Add-On Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex A Placebo-Controlled Randomized Clinical Trial

IMPORTANCE Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medicationresistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. INTERVENTIONS Patients received oral cannabidiol at 25mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES The prespecified primary outcomewas the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. RESULTS Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6%(95%CI, 40.4%-55.8%) for the CBD25 group, 47.5%(95%CI, 39.0%-54.8%) for the CBD50 group, and 26.5%(95%CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95%CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5%(95%CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. CONCLUSIONS AND RELEVANCE Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0254476

Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials

OBJECTIVE: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. SIGNIFICANCE: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period

Community views on ‘Can perinatal services safely identify Aboriginal and Torres Strait Islander parents experiencing complex trauma?’

Family and extended kinship systems which nurture healthy, happy children are central to Aboriginal and Torres Strait Islander cultures. Since colonisation, Aboriginal and Torres Strait Islander communities have been impacted by intergenerational cycles of trauma, stemming from colonial violence, genocidal policies and discrimination, including the forced removal of children from their families. Becoming a parent offers a unique life-course opportunity for trauma recovery and preventing intergenerational trauma. However, identifying or ‘recognising’ complex trauma carries significant risk of harm for Aboriginal and Torres Strait Islander parents due to reactive prenatal child protection involvement potentially compounding experiences of trauma, and limited benefits due to lack of culturally appropriate support. The Aboriginal-led participatory Healing the Past by Nurturing the Future project aims to co-design safe, accessible and feasible perinatal awareness, recognition, assessment and support strategies for Aboriginal and Torres Strait Islander parents experiencing complex trauma. This paper presents views of 38 workshop participants to determine prerequisites for ensuring benefits outweigh risks of assessment to safely recognise parents experiencing complex trauma, consistent with screening criteria. Six essential elements were identified from thematic analysis: high-quality holistic care; cultural, social and emotional safety; empowerment, choice and control; flexible person-centred approaches; trusting relationships; and sensitive, skilled communication

HIPASS High-Velocity Clouds: Properties of the Compact and Extended Populations

A catalog of Southern anomalous-velocity HI clouds at Decl. < +2 deg is presented, based on data from the HI Parkes All-Sky Survey (HIPASS). The improved sensitivity (5sigma: T_B = 0.04 K) and resolution (15.5') of the HIPASS data results in a substantial increase in the number of individual clouds (1956, as well as 41 galaxies) compared to previous surveys. Most high-velocity emission features, HVCs, have a filamentary morphology and are loosely organized into large complexes extending over tens of degrees. In addition, 179 compact and isolated anomalous-velocity objects, CHVCs, are identified based on their size and degree of isolation. 25% of the CHVCs originally classified by Braun & Burton (1999) are reclassified. Both the entire population of high-velocity emission features and the CHVCs alone have typical HI masses of ~ 4.5 D(kpc)^2 solar masses and have similar slopes for their column density and flux distributions. On the other hand, the CHVCs appear to be clustered and the population can be broken up into three spatially distinct groups, while the entire population of clouds is more uniformly distributed with a significant percentage aligned with the Magellanic Stream. The median velocities are V_GSR = -38 km/s for the CHVCs and -30 km/s for all of the anomalous-velocity clouds. Based on the catalog sizes, high-velocity features cover 19% of the southern sky and CHVCs cover 1%. (abridged)Comment: 32 pages, 26 figures in gif format, 2 ascii tables, to appear in the Jan 2002 issue of The Astronomical Journal, high resolution version available at http://origins.Colorado.EDU/~mputman/pubs.htm

Observations of red-giant variable stars by Aboriginal Australians

Aboriginal Australians carefully observe the properties and positions of stars, including both overt and subtle changes in their brightness, for subsistence and social application. These observations are encoded in oral tradition. I examine two Aboriginal oral traditions from South Australia that describe the periodic changing brightness in three pulsating, red-giant variable stars: Betelgeuse (Alpha Orionis), Aldebaran (Alpha Tauri), and Antares (Alpha Scorpii). The Australian Aboriginal accounts stand as the only known descriptions of pulsating variable stars in any Indigenous oral tradition in the world. Researchers examining these oral traditions over the last century, including anthropologists and astronomers, missed the description of these stars as being variable in nature as the ethnographic record contained several misidentifications of stars and celestial objects. Arguably, ethnographers working on Indigenous Knowledge Systems should have academic training in both the natural and social sciences.Comment: The Australian Journal of Anthropology (2018

The HIPASS Catalogue - II. Completeness, Reliability, and Parameter Accuracy

The HI Parkes All Sky Survey (HIPASS) is a blind extragalactic HI 21-cm emission line survey covering the whole southern sky from declination -90 to +25. The HIPASS catalogue (HICAT), containing 4315 HI-selected galaxies from the region south of declination +2, is presented in Meyer et al. (2004a, Paper I). This paper describes in detail the completeness and reliability of HICAT, which are calculated from the recovery rate of synthetic sources and follow-up observations, respectively. HICAT is found to be 99 per cent complete at a peak flux of 84 mJy and an integrated flux of 9.4 Jy km/s. The overall reliability is 95 per cent, but rises to 99 per cent for sources with peak fluxes >58 mJy or integrated flux > 8.2 Jy km/s. Expressions are derived for the uncertainties on the most important HICAT parameters: peak flux, integrated flux, velocity width, and recessional velocity. The errors on HICAT parameters are dominated by the noise in the HIPASS data, rather than by the parametrization procedure.Comment: Accepted for publication in MNRAS. 12 pages, 11 figures. Paper with higher resolution figures can be downloaded from http://hipass.aus-vo.or

The Large Scale Distribution of Neutral Hydrogen in the Fornax Region

Using HIPASS data, we have searched for HI in a ~25x25 sq.deg. region centred on the Fornax cluster. Within a velocity search range of 300 - 3700 km/s and a lower flux limit of ~40 mJy, 110 galaxies with HI emission were detected, one of which is previously uncatalogued. None of the detections has early-type morphology. Previously unknown velocities for 14 galaxies have been determined, with a further 4 velocity measurements being significantly dissimilar to published values. Identification of an optical counterpart is relatively unambiguous for more than ~90% of our HI galaxies. The galaxies appear to be embedded in a sheet at the cluster velocity which extends for more than 30 deg across the search area. At the nominal cluster distance of ~20 Mpc, this corresponds to an elongated structure more than 10 Mpc in extent. A velocity gradient across the structure is detected, with radial velocities increasing by \~500 km/s from SE to NW. The clustering of galaxies evident in optical surveys is only weakly suggested in the spatial distribution of our HI detections. Our results suggest a considerable deficit of HI-rich galaxies in the centre of the cluster. However, relative to the field, there is a 3(+/-1)-fold excess of HI-rich galaxies in the outer parts of the cluster where galaxies may be infalling towards the cluster for the first time.Comment: 16 pages, 14 figures, 110 HI spectra. To be published in MNRA

An Extragalactic HI Cloud with No Optical Counterpart?

We report the discovery, from the HI Parkes All-Sky Survey (HIPASS), of an isolated cloud of neutral hydrogen which we believe to be extragalactic. The HI mass of the cloud (HIPASS J1712-64) is very low, 1.7 x 10^7 Msun, using an estimated distance of ~3.2 Mpc. Most significantly, we have found no optical companion to this object to very faint limits (mu(B)~ 27 mag arcsec^-2). HIPASS J1712-64 appears to be a binary system similar to, but much less massive than, HI 1225+01 (the Virgo HI Cloud) and has a size of at least 15 kpc. The mean velocity dispersion, measured with the Australia Telescope Compact Array (ATCA), is only 4 km/s for the main component and because of the weak or non-existent star-formation, possibly reflects the thermal linewidth (T<2000 K) rather than bulk motion or turbulence. The peak column density for HIPASS J1712-64, from the combined Parkes and ATCA data, is only 3.5 x 10^19 cm^-2, which is estimated to be a factor of two below the critical threshold for star formation. Apart from its significantly higher velocity, the properties of HIPASS J1712-64 are similar to the recently recognised class of Compact High Velocity Clouds. We therefore consider the evidence for a Local Group or Galactic origin, although a more plausible alternative is that HIPASS J1712-64 was ejected from the interacting Magellanic Cloud/Galaxy system at perigalacticon ~ 2 x 10^8 yr ago.Comment: 23 pages, 7 figures, AJ accepte

The 1000 Brightest HIPASS Galaxies: HI Mass Function and Omega_HI

We present a new accurate measurement of the HI mass function of galaxies from the HIPASS Bright Galaxy Catalog, a sample of 1000 galaxies with the highest HI peak flux densities in the southern hemisphere (Koribalski et al. 2003). This sample spans nearly four orders of magnitude in HI mass (from log M_HI/M_sun=6.8 to 10.6, H0=75) and is the largest sample of HI selected galaxies to date. We develop a bivariate maximum likelihood technique to measure the space density of galaxies, and show that this is a robust method, insensitive to the effects of large scale structure. The resulting HI mass function can be fitted satisfactorily with a Schechter function with faint-end slope alpha=-1.30. This slope is found to be dependent on morphological type, with later type galaxies giving steeper slopes. We extensively test various effects that potentially bias the determination of the HI mass function, including peculiar motions of galaxies, large scale structure, selection bias, and inclination effects, and quantify these biases. The large sample of galaxies enables an accurate measurement of the cosmological mass density of neutral gas: Omega_HI=(3.8 +/- 0.6) x 10^{-4}. Low surface brightness galaxies contribute only 15% to this value, consistent with previous findings.Comment: accepted for publication in Astronomical Journal, 16 pages, including 17 figures. Corrected typos and reference

Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue

BACKGROUND &amp; AIMS: Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domaincontaining 5 (NLRC5), in patients and mice with Helicobacter infection. METHODS: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5(memptysetKO)) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5(-/-) THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed. RESULTS: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection ( P &lt;.01), and correlated with gastritis severity (P&lt;.05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5(-/-) THP-1 macrophages than by control THP- 1 cells (P&lt;.05). After 3 months of infection with H felis, Nlrc5(memptyset-KO) mice developed gastric hyperplasia (P&lt;.0001), splenomegaly (P &lt;.0001), and increased serum antibody titers (P&lt;.01), whereas control mice did not. Nlrc5(memptyset-KO) mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P&lt;.0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell-activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5(memptyset-KO) mice. CONCLUSIONS: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection