From environmental issue to purification aid: Novel positively charged functionalized algal biochar as robust modifier of composite nanofiltration membranes.

Robust membrane modifiers were achieved for the first time by functionalizing the algal biochar of unique porous structure. The biochar was prepared through the pyrolysis of Cladophora glomerata, the most widespread freshwater macroalga, functionalized by diethylenetriamine and dendrimer poly(amidoamine), and employed to fabricate positively charged composite nanofiltration membranes. The presence of hydrophilic functionalizers of positive charge on the membrane was verified through Fourier transform infrared and energy dispersive X-ray analyses and atomic force microscopy and zeta potential measurements were performed to determine surface roughness and confirm positive charge of the modified membranes. Dispersion of modifiers on the surface and morphology of the were also revealed through field-emission scanning electron microscopy images. It has shown that, compared to the pristine membrane, pure water fluxes were increased by 214% and 185%, and water contact angles were reduced from 66.1° to 39.5° and 43.3° in those modified by biochar functionalized with dendrimer poly(amidoamine) and diethylenetriamine, respectively. More than 90% dye rejections and salt and heavy metals removals were recorded for the membranes possessed 0.6 wt% of modifiers. Finally, a comparative study conducted between the novel modifier introduced in this study and those reported in the literature, indicated that C. glomerata biochar decorated with amine functional groups could be considered as a robust and practical alternative to the common modifiers used to manipulate nanocomposite membranes characteristics.

Pitfalls of using video-EEG for a trial endpoint in children aged <4 years with focal seizures.

OBJECTIVE: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability. We evaluated inter-reader agreement in video-EEG interpretation in SP0967, which to our knowledge, are the first such data for very young children with focal seizures from a placebo-controlled trial. METHODS: Local investigator and central reader agreement in video-EEG interpretation was analyzed post hoc. RESULTS: Analysis included 105 EOB and 98 EOM video-EEGs. Local investigators and central reader showed poor agreement based on ≥2 focal seizures at EOB (Kappa = 0.01), and fair agreement based on ≥2 focal seizures at EOM (Kappa = 0.23). Local investigator and central reader seizure count interpretations varied substantially, particularly for focal seizures, but also primary generalized and unclassified epileptic seizures, at both timepoints. INTERPRETATION: High inter-reader variability and low inter-reader reliability of the interpretation of seizure types and counts prevent confident conclusion regarding the lack of efficacy of lacosamide in this population. We recommend studies in very young children do not employ video-EEGs exclusively for accurate study inclusion or as an efficacy measure.

Efficacy and tolerability of adjunctive lacosamide in patients aged <4 years with focal seizures.

OBJECTIVE: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures. METHODS: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age. After a 20-day titration period, patients who reached target-dose range (8-12 mg/kg/day) entered a 7-day maintenance period. Region-specific primary efficacy variables were based on ≤72-h video-electroencephalograms: change in average daily frequency (ADF) of electrographic focal seizures as measured on end-of-maintenance video-electroencephalogram versus end-of-baseline video-electroencephalogram (United States); 50% responder rate (≥50% reduction in ADF of focal seizures) during maintenance (European Union). RESULTS: In total, 255 patients were randomized (lacosamide/placebo: 128/127) and received ≥1 trial medication dose. Percentage reduction in ADF of focal seizures for lacosamide (116 patients) versus placebo (120 patients) was 3.2% (95% confidence interval = -13.6 to 17.5, p = 0.69). 50% responder rate was 41.4% for lacosamide (116 patients), 37.5% for placebo (120 patients) (p = 0.58). Treatment-emergent adverse events were reported by 44.5% of lacosamide-treated patients (placebo 51.2%). INTERPRETATION: Adjunctive lacosamide did not show superior efficacy versus placebo in young children with focal seizures. However, efficacy variables were potentially affected by high variability and low reliability between readers in video-electroencephalogram interpretation. Lacosamide was generally well tolerated; safety profile was acceptable and consistent with that in adults and children aged ≥4 years.

Comparison of bioleaching of a sulfidic copper ore (chalcopyrite) in column percolators and in stirred-tank bioreactors including microbial community analysis.

Chalcopyrite is the most abundant Cu-sulfide and economically the most important copper mineral in the world. It is known to be recalcitrant in hydrometallurgical processing and therefore chalcopyrite bioleaching has been thoroughly studied for improvement of processing. In this study, the microbial diversity in 22 samples from the Sarcheshmeh copper mine in Iran was investigated via 16S rRNA gene sequencing. In total, 1063 species were recognized after metagenomic analysis including the ferrous iron- and sulfur-oxidizing acidophilic genera Acidithiobacillus, Leptospirillum, Sulfobacillus and Ferroplasma. Mesophilic as well as moderately thermophilic acidophilic ferrous iron- and sulfur-oxidizing microorganisms were enriched from these samples and bioleaching was studied in shake flask experiments using a chalcopyrite-containing ore sample from the same mine. These enrichment cultures were further used as inoculum for bioleaching experiments in percolation columns for simulating heap bioleaching. Addition of 100 mM NaCl to the bioleaching medium was assessed to improve the dissolution rate of chalcopyrite. For comparison, bioleaching in stirred tank reactors with a defined microbial consortium was carried out as well. While just maximal 32% copper could be extracted in the flask bioleaching experiments, 73% and 76% of copper recovery was recorded after 30 and 10 days bioleaching in columns and bioreactors, respectively. Based on the results, both, the application of moderately thermophilic acidophilic bacteria in stirred tank bioreactors, and natural enrichment cultures of mesoacidophiles, with addition of 100 mM NaCl in column percolators with agglomerated ore allowed for a robust chalcopyrite dissolution and copper recovery from Sarcheshmeh copper ore via bioleaching.

Low incidence of microsatellite instability in gastric cancers and its association with the clinicopathological characteristics: a comparative study.

Gastric cancer is a complex heterogeneous disease with different molecular subtypes that have clinical implications. It is characterized by high mortality rates and limited effective therapies. Microsatellite instability (MSI) has been recognized as a subgroup with a good prognosis based on TCGA and ACRG categorizations. Besides its prognostic and predictive value, gastric cancers with high MSI exhibit different clinical behaviors. The prevalence of high MSI has been assessed in gastric cancer worldwide, especially in East Asia, but there is a lack of such information in the Middle East. Therefore, this study aimed to investigate the incidence and status of MSI in Iranian gastric cancer patients using 53 samples collected from 2015 to 2020 at Taleghani Hospital Medical Center. DNA from tumoral and normal tissues were extracted and assessed through multiplex-PCR based on five mononucleotide repeats panel. Clinicopathological variables, including age, sex, Lauren classification, lymph node involvement, TNM stage, differentiation, localization, and tumor size, were also analyzed. With 2 males and 2 females, high microsatellite instability represented a small subgroup of almost 7.5% of the samples with a median age of 60.5 years. High microsatellite instability phenotypes were significantly associated with patients aged 68 years and older (p­value of 0.0015) and lower lymph node involvement (p­value of 0.0004). Microsatellite instability was also more frequent in females, with distal gastric location, bigger tumor size, and in the intestinal type of gastric cancer rather than the diffuse type.

Safety, tolerability, and efficacy of adjunctive lacosamide in pediatric patients with epilepsy syndromes associated with generalized seizures: Phase 2, open-label exploratory trial.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of lacosamide (LCM) (up to 12 mg/kg/day or 600 mg/day) as adjunctive therapy in pediatric patients with epilepsy syndromes associated with generalized seizures. METHODS: Phase 2, multicenter, open-label exploratory trial (SP0966; NCT01969851; 2012-001446-18) of oral LCM for epilepsy syndromes associated with generalized seizures in pediatric patients ≥1 month to <18 years of age taking one to three concomitant antiseizure medications. The trial comprised a 6-week prospective baseline period, 6-week flexible titration period, and 12-week maintenance period. RESULTS: Fifty-five patients (mean age: 9.2 years; 56.4% male) took at least one dose of LCM and had at least one post-baseline efficacy-related assessment. The median treatment duration was 127.0 days. There were no clinically significant mean or median changes or worsening from baseline to end of the titration period in the count of generalized spike-wave discharges per interpretable hour on 24-h ambulatory electroencephalogram recordings, or from baseline to the maintenance period in mean and median days with any generalized or focal to bilateral tonic-clonic seizures per 28 days. Treatment-emergent adverse events (TEAEs) were reported by 49 patients (89.1%), and three patients (5.5%) discontinued due to TEAEs. The median change and median percentage change in days with any generalized or focal to bilateral tonic-clonic seizures per 28 days from baseline to the maintenance period were both 0. Trends toward improvement (decrease) were observed in median change and median percentage change in days with each individual seizure type (absence, myoclonic, clonic, tonic, tonic-clonic, atonic, and focal to bilateral tonic-clonic) per 28 days. SIGNIFICANCE: Safety findings were consistent with the known safety profile of LCM and were as expected for the pediatric population. There was no worsening of generalized seizures with LCM. Limitations include the inability to correlate spike and wave data with clinical outcomes, and the lack of similar studies against which the results can be compared.

Physician- and patient-reported perspectives on myasthenia gravis in Europe: a real-world survey.

BACKGROUND: Myasthenia gravis (MG) is a rare, chronic, debilitating, unpredictable, and potentially life-threatening neuromuscular disease. There is a lack of real-world data on disease management that could be used to further understand and address unmet patient needs and burden. We aimed to provide comprehensive real-world insights in the management of MG in five European countries. METHODS: Data were collected using the Adelphi Real World Disease Specific Programme™ in MG, a point-in-time survey of physicians and their patients with MG in France, Germany, Italy, Spain, and the United Kingdom (UK). Physician- and patient-reported clinical data were collected, including demographics, comorbidities, symptoms, disease history, treatments, healthcare resource utilization (HCRU), and quality of life outcomes. RESULTS: In total, 144 physicians completed 778 patient record forms from March to July 2020 in the UK, and from June to September 2020 in France, Germany, Italy and Spain. Mean patient age at symptom onset was 47.7 years, with a mean time from symptom onset to diagnosis of 332.4 days (10.97 months). At diagnosis, 65.3% of patients were classified as Myasthenia Gravis Foundation of America Class II or above. Mean number of symptoms reported at diagnosis per patient was five, with ocular myasthenia reported in at least 50% of patients. At time of survey completion, the mean number of symptoms reported per patient was five and ocular myasthenia and ptosis were each still present in more than 50% of patients. Acetylcholinesterase inhibitors were the most commonly prescribed chronic treatments in all countries. Of 657 patients treated with chronic treatment at the time of the survey, 62% continued to experience moderate-to-severe symptoms. On average, 3.1 healthcare professionals (HCPs) were involved in patient management, 6.2 consultations were made per patient with any HCP over the last 12 months, and 178 (22.9%) patients were hospitalized in the last 12 months. Overall, HCRU and disease management were similar across all countries. CONCLUSIONS: Our findings demonstrated the high burden of MG despite current treatment options for patients with MG.

Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study.

BACKGROUND: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating autoimmune disease. New treatments for this disease are needed because conventional therapies have limitations, such as side-effects (eg, increased infection risk) or inadequate control of symptoms. Rozanolixizumab is a neonatal Fc receptor blocker that might provide a novel therapeutic option for myasthenia gravis. We aimed to assess the safety and efficacy of rozanolixizumab for generalised myasthenia gravis. METHODS: MycarinG is a randomised, double-blind, placebo-controlled, adaptive phase 3 study done at 81 outpatient centres and hospitals in Asia, Europe, and North America. We enrolled patients (aged ≥18 years) with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) autoantibody-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America class II-IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis score of at least 11. Patients were randomly assigned (1:1:1) to receive subcutaneous infusions once a week for 6 weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg, or placebo. Randomisation was stratified by AChR and MuSK autoantibody status. Investigators, patients, and people assessing outcomes were masked to random assignments. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03971422) and EudraCT (2019-000968-18); an open-label extension study has been completed (NCT04124965; EudraCT 2019-000969-21) and another is underway (NCT04650854; EudraCT 2020-003230-20). FINDINGS: Between June 3, 2019, and June 30, 2021, 300 patients were assessed for eligibility, of whom 200 were enrolled. 66 (33%) were randomly assigned to rozanolixizumab 7 mg/kg, 67 (34%) to rozanolixizumab 10 mg/kg, and 67 (34%) to placebo. Reductions in MG-ADL score from baseline to day 43 were greater in the rozanolixizumab 7 mg/kg group (least-squares mean change -3·37 [SE 0·49]) and in the rozanolixizumab 10 mg/kg group (-3·40 [0·49]) than with placebo (-0·78 [0·49]; for 7 mg/kg, least-squares mean difference -2·59 [95% CI -4·09 to -1·25], p<0·0001; for 10 mg/kg, -2·62 [-3·99 to -1·16], p<0·0001). TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhoea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. INTERPRETATION: Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with generalised myasthenia gravis, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. These findings support the mechanism of action of neonatal Fc receptor inhibition in generalised myasthenia gravis. Rozanolixizumab represents a potential additional treatment option for patients with generalised myasthenia gravis. FUNDING: UCB Pharma.

Treatment patterns in myasthenia gravis: A United States health claims analysis.

INTRODUCTION/AIMS: Limited knowledge exists on treatment patterns in clinical practice in patients with myasthenia gravis (MG). In this study we examined MG treatment patterns in the United States. METHODS: Adult patients newly diagnosed with MG were identified from the IBM MarketScan insurance claims database. Patients with ≥2 MG International Classification of Disease diagnosis codes ≥3 months apart were retrospectively followed from the date of their first MG diagnosis record or start of treatment with acetylcholinesterase inhibitors (AChEI), intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig), or plasma exchange (PLEx) therapy. Based on treatment received at any time during the follow-up period, patients were segmented into six main treatment cohorts. Exacerbations and use of IVIg, SCIg, or PLEx after the index date were identified. RESULTS: During 2010 to 2019, 7,194 patients were followed for up to 10 (median, 2.3) years. Of 6,539 treated patients, 6,462 (99%) were ever treated with AChEI and/or corticosteroids (CS); 95% were first treated with AChEI and/or CS only; 33% received ≥1 nonsteroid immunosuppressive treatment (IST) and 2% received a biologic. During treatment with first IST (n = 2,166), patients experienced 42% and 94% higher incidence rates of exacerbations and IVIg, respectively, compared with AChEI and/or CS (n = 6,242), and 33% and 23% higher, respectively, compared with a second IST (n = 353). DISCUSSION: Many patients experienced exacerbations and received rescue therapy despite treatment, suggesting current treatments may not provide adequate disease control for some patients and that additional treatment options should be explored.

Healthcare resource use in myasthenia gravis: a US health claims analysis.

Background: There are limited data on the impact of myasthenia gravis (MG) on real-world healthcare resource use (HCRU) and patient burden in the United States. Objectives: This study aims to assess HCRU in patients with MG using data from a US health claims database. Design: A retrospective, database study of adult patients newly diagnosed with MG, using the IBM® MarketScan® Commercial Claims and Encounters and Medicare supplemental health insurance claims database. Methods: Patients with ⩾2 MG International Classification of Disease diagnosis codes ⩾3 months apart were followed from the date of their first MG diagnosis record or start of treatment. HCRU and use of immunoglobulins and plasma exchange during follow-up was assessed, as well as comorbidities, hospitalizations, emergency room (ER) visits, intensive care unit (ICU) admissions, and specialist visits per year after diagnosis, and compared with age- and sex-matched non-MG controls. Results: During 2010-2019, 7194 patients were followed for up to 10 years (median = 2.3 years). During follow-up, patients with MG were 2.6-fold more likely than controls to be hospitalized, and 4.5-fold more likely to be admitted to an ICU. Risk and numbers of ER admission, hospitalization, and ICU visits were the highest in the 12 months post-diagnosis of MG and were consistently higher than controls during follow-up. MG was the main cause for most hospitalizations. Conclusion: Patients with MG have higher HCRU, compared with the age- and sex-matched non-MG controls. The early years after MG diagnosis are a period of particularly high healthcare burden, with many patients requiring hospitalization and ICU care to manage serious exacerbations.

Safety and tolerability of short-term infusions of intravenous lacosamide in pediatric patients with epilepsy: An open-label, phase 2/3 trial.

OBJECTIVE: The objective of this study is to evaluate the safety and tolerability of intravenous (IV) lacosamide infusion in patients aged ≥1 month to <17 years with epilepsy. METHODS: This Phase 2/3 open-label trial (EP0060; NCT02710890) enrolled patients in two age cohorts (cohort 1: ≥8 to <17 years; cohort 2: ≥1 month to <8 years). Eligible patients were receiving oral lacosamide as adjunctive treatment or monotherapy (in an open-label long-term trial or by prescription) or were not receiving lacosamide before enrolment. Patients initiated IV lacosamide (2-12 mg/kg/day or 100-600 mg/day; 15-60 minutes infusion) as a replacement for oral lacosamide or as adjunctive treatment. The primary outcomes were treatment-emergent adverse events (TEAEs) and discontinuations due to TEAEs. RESULTS: In total, 103 patients were enrolled and completed the trial; 55 patients were included in cohort 1 (≥8 to <17 years), 48 in cohort 2 (≥1 month to <8 years). During the 4 weeks before screening, 74 (71.8%) patients had focal seizures, 12 (11.7%) had generalized seizures, and two (1.9%) had unclassified seizures. Most patients (74 [71.8%]) initiated lacosamide as adjunctive IV treatment. The mean overall duration of exposure to IV lacosamide was 1.18 days. Seventy-nine (76.7%) patients had one IV lacosamide infusion, 20 (19.4%) had two, one (1.0%) had three, and three (2.9%) had 10 infusions. Overall, five (4.9%) patients had a total of seven TEAEs. The only TEAEs reported in two or more patients were increased blood triglycerides (two [1.9%]). No serious or severe TEAEs were reported, and no patients discontinued due to TEAEs. No TEAEs were considered drug-related by the investigator. No consistent or clinically relevant treatment-related changes from baseline were observed for hematology, clinical chemistry parameters, vital signs, or 12-lead electrocardiograms. SIGNIFICANCE: IV lacosamide was generally well tolerated in pediatric patients (≥1 month to <17 years) with epilepsy, and no new safety concerns were identified.

Physician-Reported Perspectives on Myasthenia Gravis in the United States: A Real-World Survey.

INTRODUCTION: Myasthenia gravis (MG) is a rare, debilitating, chronic disorder caused by the production of pathogenic immunoglobulin G autoantibodies against the neuromuscular junction. A lack of real-world studies in rare diseases reflects a relatively limited understanding of the significant unmet needs and burden of disease for patients. We aimed to provide comprehensive real-world insights into the management and burden of MG from treating physicians in the United States (US). METHODS: Data were collected using the Adelphi Real World MG Disease Specific Programme™, a point-in-time survey of physicians and their patients with MG, in the US between March and July 2020. Physician-reported clinical data, including demographics, comorbidities, symptoms, disease history, treatments, and healthcare resource utilization, were collected. RESULTS: In total, 456 patient record forms were completed by 78 physicians based in the US. At time of survey completion, patient mean age was 54.5 years. Mean time from symptom onset to diagnosis was 9.0 months (n = 357). Ocular symptoms were reported in 71.7% of patients. General fatigue affected 47.1% of patients and over half of those reported the severity as moderate or severe (59.5%, n = 128). Acetylcholinesterase inhibitors and/or steroids were the most frequently prescribed first-line treatment type among patients receiving treatment at time of survey completion and with moderate-to-severe symptoms (77.9%, n = 159/204). High-dose steroids (n = 14) and intravenous immunoglobulin (n = 13) were the most prescribed acute treatments among those receiving an acute treatment at time of survey completion (n = 36), with symptom exacerbations or myasthenic crises being the most common reasons for acute treatment. On average, 2.5 healthcare professionals were involved in patient management and 5.0 consultations were made per patient over the last 12 months. CONCLUSIONS: Our findings indicated that, despite treatment, there is a proportion of patients with MG in the US who had a significant need for improved disease management.

Pharmacokinetics, safety, and tolerability of intravenous brivaracetam in pediatric patients with epilepsy: An open-label trial.

OBJECTIVE: To evaluate the pharmacokinetics, safety, and tolerability of brivaracetam (BRV) as 15-min intravenous (IV) infusion and bolus (≤2-min injection). METHODS: EP0065 (ClinicalTrials.gov: NCT03405714) was a Phase 2, multicenter, open-label trial in patients ≥1 month to <16 years of age with epilepsy. Patients received up to 5 mg/kg/day BRV (not exceeding 200 mg/day). Enrollment was sequential by descending age, depending on safety review. Outcomes included BRV plasma concentrations before and after IV administration, treatment-emergent adverse events (TEAEs), and discontinuations due to TEAEs. RESULTS: Fifty patients were enrolled, received BRV, and completed the trial. Twenty-six patients (52.0%) received 15-min infusions and 24 (48.0%) received bolus injections. Most patients (80.0%) received one IV dose. In the 15-min infusion group, geometric mean (GeoMean) BRV concentrations 15 (±2) min (n = 21) and 3 h (±15 min) (n = 21) post dose were 1903.0 ng/mL (geometric coefficient of variation [GeoCV]: 60.7%) and 1130.3 ng/mL (58.8%), respectively. In the bolus group, GeoMean BRV concentrations 15 (±2) min (n = 19) and 3 h (±15 min) (n = 21) post dose were 1704.8 ng/mL (GeoCV: 74.5%) and 1383.9 ng/mL (85.0%), respectively. Overall, 14 patients (28.0%) had TEAEs (15-min infusion: 8 [30.8%]; bolus: 6 [25.0%]), most commonly (≥5% of patients) somnolence (3 [6.0%]). Ten patients (20.0%) had drug-related TEAEs (15-min infusion: 6 [23.1%]; bolus: 4 [16.7%]). No patients discontinued due to TEAEs, and no deaths occurred. SIGNIFICANCE: IV BRV (up to 200 mg/day) was well tolerated in patients ≥1 month to <16 years of age, regardless of whether BRV was administered as 15-min infusion or bolus. No unexpected safety or pharmacokinetic differences were observed between patients receiving 15-min infusions or bolus, and plasma concentrations were in the expected range. Safety results were consistent with the known safety profile of oral BRV, with no new safety concerns identified.

Effect of light intensity and wavelength on nitrogen and phosphate removal from municipal wastewater by microalgae under semi-batch cultivation.

Domestic, agricultural and industrial water activities lead to organic and inorganic pollution of the environment. Biotreatment of municipal wastewater with the potential production of biomass is a valuable feature of microalgae. In this study we evaluated the effects of wavelength and light intensity on phosphate and ammonium removal on the one hand, and biomass and protein production on the other hand by Spirulina platensis in municipal wastewater treatment under semi batch cultivation. S. platensis was inoculated at 40% in artificial wastewater open pond system. Red, blue and purple light with 3800, 4800 and 5800 lux light intensity under 12 h light and 12 h darkness were investigated. Cultivation was conducted in semi-batch conditions; after four days cultivation, one third of the culture was replaced with fresh medium. The highest biomass and protein concentrations were observed under blue light at 5800 lux light intensity, 5.45 and 3 g/l respectively cumulatively; while the highest amount of phosphate and ammonium removal were about 145 and 218 mg/l under purple light at 5800 lux intensity, respectively. The amounts of biomass and protein produced, as well as phosphate and ammonium removed, are therefore impacted by wavelength, light intensity, results show that light intensity and wavelength can be customized to reach on the one hand the highest biomass and protein production, and on the other hand to maximize the removal of phosphorous and ammonium.

Analyses of seizure responses supportive of a novel trial design to assess efficacy of antiepileptic drugs in infants and young children with epilepsy: Post hoc analyses of pediatric levetiracetam and lacosamide trials.

OBJECTIVE: Recently, a novel trial design has been proposed to overcome challenges with traditional placebo-controlled trials of antiepileptic drugs in infants and young children (≥1 month of age) (Auvin S, et al. Epilepsia Open 2019;4:537-43). The proposed time-to-event trial design involves seizure counting by caregivers and allows adjustment of the duration of the baseline period and duration of exposure to placebo or potentially ineffective treatment based on the patient's seizure burden and response. We performed post hoc analyses to mimic this trial design and evaluate its viability. As these analyses required trials with prolonged baseline and treatment periods and diary data, which is not a typical design of trials in infants and young children (1 month to <4 years of age), data from two trials in pediatric patients (4-16 years of age) were used. METHODS: We performed post hoc analyses of two randomized, double-blind, placebo-controlled trials of adjunctive levetiracetam (N159; NCT00615615) and lacosamide (SP0969; NCT01921205) in children and adolescents (4-16 years of age) with focal-onset seizures. In these analyses, patients were followed until they completed the 10-week maintenance period, discontinued during the maintenance period, or reached their "nth" seizure (n = number of seizures patient had during baseline). Efficacy was assessed by determining time to nth seizure. RESULTS: In the analyses of both trials, patients on levetiracetam or lacosamide had a 34% lower risk of reaching their baseline seizure count during their 10-week maintenance period than patients on placebo. The previously published primary results of these trials also demonstrated efficacy of adjunctive levetiracetam and lacosamide. SIGNIFICANCE: Although these were post hoc analyses of trials in older children (4-16 years of age), our results provide supportive evidence for the utility of the novel time-to-event trial design for future trials in infants and young children (1 month to <4 years of age).

Lacosamide in patients with epilepsy of cerebrovascular etiology.

OBJECTIVES: To assess tolerability and efficacy of lacosamide in adults with cerebrovascular epilepsy etiology (CVEE). MATERIALS AND METHODS: Exploratory post hoc analyses of a double-blind, initial monotherapy trial of lacosamide vs carbamazepine-controlled release (carbamazepine-CR) (SP0993; NCT01243177); a double-blind conversion to lacosamide monotherapy trial (SP0902; NCT00520741); and an observational study of adjunctive lacosamide added to one antiepileptic drug (SP0973 VITOBA; NCT01098162). Patients with CVEE were identified based on epilepsy etiology recorded at baseline. RESULTS: In the initial monotherapy trial, 61 patients had CVEE (lacosamide: 27; carbamazepine-CR: 34). 20 (74.1%) patients on lacosamide (27 [79.4%] on carbamazepine-CR) reported treatment-emergent adverse events (TEAEs), most commonly (≥10%) headache, dizziness, and fatigue (carbamazepine-CR: headache, dizziness). A numerically higher proportion of patients on lacosamide than carbamazepine-CR completed 6 months (22 [81.5%]; 20 [58.8%]) and 12 months (18 [66.7%]; 17 [50.0%]) treatment without seizure at last evaluated dose. In the conversion to monotherapy trial, 26/30 (86.7%) patients with CVEE reported TEAEs, most commonly (≥4 patients) dizziness, convulsion, fatigue, headache, somnolence, and cognitive disorder. During lacosamide monotherapy, 17 (56.7%) patients were 50% responders and six (20.0%) were seizure-free. In the observational study, 36/83 (43.4%) patients with CVEE reported TEAEs, most commonly (≥5%) fatigue and dizziness. Effectiveness was assessed for 75 patients. During the last 3 months, 60 (80%) were 50% responders and 42 (56.0%) were seizure-free. CONCLUSIONS: These exploratory post hoc analyses suggested lacosamide was generally well tolerated and effective in patients with CVEE, with data from the initial monotherapy trial suggesting numerically better efficacy than carbamazepine-CR.

Efficacy and tolerability of adjunctive lacosamide in pediatric patients with focal seizures.

OBJECTIVE: To evaluate efficacy and tolerability of adjunctive lacosamide in children and adolescents with uncontrolled focal (partial-onset) seizures. METHODS: In this double-blind trial (SP0969; NCT01921205), patients (age ≥4-<17 years) with uncontrolled focal seizures were randomized (1:1) to adjunctive lacosamide/placebo. After a 6-week titration, patients who reached the target dose range for their weight (<30 kg: 8-12 mg/kg/d oral solution; ≥30-<50 kg: 6-8 mg/kg/d oral solution; ≥50 kg: 300-400 mg/d tablets) entered a 10-week maintenance period. The primary outcome was change in focal seizure frequency per 28 days from baseline to maintenance. RESULTS: Three hundred forty-three patients were randomized; 306 (lacosamide 152 of 171 [88.9%]; placebo 154 of 172 [89.5%]) completed treatment (titration and maintenance). Adverse events (AEs) were the most common reasons for discontinuation during treatment (lacosamide 4.1%; placebo 5.8%). From baseline to maintenance, percent reduction in focal seizure frequency per 28 days for lacosamide (n = 170) vs placebo (n = 168) was 31.7% (p = 0.0003). During maintenance, median percent reduction in focal seizure frequency per 28 days was 51.7% for lacosamide and 21.7% for placebo. Fifty percent responder rates (≥50% reduction) were 52.9% and 33.3% (odds ratio 2.17, p = 0.0006). During treatment, treatment-emergent AEs were reported by 67.8% lacosamide-treated patients (placebo 58.1%), most commonly (≥10%) somnolence (14.0%, placebo 5.2%) and dizziness (10.5%, placebo 3.5%). CONCLUSIONS: Adjunctive lacosamide was efficacious in reducing seizure frequency and generally well tolerated in patients (age ≥4-<17 years) with focal seizures. CLINICALTRIALSGOV IDENTIFIER: NCT01921205. CLASSIFICATION OF EVIDENCE: This trial provides Class I evidence that for children and adolescents with uncontrolled focal seizures, adjunctive lacosamide reduces seizure frequency.

Immunogenicity of HPV and HBV vaccines: adjuvanticity of synthetic analogs of monophosphoryl lipid A combined with aluminum hydroxide.

Monophosphoryl lipid A (MPL), a purified and detoxified product of lipopolysaccharide (LPS) of Salmonella minnesota R595, has been used as an adjuvant in different vaccines. In this study, the efficacy of human papillomaviruses (HPV) and hepatitis B virus (HBV) vaccines formulated with aluminum hydroxide combined with two different synthetic MPLs, 3D-(6-acyl)-PHAD or 3D-PHAD, or aluminum hydroxide combined with the mixtures of such MPLs, has been assessed. The immunogenicity in female BALB/c mice was verified by two intramuscular injections of differently formulated HPV and HBV vaccines and the total immunoglobulin G (IgG) antibody response was considered to compare the employed adjuvants. As verified experimentally, a mixture of 3D-(6-acyl)-PHAD and 3D-PHAD was able to induce significantly higher antibody titer than that of either 3D-(6-acyl)-PHAD or 3D-PHAD, when used individually. Interestingly, based on the responses achieved in terms of the total antibody levels, such mixture of synthetic MPLs was found to be even more effective than the bacterially derived MPL. Accordingly, the obtained results indicated that, if designed appropriately, synthetic MPL molecules could provide improved adjuvanticity with high level of consistency.

Using a hybrid-like supported catalyst to improve green fuel production through hydrothermal liquefaction of Scenedesmus obliquus microalgae.

Hydrothermal liquefaction of Scenedesmus obliquus has been optimized in a micro reactor using response surface methodology. Temperature, residence time and feedstock concentration were studied through central composite design to verify the optimized conditions leading to the highest yield of bio-crude and energy recovery. Based on the non-catalytic studies, temperature, feedstock concentration, and their interaction were respectively determined as the most effective variables. In order to improve the quality of produced bio-crude, the one step upgrading procedure was carried out in the presence of synthesized heterogeneous catalysts including Ni/AC, Ni/AC-CeO2 nanorods and Ni/CeO2 nanorods. Although, it was found that, more or less, all the catalysts were able to improve the bio-crude yield and quality based on their specific characteristics, however using Ni/AC-CeO2 hybrid like nanorods, not only the bio-crude yield would be improved by more than 9% but also the bio-crude could be upgraded to a green bio-based fuel.

Novel Dimensionally Controlled Nanopore Forming Template in Forward Osmosis Membranes.

To lower the unfavorable internal concentration polarization effect in forward osmosis (FO) membranes, support layers of highly porous interconnected structures with specifically large surface-to-volume ratios are indispensable. Herein, zinc oxide (ZnO) has been introduced as a new template to manipulate the porous structure of poly(ether sulfone) (PES) support layer. The ZnO can be readily synthesized as desired in different dimensionally controlled nanostructures. The performance of the FO membrane was initially ameliorated in terms of permeability and selectivity through simple incorporation of ZnO nanostructures in the PES support layer. The PES support layer was blended with appropriate amounts of ZnO nanostructures, casted on a glass plate, and subsequently acid washed to leach out the embedded ZnO nanostructures. Different nanoporous structures were achieved when ZnO of different nanostructures was used to modify the PES support layer. The experimental results indicated that the permeability of FO membranes could be simply improved by incorporation of ZnO nanostructures in PES support layer. Higher hydrophilicity and formation of suitable internal pores were mainly responsible for such observation. Although surface hydrophilicity of the support layers was reduced after being acid washed, water permeation through the membrane was intensified due to the formation of interconnected porous structure.