The nexus of immigration regulation and health governance: a scoping review of the extent to which right to access healthcare by migrants, refugees and asylum seekers was upheld in the United Kingdom during COVID-19.

OBJECTIVES: Complementing the well-established evidence base on health inequalities experienced by migrants, refugees and asylum seekers in the UK; we examined the extent to which their right to equal non-discriminatory access to health services (promotive, preventive, curative) was upheld during the COVID-19 pandemic. STUDY DESIGN: Arksey and O'Malley's scoping review framework. METHODS: A comprehensive search was conducted on Medline, PubMed, and CINAHL using detailed MESH terms, for literature published between 01 January 2020 and 01 January 2024. The process was supported by a ten-page Google search and hand searching of reference lists. 42 records meeting the inclusion criteria were charted, coded inductively and analysed thematically in an integrated team-based approach. RESULTS: Dissonance between immigration regulation and health governance is illustrated in four themes: Health systems leveraged to (re)enforce the hostile environment; Dissonance between health rights on paper and in practice; Structural failures to overcome communication and digital exclusion; and COVID-19 vaccine (in)equity exacerbated fear, mistrust and exclusion. Migrants, refugees and asylum seekers encountered substantial individual, structural and policy-level barriers to accessing healthcare in the UK during COVID-19. Insecure immigration status, institutional mistrust, data-sharing and charging fears, communication challenges and digital exclusion impacted heavily on their ability to access healthcare in an equitable non-discriminatory manner. CONCLUSIONS: An inclusive and innovative health equity and rights-based responses reaching all migrants, refugees and asylum seekers are warranted if the National Health Service is to live up to its promise of 'leaving no one behind' in post-pandemic and future responses.

Perivascular neurons instruct 3D vascular lattice formation via neurovascular contact.

The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.

Evaluation of the Thermal, Chemical, Mechanical, and Microbial Stability of New Nanohybrids Based on Carboxymethyl-Scleroglucan and Silica Nanoparticles for EOR Applications.

Scleroglucan (SG) is resistant to harsh reservoir conditions such as high temperature, high shear stresses, and the presence of chemical substances. However, it is susceptible to biological degradation because bacteria use SG as a source of energy and carbon. All degradation effects lead to viscosity loss of the SG solutions, affecting their performance as an enhanced oil recovery (EOR) polymer. Recent studies have shown that nanoparticles (NPs) can mitigate these degradative effects. For this reason, the EOR performance of two new nanohybrids (NH-A and NH-B) based on carboxymethyl-scleroglucan and amino-functionalized silica nanoparticles was studied. The susceptibility of these products to chemical, mechanical, and thermal degradation was evaluated following standard procedures (API RP 63), and the microbial degradation was assessed under reservoir-relevant conditions (1311 ppm and 100 °C) using a bottle test system. The results showed that the chemical reactions for the nanohybrids obtained modified the SG triple helix configuration, impacting its viscosifying power. However, the nanohybrid solutions retained their viscosity during thermal, mechanical, and chemical degradation experiments due to the formation of a tridimensional network between the nanoparticles (NPs) and the SG. Also, NH-A and NH-B solutions exhibited bacterial control because of steric hindrances caused by nanoparticle modifications to SG. This prevents extracellular glucanases from recognizing the site of catalysis, limiting free glucose availability and generating cell death due to substrate depletion. This study provides insights into the performance of these nanohybrids and promotes their application in reservoirs with harsh conditions.

Synthesis and Characterization of New Nanohybrids Based on Carboxymethyl Scleroglucan and Silica Nanoparticles.

In this study, two new nanohybrids (NH-A and NH-B) were synthesized through carbodiimide-assisted coupling. The reaction was performed between carboxymethyl-scleroglucans (CMS-A and CMS-B) with different degrees of substitution and commercial amino-functionalized silica nanoparticles using 4-(dimethylamino)-pyridine (DMAP) and N,N'-dicyclohexylcarbodiimide (DCC) as catalysts. The morphology and properties of the nanohybrids were investigated by using transmission (TEM) and scanning electron microscopy (SEM), electron-dispersive scanning (EDS), attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FT-IR), X-ray photoelectron spectroscopy (XPS), powder X-ray diffraction (XRD), inductively coupled plasma atomic emission spectroscopy (ICP-OES), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic light scattering (DLS). The nanohybrids exhibited differences in structure due to the incorporation of polyhedral oligomeric silsesquioxane (POSS) materials. The results reveal that hybrid nanomaterials exhibit similar thermal properties but differ in morphology, chemical structure, and crystallinity properties. Finally, a viscosity study was performed on the newly obtained nanohybrid materials; viscosities of nanohybrids increased significantly in comparison to the carboxymethyl-scleroglucans, with a viscosity difference of 7.2% for NH-A and up to 32.6% for NH-B.

Linear Muscle Segmentation for Metastatic Renal Cell Carcinoma: Changes in Clinic-Friendly Estimation Predict Survival Following Cytoreductive Nephrectomy.

INTRODUCTION: Baseline sarcopenia and postoperative changes in muscle mass are independently associated with overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN). Here we examine the relationships between preoperative (baseline), postoperative changes in muscle quantity, and survival outcomes following CN as determined by linear segmentation, a clinic-friendly tool that rapidly estimates muscle mass. MATERIALS AND METHODS: Our nephrectomy database was reviewed for patients with metastatic disease who underwent CN for RCC. Linear segmentation of the bilateral psoas/paraspinal muscles was completed for baseline imaging within 60 days of surgery and imaging 30 to 365 days postoperatively. Kruskal-Wallis for numerical and Fisher's exact test for categorical variables were used to test for differences between groups according to percent change in linear muscle index (LMI, cm2/m2). Multivariable Cox proportional hazards models evaluated associations between LMI percent change and cancer-specific (CSM) and all-cause mortality (ACM). Kaplan Meier curves estimated cancer-specific (CSS) and overall survival (OS). RESULTS: From 2004-2020, 205 patients were included of whom 52 demonstrated stable LMI (25.4%; LMI change < 5% [0Δ]), 60 increase (29.3%; LMI +5% [+Δ]), and 92 decrease (44.9%; LMI -5% [-Δ]). Median time from baseline imaging to surgery was 18 days, and time from surgery to postoperative imaging was 133 days. Median CSS and OS were highest among patients with 0Δ LMI (CSS: 133.6 [0Δ] vs. 61.9 [+Δ] vs. 37.4 [-Δ] months; P = .0018 || OS: 67.2 [0Δ] vs. 54.8 [+Δ] vs. 29.5 [-Δ] months; P = .0007). Stable LMI was a protective factor for CSM (HR 0.48; P = .024) and ACM (HR 0.59; P = .040) on multivariable analysis. DISCUSSION: Change in muscle mass after CN, as measured by the linear muscle segmentation technique, is independently associated with OS and CSS in patients following CN. Of note, lack of change was associated with longer survival.

Metabolic and Environmental Biomarkers in Mild Cognitive Impairment and Dementia: An Exploratory Study.

Objective: To determine the frequency with which suspected pathogenic factors, including metals and metabolites that might contribute to Alzheimer's disease (AD), may be found in patients with cognitive impairment through commonly available blood tests. Methods: A variety of serum studies, including metals, ammonia, homocysteine, vitamin B12, folate, thyroid tests, metabolic products, and inflammatory markers, were measured in two cohorts: one meeting mild cognitive impairment (MCI) criteria and the other meeting mild-to-moderate dementia (DE) criteria. Medications these patients received were reviewed. Results: Metal abnormalities were detected in over half the subjects, including evidence of mercury, lead, and arsenic elevation as well as instances of excessive essential metals, iron (Fe), and copper. Some metal aberration was detected in 64% of the DE group and 66% of the MCI group. Females were more likely to have elevated copper, consistent with hormonal effects on copper excretion. Homocysteinemia was the most common abnormality, detected in 71% with DE and 67% with MCI, while methylmalonic acid was not elevated. Slight hyperammonemia was moderately common (38%) suggesting a hepatic factor in this subset. Findings of moderate insulin resistance were present in nearly half (44% DE, 52% MCI). Sixty of 65 (92%) had at least one abnormal biomarker and 60% had two or more. The most common drug taken by the total cohort was proton pump inhibitors at 22% DE and 38% MCI. Conclusions: This study suggests that both toxic metals and excessive vital metals such as copper and iron, as well as common metabolic and hepatic factors are detectable at both stages of MCI and DE. There appears to be a multiplicity of provocative factors leading to DE. Individualized interventions based on these parameters may be a means to reduce cognitive decline leading to DE. A more comprehensive prospective study of these environmental and metabolic factors with corrective early interventions appears warranted.

Experimental Investigation of the Viscosity and Stability of Scleroglucan-Based Nanofluids for Enhanced Oil Recovery.

Biopolymers emerge as promising candidates for enhanced oil recovery (EOR) applications due to their molecular structures, which exhibit better stability than polyacrylamides under harsh conditions. Nonetheless, biopolymers are susceptible to oxidation and biological degradation. Biopolymers reinforced with nanoparticles could be a potential solution to the issue. The nanofluids' stability and performance depend on the nanoparticles' properties and the preparation method. The primary objective of this study was to evaluate the effect of the preparation method and the nanoparticle type (SiO2, Al2O3, and TiO2) on the viscosity and stability of the scleroglucan (SG). The thickening effect of the SG solution was improved by adding all NPs due to the formation of three-dimensional structures between the NPs and the SG chains. The stability test showed that the SG + Al2O3 and SG + TiO2 nanofluids are highly unstable, but the SG + SiO2 nanofluids are highly stable (regardless of the preparation method). According to the ANOVA results, the preparation method and standing time influence the nanofluid viscosity with a statistical significance of 95%. On the contrary, the heating temperature and NP type are insignificant. Finally, the nanofluid with the best performance was 1000 ppm of SG + 100 ppm of SiO2_120 NPs prepared by method II.

Carboxymethyl Scleroglucan Synthesized via O-Alkylation Reaction with Different Degrees of Substitution: Rheology and Thermal Stability.

This paper presents the methodology for synthesizing and characterizing two carboxymethyl EOR-grade Scleroglucans (CMS-A and CMS-B). An O-Alkylation reaction was used to insert a hydrophilic group (monochloroacetic acid-MCAA) into the biopolymer's anhydroglucose subunits (AGUs). The effect of the degree of the carboxymethyl substitution on the rheology and thermal stability of the Scleroglucan (SG) was also evaluated. Simultaneous thermal analysis (STA/TGA-DSC), differential scanning calorimetry (DSC), X-ray Diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, Scanning Electron Microscopy, and Energy Dispersive Spectroscopy (SEM/EDS) were employed to characterize both CMS products. FTIR analysis revealed characteristic peaks corresponding to the carboxymethyl functional groups, confirming the modification. Also, SEM analysis provided insights into the structural changes in the polysaccharide after the O-Alkylation reaction. TGA results showed that the carboxymethylation of SG lowered its dehydroxylation temperature but increased its thermal stability above 300 °C. The CMS products and SG exhibited a pseudoplastic behavior; however, lower shear viscosities and relaxation times were observed for the CMS products due to the breakage of the SG triple helix for the chemical modification. Despite the viscosity results, the modified Scleroglucans are promising candidates for developing new engineering materials for EOR processes.

Performance of Future Glomerular Filtration Rate Equation by Race in a Large, Racially Diverse Patient Cohort Undergoing Nephrectomy for Renal Cell Carcinoma.

OBJECTIVE: To examine the performance of the Palacios et al [Aguilar Palacios D, Wilson B, Ascha M, et al. New baseline renal function after radical or partial nephrectomy: a simple and accurate predictive model. J Urol. 2021;205:1310-1320] post-nephrectomy future glomerular function rate (fGFR) equation in a diverse cohort using both the Chronic Kidney Disease Epidemiology (CKD-EPI) 2009 equation with race, used in the creation of the formula, as well as the CKD-EPI 2021 equation without race. METHODS: Patients who underwent partial or radical nephrectomy for renal cell carcinoma from 2005-2021 were identified in our institutional database. Patients with creatinine values preoperatively and 3-12 months postoperatively were included. Correlation/bias/accuracy/precision of the fGFR equation (fGFR = 35+ [preoperative eGFR × 0.65] - 18 [if radical] - [age × 0.25] + 3 [if tumor >7 cm] - 2 [if diabetes]) with observed postoperative eGFR was determined by both the CKD-EPI-2021 and CKD-EPI 2009 equations. RESULTS: A total of 1443 patients were analyzed. Seventy-one percent (1024) were White and 22.9% (331) were Black. Most underwent radical nephrectomy (60.3%). 40% T3-T4 renal cell carcinoma (RCC), with 14.8% of patients having M1 disease. Median observed vs predicted fGFR was 58.0 vs 58.7 mL/min/1.73 m2 for CKD-EPI 2021 and 56.0 vs 57.5 for CKD-EPI 2009. For the total cohort, the correlation/bias/accuracy/precision of the fGFR equation was 0.805/-0.5/81.7/7.9-9.0 for CKD-EPI 2021 and 0.809/-0.8/81.3/-8.1 to 8 for CKD-EPI 2009. In Black patients, fGFR equation demonstrated >75% accuracy with both CKD-EPI equations; however, accuracy was lower in black patients with the CKD-EPI2021 equation (76.1% vs 83.4%, P = .003). CONCLUSION: The fGFR equation performed well in our large, diverse cohort, though accuracy was relatively lower when using CKD-EPI 2021 compared to CKD-EPI 2009.

Fenfluramine increases survival and reduces markers of neurodegeneration in a mouse model of Dravet syndrome.

OBJECTIVE: In patients with Dravet syndrome (DS), fenfluramine reduced convulsive seizure frequency and provided clinical benefit in nonseizure endpoints (e.g., executive function, survival). In zebrafish mutant scn1 DS models, chronic fenfluramine treatment preserved neuronal cytoarchitecture prior to seizure onset and prevented gliosis; here, we extend these findings to a mammalian model of DS (Scn1a+/- mice) by evaluating the effects of fenfluramine on neuroinflammation (degenerated myelin, activated microglia) and survival. METHODS: Scn1a+/- DS mice were treated subcutaneously once daily with fenfluramine (15 mg/kg) or vehicle from postnatal day (PND) 7 until 35-37. Sagittal brain sections were processed for immunohistochemistry using antibodies to degraded myelin basic protein (D-MBP) for degenerated myelin, or CD11b for activated (inflammatory) microglia; sections were scored semi-quantitatively. Apoptotic nuclei were quantified by TUNEL assay. Statistical significance was evaluated by 1-way ANOVA with post-hoc Dunnett's test (D-MBP, CD11b, and TUNEL) or Logrank Mantel-Cox (survival). RESULTS: Quantitation of D-MBP immunostaining per 0.1 mm2 unit area of the parietal cortex and hippocampus CA3 yielded significantly higher spheroidal and punctate myelin debris counts in vehicle-treated DS mice than in wild-type mice. Fenfluramine treatment in DS mice significantly reduced these counts. Activated CD11b + microglia were more abundant in DS mouse corpus callosum and hippocampus than in wild-type controls. Fenfluramine treatment of DS mice resulted in significantly fewer activated CD11b + microglia than vehicle-treated DS mice in these brain regions. TUNEL staining in corpus callosum was increased in DS mice relative to wild-type controls. Fenfluramine treatment in DS mice lowered TUNEL staining relative to vehicle-treated DS mice. By PND 35-37, 55% of control DS mice had died, compared with 24% of DS mice receiving fenfluramine treatment (P = 0.0291). SIGNIFICANCE: This is the first report of anti-neuroinflammation and pro-survival after fenfluramine treatment in a mammalian DS model. These results corroborate prior data in humans and animal models and suggest important pharmacological activities for fenfluramine beyond seizure reduction. PLAIN LANGUAGE SUMMARY: Dravet syndrome is a severe epilepsy disorder that impairs learning and causes premature death. Clinical studies in patients with Dravet syndrome show that fenfluramine reduces convulsive seizures. Additional studies suggest that fenfluramine may have benefits beyond seizures, including promoting survival and improving control over emotions and behavior. Our study is the first to use a Dravet mouse model to investigate nonseizure outcomes of fenfluramine. Results showed that fenfluramine treatment of Dravet mice reduced neuroinflammation significantly more than saline treatment. Fenfluramine-treated Dravet mice also lived longer than saline-treated mice. These results support clinical observations that fenfluramine may have benefits beyond seizures.

Protracted neuronal recruitment in the temporal lobes of young children.

The temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs1-4. The human EC continues to develop during childhood5, but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimer's disease, and previous work has linked cognitive decline to the loss of LAMP5+RELN+ cells6,7. Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood.

Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus.

The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei. Pseudotime trajectories provided insights into the genes driving formation of these nuclei. Comparisons to single-cell transcriptomic data from the mouse hypothalamus suggested extensive conservation of neuronal subtypes despite certain differences in species-enriched gene expression. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. These results provide a comprehensive transcriptomic view of human hypothalamus development through gestation and adulthood at cellular resolution.

Single-cell analysis of prenatal and postnatal human cortical development.

We analyzed >700,000 single-nucleus RNA sequencing profiles from 106 donors during prenatal and postnatal developmental stages and identified lineage-specific programs that underlie the development of specific subtypes of excitatory cortical neurons, interneurons, glial cell types, and brain vasculature. By leveraging single-nucleus chromatin accessibility data, we delineated enhancer gene regulatory networks and transcription factors that control commitment of specific cortical lineages. By intersecting our results with genetic risk factors for human brain diseases, we identified the cortical cell types and lineages most vulnerable to genetic insults of different brain disorders, especially autism. We find that lineage-specific gene expression programs up-regulated in female cells are especially enriched for the genetic risk factors of autism. Our study captures the molecular progression of cortical lineages across human development.

A cross-species proteomic map reveals neoteny of human synapse development.

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.

LIF signaling regulates outer radial glial to interneuron fate during human cortical development.

Radial glial (RG) development is essential for cerebral cortex growth and organization. In humans, the outer radial glia (oRG) subtype is expanded and gives rise to diverse neurons and glia. However, the mechanisms regulating oRG differentiation are unclear. oRG cells express leukemia-inhibitory factor (LIF) receptors during neurogenesis, and consistent with a role in stem cell self-renewal, LIF perturbation impacts oRG proliferation in cortical tissue and organoids. Surprisingly, LIF treatment also increases the production of inhibitory interneurons (INs) in cortical cultures. Comparative transcriptomic analysis identifies that the enhanced IN population resembles INs produced in the caudal ganglionic eminence. To evaluate whether INs could arise from oRGs, we isolated primary oRG cells and cultured them with LIF. We observed the production of INs from oRG cells and an increase in IN abundance following LIF treatment. Our observations suggest that LIF signaling regulates the capacity of oRG cells to generate INs.

Osteopontin drives retinal ganglion cell resiliency in glaucomatous optic neuropathy.

Chronic neurodegeneration and acute injuries lead to neuron losses via diverse processes. We compared retinal ganglion cell (RGC) responses between chronic glaucomatous conditions and the acute injury model. Among major RGC subclasses, αRGCs and intrinsically photosensitive RGCs (ipRGCs) preferentially survive glaucomatous conditions, similar to findings in the retina subject to axotomy. Focusing on an αRGC intrinsic factor, Osteopontin (secreted phosphoprotein 1 [Spp1]), we found an ectopic neuronal expression of Osteopontin (Spp1) in other RGCs subject to glaucomatous conditions. This contrasted with the Spp1 downregulation subject to axotomy. αRGC-specific Spp1 elimination led to significant αRGC loss, diminishing their resiliency. Spp1 overexpression led to robust neuroprotection of susceptible RGC subclasses under glaucomatous conditions. In contrast, Spp1 overexpression did not significantly protect RGCs subject to axotomy. Additionally, SPP1 marked adult human RGC subsets with large somata and SPP1 expression in the aqueous humor correlated with glaucoma severity. Our study reveals Spp1's role in mediating neuronal resiliency in glaucoma.

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial.

OBJECTIVE: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. RESULTS: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. SIGNIFICANCE: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.