Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

OBJECTIVE: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

Predicting the effects of climate change on the cross-scale epidemiological dynamics of a fungal plant pathogen.

The potential for climate change to exacerbate the burden of human infectious diseases is increasingly recognized, but its effects on infectious diseases of plants have received less attention. Understanding the impacts of climate on the epidemiological dynamics of plant pathogens is imperative, as these organisms play central roles in natural ecosystems and also pose a serious threat to agricultural production and food security. We use the fungal 'flax rust' pathogen (Melampsora lini) and its subalpine wildflower host Lewis flax (Linum lewisii) to investigate how climate change might affect the dynamics of fungal plant pathogen epidemics using a combination of empirical and modeling approaches. Our results suggest that climate change will initially slow transmission at both the within- and between-host scales. However, moderate resurgences in disease spread are predicted as warming progresses, especially if the rate of greenhouse gas emissions continues to increase at its current pace. These findings represent an important step towards building a holistic understanding of climate effects on plant infectious disease that encompasses demographic, epidemiological, and evolutionary processes. A core result is that neglecting processes at any one scale of plant pathogen transmission may bias projections of climate effects, as climate drivers have variable and cascading impacts on processes underlying transmission that occur at different scales.

Second Thoughts: Pseudo-reality Between Hypnosis and Spectacle.

"Second Thoughts: Pseudo-Reality Between Hypnosis and Spectacle" expands the discussion of Endre Koritar's and Robert Prince's presentations in the 2021 International Sándor Ferenczi Network webinar series, Listening with Ferenczi (Koritar, 2022a; Prince, 2022). Beginning with a segue from Prince's reference to Thomas Mann's "Mario and the Magician," the present paper expands focus from the dynamics of leadership to the grooming of followership along the pathway of image as the American national addiction to pseudo-reality, a fascinating and omnipotently expected, always disappointing entitlement (Boorstin, 1961). Political spectacle, ascendant in American executive, legislative, and judicial performance since 2016, functions as image-supercharged, with its guarantee of gratification powerfully overcoming disappointment.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy.

BACKGROUND: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. METHODS: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). RESULTS: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). CONCLUSIONS: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02324673).

The gut-brain axis: historical reflections.

The gut-brain axis and the microbiome have recently acquired an important position in explaining a wide range of human behaviours and emotions. Researchers have typically presented developments in understandings of the microbiome as radical and new, offering huge potential for better understandings of our bodies and what it means to be human. Without refuting the value of this research, this article insists that, traditionally, doctors and patients acknowledged the complex interactions between their guts and emotions, although using alternative models often based on nerves or psychology. For example, nineteenth-century doctors and patients would have been well acquainted with the idea that their stomachs and minds were somehow connected, and that this interaction could produce positive or negative physical and mental health impacts. To demonstrate this, this article offers a snapshot of medical and public thought on (what we currently call) the gut-brain axis in the nineteenth and twentieth centuries, using Britain as a key case study due to the prevalence of gastric problems in that country. It commences by exploring how nineteenth-century doctors and patients took for granted the intimate relations between gut and mind and used their ideas on this to debate personal health, medical theory and social and political discourse. The article then moves on to argue that various medical sub-disciplines emerged (anatomy, physiology, surgery) that threatened to reduce the stomach to a physiologically complex organ but, in doing so, inadvertently began to erase ideas of a gut-mind connection. However, these new models proved unsatisfactory, allowing more holistic ideas of the body-mind relationship to continue to carry currency in twentieth-century psychological and medical thought. In the late century, pharmacological developments once again threatened to minimise the gut-brain axis, before it once again became popular in the early twenty-first century, now debated through a new language of microbiology.

Remote Control of Mammalian Cells with Heat-Triggered Gene Switches and Photothermal Pulse Trains.

Engineered T cells are transforming broad fields in biomedicine, yet our ability to control cellular activity at specific anatomical sites remains limited. Here we engineer thermal gene switches to allow spatial and remote control of transcriptional activity using pulses of heat. These gene switches are constructed from the heat shock protein HSP70B' (HSPA6) promoter, show negligible basal transcriptional activity, and activate within an elevated temperature window of 40-45 °C. Using engineered Jurkat T cells implanted in vivo, we use plasmonic photothermal heating to trigger gene expression at specific sites to levels greater than 200-fold. We show that delivery of heat as thermal pulse trains significantly increase cellular thermal tolerance compared to continuous heating curves with identical area-under-the-curve (AUC), enabling long-term control of gene expression in Jurkat T cells. This approach expands the toolkit of remotely controlled genetic devices for basic and translational applications in synthetic immunology.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. SIGNIFICANCE: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. FUNDING: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial.

OBJECTIVE: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. METHODS: Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. RESULTS: All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was -37.9% in the active and -17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. SIGNIFICANCE: Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

The chemistry of famine: nutritional controversies and the Irish Famine, c.1845-7.

The activities of Irish medical practitioners in relieving the impact of the Irish Famine (c.1845-52) have been well documented. However, analysis of the function of contemporary medico-scientific ideas relating to food has remained mostly absent from Famine historiography. This is surprising, given the burgeoning influence of Liebigian chemistry and the rising social prominence of nutritional science in the 1840s. Within this article, I argue that the Famine opened up avenues for advocates of the social value of nutritional science to engage with politico-economic discussion regarding Irish dietary, social and economic transformation. Nutritional science was prominent within the activities of the Scientific Commission, the Central Board of Health and in debates regarding soup kitchen schemes. However, the practical inefficacy of many scientific suggestions resulted in public associations being forged between nutritional science and the inefficiencies of state relief policy, whilst emergent tensions between the state, science and the public encouraged scientists in Ireland to gradually distance themselves from state-sponsored relief practices.

Anorexigenic C75 alters c-Fos in mouse hypothalamic and hindbrain subnuclei.

The fatty acid synthase inhibitor C75 reduces feeding rapidly and for several days. We investigated brain sites potentially involved in actions of i.p. C75 in mice by examining c-Fos. At 3 h C75 increased numbers of c-Fos-immunoreactive cells in hindbrain feeding-related nuclei, and in the paraventricular nucleus (PVN), lateral aspects of the arcuate nucleus (ARC), and in the central amygdala. At 24 h C75 prevented fasting-induced c-Fos expression in the medial ARC and three of its targets: lateral magnocellular PVN, lateral hypothalamus, and dorsomedial hypothalamus. C75, but not fasting, increased c-Fos in parvocellular PVN. This pattern of results suggests a shift from hindbrain-initiated short-term actions to activation of hypothalamic mechanisms that could mediate the long-term anorectic responses to C75.

C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase.

Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK alpha subunit (pAMPKalpha) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKalpha levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKalpha levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKalpha and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus.

C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism.

C75, a synthetic inhibitor of fatty acid synthase (FAS), is hypothesized to alter the metabolism of neurons in the hypothalamus that regulate feeding behavior to contribute to the decreased food intake and profound weight loss seen with C75 treatment. In the present study, we characterize the suitability of primary cultures of cortical neurons for studies designed to investigate the consequences of C75 treatment and the alteration of fatty acid metabolism in neurons. We demonstrate that in primary cortical neurons, C75 inhibits FAS activity and stimulates carnitine palmitoyltransferase-1 (CPT-1), consistent with its effects in peripheral tissues. C75 alters neuronal ATP levels and AMP-activated protein kinase (AMPK) activity. Neuronal ATP levels are affected in a biphasic manner with C75 treatment, decreasing initially, followed by a prolonged increase above control levels. Cerulenin, a FAS inhibitor, causes a similar biphasic change in ATP levels, although levels do not exceed control. C75 and cerulenin modulate AMPK phosphorylation and activity. TOFA, an inhibitor of acetyl-CoA carboxylase, increases ATP levels, but does not affect AMPK activity. Several downstream pathways are affected by C75 treatment, including glucose metabolism and acetyl-CoA carboxylase (ACC) phosphorylation. These data demonstrate that C75 modulates the levels of energy intermediates, thus, affecting the energy sensor AMPK. Similar effects in hypothalamic neurons could form the basis for the effects of C75 on feeding behavior.

The effect of UV absorbing sunscreens on the reflectance and the consequent protection of skin.

The in vivo reflectance spectra of Caucasian skin, coated with preparations containing sunscreen vehicle, vehicle with olive oil and vehicle with the UVB and UVA absorbers 2-ethylhexyl-4-methoxycinnamate and 4-t-butyl-4'-methoxydibenzoylmethane were determined. All preparations reduced the reflectance of skin throughout the UVA spectral range (320 to 400 nm), with the sunscreen preparations containing the UVB and UVB plus UVA absorbers reducing the reflectance more than the sunscreen vehicle alone. This phenomenon, which facilitates the penetration of UV radiation to the lower epidermis and dermal layers of skin and therefore lessens sunscreen efficacy, is attributed to optical coupling mediated by refractive index matching of the sunscreen to the upper epidermis. The greater reduction in skin diffuse reflectance caused by sunscreens containing methoxycinnamate is associated with this compound's high refractive index. Also, by determining the excitation spectra of the autofluorescence originating from the dermal layer of skin, the transmission spectra of the various components of sunscreen on skin were established, and these were in good general agreement with previously published spectra.