Assessment of the long-term efficacy and safety of adjunctive perampanel in adolescent patients with epilepsy: Post hoc analysis of open-label extension studies.

OBJECTIVE: This post hoc analysis of four open-label extension (OLEx) studies evaluated the long-term efficacy and safety of adjunctive perampanel in adolescent patients (aged 12 to ≤17 years) with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS). METHODS: Patients who completed one of six double-blind, placebo-controlled studies could enter one of four OLEx studies comprising a blinded Conversion Period (6-16 weeks) followed by a Maintenance Phase (27 to ≤256 weeks; perampanel dose: ≤12 mg/day). Exposure, retention, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. Efficacy outcomes were analyzed using observed case and last observation carried forward (LOCF) approaches; the latter was used to account for early dropouts. RESULTS: The Full Analysis Set comprised 309 adolescents with FOS (FBTCS, n = 109) and 19 with GTCS, and the Safety Analysis Set comprised 311 with FOS (FBTCS, n = 110) and 19 with GTCS. Mean (standard deviation) cumulative duration of perampanel exposure (weeks) was: FOS, 77.7 (58.7); FBTCS, 88.7 (63.8); and GTCS, 97.0 (35.5). Retention rates were maintained for ≤2 years (FOS, 50.0 %; FBTCS, 57.1 %; GTCS, 41.7 %). Seizure control (median percent reduction in seizure frequency/28 days) was sustained for up to 2 years; FOS (59.4 %, n = 113), FBTCS (64.6 %, n = 53), and GTCS (86.5 %, n = 17). At Year 2, 50 % responder rates were: FOS, 58.4 % (n = 66); FBTCS, 54.7 % (n = 29); and GTCS, 82.4 % (n = 14); seizure-freedom rates were: FOS, 5.3 % (n = 6); FBTCS, 24.5 % (n = 13); and GTCS, 35.3 % (n = 6). Long-term seizure control was observed even in LOCF analyses. The incidence of TEAEs was highest during Year 1 (FOS, n = 269 [86.5 %]; FBTCS, n = 95 [86.4 %]; GTCS, n = 15 [78.9 %]), compared with Years 2-4; the most common (≥10 % of patients) were dizziness, somnolence, and nasopharyngitis. No new safety signals emerged with long-term treatment. CONCLUSIONS: This post hoc analysis suggests that long-term (≤2 years) adjunctive perampanel (≤12 mg/day) is efficacious and generally well tolerated in adolescent patients with FOS, with or without FBTCS, or GTCS.

[Severe bowel complications in SARS-CoV-2 patients receiving protocolized care]. / Complicaciones intestinales graves en pacientes SARS-CoV-2 recibiendo manejo protocolizado.

Introduction and aims: A case series of ten patients that received protocolized care for SARS-CoV-2 infection and developed severe gastrointestinal complications, is presented. The aim of our study was to contribute to the ongoing discussion regarding gastrointestinal complications related to SARS-CoV-2 infection. After reviewing the current literature, ours appears to be the first detailed case series on the topic. Materials and methods: A retrospective filtered search of all patients admitted to our hospital for SARS-CoV-2 infection, who developed severe gastrointestinal complications, was performed. All relevant data on hospital patient management, before and after surgery, were collected from the medical records. Results: Of the 905 patients admitted to our hospital due to SARS-CoV-2 infection, as of August 26, 2020, ten of them developed severe gastrointestinal complications. Seven of those patients were men. There were four cases of perforation of the proximal jejunum, three cases of perforations of the ascending colon, one case of concomitant perforation of the sigmoid colon and terminal ileum, one case of massive intestinal necrosis, and one preoperative death. Three right colectomies, four intestinal resections, one Hartmann's procedure with bowel resection, and one primary repair of the small bowel were performed. The mortality rate of the patients analyzed was 50%. Conclusion: Spontaneous bowel perforations and acute mesenteric ischemia are emerging as severe, life-threatening complications in hospitalized SARS-CoV-2 patients. More evidence is needed to identify risk factors, establish preventive measures, and analyze possible adverse effects of the current treatment protocols.

Efficacy and safety of adjunctive perampanel in adolescent patients with epilepsy: Post hoc analysis of six randomized studies.

OBJECTIVE: This post hoc analysis of six randomized, double-blind, Phase II and III studies evaluated efficacy and safety of adjunctive perampanel (2-12 mg/day) in adolescent patients (aged ≥12 to ≤17 years) with uncontrolled partial-onset seizures, with or without secondarily generalized (SG) seizures, or primary generalized tonic-clonic (PGTC) seizures. METHODS: Adolescent patients from Studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), 335 (NCT01618695), 235 (NCT01161524), and 332 (NCT01393743) were included. Efficacy assessments (split by seizure type) included median percent change in seizure frequency per 28 days from baseline and seizure-freedom rates. Safety assessments (all seizure types combined) included monitoring of treatment-emergent adverse events (TEAEs). RESULTS: The Safety Analysis Set included 372 adolescent patients (placebo, n = 114; perampanel, n = 258); the Full Analysis Set included 346 patients with partial-onset seizures (placebo, n = 103; perampanel, n = 243), of whom 125 experienced SG seizures during baseline (placebo, n = 37; perampanel, n = 88), and 22 with PGTC seizures (placebo, n = 9; perampanel, n = 13). Compared with placebo, perampanel 8 and 12 mg/day conferred greater median percent reductions in seizure frequency per 28 days for partial-onset seizures (18.0% vs 35.9% and 53.8% [both P < 0.01]) and SG seizures (24.4% vs 72.8% [P < 0.001] and 57.8% [P < 0.01]), and greater seizure-freedom rates (partial-onset: 7.8% vs 13.2% and 11.8% [not statistically significant]; SG: 8.1% vs 40.7% [P < 0.001] and 41.7% [P < 0.01]). For PGTC seizures, and compared with placebo, perampanel 8 mg/day was also associated with greater median percent reductions in seizure frequency per 28 days (29.8% vs 88.0%) and greater seizure-freedom rates (11.1% vs 23.1%). Treatment-emergent adverse events were reported in 76 (66.7%) placebo- and 192 (74.4%) perampanel-treated patients (most common: dizziness, somnolence, headache, and nasopharyngitis). Serious TEAEs occurred in 5 (4.4%) placebo- and 11 (4.3%) perampanel-treated patients. CONCLUSIONS: Adjunctive perampanel was efficacious and generally well tolerated in adolescent patients with partial-onset, SG, or PGTC seizures and represents a potentially beneficial treatment option for adolescents with uncontrolled epilepsy.

Long-term safety and tolerability of adjunctive eslicarbazepine acetate in children with focal seizures.

OBJECTIVE: The objective of this study was to evaluate long-term safety and tolerability outcomes in two open-label extension (OLE) studies of adjunctive eslicarbazepine acetate (ESL) in children with focal seizures. METHODS: Safety data from patients aged 4-17 years in OLEs of Studies 2093-208 and -305 were pooled and analyzed. Studies 208 and 305 were randomized, double-blind, placebo-controlled studies of adjunctive treatment with ESL in children with focal seizures refractory to treatment with 1-2 antiseizure drugs; patients could continue into uncontrolled OLEs (up to 5 years total duration). The OLEs evaluated the safety and tolerability of ESL (10-30 mg/kg/day; maximum 1200 mg/day). RESULTS: The 1-year OLE and post-1-year OLE safety populations comprised 337 and 177 ESL-treated patients, respectively. The overall incidence of treatment-emergent adverse events (TEAEs) with ESL was 64.1% during the 1-year OLE and 52.5% during the post-1-year OLE. Nasopharyngitis, partial seizures, vomiting, pyrexia, headache, somnolence, and respiratory tract infection were the most frequently reported TEAEs during the 1-year OLE. The overall incidence of serious adverse events (AEs) was 8.9% during the 1-year OLE and 10.2% during the post-1-year OLE. Partial seizures (1.2%) and pneumonia (1.2%) were the most frequently reported serious AEs during the 1-year OLE. The overall incidence of TEAEs leading to discontinuation was 4.2% during the 1-year OLE and 0.6% during the post-1-year OLE. Partial seizures (1.5%) was the most frequently reported TEAE leading to discontinuation during the 1-year OLE. CONCLUSIONS: Overall, long-term treatment with ESL was generally well tolerated in pediatric patients aged 4-17 years with focal seizures. TEAEs were comparable to those observed in adults with no new events of concern.

NWChem: Past, present, and future.

Specialized computational chemistry packages have permanently reshaped the landscape of chemical and materials science by providing tools to support and guide experimental efforts and for the prediction of atomistic and electronic properties. In this regard, electronic structure packages have played a special role by using first-principle-driven methodologies to model complex chemical and materials processes. Over the past few decades, the rapid development of computing technologies and the tremendous increase in computational power have offered a unique chance to study complex transformations using sophisticated and predictive many-body techniques that describe correlated behavior of electrons in molecular and condensed phase systems at different levels of theory. In enabling these simulations, novel parallel algorithms have been able to take advantage of computational resources to address the polynomial scaling of electronic structure methods. In this paper, we briefly review the NWChem computational chemistry suite, including its history, design principles, parallel tools, current capabilities, outreach, and outlook.

Nasal eosinophilic angiocentric fibrosis with IgG4-positive plasma cell infiltration.

INTRODUCTION: Eosinophilic angiocentric fibrosis (EAF) is a rare lesion that predominantly affects the upper respiratory tract. Its etiology is unknown and it has been recently associated with the IgG4- related disease (IgG4-RD) spectrum. To the author's knowledge, this is the sixth case report of the relationship between EAF and IgG4-RD. CASE REPORT: We report the case of a 37-year-old woman with nasal deformity and facial pain. The lesion was surgically excised. Histological examination revealed features of EAF with an IgG4/IgG plasma cell ratio ≷73% and 31 IgG4 stained cells per high power field. No clinical or radiological recurrence was detected during follow-up. Serum IgG4 quantification one year after surgery was within normal limits. DISCUSSION: The relationship between both entities may have therapeutic impact because IgG4-RD of the head and neck has a high remission rate with corticosteroids and immunosuppressive therapy. Additional reports of this infrequent disease are necessary to elucidate appropriate treatment and prognosis.

Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors.

Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD.

Skin cancer prevention campaign in childhood: survey based on 3676 children in Brazil.

BACKGROUND AND OBJECTIVES: Primary skin cancer prevention campaigns are essential and more effective among children, not only because of the importance of sun exposure effects during this period, but also because this age is when individuals are developing behaviours. The Brazilian Society of Dermatology - Regional State of Sao Paulo developed and conducted the programme named 'The Sun, Friend of Childhood', a school health education and disease prevention project for children and parents. Our objective was to evaluate the cognitive and behavioural effects of the children and parents before and after an education model-based intervention of sun protection. METHODS: We carried out a study on a school population of Social Service of Industry - Regional State of São Paulo, from the first to the fifth years of the regular course (6-10 years). Our educational project was planned to be based on two children's learning tools (comic magazine and a DVD cartoon). Questionnaires in relation to habits and knowledge in sun exposure were applied to the children (3776) before and (2748) after the intervention. A questionnaire was applied to 3663 parents regarding personal details and habits of their children. RESULTS: According to the McNemar's statistical test, all changes in the children in acquiring new knowledge about good practices for sun exposure were statistically significant. CONCLUSIONS: Educative sun exposure programmes in childhood are a relevant tool to modify the history of life for next generations, to concern the skin cancer and good health practices.

Serum-mediated Haemonchus contortus larval aggregation differs by larval stage and is enhanced by complement.

The objectives of this study were to measure Haemonchus contortus larval aggregation by complement/antibody complexes, determine effect of breed resistance and infection status and determine the effect of larval maturation on larval aggregation in vitro. Larval binding assays were performed on H. contortus L3, exsheathed L3 and L4 incubated with serum from either parasite naïve or H. contortus primed St. Croix (resistant) and Suffolk (susceptible) lambs. No differences in L3 aggregation were observed between serum from either breed or infection status. Exsheathed L3 (60%) and L4 (42%) aggregation by primed Suffolk serum was significantly reduced compared with L3 (80%, P<.001). Removal of either complement or antibody effectively eliminated L3 aggregation (P<.001). Combination of antibody-depleted and complement-inactivated serum restored L3 aggregation to levels consistent with unprocessed serum, supporting a role for antibody and complement in aggregation (P<.001). Use of fluorescence-labelled anti-sheep IgG antibody allowed documentation of IgG bound to serum complexes within L3 masses and was present only in larvae incubated with normal serum, and complement- and antibody-depleted serum combination. These data indicate that complement/antibody complexes inhibit larval motility through larval aggregation which may be critical in early larval clearance of H. contortus.

The effect of ovine peripheral blood mononuclear cells on Haemonchus contortus larval morbidity in vitro.

The objective of this study was to determine the effects of peripheral blood mononuclear cells (PBMC), derived from parasite-resistant St. Croix (STC) hair sheep and parasite-susceptible Suffolk (SUF) sheep, on Haemonchus contortus L3 stage larval death in vitro, with or without autologous serum. Larval morbidity was quantified by measuring larval ATP concentration following incubation with PBMC. Larvae exposed to either STC- or SUF-derived PBMC had lower ATP than live larvae (0.12 µmol/L ATP and 0.16 µmol/L ATP vs 0.27 µmol/L ATP, respectively) (P<.001) and greater ATP of dead larvae (0.03 µmol/L ATP) (P<.001). Breed differences were observed with addition of autologous serum. Larvae exposed to SUF-derived PBMC with autologous serum were not significantly different from live larval ATP. STC-derived serum did not significantly reduce larval ATP compared to PBMC alone (0.11 µmol/L ATP), but was significantly reduced compared to live larvae (0.22 µmol/L ATP) and SUF-derived PBMC with autologous serum (0.23 µmol/L ATP) (P<.001). These data indicate that a cellular response alone is capable of significantly reducing larval ATP in a breed-independent manner. However, addition of serum to SUF-PBMC failed to reduce larval ATP, indicating breed-dependent humoral response to H. contortus.

Assessment of treatment patterns and healthcare costs associated with probable Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is a chronic and severe form of epilepsy characterized by intractable seizures, cognitive impairment, and abnormal electroencephalogram findings with slow spike-wave complexes. It typically presents before age 8, but symptoms continue into adulthood and require lifelong treatment associated with significant clinical burden. Data on LGS-associated healthcare utilization and costs are limited. In this study we use a claims-based LGS classifier based on random forest methodology to identify patients with probable LGS from the a Medicaid multi-state database and assess its prevalence across the age spectrum, healthcare utilization, treatment patterns, costs, and comorbid conditions. The classifier identified patients with probable LGS across all ages, with up to 8% of 10-year-old patients with epilepsy identified as having probable LGS. The prevalence of probable LGS was lower in older age cohorts, indicating that it may be under-recognized in older patients. Our analysis showed that probable LGS is associated with considerably higher total healthcare and medical costs than non-LGS patients. The costs were generally consistent between age cohorts, suggesting that the cost burden extends beyond childhood and has a lifelong impact. Analysis of treatment patterns suggest that while the majority of probable LGS patients in this study received widest-spectrum AEDs, a considerable proportion did not and therefore may have been inadequately treated. Further, usage of clobazam and rufinamide was decreased in older compared to younger patient cohorts, indicating that older patient cohorts are less likely to be receiving optimum treatment for LGS. These findings indicate the need for increased clinical attention to LGS beyond pediatric years, with a focus on optimization of treatment for LGS patients of all ages with widest-spectrum AEDs. Timely recognition and adequate treatment of LGS are likely to result in improved outcomes and less costly management of this condition.

Special situations in inflammatory bowel disease: First Latin American consensus of the Pan American Crohn's and Colitis Organisation (PANCCO) (Second part). / Situaciones especiales en la enfermedad inflamatoria intestinal: primer consenso latinoamericano de la Pan American Crohn's and Colitis Organisation (PANCCO) (Segunda parte).

This is the first Latin American Consensus of the Pan American Crohn's and Colitis Organisation (PANCCO) regarding special situations in patients with inflammatory bowel disease (IBD). The aim of this consensus is to raise awareness in the medical community in all Latin American countries with respect to pregnancy, vaccinations, infections, neoplasms, including colorectal cancer, and pediatric issues in patients with IBD.

I. EXECUTIVE CONTROL IN EARLY CHILDHOOD.

Executive control (EC) is a central construct in developmental science, although measurement limitations have hindered understanding of its nature and development in young children, relation to social risk, and prediction of important outcomes. Disentangling EC from the foundational cognitive abilities it regulates and that are inherently required for successful executive task completion (e.g., language, visual/spatial perception, and motor abilities) is particularly challenging at preschool age, when these foundational abilities are still developing and consequently differ substantially among children. A novel latent bifactor modeling approach delineated respective EC and foundational cognitive abilities components that undergird executive task performance in a socio demographically stratified sample of 388 preschoolers in a longitudinal, cohort-sequential study. The bifactor model revealed a developmental shift, where both EC and foundational cognitive abilities contributed uniquely to executive task performance at ages 4.5 and 5.25 years, but were not separable at ages 3 and 3.75. Contrary to the view that EC is vulnerable to socio-familial risk, the contributions of household financial and learning resources to executive task performance were not specific to EC but were via their relation to foundational cognitive abilities. EC, though, showed a unique, discriminant relation with hyperactive symptoms late in the preschool period, whereas foundational cognitive abilities did not predict specific dimensions of dysregulated behavior. These findings form the basis for a new, integrated approach to the measurement and conceptualization of EC, which includes dual consideration of the contributions of EC and foundational cognitive abilities to executive task performance, particularly in the developmental context of preschool.

Kinship analyses identify fish dispersal events on a temperate coastline.

Connectivity is crucial for the persistence and resilience of marine species, the establishment of networks of marine protected areas and the delineation of fishery management units. In the marine environment, understanding connectivity is still a major challenge, due to the technical difficulties of tracking larvae. Recently, parentage analysis has provided a means to address this question effectively. To be effective, this method requires limited adult movement and extensive sampling of parents, which is often not possible for marine species. An alternative approach that is less sensitive to constraints in parental movement and sampling could be the reconstruction of sibships. Here, we directly measure connectivity and larval dispersal in a temperate marine ecosystem through both analytical approaches. We use data from 178 single nucleotide polymorphism markers to perform parentage and sibship reconstruction of the black-faced blenny (Tripterygion delaisi) from an open coastline in the Mediterranean Sea. Parentage analysis revealed a decrease in dispersal success in the focal area over 1 km distance and approximately 6.5% of the juveniles were identified as self-recruits. Sibship reconstruction analysis found that, in general, full siblings did not recruit together to the same location, and that the largest distance between recruitment locations was much higher (11.5 km) than found for parent-offspring pairs (1.2 km). Direct measurements of dispersal are essential to understanding connectivity patterns in different marine habitats, and show the degree of self-replenishment and sustainability of populations of marine organisms. We demonstrate that sibship reconstruction allows direct measurements of dispersal and family structure in marine species while being more easily applied in those species for which the collection of the parental population is difficult or unfeasible.

Search for solar axions by the CERN axion solar telescope with 3He buffer gas: closing the hot dark matter gap.

The CERN Axion Solar Telescope has finished its search for solar axions with (3)He buffer gas, covering the search range 0.64 eV ≲ ma ≲ 1.17 eV. This closes the gap to the cosmological hot dark matter limit and actually overlaps with it. From the absence of excess x rays when the magnet was pointing to the Sun we set a typical upper limit on the axion-photon coupling of gaγ ≲ 3.3 × 10(-10) GeV(-1) at 95% C.L., with the exact value depending on the pressure setting. Future direct solar axion searches will focus on increasing the sensitivity to smaller values of gaγ, for example by the currently discussed next generation helioscope International AXion Observatory.