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Neurodegenerative diseases are among the main causes of death in the United States, leading to irreversible disintegration of neurons. Despite intense international research efforts, cellular mechanisms that initiate neurodegeneration remain elusive, thus inhibiting the development of effective preventative and early onset medical treatment. To identify underlying cellular mechanisms that initiate neuron degeneration, it is critical to identify histological and cellular hallmarks that can be linked to underlying biochemical processes. Due to the poor tissue preservation of degenerating mammalian brain tissue, our knowledge regarding histopathological hallmarks of early to late degenerative stages is only fragmentary. Here, we introduce a novel model organism to study histological hallmarks of neurodegeneration, the spider Cupiennius salei. We utilized toluidine blue-stained 0.9-μm serial semithin and 50-nm ultrathin sections of young and old spider nervous tissue. Our findings suggest that the initial stages of neurodegeneration in spiders may be triggered by (1) dissociation of neuron- and glia-derived microtubules, and (2) the weakening of microtubule-associated desmosomal junctions that lead to the unraveling of neuron-insulating macroglia, compromising the structural integrity of affected neurons. The involvement of macroglia in the disposal of neuronal debris described here-although different in the proposed transport mechanisms-shows resemblance to the mammalian glymphatic system. We propose that this model system is highly suitable to investigate invertebrate neurodegenerative processes from early onset to scar formation and that this knowledge may be useful for the study of neurodegeneration in mammalian tissue.

A bladeless wind turbine utilizes vortex formation to extract energy from the wind. Vortex formation are small swirls of air which occur as a result of the geometric shape of the device. This study designed a bladeless wind turbine which incorporates a structural support at a distance offset from the center axis of the cylindrical mast. Springs were added to the final design as means to provide the stiffness required to obtain resonance with the vortex shedding frequency and to also assist in supporting the structure. The analysis was conducted at wind speeds 1m/s, 4m/s and 7m/s, where the geometrical properties of the device remained constant. MATLAB was used to analyze the equation of motion derived for the device. The variables of interest in the studies were mainly the angular acceleration, power coefficient and the resonant frequency. The results obtained showed that for wind speeds above and below the designed wind speed of 4m/s the angular velocity remained the same. Results of this model showed that high amplitudes occur only at resonance. Results showed that with the current power generating mechanism, the average efficiency attainable is approximately 2% at steady state. This is the theoretical efficiency which could be achieved based on the current model. It was discovered that for linearly tapered cylinders, increased oscillations occurred during the ‘lock-in range’ for a range of reduced velocities. The reduced velocity of the designed wind speed is approximately Vr = 5m/s. This value lies within the theoretical range lock in range where increased oscillations are expected to occur between reduced velocities of 4.75m/s and 8m/s [1].

In Quebec, three pneumococcal conjugate vaccines (PCV) were used sequentially starting in December 2004. The objective of the study was to investigate the association between exposure to different PCV regimens and hospitalizations for lower respiratory tract infection (LRTI).Records with a main diagnosis of LRTI in children born in 2000-2012 and observed up to their second birthday were extracted from the provincial hospital administrative database. Main vaccine regimen in different birth cohorts was derived from the Quebec City Immunization Registry. Hospital admission risk was analyzed by Poisson regression models adjusting for age, season of birth, ambient air temperature, circulation of respiratory viruses, and the weekly hospital admission rate for all other causes excluding LRTI to control for temporal changes in hospital admission practices.In univariate analyses, hospitalizations for LRTI, pneumonia, and bronchiolitis were less frequent in cohorts exposed to PCVs than in unvaccinated cohorts with no difference between PCV regimens. For pneumonia, the difference in cumulative incidence was 16% (13%; 18%). In multivariate analyses, exposure to any PCV schedule was associated with a lower although statistically non-significant hospitalization risk for pneumonia as compared with unvaccinated cohorts. Again, differences between PCV regimens were minimal.Interpretation of results of this ecological study should be made with care as many factors could influence hospitalizations for respiratory infection in young children. Results are compatible with a modest effect of PCVs in reducing hospitalizations for pneumonia in children. No substantial differences between various PCV schedules were observed.RéSUMé: OBJECTIVES: Au Québec, trois vaccins pneumocoques conjugués (VPC) ont été utilisés de manière séquentielle depuis décembre 2004. L’objectif de l’étude était d’étudier l’association entre l’exposition aux différents calendriers vaccinaux de VPC et le risque d’hospitalisation pour infection respiratoire basse (IRB). MéTHODES: Les enregistrements avec un diagnostic principal d’IRB chez les enfants nés en 2000–2012 et observés jusqu’au 2ième anniversaire ont été extraits de la base provinciale de données hospitalières administratives. Le principal calendrier vaccinal utilisé pour chaque cohorte mensuelle de naissances a été identifié à l’aide du Registre de vaccination de la région de Québec. Le risque d’hospitalisation a été analysé par régression de Poisson en ajustant pour l’âge, la saison de naissance, la température ambiante, la circulation de virus respiratoires et le taux d’hospitalisation hebdomadaire de toutes causes excluant les IRB afin de contrôler les changements temporels dans les pratiques d’admission. RéSULTATS: Dans l’analyse univariée, les taux d’hospitalisation pour l’IRB, pour pneumonie et pour bronchiolite étaient plus faibles dans les cohortes exposées aux VPC que dans les cohortes non vaccinées et sans qu’existe de différences substantielles entre les différents calendriers vaccinaux. Pour la pneumonie, la différence du taux cumulatif à 2 ans était de 16 % [13 %; 18 %]. Dans l’analyse multivariée, l’exposition à n’importe quel calendrier vaccinal était associée à un risque moins élevé mais statistiquement non significatif d’hospitalisation et les différences entre les différents calendriers étaient faibles. CONCLUSIONS: L’interprétation des résultats d’une étude écologique doit être prudente, car de multiples facteurs peuvent influencer l’hospitalisation pour une infection respiratoire chez les jeunes enfants. Nos résultats sont compatibles avec un effet modeste du VPC dans la réduction des hospitalisations pour la pneumonie chez les enfants sans que des différences substantielles aient été observées entre les différents calendriers et vaccins.

To estimate the risk of recurrence of adverse events following immunization (AEFIs) upon revaccination and to determine among patients with suspected vaccine allergy whether allergy skin test positivity was associated with AEFI recurrence.This prospective observational study included patients assessed in the Canadian Special Immunization Clinic Network from 2013 to 2019 with AEFIs who required revaccination with the vaccine temporally associated with their AEFI. Participants underwent standardized assessment and data collection. Special Immunization Clinic physicians used guidelines to inform their recommendations. Participants were followed up after revaccination to capture AEFI recurrences. Data were transferred to a central database for descriptive analysis.Overall, 588 participants were assessed for 627 AEFIs; 570 (91%) AEFIs occurred in children18 years of age. AEFIs included immediate hypersensitivity (130/627; 21%), large local reactions (110/627; 18%), nonurticarial rash (51/627; 8%), seizures (26/627; 4%), and thrombocytopenia (11/627; 2%). Revaccination was recommended to 513 of 588 (87%) participants. Among participants recommended and due for revaccination during the study period, 63% (299/477) were revaccinated. AEFI recurrence was 10% (31/299) overall, 31% (15/49) for large local reactions, and 7% (5/66) for immediate hypersensitivity. No recurrence was serious. Among 92 participants with suspected vaccine allergy who underwent skin testing and were revaccinated, the negative predictive value of skin testing for AEFI recurrence was 96% (95% CI 92.5%-99.5%).Most individuals with AEFIs were safely revaccinated. Among those with suspected vaccine allergy, skin testing may help determine the safety of revaccination.

Background Maintenance ART with dolutegravir-based dual regimens have proved their efficacy among HIV-1-infected subjects in randomized trials. However, real-life data are scarce, with limited populations and follow-up. Objectives We assessed virological failure (VF) and resistance-associated mutations (RAMs) on dolutegravir maintenance regimens in combination with rilpivirine or with lamivudine or emtricitabine (xTC) and analysed the factors associated with VF. Methods Between 2014 and 2018, all HIV-1-infected adults included in the Dat’AIDS cohort and starting dolutegravir/rilpivirine or dolutegravir/xTC as a maintenance dolutegravir-based dual regimen were selected. VF was defined as two consecutive HIV RNA values >50 copies/mL or a single value >400 copies/mL. We compared cumulative genotypes before initiation of a maintenance dolutegravir-based dual regimen with genotype at VF. Results We analysed 1374 subjects (799 on dolutegravir/rilpivirine and 575 on dolutegravir/xTC) with a median follow-up of 20 months (IQR = 11–31) and 19 months (IQR = 11–31), respectively. VF occurred in 3.8% (n = 30) of dolutegravir/rilpivirine subjects and 2.6% (n = 15) of dolutegravir/xTC subjects. Among subjects receiving dolutegravir/rilpivirine, two genotypes harboured emerging RAMs at VF: E138K on NNRTI (n = 1); and E138K+K101E on NNRTI and N155H on INSTI (n = 1). Among subjects receiving dolutegravir/xTC, no new RAM was detected. The only predictive factor of VF on dolutegravir/rilpivirine was the history of failure on an NNRTI-based regimen (adjusted HR = 2.97, 95% CI = 1.28–6.93). No factor was associated with VF on dolutegravir/xTC. Conclusions In this large real-life cohort, dolutegravir/rilpivirine and dolutegravir/xTC sustained virological suppression and were associated with a low rate of VF and RAM emergence. Careful virological screening is essential before switching to dolutegravir/rilpivirine in virologically suppressed patients with a history of NNRTI therapy.

International audience; Organs consist of multiple cell types that ensure proper architecture and function. How different cell types coexist and interact to maintain their homeostasis in vivo remains elusive. The skin epidermis comprises mostly epithelial cells, but also harbours Langerhans cells (LCs) and dendritic epidermal T cells (DETCs). Whether and how distributions of LCs and DETCs are regulated during homeostasis is unclear. Here, by tracking individual cells in the skin of live adult mice over time, we show that LCs and DETCs actively maintain a non-random spatial distribution despite continuous turnover of neighbouring basal epithelial cells. Moreover, the density of epithelial cells regulates the composition of LCs and DETCs in the epidermis. Finally, LCs require the GTPase Rac1 to maintain their positional stability, density and tiling pattern reminiscent of neuronal self-avoidance. We propose that these cellular mechanisms provide the epidermis with an optimal response to environmental insults.

Background In May 2014, a mass vaccination campaign with four-component meningococcal serogroup B (4CMenB) vaccine was launched in a localized region of Quebec, Canada experiencing high invasive meningococcal B disease endemicity. Active post-marketing surveillance identified several cases of nephrotic syndrome (NS) among ∼49,000 vaccinated individuals aged 2 months to 20 years. We report the epidemiologic investigation of this potential vaccine safety signal. Methods Active vaccine safety surveillance was conducted electronically, with participants completing an online questionnaire prompted at 7 days after each dose and 6 months following the last dose. Additional NS cases were sought from provincial hospitalization and emergency room databases. Results In the year following the first dose of 4CMenB vaccination, four confirmed NS cases (three hospitalized) were identified among vaccinated children 2–5-years-old with onset several months post-vaccination. None had renal biopsy but given their age, and positive response to steroids, idiopathic NS was presumptively diagnosed. Among vaccinated children 1–9-years-old, the NS incidence in the year post-vaccination was 17.7 per 100,000 (1 per 5650 vaccinees) with an NS hospitalization rate (i.e. excluding the outpatient case) that was 3.6-fold higher (95%CI = 0.7–11.8; p = 0.12) than the rest of the province for the same period, and 8.3-fold greater (95%CI = 1.1–62.0; p = 0.039) than during the eight years preceding the immunization campaign in the affected region. Conclusion Active safety surveillance identified an unexpected increase in NS incidence following 4CMenB vaccination. Further epidemiological investigation identified four vaccinated cases in total over a 12 month period of follow up. The greater risk in vaccinees had wide confidence intervals with he lower limit including or just above the nul value, an observation with no or marginal statistical significance. The temporal association with vaccination may be explained by other causes and/or chance clustering of a rare event unrelated to vaccination. To confirm or refute a potential link to vaccination, surveillance in other jurisdictions administering 4CMenB to children 1–9-years-old is needed.

Vaccination has a huge public health impact. Maintaining vaccine coverage is key to avoid the devastating consequences of resurgence. In the Province of Quebec, vaccine coverage in young children are sub-optimal, mostly due to ambivalence toward vaccine safety and efficacy. We previously conducted a regional study in the Quebec’s Eastern Townships region, the PromoVac Study, to test a new educational intervention, based on motivational interviewing techniques, aimed at promoting infant vaccination. This first study evidenced that the intervention led to a marked increase in mothers’ intention to vaccinate, and vaccine coverage in their infants. The current study protocol aims at scaling up these results at a provincial level using a randomized controlled trial design. This pragmatic, randomized, controlled, parallel-group clinical trial will compare the effectiveness of the motivational interviewing to an educational intervention, including the distribution of an information flyer as standard of care on vaccination coverage in four maternity wards across the Province of Quebec (PromovaQ). Adult mothers of children born in participating maternity wards were recruited between March 2014 and February 2015. Vaccination coverage will be assessed at 3-years of age, thus the trial is expected to be completed in March 2019. Statistical analyses will be conducted under the intention-to-treat principle. Vaccine coverage will be analyzed using Chi-squared distribution testing and logistic regression to identify determinant factors. Secondary outcomes will include vaccine hesitation and intention scores, mother’s knowledge, attitudes and beliefs about immunization, and psychosocial determinants of intention to vaccinate. In the case results of this Provincial RCT be confirmed, serious consideration should then be given by Ministry of Health authorities to the possible implementation of MI-based strategies across provincial maternity wards. To ensure adequate input and secure implementation, study design and results will be reviewed with relevant stakeholders, including the children’s families, and provincial and regional decision-makers. Results will be adapted and shared with all stakeholders. ClinicalTrials.gov NCT02666872 (Retrospectively registered as January 28, 2016).

OBJECTIVES Here, we examine (1) if the sex-related differences in iron (Fe) and copper (Cu) isotope ratios, represented as δ56 Fe and δ65 Cu values, respectively observed in humans exist in bulk occipital bone and incisors of male and female non-human primates, and (2) if the variation of Fe and Cu isotope ratios, known to vary in human blood as a factor of age are similar in non-human primate bone. MATERIALS AND METHODS Isotope ratios were measured from the skeletal elements of 20 rhesus macaques (Macaca mulatta) with known life history traits. The metals were purified by column chromatography and their isotope ratios measured by MC-ICP-MS. Data were analyzed using generalized additive models (GAM). RESULTS When accounting for age and sex independently, we found a significant relationship between δ65 Cu values and occipital bone, but not in incisors. There were no significant relationships observed between δ56 Fe values, occipital bone, or incisors. Similarly, there were no significant relationships observed between δ56 Fe values, δ65 Cu values, and age. DISCUSSION We suggest that Cu and Fe isotope ratios have the potential to be useful supplementary tools in future research in biological anthropology, but additional studies are needed to further verify the relationship between sex, age, δ65 Cu, and δ56 Fe values in primates.

A suite of genetic components and computational models enables the predictive design of mammalian cellular functions., Genetically engineering cells to perform customizable functions is an emerging frontier with numerous technological and translational applications. However, it remains challenging to systematically engineer mammalian cells to execute complex functions. To address this need, we developed a method enabling accurate genetic program design using high-performing genetic parts and predictive computational models. We built multifunctional proteins integrating both transcriptional and posttranslational control, validated models for describing these mechanisms, implemented digital and analog processing, and effectively linked genetic circuits with sensors for multi-input evaluations. The functional modularity and compositional versatility of these parts enable one to satisfy a given design objective via multiple synonymous programs. Our approach empowers bioengineers to predictively design mammalian cellular functions that perform as expected even at high levels of biological complexity.

Our organs consist of multiple cell types that ensure proper architecture and function. How different cell types coexist and interact to maintain their homeostasis in vivo remain elusive. The skin epidermis comprises mostly epithelial cells, but also harbors Langerhans cells (LCs) and Dendritic Epidermal T cells (DETCs). In response to injury or infection, LCs and DETCs become activated and play critical immunological roles. During homeostasis, they coexist with epithelial cells in the basal layer of the epidermis. Whether, and how, distributions of LCs and DETCs are regulated during homeostasis is unclear. Here, we addressed this question by tracking LCs, DETCs and epithelial basal cells over time within the skin of live adult mice. We show that LCs and DETCs maintain their overall position despite continuous turnover of neighboring basal epithelial stem cells. Moreover, LCs and DETCs rapidly and maximally explore basal epithelial cell junctions through their dendritic extensions. Altering the epithelial cell density triggers corresponding changes in the immune cell density, but not vice versa, suggesting that epithelial cells determine immune tissue composition in the epidermis. Moreover, LCs and DETCs are organized in a tiling pattern that is actively maintained. When LCs or DETCs are ectopically removed, neighboring epidermal LCs or DETCs, respectively, move into the emptied spaces and re-establish the tiling pattern. Finally, LCs require the GTPase Rac1 to maintain their positional stability, density and tiling pattern. Overall, we discovered that epidermal cells regulate the density of immune cells during homeostasis, and that immune cells actively maintain a non-random spatial distribution, reminiscent of neuronal self-avoidance. We propose that these cellular mechanisms provide the epidermis with an optimal response to environmental insults.

In the last few decades there has been increasing interest in the application of microwaves as an energy source in extractive metallurgy for the treatment of ores and concentrates. The fundamental parameters required for the design of industrial systems are the real and the imaginary permittivities, which are both frequency and temperature dependent. However, there is a dearth of data on the permittivities, of not only the ores and the concentrates, but also the minerals that comprise the ores. In the present research, the permittivities of selected hydroxide minerals were determined using the cavity perturbation technique as a function of both temperature and frequency. The behaviours of the permittivities were interpreted using both thermogravimetric analysis (TGA) and thermodynamic modelling. The water in these minerals, in its various forms, makes a significant contribution to the permittivities. Also, generally, the higher iron-bearing hydroxides have higher permittivities than the magnesium silicates or aluminosilicates. It is shown that the permittivities of the hydroxide minerals are low, but the hydroxyl ion makes a significant contribution. The effect of frequency is more pronounced both during dehydroxylation and at high temperatures and, in both cases, is attributed to increases in the ac conductivity.

The mining of ultramafic ores is required to meet society’s continued demand for nickel. These deposits, however, are difficult to process due to their high serpentine content. Serpentine, a gangue mineral, increases slurry viscosity, slime-coats the valuable Ni-bearing mineral pentlandite, and reports to and dilutes the froth during flotation via the formation of bubble-fibre aggregates. Microwave pre-treatment can be used to convert the serpentine gangue to olivine, which should improve ore processing. However, the fundamental microwave properties and heating behaviour of ultramafic ores must be understood to develop a robust process. Microwave heating curves were developed for, and high temperature permittivity analysis was conducted on, two ultramafic nickel ores (Pipe and OK ore). Subsequently, TGA/DSC (thermogravimetric analysis/differential scanning calorimetry) and HTXRD (high-temperature x-ray diffraction) tests, along with a thermodynamic analysis using FactSage 7.3, were done to explain the heating behaviours and permittivity data. An unusual peak in the permittivity data was detected at 950 °C for the Pipe ore with both increasing and decreasing temperature; however, no phase transitions were detected in the TGA/DSC analysis. HTXRD of the Pipe ore revealed the presence of heazlewoodite at higher temperatures (950 to 1100 °C). Thermodynamic modeling of the Pipe ore system suggests that melting at higher temperatures is responsible for the decrease in the permittivities of this ore. To mitigate the melting and clumping of the ore particles, it is necessary to ensure that the processing temperature does not exceed 800 °C during microwave treatment. The OK ore, which contained less microwave response minerals than the Pipe ore, reached a maximum temperature of 500 °C after only 5 min of heating time, and therefore overheating was not an issue.

Splitting bioactive proteins into conditionally reconstituting fragments is a powerful strategy for building tools to study and control biological systems. However, split proteins often exhibit a high propensity to reconstitute, even without the conditional trigger, limiting their utility. Current approaches for tuning reconstitution propensity are laborious, context-specific or often ineffective. Here, we report a computational design strategy grounded in fundamental protein biophysics to guide experimental evaluation of a sparse set of mutants to identify an optimal functional window. We hypothesized that testing a limited set of mutants would direct subsequent mutagenesis efforts by predicting desirable mutant combinations from a vast mutational landscape. This strategy varies the degree of interfacial destabilization while preserving stability and catalytic activity. We validate our method by solving two distinct split protein design challenges, generating both design and mechanistic insights. This new technology will streamline the generation and use of split protein systems for diverse applications.

Background Many countries are grappling with growing numbers of parents who delay or refuse recommended vaccinations for their children. This has created a need for strategies to address vaccine hesitancy (VH) and better support parental decision-making regarding vaccination. Aim To assess vaccination intention (VI) and VH among parents who received an individual motivational-interview (MI) based intervention on infant immunisation during post-partum stay at a maternity ward between March 2014 and February 2015. Methods This non-controlled pre-/post-intervention study was conducted using the results from parents enrolled in the intervention arm of the PromoVaQ randomised control trial (RCT), which was conducted in four maternity wards across the Province of Quebec. Participants (n = 1,223) completed pre- and post-intervention questionnaires on VI and VH using Opel’s score. Pre-/post-intervention measures were compared using McNemar’s test for categorical variables and Wilcoxon signed-rank test for continuous variables. Results Pre-intervention: overall VI was 78% and significantly differed across maternity wards (74%, 77%, 84%, 79%, p = 0.02). Post-intervention: VI rose significantly across maternity wards (89%, 85%, 95%, 93%) and the overall increase in VI was 12% (78% vs 90%, p Conclusions Compared with pre-intervention status, participants who received the MI-based intervention on immunisation displayed lower hesitancy and greater intention to vaccinate their infant at 2 months of age.

Return of samples from the surface of Mars has been a goal of the international Mars science community for many years. Affirmation by NASA and ESA of the importance of Mars exploration led the agencies to establish the international MSR Objectives and Samples Team (iMOST). The purpose of the team is to re-evaluate and update the sample-related science and engineering objectives of a Mars Sample Return (MSR) campaign. The iMOST team has also undertaken to define the measurements and the types of samples that can best address the objectives. Seven objectives have been defined for MSR, traceable through two decades of previously published international priorities. The first two objectives are further divided into sub-objectives. Within the main part of the report, the importance to science and/or engineering of each objective is described, critical measurements that would address the objectives are specified, and the kinds of samples that would be most likely to carry key information are identified. These seven objectives provide a framework for demonstrating how the first set of returned Martian samples would impact future Martian science and exploration. They also have implications for how analogous investigations might be conducted for samples returned by future missions from other solar system bodies, especially those that may harbor biologically relevant or sensitive material, such as Ocean Worlds (Europa, Enceladus, Titan) and others. Summary of Objectives and Sub-Objectives for MSR Identified by iMOST: Objective 1 Interpret the primary geologic processes and history that formed the Martian geologic record, with an emphasis on the role of water. Intent To investigate the geologic environment(s) represented at the Mars 2020 landing site, provide definitive geologic context for collected samples, and detail any characteristics that might relate to past biologic processesThis objective is divided into five sub-objectives that would apply at different landing sites. 1.1 Characterize the essential stratigraphic, sedimentologic, and facies variations of a sequence of Martian sedimentary rocks. Intent To understand the preserved Martian sedimentary record. Samples A suite of sedimentary rocks that span the range of variation. Importance Basic inputs into the history of water, climate change, and the possibility of life 1.2 Understand an ancient Martian hydrothermal system through study of its mineralization products and morphological expression. Intent To evaluate at least one potentially life-bearing “habitable” environment Samples A suite of rocks formed and/or altered by hydrothermal fluids. Importance Identification of a potentially habitable geochemical environment with high preservation potential. 1.3 Understand the rocks and minerals representative of a deep subsurface groundwater environment. Intent To evaluate definitively the role of water in the subsurface. Samples Suites of rocks/veins representing water/rock interaction in the subsurface. Importance May constitute the longest-lived habitable environments and a key to the hydrologic cycle. 1.4 Understand water/rock/atmosphere interactions at the Martian surface and how they have changed with time. Intent To constrain time-variable factors necessary to preserve records of microbial life. Samples Regolith, paleosols, and evaporites. Importance Subaerial near-surface processes could support and preserve microbial life. 1.5 Determine the petrogenesis of Martian igneous rocks in time and space. Intent To provide definitive characterization of igneous rocks on Mars. Samples Diverse suites of ancient igneous rocks. Importance Thermochemical record of the planet and nature of the interior. Objective 2 Assess and interpret the potential biological history of Mars, including assaying returned samples for the evidence of life. Intent To investigate the nature and extent of Martian habitability, the conditions and processes that supported or challenged life, how different environments might have influenced the preservation of biosignatures and created nonbiological “mimics,” and to look for biosignatures of past or present life.This objective has three sub-objectives: 2.1 Assess and characterize carbon, including possible organic and pre-biotic chemistry. Samples All samples collected as part of Objective 1. Importance Any biologic molecular scaffolding on Mars would likely be carbon-based. 2.2 Assay for the presence of biosignatures of past life at sites that hosted habitable environments and could have preserved any biosignatures. Samples All samples collected as part of Objective 1. Importance Provides the means of discovering ancient life. 2.3 Assess the possibility that any life forms detected are alive, or were recently alive. Samples All samples collected as part of Objective 1. Importance Planetary protection, and arguably the most important scientific discovery possible. Objective 3 Quantitatively determine the evolutionary timeline of Mars. Intent To provide a radioisotope-based time scale for major events, including magmatic, tectonic, fluvial, and impact events, and the formation of major sedimentary deposits and geomorphological features. Samples Ancient igneous rocks that bound critical stratigraphic intervals or correlate with crater-dated surfaces. Importance Quantification of Martian geologic history. Objective 4 Constrain the inventory of Martian volatiles as a function of geologic time and determine the ways in which these volatiles have interacted with Mars as a geologic system. Intent To recognize and quantify the major roles that volatiles (in the atmosphere and in the hydrosphere) play in Martian geologic and possibly biologic evolution. Samples Current atmospheric gas, ancient atmospheric gas trapped in older rocks, and minerals that equilibrated with the ancient atmosphere. Importance Key to understanding climate and environmental evolution. Objective 5 Reconstruct the processes that have affected the origin and modification of the interior, including the crust, mantle, core and the evolution of the Martian dynamo. Intent To quantify processes that have shaped the planet's crust and underlying structure, including planetary differentiation, core segregation and state of the magnetic dynamo, and cratering. Samples Igneous, potentially magnetized rocks (both igneous and sedimentary) and impact-generated samples. Importance Elucidate fundamental processes for comparative planetology. Objective 6 Understand and quantify the potential Martian environmental hazards to future human exploration and the terrestrial biosphere. Intent To define and mitigate an array of health risks related to the Martian environment associated with the potential future human exploration of Mars. Samples Fine-grained dust and regolith samples. Importance Key input to planetary protection planning and astronaut health. Objective 7 Evaluate the type and distribution of in-situ resources to support potential future Mars exploration. Intent To quantify the potential for obtaining Martian resources, including use of Martian materials as a source of water for human consumption, fuel production, building fabrication, and agriculture. Samples Regolith. Importance Production of simulants that will facilitate long-term human presence on Mars. Summary of iMOST Findings: Several specific findings were identified during the iMOST study. While they are not explicit recommendations, we suggest that they should serve as guidelines for future decision making regarding planning of potential future MSR missions. The samples to be collected by the Mars 2020 (M-2020) rover will be of sufficient size and quality to address and solve a wide variety of scientific questions. Samples, by definition, are a statistical representation of a larger entity. Our ability to interpret the source geologic units and processes by studying sample sub sets is highly dependent on the quality of the sample context. In the case of the M-2020 samples, the context is expected to be excellent, and at multiple scales. (A) Regional and planetary context will be established by the on-going work of the multi-agency fleet of Mars orbiters. (B) Local context will be established at field area- to outcrop- to hand sample- to hand lens scale using the instruments carried by M-2020. A significant fraction of the value of the MSR sample collection would come from its organization into sample suites, which are small groupings of samples designed to represent key aspects of geologic or geochemical variation. If the Mars 2020 rover acquires a scientifically well-chosen set of samples, with sufficient geological diversity, and if those samples were returned to Earth, then major progress can be expected on all seven of the objectives proposed in this study, regardless of the final choice of landing site. The specifics of which parts of Objective 1 could be achieved would be different at each of the final three candidate landing sites, but some combination of critically important progress could be made at any of them. An aspect of the search for evidence of life is that we do not know in advance how evidence for Martian life would be preserved in the geologic record. In order for the returned samples to be most useful for both understanding geologic processes (Objective 1) and the search for life (Objective 2), the sample collection should contain BOTH typical and unusual samples from the rock units explored. This consideration should be incorporated into sample selection and the design of the suites. The retrieval missions of a MSR campaign should (1) minimize stray magnetic fields to which the samples would be exposed and carry a magnetic witness plate to record exposure, (2) collect and return atmospheric gas sample(s), and (3) collect additional dust and/or regolith sample mass if possible.

BACKGROUND For patients who have experienced adverse events following immunization (AEFI) or who have specific medical conditions, there is limited evidence regarding the best approach to immunization. The Special Immunization Clinics (SICs) Network was established to standardize patient management and assess outcomes after reimmunization. The study objective was to describe the first 2 years of the network's implementation. METHODS Twelve SICs were established across Canada by infectious diseases specialists and allergists. Inclusion criteria were as follows: local reaction ≥ 10 cm, allergic symptoms < 24 hours postimmunization, neurologic symptoms and other AEFI or medical conditions of concern. Eligible patients underwent a standardized evaluation, causality assessment was performed, immunization recommendations were made by expert physicians and patients were followed up to capture AEFI. After individual consent, data were transferred to a central database for analysis. RESULTS From June 2013 to May 2015, 151 patients were enrolled. Most were referred for prior AEFI (132/151, 87%): 42 (32%) for allergic-like reactions, 31 (23%) for injection-site reactions, 20 (15%) for neurologic symptoms and 39 (30%) for other systemic symptoms. Nineteen patients (13%) were seen for underlying conditions that complicated immunization. Reimmunization was recommended for 109 patients, 60 of whom (55%) were immunized and followed up. Eleven patients (18%) experienced recurrence of their AEFI; none were serious (eg, resulting in hospitalization, permanent disability or death). CONCLUSIONS The most frequent reasons for referral to a SIC were allergic-like events and injection site reactions. Reimmunization was safe in most patients. Larger studies are needed to determine outcomes for specific types of AEFI.

Tracking stem cell fate in time and space After injury and during homeostasis, tissues rely on the balance of cell loss and renewal. Rompolas et al. visualized individual stem cells over their lifetime in the epidermis of live mice. Tracking stem cells over multiple generations revealed that tissue homeostasis in the mouse epidermis is not maintained by asymmetric cell division as previously thought, but through the coordination of sibling cell fate and lifetimes. Furthermore, differentiating stem cells reused the existing spatial organization of the epidermis. Science , this issue p. 1471

L’acide folique (vitamine B9) est une vitamine hydrosoluble du groupe B. On le trouve dans les aliments sous forme de folate et dans les supplements sous forme d’acide folique, dont la biodisponibilite est plus importante. Le folate joue un role essentiel dans la synthese et la reparation de l’ADN, ainsi que dans la croissance et la division cellulaires. Il contribue egalement a la methylation de l’ADN et est donc important pour la regulation epigenomique.

Periconceptional folic acid significantly reduces the risk of neural tube defects. It is difficult to achieve optimal levels of folate by diet alone, even with fortification of flour, especially because flour consumption in Canada is slightly decreasing. Intermittent concerns have been raised concerning possible deleterious effects of folate supplementation, including the masking of symptoms of vitamin B12 deficiency and an association with cancer, especially colorectal cancer. Both concerns have been disproved. The Canadian Paediatric Society endorses the following steps to enhance folate intake in women of child-bearing age: encouraging the consumption of folate-rich foods such as leafy vegetables, increasing the level of folate food fortification, taking a supplement containing folate and B12, and providing free folate supplementation to disadvantaged women of child-bearing age. These recommendations are consistent with those of the Society of Obstetricians and Gynaecologists of Canada.La consommation d’acide folique pendant la période périconcep- tionnelle réduit considérablement le risque d’anomalie du tube neural. Il est difficile d’atteindre un taux optimal de folate à partir du seul régime alimentaire, malgré l’enrichissement de la farine, surtout que la consommation de ce produit diminue légèrement au Canada. Les effets délétères possibles des suppléments de folate ont suscité sporadiquement des inquiétudes, y compris le camouflage des symptômes de carence en vitamine B

Histoplasmosis is a common fungal infection, normally infecting people exposed to demolition sites or bat/bird droppings in the central and eastern states. When a child presents with a chest mass and eosinophilia in a non-endemic region the likelihood of an infectious process like pulmonary histoplasmosis is unknown. A seven year old immunocompetent child with a mediastinal mass and eosinophilia presented with acute cough, fever, non-bloody emesis, and four pound weight loss. A neoplastic work up was negative. Further evaluation showed a positive M band (chronic histoplasmosis infection) and negative H band (acute infection). Tissue obtained by thoracotomy demonstrated necrotizing granulomatous inflammation with calcification consistent with histoplasmosis. Patient recovered after completion of a twelve week course of itraconazole. A mediastinal mass in a symptomatic child has a 50% risk of cancer as the primary diagnosis. The Infectious Disease Society of America guidelines recommend treatment of histoplasmosis granulomatous disease with itraconazole if symptomatic and surgery only for obstruction. Thus our patient did not have a clear indication for surgery. In a child with a mediastinal mass, despite low risk factors should they be evaluated for a fungal infection prior to invasive surgery? This case demonstrates that histoplasmosis can cause a granuloma in a non-endemic region and that an infectious etiology ought to be considered when working up a symptomatic child with a chest mass as it may prevent unnecessary surgery. Keywords: Histoplasmosis, Fungal, Cough, Chest mass, Eosinophilia, Thoracotomy, Mediastinal

In Quebec, Canada, eligibility for palivizumab (PVZ) immunoprophylaxis was expanded in fall 2016 to include healthy-full-term (HFT) infants residing in the circumpolar region of Nunavik and aged

Hepatitis B virus (HBV) and hepatitis C virus (HCV) affect more than 320 million people worldwide, which is more than HIV, tuberculosis (TB) and malaria combined. Elimination of HBV and HCV will, therefore, produce substantial public health and economic benefits and, most importantly, the prevention of 1.2 million deaths per year. In 2016, member states of the World Health Assembly unanimously adopted a resolution declaring that viral hepatitis should be eliminated by 2030. Currently, few countries have elimination programmes in place and even though the tools to achieve elimination are available, the right resources, commitments and allocations are lacking. During the fifth International Viral Hepatitis Elimination Meeting (IVHEM), 7-8 December 2018, Amsterdam, the Netherlands, an expert panel of clinicians, virologists and public health specialists discussed the current status of viral hepatitis elimination programmes across multiple countries, challenges in achieving elimination and the core indicators for monitoring progress, approaches that have failed and successful elimination plans. © 2019 Mediscript Ltd. All rights reserved.

Purpose To compare the frequency and the severity of influenza and respiratory syncytial viruses (RSV) infections among children

Summary Maintenance of adult tissues depends on sustained activity of resident stem cell populations, but the mechanisms that regulate stem cell self-renewal during homeostasis remain largely unknown. Using an imaging and tracking approach that captures all epidermal stem cell activity in large regions of living mice, we show that self-renewal is locally coordinated with epidermal differentiation, with a lag time of 1 to 2 days. In both homeostasis and upon experimental perturbation, we find that differentiation of a single stem cell is followed by division of a direct neighbor, but not vice versa. Finally, we show that exit from the stem cell compartment is sufficient to drive neighboring stem cell self-renewal. Together, these findings establish that epidermal stem cell self-renewal is not the constitutive driver of homeostasis. Instead, it is precisely tuned to tissue demand and responds directly to neighbor cell differentiation.

Decreased active and passive range of motion (ROM) accompanied by pain in the shoulder is a common presentation for patients with frozen shoulder, and it can be difficult to restore normal function. Through the fascial distortion model, physicians can apply a manual technique to rapidly and effectively increase ROM and decrease pain. A 28-year-old man presented 18 months after sustaining a shoulder hyperextension injury. On active and passive ROM examination, he had approximately 90° of shoulder abduction and moderately reduced internal rotation associated with 8/10 pain. After 2 applications of the fascial distortion model, his shoulder restored to full abduction and internal rotation with no pain.

Fibroblasts are an essential cellular and structural component of our organs. Despite several advances, the critical behaviors that fibroblasts utilize to maintain their homeostasis in vivo have remained unclear. Here, by tracking the same skin fibroblasts in live mice, we show that fibroblast position is stable over time and that this stability is maintained despite the loss of neighboring fibroblasts. In contrast, fibroblast membranes are dynamic during homeostasis and extend to fill the space of lost neighboring fibroblasts in a Rac1-dependent manner. Positional stability is sustained during aging despite a progressive accumulation of gaps in fibroblast nuclei organization, while membrane occupancy continues to be maintained. This work defines positional stability and cell occupancy as key principles of skin fibroblast homeostasis in vivo, throughout the lifespan of mice, and identifies membrane extension in the absence of migration as the core cellular mechanism to carry out these principles.

SUMMARYYoung age, adverse environmental conditions and infectious agents are established risk factors of lower respiratory tract infection (LRTI), whereas pneumococcal conjugate vaccines may be protective. To explore their relative role as predictors of hospitalizations under the continental climate prevailing in the province of Quebec, Canada, an ecological study was performed. Records with a main diagnosis of LRTI in children born during 2007–2010 and observed up to their second-year anniversary were extracted from the provincial hospital administrative database. Respiratory virus surveillance data and statistics on ambient air temperature were obtained. Vaccine use in different birth cohorts was derived from the Quebec City Immunization Registry. Additive and multiplicative Poisson regression models were applied to estimate attributable fractions. Age, month of birth, ambient temperature, and respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza-positive test proportions were significant predictors of LRTI hospitalizations. No substantial differences were observed in cohorts exposed to the 7-valent or 10-valent pneumococcal conjugate vaccines. In the additive model, the fraction of hospitalizations explained by temperature variation was 37%, whereas RSV circulation explained 28%, hMPV 4% and influenza 1%. Complex interplay between biological, environmental and social mechanisms may explain the important role of ambient air temperature in predicting LRTI hospitalization risk in young children.

Paradoxical immune reconstitution inflammatory syndrome is a well-described entity even in immunocompetent children, principally in association with Mycobacterium tuberculosis infections. Central nervous system involvement is a potential life-threatening form, sometimes refractory to standard treatment. We report the case of an HIV-negative refugee teenager, who presented with brain tuberculomas and pseudoabscesses responsive only to thalidomide.

SUMMARYStreptococcus pneumoniaeis an important cause of community-acquired pneumonia and pneumococcal conjugate vaccines (PCVs) may reduce this burden. This study's goal was to analyse trends in lower respiratory tract infections (LRTI) hospitalisations before and during a routine vaccination programme targeting all newborns with PCV was started in the province of Quebec, Canada in December 2004. The study population included hospital admissions with a main diagnosis of LRTI among 6–59 month-old Quebec residents from April 2000 to December 2014. Trends in proportions and rates were analysed using Cochran-Armitage tests and Poisson regression models. We observed a general downward trend in all LTRI hospitalisations rate: from 11·55/1000 person-years in 2000–2001 to 9·59/1000 in 2013–2014, a 17·0% reduction, which started before the introduction of PCV vaccination. Downward trends in hospitalisation rates were more pronounced for all-cause of pneumonia (minus 17·8%) than for bronchiolitis (minus 15·4%). There was also a decrease in the mean duration of hospital stay. There was little evidence that all-cause pneumonia decreased over the study period due mainly to the introduction of PCVs. Trends may be related to changes in clinical practice. This study casts doubt on the interpretation of ecological analyses of the implementation of PCV vaccination programmes.

Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes1–3. It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells. Here we use intravital imaging to track the fate of mouse skin epithelium burdened with varying numbers of activated Wnt/β-catenin stem cells. We show that all resulting growths that deform the skin tissue architecture regress, irrespective of their size. Wild-type cells are required for the active elimination of mutant cells from the tissue, while utilizing both endogenous and ectopic cellular behaviours to dismantle the aberrant structures. After regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. Furthermore, tissue aberrancies generated from oncogenic Hras, and even mutation-independent deformations to the tissue, can also be corrected, indicating that this tolerance phenomenon reflects a conserved principle in the skin. This study reveals an unanticipated plasticity of the adult skin epithelium when faced with mutational and non-mutational insult, and elucidates the dynamic cellular behaviours used for its return to a homeostatic state.

Many adult tissues are dynamically sustained by the rapid turnover of stem cells. Yet, how cell fates such as self-renewal and differentiation are orchestrated to achieve long-term homeostasis remains elusive. Studies utilizing clonal tracing experiments in multiple tissues have argued that while stem cell fate is balanced at the population level, individual cell fate - to divide or differentiate – is determined intrinsically by each cell seemingly at random ( 1 2 3 4 5). These studies leave open the question of how cell fates are regulated to achieve fate balance across the tissue. Stem cell fate choices could be made autonomously by each cell throughout the tissue or be the result of cell coordination ( 6 7). Here we developed a novel live tracking strategy that allowed recording of every division and differentiation event within a region of epidermis for a week. These measurements reveal that stem cell fates are not autonomous. Rather, direct neighbors undergo coupled opposite fate decisions. We further found a clear ordering of events, with self-renewal triggered by neighbor differentiation, but not vice-versa. Typically, around 1-2 days after cell delamination, a neighboring cell entered S/G2 phase and divided. Functional blocking of this local feedback showed that differentiation continues to occur in the absence of cell division, resulting in a rapid depletion of the epidermal stem cell pool. We thus demonstrate that the epidermis is maintained by nearest neighbor coordination of cell fates, rather than by asymmetric divisions or fine-tuned cell-autonomous stochastic fate choices. These findings establish differentiation-dependent division as a core feature of homeostatic control, and define the relevant time and length scales over which homeostasis is enforced in epithelial tissues.

Resume Introduction Dans le cadre de l’amelioration de la prise en charge des escarres, les pharmaciens du centre hospitalier animent en collaboration avec la direction des soins un groupe pluridisciplinaire. Ce dernier mene des evaluations des pratiques professionnelles des services depuis 2006. Methode La demarche du groupe « escarre » s’est fondee sur la methode Plan Do Check Act ou PDCA qui decrit un cycle de conduite et d’amelioration de projet. Depuis 6 ans, 4 enquetes ont ete mises en place : 2006, 2008, 2010 et 2012. Il s’agit de combiner des enquetes de pratiques ciblees sur l’encadrement et les equipes soignantes avec des enquetes de prevalence. Lors de la derniere vague d’enquetes, un audit du dossier de soins a egalement ete realise. Conclusion Ainsi, ces differentes investigations ont permis d’orienter les actions d’amelioration conduites par le groupe.

Background: Gap junctions enable small molecules to diffuse between adjacent cells and have been associated with greater cytotoxicity of radiation and anti-cancer drugs. We investigated whether this gap junctional intercellular communication (GJIC) affected the cytotoxicity of the classic ribonucleotide reductase (RR) inhibitor and anti-cancer agent, hydroxyurea (HU). Materials and Methods: We used GJIC-proficient and deficient, connexin 43-expressing WB rat liver epithelial cell lines. We compared HU toxicity by crystal violet assay, effects of the drug on deoxynucleotide pools by HPLC, and ability of GJIC to increase toxicity of HU-resistant cells through a bystander effect in co-culture experiments. Results: GJIC-proficient cells were three- to five-fold more sensitive (IC50 0.1 mM) to HU than GJIC-deficient derivatives (IC50 0.3 - 0.5 mM). This sensitivity depended upon GJIC because treatment of GJIC-proficient cells with the GJIC blocker oleamide decreased HU toxicity by approximately 60% - 80% and restoration of GJIC in GJIC-deficient cells by stable transduction of connexin 32-encoding Gjb1 increased HU toxicity (IC500.1 mM). The effects were not due to connexin expression per se or its localization since all cell lines expressed comparable quantities of connexin 43 that was localized to the plasma membrane. Also HU sensitivity was not related to differential effects on nucleotide metabolism in the cells. Thymidine triphosphate levels increased and deoxyadenosine triphosphate levels decreased similarly (15% - 20%) in GJIC-proficient and deficient cells over 24 h of HU treatment. More importantly, when HU-resistant cells were co-cultured with sensitive cells, the resistant cells were killed only when GJIC was present. Conclusion: The data suggest that GJIC enhances cytotoxicity and decreases resistance to HU. These results may be important clinically if GJIC can be enhanced in drug-resistant cells.

Within the framework of the International Lunar Surface Operation - In-Situ Resource Utilization Analogue Test held on January 27 - February 11, 2010 on the Mauna Kea volcano in Hawaii, a number of scientific instrument teams collaborated to characterize the field site and test instrument capabilities outside laboratory environments. In this paper, we provide a geological setting for this new field-test site, a description of the instruments that were tested during the 2010 ILSO-ISRU field campaign, and a short discussion for each instrument about the validity and use of the results obtained during the test. These results will form a catalogue that may serve as reference for future test campaigns. In this paper we provide a description and regional geological setting for a new field analogue test site for lunar resource exploration, and discuss results obtained from the 2010 ILSO-ISRU field campaign as a reference for future field-testing at this site. The following instruments were tested: a multispectral microscopic imager, MMI, a Mossbauer spectrometer, an evolved gas analyzer, VAPoR, and an oxygen and volatile extractor called RESOLVE. Preliminary results show that the sediments change from dry, organic-poor, poorly-sorted volcaniclastic sand on the surface, containing basalt, iron oxides and clays, to more water- and organic-rich, fine grained, well-sorted volcaniclastic sand, primarily consisting of iron oxides and depleted of basalt and clays. Furthermore, drilling experiments showed a very close correlation between drilling on the Moon and drilling at the test site. The ILSO-ISRU test site was an ideal location for testing strategies for in situ resource exploration at the lunar or martian surface.