: 1.06; 95% CI: 1.02, 1.10; P = .003), acquired kidney disease (OR: 1.95; 95% CI: 1.004, 3.78; P = .049), and nephrotoxic antibiotic exposure (OR: 2.86; 95% CI: 1.55, 5.25; P < .001). Intravenous ICM exposure was not predictive (OR: 0.91; 95% CI: 0.51, 1.64; P > .05). Conclusion Hospitalized children with stable kidney function who underwent CT with intravenous iodinated contrast material (ICM) had a similar frequency of acute kidney injury (AKI) compared with a propensity score-matched ICM-unexposed patient group. In pediatric inpatients with estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73 m 2 , ICM was not independently associated with AKI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Paltiel in this issue.

Background: Cardiac rehabilitation (CR) is recommended in clinical practice guidelines, but dose prescribed varies highly by country. This study characterized the dose offered in supervised CR programs and alternative models worldwide and their potential correlates., Methods and Results: In this cross-sectional study, an online survey was administered to CR programs globally. Cardiac associations and local champions facilitated program identification. Countries were classified based on region and income categories. Dose was operationalized as program duration×sessions per week. Generalized linear mixed models were performed to assess correlates. Of 203 countries in the world, 111 (54.7%) offered CR; data were collected in 93 (83.8% country response rate; n=1082 surveys, 32.1% program response rate). Globally, supervised CR programs were a median of 24 sessions (n=619, 57.3% programs ≥12 sessions); home-based and community-based programs offered 6 and 20 sessions, respectively. There was significant variation in supervised CR dose by region ( P ≤0.001), with the Americas (median, 36 sessions) offering a significantly greater dose than several other regions; there was also a trend for variation by country income classification. There was no difference in home-based dose by region ( P =0.43) but there was for community-based programs ( P <0.05; Americas offering greater dose). There was a significant dose variation in both home- and community-based programs by income classification ( P =0.002 and P <0.001, respectively), with higher doses offered by upper-middle-income than high-income countries. Correlates of supervised CR dose included more involvement of physicians ( P =0.026), proximity to other programs ( P =0.002), and accepting patients with noncardiac indications ( P =0.037)., Conclusions: CR programs in many countries may need to increase their dose, which could be supported through physician champions.

Background: Although the national obesity epidemic has been well documented, less is known about obesity at the U.S. state level. Current estimates are based on body measures reported by persons themselves that underestimate the prevalence of obesity, especially severe obesity., Methods: We developed methods to correct for self-reporting bias and to estimate state-specific and demographic subgroup-specific trends and projections of the prevalence of categories of body-mass index (BMI). BMI data reported by 6,264,226 adults (18 years of age or older) who participated in the Behavioral Risk Factor Surveillance System Survey (1993-1994 and 1999-2016) were obtained and corrected for quantile-specific self-reporting bias with the use of measured data from 57,131 adults who participated in the National Health and Nutrition Examination Survey. We fitted multinomial regressions for each state and subgroup to estimate the prevalence of four BMI categories from 1990 through 2030: underweight or normal weight (BMI [the weight in kilograms divided by the square of the height in meters], <25), overweight (25 to <30), moderate obesity (30 to <35), and severe obesity (≥35). We evaluated the accuracy of our approach using data from 1990 through 2010 to predict 2016 outcomes., Results: The findings from our approach suggest with high predictive accuracy that by 2030 nearly 1 in 2 adults will have obesity (48.9%; 95% confidence interval [CI], 47.7 to 50.1), and the prevalence will be higher than 50% in 29 states and not below 35% in any state. Nearly 1 in 4 adults is projected to have severe obesity by 2030 (24.2%; 95% CI, 22.9 to 25.5), and the prevalence will be higher than 25% in 25 states. We predict that, nationally, severe obesity is likely to become the most common BMI category among women (27.6%; 95% CI, 26.1 to 29.2), non-Hispanic black adults (31.7%; 95% CI, 29.9 to 33.4), and low-income adults (31.7%; 95% CI, 30.2 to 33.2)., Conclusions: Our analysis indicates that the prevalence of adult obesity and severe obesity will continue to increase nationwide, with large disparities across states and demographic subgroups. (Funded by the JPB Foundation.)., (Copyright © 2019 Massachusetts Medical Society.)

Novel mechanisms and health benefits have been recently suggested for the antidepressant drug phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT: Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Semicarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: To evaluate the combined effect of lesion activity and pathologic processes occurring in both chronically demyelinated lesions and normal-appearing white matter (NAWM) on brain atrophy in MS., Methods: Pre- and post-gadolinium T1, fluid attenuation inversion recovery, and diffusion tensor imaging images were acquired from 50 consecutive patients with relapsing-remitting MS (all, but one, on disease-modifying therapy) at baseline and 5 years. Brain atrophy was measured using structural image evaluation, using normalization of atrophy percent brain volume change (PBVC) analysis., Results: During follow-up, brain volume diminished by 2.0% ± 1.1%. PBVC was not associated with patient age, disease duration, sex, or type of treatment. PBVC moderately correlated with baseline lesion load ( r = -0.38, p = 0.016), but demonstrated strong association with new lesion activity ( r = -0.63, p < 0.001). Brain atrophy was also strongly linked to the increase of water diffusion within chronic MS lesions ( r = -0.62, p < 0.001). In normal-appearing white matter (NAWM), PBVC demonstrated a significant correlation with both baseline and longitudinal increase of demyelination as measured by radial diffusivity (RD, r = -0.44, p = 0.005 and r = -0.35, p = 0.026, respectively). Linear regression analysis explained 62% of the variance in PBVC. It confirmed the major role of new lesion activity ( p = 0.002, standardized beta-coefficient -0.42), whereas change in diffusivity inside chronic lesions and NAWM RD at baseline also contributed significantly ( p = 0.04 and 0.02, standardized beta-coefficient -0.31 and -0.29, respectively), increasing predictive power of the model by 55%., Conclusion: In addition to new lesion activity, progressive loss of demyelinated axons in chronic lesions and the degree of demyelination in NAWM significantly contribute to accelerated loss of brain tissue in patients with MS receiving immunomodulatory therapy., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Organ shortage is an ongoing problem in the United States. Most donor organs are procured following brain death and a significant portion of brain-dead donors result from devastating brain injury. Without a standard practice for hormone replacement therapy (HRT) in the setting of brain death, a comprehensive review of the literature was deemed necessary., Methods: A search of published literature was conducted with terms "TBI" or "brain injury" or "head injury" AND "hormone" or "management" AND "organ" AND "donor" or "donation." Abstracts and full texts were screened for relevance and inclusion of information on HRT. Additional studies were selected from references cited within these. Excluded studies were non-English, nonhuman based, or had small sample size, (i.e., case reports or series with fewer than five subjects)., Results: Fifteen studies were selected for inclusion and contained Level III or Level IV evidence. Combinations of thyroid hormone, insulin, and corticosteroids were the most commonly cited HRT. Ninety-three percent of studies found a significant increase in organ procurement rate among donors who received HRT. Hormone replacement therapy was administered after brain death declaration in eight studies. Only two studies specifically explored the effects of starting HRT earlier and identified even greater procurement rates. Four studies were specific to traumatic brain injury (TBI); the remaining 11 studies involved TBI in 22% to 89% of the sample., Conclusion: Organ shortage remains a growing problem in the United States. Donor management including HRT has been proposed to combat the endocrine derangement associated with brain death and, in particular, TBI. While the existing literature reported compelling outcomes using HRT, there remains a need for further Level I and Level II evidence studies to define optimal practice., Level of Evidence: Review article, level IV.

Background: The explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that have implications for diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels as in congenital arrhythmia syndromes, in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost, time, and labor intensive., Methods: We implemented a strategy for performing high-throughput functional evaluations of ion channel variants that repurposed an automated electrophysiological recording platform developed previously for drug discovery., Results: We demonstrated the success of this approach by evaluating 78 variants in KCNQ1, a major gene involved in genetic disorders of cardiac arrhythmia susceptibility. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. This strategy also enabled studies of dominant-negative behavior of variants exhibiting severe loss-of-function. Overall, our results provided functional data useful for reclassifying >65% of the studied KCNQ1 variants., Conclusions: Our results illustrate an efficient and high-throughput paradigm linking genotype to function for a human cardiac ion channel that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.

Abacavir is a preferred antiretroviral drug for preventing mother-to-child human immunodeficiency virus transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abacavir is a nucleoside-derived drug, we hypothesized that the nucleoside transporters, equilibrative nucleoside transporters (ENTs, SLC29A ) and/or Na + -dependent concentrative nucleoside transporters (CNTs, SLC28A ), may play a role in its passage across the placenta. To test this hypothesis, we performed uptake experiments using the choriocarcinoma-derived BeWo cell line, human fresh villous fragments, and microvillous plasma membrane (MVM) vesicles. Using endogenous substrates of nucleoside transporters, [ 3 H]-adenosine (ENTs, CNT2, and CNT3) and [ 3 H]-thymidine (ENTs, CNT1, and CNT3), we showed significant activity of ENT1 and CNT2 in BeWo cells, whereas experiments in the villous fragments and MVM vesicles, representing a model of the apical membrane of a syncytiotrophoblast, revealed only ENT1 activity. When testing [ 3 H]-abacavir uptakes, we showed that of the nucleoside transporters, ENT1 plays the dominant role in abacavir uptake into placental tissues, whereas contribution of Na + -dependent transport, most likely mediated by CNTs, was observed only in BeWo cells. Subsequent experiments with dually perfused rat term placentas showed that Ent1 contributes significantly to overall [ 3 H]-abacavir placental transport. Finally, we quantified the expression of SLC29A in first- and third-trimester placentas, revealing that SLC29A1 is the dominant isoform. Neither SLC29A1 nor SLC29A2 expression changed over the course of placental development, but there was considerable interindividual variability in their expression. Therefore, drug-drug interactions and the effect of interindividual variability in placental ENT1 expression on abacavir disposition into fetal circulation should be further investigated to guarantee safe and effective abacavir-based combination therapies in pregnancy., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: We aimed to assess whether differences in energy metabolism in fibroblast cell lines derived from patients with Huntington disease were associated with age at onset independent of the cytosine-adenine-guanine (CAG) repeat number in the mutant allele., Methods: For this study, we selected 9 pairs of patients with Huntington disease matched for mutant CAG repeat size and sex, but with a difference of at least 10 years in age at onset, using the Leiden Huntington disease database. From skin biopsies, we isolated fibroblasts in which we (1) quantified the ATP concentration before and after a hydrogen-peroxide challenge and (2) measured mitochondrial respiration and glycolysis in real time, using the Seahorse XF Extracellular Flux Analyzer XF24., Results: The ATP concentration in fibroblasts was significantly lower in patients with Huntington disease with an earlier age at onset, independent of calendar age and disease duration. Maximal respiration, spare capacity, and respiration dependent on complex II activity, and indices of mitochondrial respiration were significantly lower in patients with Huntington disease with an earlier age at onset, again independent of calendar age and disease duration., Conclusions: A less efficient bioenergetics profile was found in fibroblast cells from patients with Huntington disease with an earlier age at onset independent of mutant CAG repeat size. Thus, differences in bioenergetics could explain part of the residual variation in age at onset in Huntington disease.

Background: Rituximab plus chemotherapy has been shown to be effective in patients with advanced-stage, previously untreated follicular lymphoma; nevertheless, most patients will have a relapse. Combination immunotherapy with lenalidomide and rituximab is an immunomodulatory regimen that has shown promising activity in patients with indolent B-cell non-Hodgkin's lymphoma., Methods: We conducted this multicenter, international, phase 3 superiority trial to evaluate rituximab plus lenalidomide, as compared with rituximab plus chemotherapy, in patients with previously untreated follicular lymphoma. Patients were randomly assigned to receive one of the two regimens, followed by maintenance monotherapy with rituximab. Treatment with rituximab plus lenalidomide consisted of 18 cycles of the two drugs, followed by rituximab maintenance therapy every 8 weeks for 12 cycles (six additional doses). Treatment with rituximab plus chemotherapy consisted of the investigator's choice of one of three rituximab-based regimens, followed by maintenance monotherapy with rituximab every 8 weeks for 12 cycles. The primary end points were complete response (confirmed or unconfirmed) at 120 weeks and progression-free survival., Results: A total of 1030 patients were randomly assigned to receive rituximab plus lenalidomide (513 patients) or rituximab plus chemotherapy (517 patients). The rate of confirmed or unconfirmed complete response at 120 weeks was similar in the two groups: 48% (95% confidence interval [CI], 44 to 53) in the rituximab-lenalidomide group and 53% (95% CI, 49 to 57) in the rituximab-chemotherapy group (P=0.13). The interim 3-year rate of progression-free survival was 77% (95% CI, 72 to 80) and 78% (95% CI, 74 to 82), respectively. A higher percentage of patients in the rituximab-chemotherapy group had grade 3 or 4 neutropenia (32% vs. 50%) and febrile neutropenia of any grade (2% vs. 7%), and a higher percentage of patients in the rituximab-lenalidomide group had grade 3 or 4 cutaneous reactions (7% vs. 1%)., Conclusions: Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).

Purpose To investigate the topologic architecture of white matter connectivity networks in preschool-aged children with a diagnosis of autism spectrum disorder (ASD) versus typical development (TD). Materials and Methods Forty-two participants were enrolled, including 21 preschool children with ASD (14 male children and seven female children; mean age, 4.56 years ± 0.97 [standard deviation]) and 21 children with TD (11 males and 10 females; mean age, 5.13 years ± 0.82). The diagnosis of ASD was determined according to the Diagnostic and Statistical Manual of Mental Disorders Global Assessment of Functioning scores (mean score, 8.00 ± 0.50). All participants underwent diffusion-tensor imaging (DTI) and T2-weighted imaging on a 3-T magnetic resonance system. A graph theoretical analysis was applied to investigate the topologic organization of the brain network including global and local topologic parameters. Statistical analysis was then performed for the comparison between the groups. Results Compared with the TD group, children with ASD demonstrated shortened characteristic path length (t 1 = 0.536, t 2 = 0.534, t 3 = 0.523, t 4 = 0.510, and t 5 = 0.501; P < .05) and increased global efficiency (t 1 = 0.499, t 2 = 0.497, t 3 = 0.486, t 4 = 0.473, and t 5 = 0.465; P < .05) and clustering coefficient (t 1 = 0.673, t 2 = 0.750, t 3 = 0.757, t 4 = 0.738, and t 5 = 0.741; P < .05). Significant increases in nodal efficiency were mainly found in left pallidum (0.037 vs 0.032, respectively; P < .01) and right caudate nucleus (0.037 vs 0.032, respectively; P < .01) of the basal ganglia network. Conclusion Significantly altered patterns of global and local brain network topography may underlie the abnormal brain development in preschool children with ASD compared with those who have TD. The identification of altered structural connectivity in basal ganglia and paralimbic-limbic networks may point toward potential imaging biomarkers for preschool-age patients with ASD. © RSNA, 2018.

Purpose To compare the cost-effectiveness of computed tomographic (CT) colonography and colonoscopy screening by using data on unit costs and participation rates from a randomized controlled screening trial in a dedicated screening setting. Materials and Methods Observed participation rates and screening costs from the Colonoscopy or Colonography for Screening, or COCOS, trial were used in a microsimulation model to estimate costs and quality-adjusted life-years (QALYs) gained with colonoscopy and CT colonography screening. For both tests, the authors determined optimal age range and screening interval combinations assuming a 100% participation rate. Assuming observed participation for these combinations, the cost-effectiveness of both tests was compared. Extracolonic findings were not included because long-term follow-up data are lacking. Results The participation rates for colonoscopy and CT colonography were 21.5% (1276 of 5924 invitees) and 33.6% (982 of 2920 invitees), respectively. Colonoscopy was more cost-effective in the screening strategies with one or two lifetime screenings, whereas CT colonography was more cost-effective in strategies with more lifetime screenings. CT colonography was the preferred test for willingness-to-pay-thresholds of €3200 per QALY gained and higher, which is lower than the Dutch willingness-to-pay threshold of €20 000. With equal participation, colonoscopy was the preferred test independent of willingness-to-pay thresholds. The findings were robust for most of the sensitivity analyses, except with regard to relative screening costs and subsequent participation. Conclusion Because of the higher participation rates, CT colonography screening for colorectal cancer is more cost-effective than colonoscopy screening. The implementation of CT colonography screening requires previous satisfactory resolution to the question as to how best to deal with extracolonic findings. © RSNA, 2018 Online supplemental material is available for this article.

Background: Mesenchymal stem cells (MSCs) have been shown to mitigate vascular permeability in hemorrhagic shock (HS) and trauma-induced brain and lung injury. Mechanistically, paracrine factors secreted from MSCs have been identified that can recapitulate many of the potent biologic effects of MSCs in animal models of disease. Interestingly, MSC-derived extracellular vesicles (EVs), contain many of these key soluble factors, and have therapeutic potential independent of the parent cells. In this study we sought to determine whether MSC-derived EVs (MSC EVs) could recapitulate the beneficial therapeutic effects of MSCs on lung vascular permeability induced by HS in mice., Methods: Mesenchymal stem cell EVs were isolated from human bone marrow-derived MSCs by ultracentrifugation. A mouse model of fixed pressure HS was used to study the effects of shock, shock + MSCs and shock + MSC EVs on lung vascular endothelial permeability. Mice were administered MSCs, MSC EVs, or saline IV. Lung tissue was harvested and assayed for permeability, RhoA/Rac1 activation, and for differential phosphoprotein expression. In vitro, human lung microvascular cells junctional integrity was evaluated by immunocytochemistry and endothelial cell impedance assays., Results: Hemorrhagic shock-induced lung vascular permeability was significantly decreased by both MSC and MSC EV infusion. Phosphoprotein profiling of lung tissue revealed differential activation of proteins and pathways related to cytoskeletal rearrangement and regulation of vascular permeability by MSCs and MSC EVs. Lung tissue from treatment groups demonstrated decreased activation of the cytoskeletal GTPase RhoA. In vitro, human lung microvascular cells, MSC CM but not MSC-EVs prevented thrombin-induced endothelial cell permeability as measured by electrical cell-substrate impedance sensing system and immunocytochemistry of VE-cadherin and actin., Conclusion: Mesenchymal stem cells and MSC EVs modulate cytoskeletal signaling and attenuate lung vascular permeability after HS. Mesenchymal stem cell EVs may potentially be used as a novel "stem cell free" therapeutic to treat HS-induced lung injury.

Objective: To investigate primary retinal functional changes in non-optic neuritis (ON) eyes of patients with MS by full-field electroretinography (ERG)., Methods: Seventy-seven patients with relapsing-remitting MS with no history of clinical ON in at least 1 eye and 30 healthy controls were recruited in the cohort study. Full-field ERGs were recorded, and retinal optical coherence tomography scans were performed to assess the thicknesses of peripapillary retinal nerve fiber layer (RNFL) and retinal ganglion cell layer-inner plexiform layer (GCL-IPL). Annual MRI scans were also carried out to evaluate the disease activity in the brain. Patients were followed up for 3 years., Results: At baseline, a delayed b-wave peak time was observed in the cone response ( p < 0.001), which was associated with the thicknesses of RNFL and GCL-IPL. The peak time of the delayed b-wave also correlated with the Expanded Disability Status Scale, T2 lesion volume, and disease duration. During the 3-year follow-up, progressive ERG amplitude reduction was observed (both a- and b-waves, p < 0.05). There was a correlation between the b-wave amplitude reduction and longitudinal RNFL loss ( p = 0.001). However, no correlation was found between longitudinal ERG changes and disease activity in the brain., Conclusions: This study demonstrated progressive inner nuclear layer dysfunction in MS. The borderline a-wave changes suggested some outer retinal dysfunction as well. The correlation between full-field ERG changes and retinal ganglion cell loss suggested that there might be subclinical retinal pathology in MS affecting both outer and inner retinal layers.