Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study.

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1-66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098-0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266-0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047-0.145]; OS: HR [95% CI]: 0.366 [0.181-0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time

Reproductive ecology of Lophelia pertusa in Mingulay Reef and the Logachev mounds (North East Atlantic): a multi‐scale comparison

This paper presents the results of a multi-scale comparison in the reproductive stage of the cold-water coral Lophelia pertusa in two areas of the North-east Atlantic: The Mingulay Reef and the Logachev Mounds. The study was carried out during the Research cruise “Changing Oceans” on board of the RRV James Cook, conducted in May-June 2012. The comparative study between the two geographical areas revealed higher fecundity for the colonies analysed from Mingulay Reef compared to the colonies from the Logachev mounds. Moreover the development stage of the oocytes was more advanced in the colonies sampled from Mingulay than in the ones collected from Logachev. The comparison between single colonies and within the same colony from the Mingulay Reef did not show any differences in the maturity stage of the oocytes, nevertheless the analyses of the reproductive stage between mesenteries within the same polyps showed high variability, which indicates that the gametogenic development within each mesentery undergoes a prolonged period of oocyte production. This probably results in a protracted spawning period, which might improve the reproductive success of the species. This work has been developed under the framework of the UKOA program (United Kingdom Ocean Acidification program) and has been supported by the National Environmental Research Council (NERC, UK)

Thiorhodococcus mannitoliphagus sp. nov., a new purple sulfur bacterium from the White Sea

A novel purple sulfur bacterium, strain WS(T), was isolated from a microbial mat from an estuary of the White Sea. Individual cells are coccoid shaped, motile by flagella and do not contain gas vesicles. The mean cell diameter is 1.85 mum (range 1.5-2.0 mum). Cell suspensions exhibit a purple-violet colour. They contain bacteriochlorophyll a and carotenoids of the rhodopinal series as photosynthetic pigments. The novel bacterium is an anoxygenic photoautotroph, using sulfide, thiosulfate, sulfite and elemental sulfur as electron donors for photosynthesis and is capable of photoassimilating several organic carbon sources in the presence of carbonate and a reduced sulfur source (sulfide and/or thiosulfate). Sulfur globules, formed during oxidation of sulfide, are stored transiently inside the cells. Optimal salinity and pH for growth are at 0.5-2.0 % NaCl and pH 7.0-7.5. The DNA base composition of strain WS(T) is 61.8 mol% G+C. 16S rRNA gene sequence analysis showed that the new isolate belongs to the genus Thiorhodococcus, with Thiorhodococcus minor CE2203(T) as the nearest relative (sequence similarity of 97.3 %). Several distinct differences from described species necessitate the description of a novel species. Thiorhodococcus mannitoliphagus sp. nov. is the proposed name, with strain WS(T) (=ATCC BAA-1228(T)=VKM B-2393(T)) as the type strain

Biallelic CPAMD8 Variants Are a Frequent Cause of Childhood and Juvenile Open-Angle Glaucoma

© 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePurpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design Retrospective, multicenter case series. Participants A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Purpose Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Methods Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main Outcome Measures Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results We identified rare (allele frequency < 4×10−5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest–derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment

Caribbean Corals in Crisis: Record Thermal Stress, Bleaching, and Mortality in 2005

BACKGROUND The rising temperature of the world's oceans has become a major threat to coral reefs globally as the severity and frequency of mass coral bleaching and mortality events increase. In 2005, high ocean temperatures in the tropical Atlantic and Caribbean resulted in the most severe bleaching event ever recorded in the basin. METHODOLOGY/PRINCIPAL FINDINGS Satellite-based tools provided warnings for coral reef managers and scientists, guiding both the timing and location of researchers' field observations as anomalously warm conditions developed and spread across the greater Caribbean region from June to October 2005. Field surveys of bleaching and mortality exceeded prior efforts in detail and extent, and provided a new standard for documenting the effects of bleaching and for testing nowcast and forecast products. Collaborators from 22 countries undertook the most comprehensive documentation of basin-scale bleaching to date and found that over 80% of corals bleached and over 40% died at many sites. The most severe bleaching coincided with waters nearest a western Atlantic warm pool that was centered off the northern end of the Lesser Antilles. CONCLUSIONS/SIGNIFICANCE Thermal stress during the 2005 event exceeded any observed from the Caribbean in the prior 20 years, and regionally-averaged temperatures were the warmest in over 150 years. Comparison of satellite data against field surveys demonstrated a significant predictive relationship between accumulated heat stress (measured using NOAA Coral Reef Watch's Degree Heating Weeks) and bleaching intensity. This severe, widespread bleaching and mortality will undoubtedly have long-term consequences for reef ecosystems and suggests a troubled future for tropical marine ecosystems under a warming climate.This work was partially supported by salaries from the NOAA Coral Reef Conservation Program to the NOAA Coral Reef Conservation Program authors. NOAA provided funding to Caribbean ReefCheck investigators to undertake surveys of bleaching and mortality. Otherwise, no funding from outside authors' institutions was necessary for the undertaking of this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study

RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged >= 65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5-0.8 mg/kg for = 3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time

Workgroup Report: Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity into International Hazard and Risk Assessment Strategies

This is the report of the first workshop on Incorporating In Vitro Alternative Methods for Developmental Neurotoxicity (DNT) Testing into International Hazard and Risk Assessment Strategies, held in Ispra, Italy, on 19–21 April 2005. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and jointly organized by ECVAM, the European Chemical Industry Council, and the Johns Hopkins University Center for Alternatives to Animal Testing. The primary aim of the workshop was to identify and catalog potential methods that could be used to assess how data from in vitro alternative methods could help to predict and identify DNT hazards. Working groups focused on two different aspects: a) details on the science available in the field of DNT, including discussions on the models available to capture the critical DNT mechanisms and processes, and b) policy and strategy aspects to assess the integration of alternative methods in a regulatory framework. This report summarizes these discussions and details the recommendations and priorities for future work

Glucose effects on long-term memory performance : duration and domain specificity.

Rational; Previous research has suggested that long term- verbal declarative memory is particularly sensitive to enhancement by glucose loading, however investigation of glucose effects on certain memory domains has hitherto been neglected. Therefore domain specificity of glucose effects merits further elucidation. Objectives; The aim of the present research was to provide a more comprehensive investigation of the possible effects of glucose administration on different aspects of memory by i) contrasting the effect of glucose administration on different memory domains (implicit/ explicit memory; verbal/ non-verbal memory, recognition/ familiarity processes), ii) investigating whether potential effects on memory domains differ depending on the dose of glucose administered (25g versus 60g), iii) exploring the duration of the glucose facilitation effect (assessment of memory performance 35 min and 1 week after encoding). Methods; a double blind, between- subjects design was used to test the effects of administration of 25 and 60g glucose on memory performance. Results; Implicit memory was improved following administration of 60g of glucose. Glucose supplementation failed to improve face recognition performance but significantly improved performance of word recall and recognition following administration of 60g of glucose. However, effects were not maintained one-week following encoding. Conclusions; Improved implicit memory performance following glucose administration has not been reported before. Furthermore the current data tentatively suggest that level of processing may determine the required glucose dosage to demonstrate memory improvement and that higher dosages may be able to exert effects on memory pertaining to both hippocampal and non-hippocampal brain regions