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The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

Supplemental material, sj-docx-1-msj-10.1177_13524585231184738 for Intravenous immunoglobulin treatment for acute attacks in myelin oligodendrocyte glycoprotein antibody disease by Itay Lotan, John J Chen, Yael Hacohen, Omar Abdel-Mannan, Sara Mariotto, Saif Huda, Emily Gibbons, Adi Wilf-Yarkoni, Mark A Hellmann, Hadas Stiebel-Kalish, Sean J Pittock, Eoin P Flanagan, Negar Molazadeh, Monique Anderson, Rebecca Salky, Gabriela Romanow, Patrick Schindler, Ankelien Solveig Duchow, Friedemann Paul and Michael Levy in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585231184738 for Intravenous immunoglobulin treatment for acute attacks in myelin oligodendrocyte glycoprotein antibody disease by Itay Lotan, John J Chen, Yael Hacohen, Omar Abdel-Mannan, Sara Mariotto, Saif Huda, Emily Gibbons, Adi Wilf-Yarkoni, Mark A Hellmann, Hadas Stiebel-Kalish, Sean J Pittock, Eoin P Flanagan, Negar Molazadeh, Monique Anderson, Rebecca Salky, Gabriela Romanow, Patrick Schindler, Ankelien Solveig Duchow, Friedemann Paul and Michael Levy in Multiple Sclerosis Journal

Additional file 4: Table S2: Spearman correlation analysis with and without rituximab intervention in the NMOSD group. n.s.: not significant; *: p < 0.01.

Additional file 1: Figure S1. The gating strategy in the NK/NKT panel of this study. After excluding doublet cells, lymphocyte subsets were extracted using FSCs and SSCs. Next, dead cells were excluded by Live/Dead staining, and nucleated cells were gated with CD45. After using CD3 and CD14, a subset of CD3-positive CD14-negative CD56-positive cells was defined as NKT cells and a subset of CD3-negative CD14-negative CD56-positive cells as NK cells for downstream analysis. For each subset, We analyzed CD16-positive, CD35-positive, CD88-positive, CD69-positive, and CD83-positive rates; for NKT cells, we also analyzed TCR Vα24-positive rates.

Additional file 3: Table S1: Spearman correlation analysis for the NMOSD group between the parameters. n.s.: not significant; *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001.

Additional file 2: Figure S2. Analysis of TCR Vα24-Jα18-positive NKT cells. The downstream analysis of NKT cells with TCR Vα24-Jα18-positive gating among the NMOSD group showed significantly higher CD83 expression against the Normal Control group (D).

BackgroundInebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770).MethodsPeripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed.FindingsInebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024-0.04] vs 0.086 [0.056-0.12]; p=0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43-0.56] vs 1.36 [1.12-1.61]; p&nbsp

Structural signatures of innovation, cooperation, and boundary spanning in agriculture knowledge networks

Purpose To highlight the clinical, neuroradiographic, neuropathologic, and molecular features of histologically identified neurocytoma in a pediatric cohort and highlight the evolving use methylation profiling in providing diagnostic clarity in difficult to diagnosis pediatric brain tumors. Methods Five consecutive children (ages 9–13, 2 girls 3 boys) were histologically diagnosed with neurocytoma at Rady Children’s Hospital San Diego from 2012 to 2018. Clinical and molecular features were analyzed with regards to treatment course and outcome. Results Presenting symptoms included seizures (n = 2), syncope (n = 1), headache (n = 2), visual disturbances (n = 2) and emesis (n = 2). Tumor location included intraventricular (n = 2), intraventricular with parenchymal spread (n = 1), and extraventricular (n = 2). Magnetic resonance imaging demonstrated reduced diffusivity (2/5), signal abnormality on susceptibility-weighted sequences (3/5), and varying degrees of contrast enhancement (4/5). All patients underwent surgical resection alone. Recurrence occurred in four children that were treated with surgery (4/4), adjuvant radiation (2/4), and chemoradiation (1/4). Neuropathologic features included positivity for GFAP (4/5), synaptophysin (4/5), NSE (2/2), NeuN (4/4), and variable Ki-67 ( Conclusion Neurocytomas are a rare clinical entity that warrants further investigation into molecular and pathologic prognosticating features. Methylation profiling may aid in differentiation of neurocytoma from other difficult to diagnose tumors who share similar histologic features.

ObjectivesTo synthesize knowledge describing the impact of social distancing measures (SDM) during the first wave of the COVID-19 pandemic on acute illness in children by focusing on the admission to pediatric emergency departments (PED) and pediatric intensive care units (PICU).MethodsWe searched Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, EPOC Register, MEDLINE, Evidence-Based Medicine Reviews, EMBASE, WHO database on COVID-19, Cochrane Resources on COVID-19, Oxford COVID-19 Evidence Service, Google Scholar for literature on COVID-19 including pre-print engines such as medRxiv, bioRxiv, Litcovid and SSRN for unpublished studies on COVID-19 in December 2020. We did not apply study design filtering. The primary outcomes of interest were the global incidence of admission to PICU and PED, disease etiologies, and elective/emergency surgeries, compared to the historical cohort in each studied region, country, or hospital.ResultsWe identified 6,660 records and eighty-seven articles met our inclusion criteria. All the studies were with before and after study design compared with the historical data, with an overall high risk of bias. The median daily PED admissions decreased to 65% in 39 included studies and a 54% reduction in PICU admission in eight studies. A significant decline was reported in acute respiratory illness and LRTI in five studies with a median decrease of 63%. We did not find a consistent trend in the incidence of poisoning, but there was an increasing trend in burns, DKA, and a downward trend in trauma and unplanned surgeries.ConclusionsSDMs in the first wave of the COVID-19 pandemic reduced the global incidence of pediatric acute illnesses. However, some disease groups, such as burns and DKA, showed a tendency to increase and its severity of illness at hospital presentation. Continual effort and research into the subject should be essential for us to better understand the effects of this new phenomenon of SDMs to protect the well-being of children.Systematic Review RegistrationClinicaltrials.gov, identifier: CRD42020221215.

Supplemental material, sj-docx-1-mso-10.1177_20552173221128170 for Autoimmune diseases and cancers overlapping with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): A systematic review by Negar Molazadeh, Gauruv Bose, Itay Lotan and Michael Levy in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X221101926 for Oral anticoagulation therapies among Medicare beneficiaries: Utilization and costs by Rohan B. Parikh, Guy Kulbak, Michael Levy, Arjun Majithia, Frederic Resnic, Sarju Ganatra and Sourbha S. Dani in Vascular Medicine

Supplemental material, sj-docx-1-mso-10.1177_20552173221128170 for Autoimmune diseases and cancers overlapping with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): A systematic review by Negar Molazadeh, Gauruv Bose, Itay Lotan and Michael Levy in Multiple Sclerosis Journal – Experimental, Translational and Clinical

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X221101926 for Oral anticoagulation therapies among Medicare beneficiaries: Utilization and costs by Rohan B. Parikh, Guy Kulbak, Michael Levy, Arjun Majithia, Frederic Resnic, Sarju Ganatra and Sourbha S. Dani in Vascular Medicine

Supplemental material, sj-pdf-2-vmj-10.1177_1358863X221101926 for Oral anticoagulation therapies among Medicare beneficiaries: Utilization and costs by Rohan B. Parikh, Guy Kulbak, Michael Levy, Arjun Majithia, Frederic Resnic, Sarju Ganatra and Sourbha S. Dani in Vascular Medicine

Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring intensive care unit (ICU) have a high incidence of hospital-acquired infections; however, data regarding hospital acquired bloodstream infections (BSI) are scarce. We aimed to investigate risk factors and outcome of BSI in critically ill coronavirus infectious disease-19 (COVID-19) patients. Patients and methods We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU study) that included 4010 COVID-19 ICU patients. For the present analysis, only those with data regarding primary outcome (death within 90 days from admission) or BSI status were included. Risk factors for BSI were analyzed using Fine and Gray competing risk model. Then, for outcome comparison, 537 BSI-patients were matched with 537 controls using propensity score matching. Results Among 4010 included patients, 780 (19.5%) acquired a total of 1066 BSI (10.3 BSI per 1000 patients days at risk) of whom 92% were acquired in the ICU. Higher SAPS II, male gender, longer time from hospital to ICU admission and antiviral drug before admission were independently associated with an increased risk of BSI, and interestingly, this risk decreased over time. BSI was independently associated with a shorter time to death in the overall population (adjusted hazard ratio (aHR) 1.28, 95% CI 1.05–1.56) and, in the propensity score matched data set, patients with BSI had a higher mortality rate (39% vs 33% p = 0.036). BSI accounted for 3.6% of the death of the overall population. Conclusion COVID-19 ICU patients have a high risk of BSI, especially early after ICU admission, risk that increases with severity but not with corticosteroids use. BSI is associated with an increased mortality rate.

BackgroundChordomas are rare malignant neoplasms that develop from the primitive notochord with < 5% of the tumors occurring in pediatric patients younger than the age of 20. Of these pediatric chordomas, those affecting the craniocervical junction (C1-C2) are even more rare; therefore, parameters for surgical management of these pediatric tumors are not well characterized.ObservationsIn this case, a 3-year-old male was found to have a clival chordoma on imaging with extension to the craniocervical junction resulting in spinal cord compression. Endoscopic-assisted transoral transclival approach for clival tumor resection was performed first. As a second stage, the patient underwent a left-sided far lateral craniotomy and cervical laminectomy for resection of the skull base chordoma and instrumented fusion of the occiput to C3. He made excellent improvements in strength and dexterity during rehab and was discharged after 3 weeks.LessonsIn pediatric patients with chordoma with extension to the craniocervical junction and spinal cord compression, decompression with additional occipito-cervical fusion appears to offer a good clinical outcome. Fusion performed as a separate surgery before or at the same time as the initial tumor resection surgery may lead to better outcomes.

A Correction to this paper has been published: https://doi.org/10.1038/s41436-021-01130-z.

ImportanceEndometrial receptivity testing is purported to improve live birth following frozen embryo transfer by identifying the optimal embryo transfer time for an individual patient; however, data are conflicting.ObjectiveTo compare live birth from single euploid frozen embryo transfer according to endometrial receptivity testing vs standardized timing.Design, Setting, and ParticipantsDouble-blind, randomized clinical trial at 30 sites within a multicenter private fertility practice in the Eastern US. Enrollment was from May 2018 to September 2020; follow-up concluded in August 2021. Participants underwent in vitro fertilization, preimplantation genetic testing for aneuploidy, endometrial receptivity testing, and frozen embryo transfer. Those with euploid blastocyst(s) and an informative receptivity result were randomized. Exclusion criteria included recurrent pregnancy loss, recurrent implantation failure, surgically aspirated sperm, donor egg(s), and unmitigated anatomic uterine cavity defects.InterventionsThe intervention group (n = 381) underwent receptivity-timed frozen embryo transfer, with adjusted duration of progesterone exposure prior to transfer, if indicated by receptivity testing. The control group (n = 386) underwent transfer at standard timing, regardless of receptivity test results.Main Outcomes and MeasuresThe primary outcome was live birth. There were 3 secondary outcomes, including biochemical pregnancy and clinical pregnancy.ResultsAmong 767 participants who were randomized (mean age, 35 years), 755 (98%) completed the trial. All randomized participants were analyzed. The primary outcome of live birth occurred in 58.5% of transfers (223 of 381) in the intervention group vs 61.9% of transfers (239 of 386) in the control group (difference, −3.4% [95% CI, −10.3% to 3.5%]; rate ratio [RR], 0.95 [95% CI, 0.79 to 1.13]; P = .38). There were no significant differences in the intervention vs the control group for the prespecified secondary outcomes, including biochemical pregnancy rate (77.2% vs 79.5%, respectively; difference, −2.3% [95% CI, −8.2% to 3.5%]; RR, 0.97 [95% CI, 0.83 to 1.14]; P = .48) and clinical pregnancy rate (68.8% vs 72.8%, respectively; difference, −4.0% [95% CI, −10.4% to 2.4%]; RR, 0.94 [95% CI, 0.80 to 1.12]; P = .25). There were no reported adverse events.Conclusions and RelevanceAmong patients for whom in vitro fertilization yielded a euploid blastocyst, the use of receptivity testing to guide the timing of frozen embryo transfer, compared with standard timing for transfer, did not significantly improve the rate of live birth. The findings do not support routine use of receptivity testing to guide the timing of embryo transfer during in vitro fertilization.Trial RegistrationClinicalTrials.gov Identifier: NCT03558399

ObjectiveTo clarify if NK and NKT cells are activated via complement in NMOSD.BackgroundInhibition of terminal complement in NMOSD using eculizumab has been shown to be helpful in preventing relapses but exactly how the drug is working is not clear. Similarly, genetic variants in the Fc Gamma receptor 3A are correlated with outcomes in NMOSD but the immune cells expressing those FcGR3A receptors are unknown. We compared FcGR3A expression on immune cells modulated by complement activity in NK cells and NKT cells in NMOSD to disease controls and healthy people.Design/MethodsPeripheral blood cell (PBMC) samples from 45 patients with NMOSD with AQP4-IgG, 18 disease controls, and 19 normal controls were analyzed for FcGR3A expression and complement receptors in vitro.ResultsAt baseline, the number of NKT cells were increased in NMOSD (p < 0.001), but the proportion that were FcGR3A positive was lower compared to healthy and disease controls (p = 0.0012). NK cell count was normal at baseline but also but the proportion that were FcGR3A positive was also relatively lower (p < 0.001). In both NK cells and NKT cells from NMOSD, C5 complement receptor expression was much higher compared to healthy and disease controls (p < 0.001 for both). We also evaluated activation markers CD69 and CD83, which were also much higher in NK and NKT cells from NMOSD patients.ConclusionsOur results support a model of immunopathogenesis model in which complement pathway activation in NK/NKT cells upregulate FcGR3A expression that bind to antibody/antigen complexes. In the context of NMOSD, these complement-sensitive cells may be responsible for escalating autoimmune activity.

Background Predicting outcomes of critically ill intensive care unit (ICU) patients with coronavirus-19 disease (COVID-19) is a major challenge to avoid futile, and prolonged ICU stays. Methods The objective was to develop predictive survival models for patients with COVID-19 after 1-to-2 weeks in ICU. Based on the COVID–ICU cohort, which prospectively collected characteristics, management, and outcomes of critically ill patients with COVID-19. Machine learning was used to develop dynamic, clinically useful models able to predict 90-day mortality using ICU data collected on day (D) 1, D7 or D14. Results Survival of Severely Ill COVID (SOSIC)-1, SOSIC-7, and SOSIC-14 scores were constructed with 4244, 2877, and 1349 patients, respectively, randomly assigned to development or test datasets. The three models selected 15 ICU-entry variables recorded on D1, D7, or D14. Cardiovascular, renal, and pulmonary functions on prediction D7 or D14 were among the most heavily weighted inputs for both models. For the test dataset, SOSIC-7’s area under the ROC curve was slightly higher (0.80 [0.74–0.86]) than those for SOSIC-1 (0.76 [0.71–0.81]) and SOSIC-14 (0.76 [0.68–0.83]). Similarly, SOSIC-1 and SOSIC-7 had excellent calibration curves, with similar Brier scores for the three models. Conclusion The SOSIC scores showed that entering 15 to 27 baseline and dynamic clinical parameters into an automatable XGBoost algorithm can potentially accurately predict the likely 90-day mortality post-ICU admission (sosic.shinyapps.io/shiny). Although external SOSIC-score validation is still needed, it is an additional tool to strengthen decisions about life-sustaining treatments and informing family members of likely prognosis.

The fetal period is a critical time for brain development, characterized by neurogenesis, neural migration, and synaptogenesis 1-3 . Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of gestation 4 and are thought to engage in a variety of processes essential for brain development and homeostasis 5-11 . Conversely, microglia phenotypes are highly regulated by the brain environment 12-14 . Mechanisms by which human brain development influences the maturation of microglia and microglia potential contribution to neurodevelopmental disorders remain poorly understood. Here, we performed transcriptomic analysis of human fetal and postnatal microglia and corresponding cortical tissue to define age-specific brain environmental factors that may drive microglia phenotypes. Comparative analysis of open chromatin profiles using bulk and single-cell methods in conjunction with a new computational approach that integrates epigenomic and single-cell RNA-seq data allowed decoding of cellular heterogeneity with inference of subtype- and development stage-specific transcriptional regulators. Interrogation of in vivo and in vitro iPSC-derived microglia models provides evidence for roles of putative instructive signals and downstream gene regulatory networks which establish human-specific fetal and postnatal microglia gene expression programs and potentially contribute to neurodevelopmental disorders.

Unicoronal craniosynostosis is notoriously difficult to treat, with long-term studies demonstrating high rates of relapse and the need for reoperation using open fronto-orbital advancement. Applying the principles of distraction osteogenesis to cranial vault remodeling has demonstrated promising short-term results that compare favorably with traditional methods, with simultaneous correction of both frontofacial and endocranial morphology, along with significant increases in intracranial volume. Here, the authors demonstrate their technique for rotation flap distraction osteogenesis in the treatment of unicoronal synostosis and provide case examples. The video can be found here: https://vimeo.com/519505008.

Supplemental material, sj-pdf-2-msj-10.1177_13524585211038291 for Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension by Sean J Pittock, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Ho Jin Kim, Celia Oreja-Guevara, Ichiro Nakashima, Michael Levy, Shulian Shang, Marcus Yountz, Larisa Miller, Róisín Armstrong and Dean M Wingerchuk in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585211038291 for Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension by Sean J Pittock, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Ho Jin Kim, Celia Oreja-Guevara, Ichiro Nakashima, Michael Levy, Shulian Shang, Marcus Yountz, Larisa Miller, Róisín Armstrong and Dean M Wingerchuk in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-msj-10.1177_13524585211038291 for Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension by Sean J Pittock, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Ho Jin Kim, Celia Oreja-Guevara, Ichiro Nakashima, Michael Levy, Shulian Shang, Marcus Yountz, Larisa Miller, Róisín Armstrong and Dean M Wingerchuk in Multiple Sclerosis Journal

The mainstay of canine rabies control is fixed point mass dog vaccination campaigns (MDVC). However, in some regions, ideal vaccination coverage in dogs is not obtained due to low participation in the MDVC. Travel distance to the vaccination sites has been identified as an important barrier to participation. We aim to increase MDVC participation by optimally placing fixed point vaccination locations to minimize walking distance to the nearest vaccination location. We quantified participation probability based on walking distance to the nearest vaccination point using a Poisson regression model. The regression was fit with survey data collected from 2016-2019. We then used a computational recursive interchange technique to solve the facility location problem to find a set of optimal placements of fixed point vaccination locations. Finally, we compared predicted participation of optimally placed vaccination sites to historical participation data from surveys collected from 2016-2019. We identified the p-median algorithm to solve the facility location problem as ideal for fixed point vaccination placement. We found a predicted increase in MDVC participation if vaccination locations are placed optimally. We also found a more even vaccination coverage with optimized vaccination sites; however, the workload in some optimized locations increased significantly. We developed a data-driven computational algorithm to combat an ongoing rabies epidemic by optimally using limited resources to maximize vaccination coverage. The main positive effects we expect if this algorithm is to be implemented would be increased overall vaccination coverage and increased spatial evenness of coverage. A potential negative effect could be the presence of long waiting lines as participation increases., Comment: 21 pages, 2 tables, 5 figures

Supplemental material, sj-pdf-1-msj-10.1177_13524585211038291 for Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension by Sean J Pittock, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Ho Jin Kim, Celia Oreja-Guevara, Ichiro Nakashima, Michael Levy, Shulian Shang, Marcus Yountz, Larisa Miller, Róisín Armstrong and Dean M Wingerchuk in Multiple Sclerosis Journal

Supplemental material, sj-pdf-1-msj-10.1177_13524585211038291 for Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension by Sean J Pittock, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Ho Jin Kim, Celia Oreja-Guevara, Ichiro Nakashima, Michael Levy, Shulian Shang, Marcus Yountz, Larisa Miller, Róisín Armstrong and Dean M Wingerchuk in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585211038291 for Eculizumab monotherapy for NMOSD: Data from PREVENT and its open-label extension by Sean J Pittock, Kazuo Fujihara, Jacqueline Palace, Achim Berthele, Ho Jin Kim, Celia Oreja-Guevara, Ichiro Nakashima, Michael Levy, Shulian Shang, Marcus Yountz, Larisa Miller, Róisín Armstrong and Dean M Wingerchuk in Multiple Sclerosis Journal

PurposeTreatment of children with CNS tumors (CNSTs) demands a complex, interdisciplinary approach that is rarely available in low- and middle-income countries. We established the Cross-Border Neuro-Oncology Program (CBNP) between Rady Children's Hospital, San Diego (RCHSD), and Hospital General, Tijuana (HGT), Mexico, to provide access to neuro-oncology care, including neurosurgic services, for children with CNSTs diagnosed at HGT. Our purpose was to assess the feasibility of the CBNP across the United States-Mexico border and improve survival for children with CNSTs at HGT by implementing the CBNP.Patients and methodsWe prospectively assessed clinicopathologic profiles, the extent of resection, progression-free survival, and overall survival (OS) in children with CNSTs at HGT from 2010 to 2017.ResultsSixty patients with CNSTs participated in the CBNP during the study period. The most common diagnoses were low-grade glioma (24.5%) and medulloblastoma (22.4%). Of patients who were eligible for surgery, 49 underwent resection at RCHSD and returned to HGT for collaborative management. Gross total resection was achieved in 78% of cases at RCHSD compared with 0% at HGT (P < .001) and was a predictor of 5-year OS (hazard ratio, 0.250; 95% CI, 0.067 to 0.934; P = .024). Five-year OS improved from 0% before 2010 to 52% in 2017.ConclusionThe CBNP facilitated access to complex neuro-oncology care for underserved children in Mexico through binational exchanges of resources and expertise. Survival for patients in the CBNP dramatically improved. Gross total resection at RCHSD was associated with higher OS, highlighting the critical role of experienced neurosurgeons in the treatment of CNSTs. The CBNP model offers an attractive alternative for children with CNSTs in low- and middle-income countries who require complex neuro-oncology care, particularly those in close proximity to institutions in high-income countries with extensive neuro-oncology expertise.

IntroductionThe Pierre-Robin sequence (PRS) is a pattern of congenital facial abnormalities comprising micrognathia, glossoptosis, and airway obstruction. Associated spinal pathologies have rarely been reported with PRS.MethodsWe explore the molecular genetic basis of this association through a systematic review of spinal disease in patients with PRS. We also present an illustrative case of a PRS patient with tethered cord in the setting of chromosome 10q terminal deletion.ResultsOur systematic literature review of spinal disease in patients with PRS revealed several patterns in the underlying genetic syndromes causing these conditions to co-occur. These principles are illustrated in the case of a 6-month-old female with PRS and a 14.34-Mb terminal deletion of chromosome 10q, who was found to have a sacral dimple during a routine outpatient checkup. Magnetic resonance imaging of the spine revealed a lumbar syrinx associated with tethered spinal cord. Surgical de-tethering was undertaken, with subsequent improvement in motor function and decrease in the size of the syrinx. The deletion of chromosome 10q in our patient had not previously been described in association with tethered cord or PRS.ConclusionSpinal pathologies are understudied contributors to disease burden in patients with PRS. The range of predisposing syndromes and mutations in patients with both PRS and spinal disorders remains poorly characterized but may be more defined than previously conceived. Clinical screening is most critical during neonatal and adolescent developmental periods with continued neurological assessment. This study emphasizes the need for early genetic testing and counseling in this patient population, in parallel with research efforts to develop molecular classifications to guide clinical management.

Supplemental material, sj-pdf-1-msj-10.1177_1352458520977771 for Evidence of subclinical quantitative retinal layer abnormalities in AQP4-IgG seropositive NMOSD by Angeliki G Filippatou, Eleni S Vasileiou, Yufan He, Kathryn C Fitzgerald, Grigorios Kalaitzidis, Jeffrey Lambe, Maureen A Mealy, Michael Levy, Yihao Liu, Jerry L Prince, Ellen M Mowry, Shiv Saidha, Peter A Calabresi and Elias S Sotirchos in Multiple Sclerosis Journal

Additional file 1. Cases description, Table S1.

The novel coronavirus disease (COVID-19) is a highly contagious respiratory disease that was first detected in Wuhan, China in December 2019, and has since spread around the globe, claiming more than 69,000 lives by the time this protocol is written. It has been widely acknowledged that the most effective public policy to mitigate the pandemic is \emph{social and physical distancing}: keeping at least six feet away from people, working from home, closing non-essential businesses, etc. There have been a lot of anecdotal evidences suggesting that social distancing has a causal effect on disease mitigation; however, few studies have investigated the effect of social distancing on disease mitigation in a transparent and statistically-sound manner. We propose to perform an optimal non-bipartite matching to pair counties with similar observed covariates but vastly different average social distancing scores during the first week (March 16th through Match 22nd) of President's \emph{15 Days to Slow the Spread} campaign. We have produced a total of $302$ pairs of two U.S. counties with good covariate balance on a total of $16$ important variables. Our primary outcome will be the average observed illness collected by Kinsa Inc. two weeks after the intervention period. Although the observed illness does not directly measure COVID-19, it reflects a real-time aspect of the pandemic, and unlike confirmed cases, it is much less confounded by counties' testing capabilities. We also consider observed illness three weeks after the intervention period as a secondary outcome. We will test a proportional treatment effect using a randomization-based test with covariance adjustment and conduct a sensitivity analysis.

In reef ecosystems, vulnerability to exploitation is species-specific and may vary with natural abundance, life history characteristics, or ease of capture. Therefore, understanding the growth parameters and exploitation rate of individual species is important, because application of a uniform management strategy in species with different responses or vulnerability to exploitation can be inappropriate. In this study, growth parameters (length at first maturity, length at optimum yield, asymptotic length, growth constant, and growth performance index) and mortality from two Acanthurus fish species were compared, to deduce whether differences in species-specific traits (spawning mating behaviour) could lead to differences in exploitation rate. Despite comparable estimates of the von Bertalanffy asymptotic length (L ∞ ) in the two species [A. triostegus (27.9–29.6) and A. leucosternon (26.1–27.4)], the growth coefficient constant (K) estimates for A. triostegus (0.85–1.23) were almost three to fivefold higher than those of A. leucosternon (0.29–0.38), suggesting that A. triostegus attains its maximum length faster than A. leucosternon. Length at first maturity (Lm), length at optimum yield (Lopt), and exploitation rate (E) were also different between the two species, specifically indicating exploitation beyond the sustainable yield in A. triostegus but not in A. leucosternon. The finding of a higher exploitation rate in A. triostegus as compared to A. leucosternon could suggest that regardless of similar body sizes, the former is more susceptible to exploitation.

Knowledge of larval dispersal and connectivity in coral reef species is crucial for understanding population dynamics, resilience, and evolution of species. Here, we use ten microsatellites and one mitochondrial marker (cytochrome b) to investigate the genetic population structure, genetic diversity, and historical demography of the powder-blue tang Acanthurus leucosternon across more than 1000 km of the scarcely studied Eastern African region. The global AMOVA results based on microsatellites reveal a low but significant F ST value (F ST = 0.00252 P

Figure S1. Facial features of individuals with the ADNP syndrome. Figure S2. Methylation patterns of specimens collected years apart in three subjects. Figure S3. DMRs differentially methylated in ADNP-1 (1–30). Figure S4. DMRs differentially methylated in ADNP-1 (31–60). Figure S5. DMRs differentially methylated in ADNP-1 (61–90). Figure S6. DMRs differentially methylated in ADNP-1 (91–120). Figure S7. DMRs differentially methylated in ADNP-1 (121–150). Figure S8. DMRs differentially methylated in ADNP-1 (151–180). Figure S9. DMRs differentially methylated in ADNP-1 (181–210). Figure S10. DMRs differentially methylated in ADNP-1 (211–240). Figure S11. DMRs differentially methylated in ADNP-1 (241–270). Figure S12. DMRs differentially methylated in ADNP-1 (271–300). Figure S13. DMRs differentially methylated in ADNP-1 (301–308). Figure S14. DMRs differentially methylated in ADNP-2 (1–30). Figure S15. DMRs differentially methylated in ADNP-2 (31–57). Figure S16. Interactive networks of genes from the ADNP episignatures. (DOCX 4248 kb)

ObjectiveTo define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS).MethodsAn International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG-positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers.ResultsAnalysis of an international database for AQP4-IgG-seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%-10.3%; subsequent 9.4%-14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2-365), vomiting (113, 72%) with a median of 5 episodes/d (2-40) lasted 1-20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2-365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort.ConclusionIsolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials.

Disentangling the contribution of biotic and abiotic factors in the structuring of the genetic diversity of reef species is critical to illuminate the diversification of evolutionary lineages in marine environment. Howevr, previous studies have mainly focused on determining the influence of pelagic larval duration on the connectivity and demographic history of reef fishes, whereas few studies have examined the effects of other biotic factors, such as mating behaviour and habitat preference. Here, we use mitochondrial DNA (ATPase 6/8) and ten microsatellite loci to compare the population genetic structure and demographic history of the spawning aggregating Acanthurus triostegus with the monogamous spawning Acanthurus leucosternon. Pairwise comparisons and discriminant analysis of principal components showed that the genetic structuring patterns of the two species are not consistent with the influence of mating behaviour, suggesting the possible role of other biotic and abiotic factors. However, demographic history estimates revealed that these species may have responded differently to sea level fluctuations during the glacial maxima.

Additional file 2: Supplementary Table 1. PCR and cloning information for vaccine candidates.

Additional file 3: Supplementary Fig. 1. Cytauxzoon felis DNA vaccination pilot study design. A total of 18 cats were divided into four groups assessed in this study: three cats vaccinated with CF-1 prior to infection (red box), four cats vaccinated with CF-Library prior to infection (blue box), eight cats that were not vaccinated prior to infection (green box), and three cats that were neither vaccinated nor infected (gray box). The eight unvaccinated, infected cats were involved in a separate study testing the efficacy of novel chemotherapeutics against cytauxzoonosis. If it became evident that vaccines or chemotherapeutics were not halting the progression of disease, cats were additionally given atovaquone and azithromycin to attempt to prevent death; these cats are noted accordingly. A&A = atovaquone and azithromycin, 4X ABX = pradofloxacin, doxycycline, clindamycin, and metronidazole.

Additional file 5: Supplementary Table 2. Additional clinical observations and information for individual cats.

Additional file 7: Supplementary Fig. 3. Serological responses to C. felis antigens are increased during chronic infection. Serologic reactivity of antigens are depicted as a heatmap in (A). Antigens are listed in rows while grouping of individuals are denoted in columns. Average signal intensity of individual antigens against serum from acute and chronic groups are depicted in (B). The majority of antigens that had a higher average reactivity against serum from chronically infected cats (n = 50), but two antigens were more reactive against serum from acutely infected cats (n = 2, denoted with yellow boxes). These two antigens were incorporated into the CF-Library vaccine as Candidates 32-33.

Individual behavior change is a critical ingredient in efforts to improve global health. Central to the focus on behavior has been a growing understanding of how the human brain makes decisions, from motivations and mindsets to unconscious biases and cognitive shortcuts. Recent work in the field of behavioral economics and related fields has contributed to a rich menu of insights and principles that can be engineered into global health programs to increase impact and reach. However, there is little research on the process of designing and testing interventions informed by behavioral insights. In a study focused on increasing household participation in a Chagas disease vector control campaign in Arequipa, Peru, we applied Datta and Mullainathan’s “behavioral design” approach to formulate and test specific interventions. In this Methodologies paper we describe the behavioral design approach in detail, including the Define, Diagnosis, Design, and Test phases. We also show how the interventions designed through the behavioral design process were adapted for a pragmatic randomized controlled field trial. The behavioral design framework provided a systematic methodology for defining thebehavior of interest, diagnosing reasons for household reluctance or refusal to participate, designing interventions to address actionable bottlenecks, and then testing those interventions in a rigorous counterfactual context. Behavioral design offered us a broader range of strategies and approaches than are typically used in vector-control campaigns. Careful attention to how behavioral design may affect internal and external validity of evaluations and the scalability of interventions is needed going forward. We recommend behavioral design as a useful complement to other intervention design and evaluation approaches in global health programs.

Additional file 6: Supplementary Table 3. Summary of supportive care administered to individual cats. Cats vaccinated with CF-Library received less overall supportive care.

Additional file 8: Supplementary Fig. 4. Serological profiles of individual vaccinated cats to candidates throughout study. Arrays containing the 32 vaccine candidates included in CF-Library and in CF-1 were probed with sera samples from individual cats. Heat map shows normalized signal intensity with red strongest, white weakest, and gray intermediate. Rows denote 32 different candidates included in vaccines listed in descending order of reactivity; candidates 19 and 3 were included in CF-1, while all listed candidates were included in CF-Library. Results are organized by individual cats (identified by number at top), and survival status of each cat is indicated as “A” (alive) or “D” (dead). Individual columns within each cat’s array represent serum samples collected at different time points through study (labeled by the day in the study the sample was collected; refer to Supplemental Fig. 2 for timeline). There was no correlation between immunization protocol, individual reactivity, and survival for most cats, with the exception of Cat 77, who had widespread yet weak reactivity against all candidates in the CF-Library vaccine prior to infection and subsequently had milder disease and did not require supportive care or antiprotozoal therapy.