Prednisolone or tetracosactide depot for infantile epileptic spasms syndrome? A prospective analysis of data embedded within two randomised controlled trials

OBJECTIVE: To report a prospectively planned analysis of two randomised controlled trials with embedded comparisons of prednisolone versus tetracosactide depot for the treatment of infantile epileptic spasms syndrome (IESS). METHODS: Individual patient data from patients randomly allocated to prednisolone or tetracosactide depot were analysed from two trials (UKISS, ICISS). The comparison was embedded within trials in which some patients also received vigabatrin but only patients receiving monotherapy with randomly allocated hormonal treatments are included in this analysis. The main outcome was cessation of spasms (Days 13-14 after randomisation). Lead time to treatment and underlying aetiology were taken into account. Cessation of spasms on Days 14-42 inclusive, electroclinical response (EEG Day 14), plus developmental and epilepsy outcomes (at 14 months in UKISS and 18 months in ICISS) are also reported. Minimum treatment was prednisolone 40 mg per day for two weeks or tetracosactide depot 0·5 mg IM on alternate days for two weeks, all followed by a reducing dose of prednisolone over two weeks. RESULTS: 126 infants were included in this study. On tetracosactide depot, 47 of 62 (76%) were free of spasms on Days 13-14 compared to 43 of 64 (67%) on prednisolone (difference 9%, 95% CI -7·2% to +25·2%, chi square 1·15, p = 0·28). For Day 14-42 cessation of spasms, on tetracosactide depot, 41 of 61 (67%) were free of spasms compared to 35 of 62 (56%) on prednisolone (difference 11%, 95% CI -6·4% to +28·4%, chi square 1·51, p = 0·22). There was no significant difference in mean VABS score between infants who received prednisolone compared with those who received tetracosactide depot (74·8 (SD 18·3) versus 78·0 (SD 20·2) t = -0·91 p = 0·36). The proportion with ongoing epilepsy at the time of developmental assessment was 20 of 61 (33%) in the tetracosactide group compared with 26 out of 63 (41%) in the prednisolone group (difference 8%, 95% CI -9·2% to +25·2%, Chi [2] 0·95, p = 0·33). SIGNIFICANCE: With hormone monotherapy, either prednisolone or tetracosactide depot may be recommended for infantile epileptic spasms syndrome

Periodontitis and outer retinal thickness:A cross-sectional analysis of the UK Biobank cohort

PurposePeriodontitis, a ubiquitous severe gum disease affecting the teeth and surrounding alveolar bone can heighten systemic inflammation. We investigated the association between very severe periodontitis and early biomarkers of age-related macular degeneration, in individuals with no eye disease.DesignCross-sectional analysis of the prospective community-based cohort United Kingdom (UK) Biobank.ParticipantsSixty-seven thousand three hundred eleven UK residents aged 40-70 years recruited between 2006-2010 underwent retinal imaging.MethodsMacular-centered optical coherence tomography images acquired at the baseline visit were segmented for retinal sublayer thicknesses. Very severe periodontitis was ascertained through a touchscreen questionnaire. Linear mixed effects regression modeled the association between very severe periodontitis and retinal sublayer thicknesses adjusting for age, sex, ethnicity, socioeconomic status, alcohol consumption, smoking status, diabetes mellitus, hypertension, refractive error, and previous cataract surgery.Main Outcome MeasuresPhotoreceptor layer (PRL) and retinal pigment epithelium-Bruch’s membrane (RPE-BM) thicknesses.ResultsAmong 36,897 participants included in the analysis, 1,571 (4.3%) reported very severe periodontitis. Affected individuals were older, lived in areas of greater socioeconomic deprivation and were more likely to be hypertensive, diabetic and current smokers (all p<0.001). On average, those with very severe periodontitis were myopic (-0.29 ± 2.40 diopters) while those unaffected were hyperopic (0.05 ± 2.27 diopters, p<0.001). Following adjusted analysis, very severe periodontitis was associated with thinner PRL (-0.55 μm, 95% CI: -0.97, -0.12, p=0.022) but there was no difference in RPE-BM thickness (0.00 μm, 95% CI: -0.12, 0.13, p=0.97). The association between PRL thickness and very severe periodontitis was modified by age (p<0.001). Stratifying individuals by age, thinner PRL was seen among those aged 60-69 years with disease (-1.19 μm, 95% CI: -1.85, -0.53, p<0.001) but not among those under 60 years.ConclusionsAmong those with no known eye disease, very severe periodontitis is statistically associated with a thinner PRL, consistent with incipient age-related macular degeneration. Optimizing oral hygiene may hold additional relevance for people at risk of degenerative retinal disease

Forward K+ production in subthreshold pA collisions at 1.0 GeV

K+ meson production in pA (A = C, Cu, Au) collisions has been studied using the ANKE spectrometer at an internal target position of the COSY-Juelich accelerator. The complete momentum spectrum of kaons emitted at forward angles, theta < 12 degrees, has been measured for a beam energy of T(p)=1.0 GeV, far below the free NN threshold of 1.58 GeV. The spectrum does not follow a thermal distribution at low kaon momenta and the larger momenta reflect a high degree of collectivity in the target nucleus.Comment: 4 pages, 3 figure

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

Autonomous Seawater \u3ci\u3ep\u3c/i\u3eCO\u3csub\u3e2\u3c/sub\u3e and pH Time Series From 40 Surface Buoys and the Emergence of Anthropogenic Trends

Ship-based time series, some now approaching over 3 decades long, are critical climate records that have dramatically improved our ability to characterize natural and anthropogenic drivers of ocean carbon dioxide (CO2) uptake and biogeochemical processes. Advancements in autonomous marine carbon sensors and technologies over the last 2 decades have led to the expansion of observations at fixed time series sites, thereby improving the capability of characterizing sub-seasonal variability in the ocean. Here , we present a data product of 40 individual autonomous moored surface ocean pCO2 (partial pressure of CO2) time series established between 2004 and 2013, 17 also include autonomous pH measurements. These time series characterie a wide range of surface ocean carbonate conditions in diffferent oceanic (17 sites), coastal (13 sites), and coral reef (10 sites) regimes. A time of trend emergence (ToE) methodology applied ot the time series that exhibit well-constrained daily to interannual variability and an estimate of decadal variability indicates that the length of sustained observations necessary to detect statistically significant anthropogenic trends varies by marine environment. The ToE estisites, and 9 to 22 years at the coral reef sites. Only two open ocean pCO2 and pH range from 8 to 15 years at the open ocean sites, 16 to 41 years at the coastal sites, and 9 to 22 years at the coral reef sites. Only two open ocean pCO2 time series, Woods Hole Oceanographic Institution Hawaii Ocean Time-series Station (WHOTS) in the subtropical North Pacific and Stratus n the South Pacific gyre, have been deployed longer than the estimated trend detection time and, for these, deseasoned monthly means show estimated anthropogenic trends of 1.9 ± 0.3 and 1.6 ± 0.3 μatm yr-1, respectively. In the future, it is possible that updates to this product will allow for the estimation of anthropogenic trends at more sites; however, the product currently provides a valuable tool in an accessible format for evaluating climatology and natural variability of surface ocean carbonate chemistry in a variety of regions. Data are available at https://doi.org/10.7289/V5DB8043 and https://www.nodc.noaa.gov/ocads/oceans/Moorings/ndp097.html (Sutton et al., 2018)

Transplantation of Specific Human Astrocytes Promotes Functional Recovery after Spinal Cord Injury

Repairing trauma to the central nervous system by replacement of glial support cells is an increasingly attractive therapeutic strategy. We have focused on the less-studied replacement of astrocytes, the major support cell in the central nervous system, by generating astrocytes from embryonic human glial precursor cells using two different astrocyte differentiation inducing factors. The resulting astrocytes differed in expression of multiple proteins thought to either promote or inhibit central nervous system homeostasis and regeneration. When transplanted into acute transection injuries of the adult rat spinal cord, astrocytes generated by exposing human glial precursor cells to bone morphogenetic protein promoted significant recovery of volitional foot placement, axonal growth and notably robust increases in neuronal survival in multiple spinal cord laminae. In marked contrast, human glial precursor cells and astrocytes generated from these cells by exposure to ciliary neurotrophic factor both failed to promote significant behavioral recovery or similarly robust neuronal survival and support of axon growth at sites of injury. Our studies thus demonstrate functional differences between human astrocyte populations and suggest that pre-differentiation of precursor cells into a specific astrocyte subtype is required to optimize astrocyte replacement therapies. To our knowledge, this study is the first to show functional differences in ability to promote repair of the injured adult central nervous system between two distinct subtypes of human astrocytes derived from a common fetal glial precursor population. These findings are consistent with our previous studies of transplanting specific subtypes of rodent glial precursor derived astrocytes into sites of spinal cord injury, and indicate a remarkable conservation from rat to human of functional differences between astrocyte subtypes. In addition, our studies provide a specific population of human astrocytes that appears to be particularly suitable for further development towards clinical application in treating the traumatically injured or diseased human central nervous system

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes