Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype

Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development

Global epidemiology of podoconiosis: a systematic review

Background Podoconiosis is one of the few diseases that could potentially be eliminated within one generation. Nonetheless, the global distribution of the disease remains largely unknown. The global atlas of podoconiosis was conceived to define the epidemiology and distribution of podoconiosis through dedicated surveys and assembling the available epidemiological data. Methods We have synthesized the published literature on the epidemiology of podoconiosis. Through systematic searches in SCOPUS and MEDLINE from inception to February 14, 2018, we identified observational and population-based studies reporting podoconiosis. To establish existence of podoconiosis, we used case reports and presence data. For a study to be included in the prevalence synthesis, it needed to be a population-based survey that involved all residents within a specific area. Studies that did not report original data were excluded. We undertook descriptive analyses of the extracted data. This study is registered with PROSPERO, number CRD42018084959. Results We identified 3,260 records, of which 27 studies met the inclusion criteria. Podoconiosis was described to exist or be endemic in 32 countries, 18 from the African Region, 3 from Asia and 11 from Latin America. Overall, podoconiosis prevalence ranged from 0·10% to 8.08%, was highest in the African region, and was substantially higher in adults than in children and adolescents. The highest reported prevalence values were in Africa (8.08% in Cameroon, 7.45% in Ethiopia, 4.52% in Uganda, 3.87% in Kenya and 2.51% in Tanzania). In India, a single prevalence of 0.21% was recorded from Manipur, Mizoram and Rajasthan states. None of the Latin American countries reported prevalence data. Conclusion Our data suggest that podoconiosis is more widespread in the African Region than in the rest of the regions, although this could be related to the fact that most podoconiosis epidemiological research has been focused in the African continent. The assembled dataset confirms that comprehensive podoconiosis control strategies such as promotion of footwear and personal hygiene are urgently needed in endemic parts of Africa. Mapping, active surveillance and a systematic approach to the monitoring of disease burden must accompany the implementation of podoconiosis control activities

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Blue Carbon Storage Capacity of Temperate Eelgrass (Zostera marina) Meadows

Despite the importance of coastal ecosystems for the global carbon budgets, knowledge of their carbon storage capacity and the factors driving variability in storage capacity is still limited. Here we provide an estimate on the magnitude and variability of carbon stocks within a widely distributed marine foundation species throughout its distribution area in temperate Northern Hemisphere. We sampled 54 eelgrass (Zostera marina) meadows, spread across eight ocean margins and 36° of latitude, to determine abiotic and biotic factors influencing organic carbon (Corg) stocks in Zostera marina sediments. The Corg stocks (integrated over 25‐cm depth) showed a large variability and ranged from 318 to 26,523 g C/m2 with an average of 2,721 g C/m2. The projected Corg stocks obtained by extrapolating over the top 1 m of sediment ranged between 23.1 and 351.7 Mg C/ha, which is in line with estimates for other seagrasses and other blue carbon ecosystems. Most of the variation in Corg stocks was explained by five environmental variables (sediment mud content, dry density and degree of sorting, and salinity and water depth), while plant attributes such as biomass and shoot density were less important to Corg stocks. Carbon isotopic signatures indicated that at most sites <50% of the sediment carbon is derived from seagrass, which is lower than reported previously for seagrass meadows. The high spatial carbon storage variability urges caution in extrapolating carbon storage capacity between geographical areas as well as within and between seagrass species

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Forme et imagination : l'image féminine dans l'Europe paléolithique

By putting the Palaeolithic female figures back in the general context of the Western Art history, the author wants to show that the woman representation largely depended on the social environment and constantly evolved through time. Therefore there can not be any oneway interpretation of the Palaeolithic specimens which were too systematical seen as fertility symbols.En situant les figurations féminines paléotlithiques dans le contexte général de l'histoire de l'art occidental, l'auteur s'efforce de montrer que l'image de la femme et ses canons dépendent largement du contexte social et qu'ils ont constamment évolué au cours du temps. Elle met ainsi en doute toute interprétation univoque des représentations féminines paléolithiques que l'on a associé de façon trop systématique à la fécondité.Russel Pamela. Forme et imagination : l'image féminine dans l'Europe paléolithique. In: Paléo, n°5,1993. pp. 375-388

A feasibility study on Ten Incorporated

Executive Summary. ...simply blows you away... This is Mahangin Inc., committed in producing quality innovative products for a dynamic, fast-growing market. Through this, Mahangin Inc. aims to achieve customer satisfaction. Not only does Mahangin Inc. want customer satisfaction but it also wants to do their role in helping the environment by using recycled paper and other biodegradable materials. Mahangin Inc. is a corporation privately owned by seven individuals. It engages in the manufacturing of gift items in the form of fans. The motivating force behind this corporation is its Mission and Vision. The company\u27s mission is to make a profit while keeping in mind the principles of social responsibility. The vision of the company, on the other hand, is it envisions itself in making affordable and trendy recycled products such as Famyfay to the market and to continue serving its purpose of making the highest profit attainable while doing its share of social responsibility. Mahangin Inc. is the producer of Famayfay. Famayfay is a fan made out of earth-friendly materials. Although there are many competitors in the market, Famayfay stands out because of its innovations. The company targets female college students, specifically undergraduates from DLSU and St. Scholastica\u27s college. Furthermore, the proponents have determined a 73.48% market acceptability rate based from the survey conducted. The competitively priced Famayfay will be sold through direct selling, bazaars and other intermediaries. Based on the survey conducted, the company plans to promote Famayfay through the use of flyers and low introductory prices. The production of Famayfay can be divided into two parts these are the preparation of the paper and the assembly of the fan itself. The proponents have a maximum plant capacity of 42 units per week and a minimum capacity of 12 units per week. The proponents believe that they can produce more than 42 units per week, pegging their projected output at a maximum rate of 61 units per week. This is possible because learning curve is taken into consideration. The company would be operating from 8:30 am to 5:30 pm, following the eight-hour minimum time for production. Based on this projected output, the company realizes a net income of Php 12,306.93 and a return on investment of 58.6%. Each of the proponents would be required to invest an amount equal to Php 3000, summing up a total of Php 21,000 initial investment. Taking into considerations the possible risks that might occur to the company, the proponents have agreed upon a set of control measures for the different risks found in each aspect of the business. The different aspects pertained to are the market-centered risks, the production centered risks, the financial risks and management/personnel-centered risks. It is very important to define measures that would ensure the smooth sailing process of the life of the business

An analysis of mechanisms of central nervous system infiltration in acute lymphoblastic leukaemia using primary cells xenografted into immunodeficient mice

Despite great advances in the treatment of paediatric acute lymphoblastic leukaemia (ALL), disease in the central nervous system (CNS) continues to pose challenges. Current diagnostic tests are insensitive and risk factors for CNS relapse are poorly understood. This results in all children receiving intensive CNS-directed therapy which may be associated with acute and/or chronic neurotoxicity. A better understanding of the mechanisms of CNS engraftment is a necessary pre-requisite for diagnostic and therapeutic advances.  To investigate if primary cells infiltrate the CNS, and whether this property resides in any particular sub-clonal compartment we undertook a comprehensive analysis of the CNS engrafting potential of primary ALL cells in immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. In addition, we used this model to investigate whether chemokine receptor expression drives CNS infiltration in pre-B ALL, as previously shown for T-ALL. CNS engraftment was seen in 18/23 pre-B ALL samples (78%). A consistent pattern of engraftment was observed with plaques of disease in the leptomeninges, relative sparing of the ventricles and complete absence of parenchymal infiltration. This implies ALL transit across the blood-CSF barrier rather than the blood-brain barrier – an important distinction, as leucocytes utilise distinct physiological trafficking mechanisms to cross these two barriers. To examine the frequency of cells with CNS-engrafting potential, intra-femoral transfer of 10 to 10,000 cells was performed.  CNS engraftment was seen with as few as 10 initial cells. In addition, the ability to engraft the CNS was not restricted to any particular immunophenotypic compartment and was seen in CD19+CD10high, CD19+CD10low, CD19+CD20low, CD19+CD20high, CD19+CD34high, CD19+CD34low fractions. These data suggest that CNS engraftment potential is present at high-frequency in the bulk leukaemic population at diagnosis. To examine candidate trafficking molecules governing CNS entry, we investigated chemokine receptor expression on pre-B ALL blasts using quantitative PCR and flow cytometry. The chemokine receptors CXCR3, CXCR4 and CXCR7 were expressed by pre-B ALL but were not up-regulated in cells retrieved from the CNS compared to the bone marrow (BM). In conclusion, in xenograft models of pre-B ALL, CNS engrafting potential is present at high frequency in patient diagnostic BM specimens and does not appear to be restricted to sub-clonal compartments. These findings have important implications for the design of risk-adapted CNS therapy. Firstly, our studies indicate that CNS entry is a common property of leukaemic blasts and therefore the current dogma of CNS-directed therapy for all patients appears to have a rational scientific basis. Secondly, it is unlikely that chemokine receptor expression profiling will be a useful biomarker for CNS disease in pre-B ALL. Finally, identifying factors that facilitate long-term survival of cells in the CNS (which may also enhance long-term survival in the bone marrow) may be a better therapeutic strategy than attempts to block cell entry

Best practice recommendations for the use of external telemetry devices on pinnipeds

Pinnipeds spend large portions of their lives at sea, submerged, or hauled-out on land, often on remote of-shore islands. This fundamentally limits access by researchers to critical parts of pinniped life history and has spurred the development and implementation of a variety of externally attached telemetry devices (ETDs) to collect informa‑ tion about movement patterns, physiology and ecology of marine animals when they cannot be directly observed. ETDs are less invasive and easier to apply than implanted internal devices, making them more widely used. However, ETDs have limited retention times and their use may result in negative short- and long-term consequences includ‑ ing capture myopathy, impacts to energetics, behavior, and entanglement risk. We identify 15 best practice recom‑ mendations for the use of ETDs with pinnipeds that address experimental justifcation, animal capture, tag design, tag attachment, efects assessments, preparation, and reporting. Continued improvement of best practices is critical within the framework of the Three Rs (Reduction, Refnement, Replacement); these best practice recommendations provide current guidance to mitigate known potential negative outcomes for individuals and local populations. These recommendations were developed specifcally for pinnipeds; however, they may also be applicable to studies of other marine taxa. We conclude with four desired future directions for the use of ETDs in technology development, valida‑ tion studies, experimental designs and data sharing