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Abstract Over the past three decades, there has been increasing interest in miniaturized percutaneous nephrolithotomy (mPCNL) techniques featuring smaller tracts as they offer potential solutions to mitigate complications associated with standard PCNL (sPCNL). However, despite this growing acceptance and recognition of its benefits, unresolved controversies and acknowledged limitations continue to impede widespread adoption due to a lack of consensus on optimal perioperative management strategies and procedural tips and tricks. In response to these challenges, an international panel comprising experts from the International Alliance of Urolithiasis (IAU) took on the task of compiling an expert consensus document on mPCNL procedures aimed at providing urologists with a comprehensive clinical framework for practice. This endeavor involved conducting a systematic literature review to identify research gaps (RGs), which formed the foundation for developing a structured questionnaire survey. Subsequently, a two-round modified Delphi survey was implemented, culminating in a group meeting to generate final evidence-based comments. All 64 experts completed the second-round survey, resulting in a response rate of 100.0%. Fifty-eight key questions were raised focusing on mPCNLs within 4 main domains, including general information (13 questions), preoperative work-up (13 questions), procedural tips and tricks (19 questions), and postoperative evaluation and follow-up (13 questions). Additionally, 9 questions evaluated the experts’ experience with PCNLs. Consensus was reached on 30 questions after the second-round survey, while professional statements for the remaining 28 key questions were provided after discussion in an online panel meeting. mPCNL, characterized by a tract smaller than 18 Fr and an innovative lithotripsy technique, has firmly established itself as a viable and effective approach for managing upper urinary tract stones in both adults and pediatrics. It offers several advantages over sPCNL including reduced bleeding, fewer requirements for nephrostomy tubes, decreased pain, and shorter hospital stays. The series of detailed techniques presented here serve as a comprehensive guide for urologists, aiming to improve their procedural understanding and optimize patient outcomes.

There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis. Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids, such as docosahexaenoic acid, and exercise in Parkinson’s disease, we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway. First, mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation. Four weeks after lesion, animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks. During this period, the animals had access to a running wheel, which they could use or not. Docosahexaenoic acid treatment, voluntary exercise, or the combination of both had no effect on (i) distance traveled in the open field test, (ii) the percentage of contraversive rotations in the apomorphine-induction test or (iii) the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta. However, the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum. Compared to docosahexaenoic acid treatment or exercise alone, the combination of docosahexaenoic acid and exercise (i) improved forelimb balance in the stepping test, (ii) decreased the striatal DOPAC/dopamine ratio and (iii) led to increased dopamine transporter levels in the lesioned striatum. The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

Abstract Cognitive decline due to Alzheimer’s disease (AD) is frequent in the geriatric population, which has been disproportionately affected by the COVID-19 pandemic. In this study, we investigated the levels of angiotensin-converting enzyme 2 (ACE2), a regulator of the renin-angiotensin system and the main entry receptor of SARS-CoV-2 in host cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein (p

Abstract The use of human derived induced pluripotent stem cells (hiPSCs) differentiated to dopaminergic (DA) neurons offers a valuable experimental model to decorticate the cellular and molecular mechanisms of Parkinson’s disease (PD) pathogenesis. However, the existing approaches present with several limitations, notably the lengthy time course of the protocols and the high variability in the yield of DA neurons. Here we report on the development of an improved approach that combines neurogenin-2 programming with the use of commercially available midbrain differentiation kits for a rapid, efficient, and reproducible directed differentiation of hiPSCs to mature and functional induced DA (iDA) neurons, with minimum contamination by other brain cell types. Gene expression analysis, associated with functional characterization examining neurotransmitter release and electrical recordings, support the functional identity of the iDA neurons to A9 midbrain neurons. iDA neurons showed selective vulnerability when exposed to 6-hydroxydopamine, thus providing a viable in vitro approach for modeling PD and for the screening of small molecules with neuroprotective proprieties.

The scientific community's efforts have increased regarding the application and assessment of the FAIR principles on Digital Objects (DO) such as publications, datasets, or research software. Consequently, openly available automated FAIR assessment services have been working on standardization, such as FAIR enough, the FAIR evaluator or FAIRsFAIR's F-UJI. Digital Competence Centers such as University Libraries have been paramount in this process by facilitating a range of activities, such as awareness campaigns, trainings, or systematic support. However, in practice, using the FAIR assessment tools is still an intricate process for the average researcher. It requires a steep learning curve since it involves performing a series of manual processes requiring specific knowledge when learning the frameworks, disengaging some some researchers in the process.We aim to use technology to close this gap and make this process more accessible by bringing the FAIR assessment to the researcher's profiles. We will develop "The FAIR extension", an open-source, user-friendly web browser extension that allows researchers to make FAIR assessment directly at the web source. Web browser extensions have been an accessible digital tool for libraries supporting scholarship (De Sarkar 2015). A remarkable example is the lightweight version of reference managers deployed as a browser service (Ferguson 2019). Moreover, it has been demonstrated that they can be a vehicle for open access, such as Lean Library Browser Extension.The FAIR extension is a service that builds on top of the community-accepted FAIR evaluator APIs, i.e. it does not intend to create yet another FAIR assessment framework from scratch. The objective of the FAIR Digital Objects Framework (FDOF) is for objects published in a digital environment to comply with a set of requirements, such as identifiability, and the use of a rich metadata record (Santos 2021, Schultes and Wittenburg 2019). The FAIR extension will connect via REST-like operations to individual FAIR metrics test endpoints, according to Wilkinson et al. (2018), Wilkinson et al. (2019) and ultimately display the FAIR metrics on the client side (Fig. 1). Ultimately, the user will get FAIR scores of articles, datasets and other DOs in real-time on a web source, such as a scholarly platform or DO repository. With the possibility of creating simple reports of the assessment.It is acknowledged that the development of web-based tools carries some constraints regarding platform versions releases, e.g. Chromium Development Calendar. Nevertheless, we are optimistic about the potential use cases. For example,A student wanting to make use of a DO (e.g. software package), but doesn't know which to choose. The FAIR extension will indicate which one is more FAIR and aid the decision making processA Data steward recommending sourcesA researcher who wants to display all FAIR metrics of her DOs on a research profileA PI that wants to evaluate an aggregated metric for a project.These use cases can be the means to bringing the open source community and FAIR DO interest groups to work together.

The objective of the FAIR Digital Objects Framework (FDOF) is for objects published in a digital environment to comply with a set of requirements, such as identifiability, and the use of a rich metadata record (Santos 2021, Schultes and Wittenburg 2019, Schwardmann 2020). With the increasing prevalence of the FAIR (Findable, Accessible, Interoperable, Reusable) principles, and FAIR Digital Objects (FDO), used within different communities and domains (Wise et al. 2019), there will be a need to evaluate whether a FDO meets the requirements of the ecosystem in which it is used.Without a dedicated framework, communities will develop isolated assessment systems from the ground up (Sun et al. 2022, Bahim et al. 2020), which will cost them time, and lead to FAIRness assessments with limited interoperability and comparability.Previous work from the FAIR Metrics working group defined a framework for deploying individual FAIR metrics tests as separate services endpoints (Wilkinson et al. 2018, Wilkinson et al. 2019). To work in accordance with this framework, each test should take a subject URL as input, and return a score, either 0 or 1, a test version, and the test execution logs. A central service can then be used to assess the FAIRness of digital objects using collections of individual assessments. Such a framework could be easily extended, but there are currently no guidelines or tools to implement and publish new FAIRness assessments complying with this framework.To amend this problem, we published the fair-test library in python and its documentation, which help with developing and deploying individual FAIRness assessments. With this library, developers define their metric tests using custom python objects, which will guide them to provide all required metadata for their test as attributes, and implement the test evaluation logic as a function. The library also provides additional helper functions for common tasks, such as retrieving metadata from a URL, or testing a metric test.These tests can then be deployed as a web API, and registered in a central FAIR evaluation service supporting the FAIR metrics working group framework, such as FAIR enough or the FAIR evaluator. Finally, users of the evaluation services will be able to group the registered metrics tests in collections used to assess the quality of publicly available digital objects.There are currently as many as 47 tests that have been defined to assess compliance with various FAIR metrics, from which 25 have been defined using the fair-test library, including assessing if the identifier used is persistent, or if the metadata record attached to a digital object complies with a specific schema. This presentation introduces a user-friendly and extensible tool, which can assess whether specific requirements are met for a digital resource. Our contributions are: Developing and publishing the fair-test library to make the development and deployment of independent FAIRness assessment tests easier.Developing and publishing tests in python for existing FAIR metrics: 23 generic tests covering most of the FAIR metrics, and 2 domain-specific tests for the Rare Disease research community.We aim to engage with the FDO community to explore potential use-cases for an extensible tool to evaluate FDOs, and discuss their expectations related to the evaluation of digital objects.Insights and guidelines from the FDO community would contribute to further improving the fair-test ecosystem. Among improvements that are currently being under consideration, we can cite improving the collaborative aspect of metadata extraction, or adding new metadata to be returned by the tests.

Providing a robotic-assisted service in scenarios involving multiple Unmanned Vehicles (UVs) in possible beyond-visual-Line-Of-Sight (LoS) operations, safety and security are critical concerns. We develop a web-oriented, human-in-the-loop infrastructure to explore how the service provider can secure their system, enforce instant access control over dynamic operator-robot connections, and ensure the integrity, availability, and traceability of communicated data. Our proposed minimal viable solution requires an authentication server to verify user identity, a back server with a database to handle user requests and state-transition events, and a RabbitMQ (RMQ) server to trace the origin of data.

Reducing friction with specialised hull coatings or air lubrication technologies has a potential reducing energy consumption and emissions in shipping. The EU project AIRCOAT combines both by developing a passive air lubrication technology inspired by nature that is implemented on a self-adhesive foil system. Besides validating the friction reduction it is of high interest to understand the underlying mechanism that causes the reduction. Therefore, a flow channel was designed, that creates a stationary turbulent flow within a square duct allowing for non-invasive measurements by laser doppler velocimetry. The high spatial resolution of the laser device makes recording velocity profiles within the boundary layer down to the viscous sublayer possible. Determination of the wall shear stress τ enables direct comparison of different friction reduction experiments. In this paper we validate the methodology by determining the velocity profile of the flat channel wall (without coatings). We further use the results to validate a CFD model in created in OpenFOAM. We find that velocities along the longitudinal axis are generally in good agreement between numerical and experimental investigations.

Abstract While the higher prevalence of Alzheimer’s disease (AD) in women is clear, studies suggest that biological sex may also influence AD pathogenesis. However, mechanisms behind these differences are not clear. To investigate physiological differences between sexes at the cellular level in the brain, we investigated the intrinsic and synaptic properties of entorhinal cortex neurons in heterozygous 3xTg-AD mice of both sexes at the age of 20 months. This brain region was selected because of its early association with AD symptoms. First, we found physiological differences between male and female non-transgenic mice, providing indirect evidence of axonal alterations in old females. Second, we observed a transgene-dependent elevation of the firing activity, post-burst afterhyperpolarization (AHP), and spontaneous excitatory postsynaptic current (EPSC) activity, without any effect of sex. Third, the passive properties and the hyperpolarization-activated current (Ih) were altered by transgene expression only in female mice, whereas the paired-pulse ratio (PPR) of evoked EPSC was changed only in males. Fourth, both sex and transgene expression were associated with changes in action potential properties. Consistent with previous work, higher levels of Aβ neuropathology were detected in 3xTg-AD females, whereas tau deposition was similar. In summary, our results support the idea that aging and AD neuropathology differentially alter the physiology of entorhinal cortex neurons in males and females.

While the publication of Linked Data has become increasingly common, the process tends to be a relatively complicated and heavy-weight one. Linked Data is typically published by centralized entities in the form of larger dataset releases, which has the downside that there is a central bottleneck in the form of the organization or individual responsible for the releases. Moreover, certain kinds of data entries, in particular those with subjective or original content, currently do not fit into any existing dataset and are therefore more difficult to publish. To address these problems, we present here an approach to use nanopublications and a decentralized network of services to allow users to directly publish small Linked Data statements through a simple and user-friendly interface, called Nanobench, powered by semantic templates that are themselves published as nanopublications. The published nanopublications are cryptographically verifiable and can be queried through a redundant and decentralized network of services, based on the grlc API generator and a new quad extension of Triple Pattern Fragments. We show here that these two kinds of services are complementary and together allow us to query nanopublications in a reliable and efficient manner. We also show that Nanobench makes it indeed very easy for users to publish Linked Data statements, even for those who have no prior experience in Linked Data publishing.

Abstract Background Despite a wide adoption of English in science, a significant amount of biomedical data are produced in other languages, such as French. Yet a majority of natural language processing or semantic tools as well as domain terminologies or ontologies are only available in English, and cannot be readily applied to other languages, due to fundamental linguistic differences. However, semantic resources are required to design semantic indexes and transform biomedical (text)data into knowledge for better information mining and retrieval. Results We present the SIFR Annotator (http://bioportal.lirmm.fr/annotator), a publicly accessible ontology-based annotation web service to process biomedical text data in French. The service, developed during the Semantic Indexing of French Biomedical Data Resources (2013–2019) project is included in the SIFR BioPortal, an open platform to host French biomedical ontologies and terminologies based on the technology developed by the US National Center for Biomedical Ontology. The portal facilitates use and fostering of ontologies by offering a set of services –search, mappings, metadata, versioning, visualization, recommendation– including for annotation purposes. We introduce the adaptations and improvements made in applying the technology to French as well as a number of language independent additional features –implemented by means of a proxy architecture– in particular annotation scoring and clinical context detection. We evaluate the performance of the SIFR Annotator on different biomedical data, using available French corpora –Quaero (titles from French MEDLINE abstracts and EMEA drug labels) and CépiDC (ICD-10 coding of death certificates)– and discuss our results with respect to the CLEF eHealth information extraction tasks. Conclusions We show the web service performs comparably to other knowledge-based annotation approaches in recognizing entities in biomedical text and reach state-of-the-art levels in clinical context detection (negation, experiencer, temporality). Additionally, the SIFR Annotator is the first openly web accessible tool to annotate and contextualize French biomedical text with ontology concepts leveraging a dictionary currently made of 28 terminologies and ontologies and 333 K concepts. The code is openly available, and we also provide a Docker packaging for easy local deployment to process sensitive (e.g., clinical) data in-house (https://github.com/sifrproject).

Root hairs are involved in water and nutrient uptake, and thereby in plant autotrophy. In legumes, they also play a crucial role in establishment of rhizobial symbiosis. To obtain a holistic view of Medicago truncatula genes expressed in root hairs and of their regulation during the first hours of the engagement in rhizobial symbiotic interaction, a high throughput RNA sequencing on isolated root hairs from roots challenged or not with lipochitooligosaccharides Nod factors (NF) for 4 h or 20 h was carried out. This provided a repertoire of genes displaying expression in root hairs, responding or not to NF and specific or not to legumes. In analyzing the transcriptome dataset, special attention was paid to pumps, transporters or channels active at the plasma membrane, to other proteins likely to play a role in nutrient ion uptake, NF electrical and calcium signaling, control of the redox status or the dynamic reprogramming of root hair transcriptome induced by NF treatment, and to the identification of papilionoid legume-specific genes expressed in root hairs. About 10 percent of the root hair expressed genes were significantly up- or down-regulated by NF treatment, suggesting their involvement in remodeling plant functions to allow establishment of the symbiotic relationship. For instance, NF-induced changes in expression of genes encoding plasma membrane transport systems or disease response proteins indicate that root hairs reduce their involvement in nutrient ion absorption and adapt their immune system in order to engage in the symbiotic interaction. It also appears that the redox status of root hair cells is tuned in response to NF perception. In addition, 1,176 genes that could be considered as papilionoid legume-specific were identified in the M. truncatula root hair transcriptome, from which 141 were found to possess an orthologue in every of the 6 legume genomes that we considered, suggesting their involvement in essential functions specific to legumes. This transcriptome provides a valuable resource to investigate root hair biology in legumes and the roles that these cells play in rhizobial symbiosis establishment. These results could also contribute to the long-term objective of transferring this symbiotic capacity to non-legume plants.

We aimed to develop an animal model of long-term blood pressure variability (BPV) and to investigate its consequences on aortic damage. We hypothesized that day-to-day BPV produced by discontinuous treatment of spontaneously hypertensive rats (SHR) by valsartan may increase arterial stiffness. For that purpose, rats were discontinuously treated, 2 days a week, or continuously treated by valsartan (30 mg/kg/d in chow) or placebo. Telemetered BP was recorded during 2 minutes every 15 min, 3 days a week during 8 weeks to cover the full BP variations in response to the treatment schedule. Pulse wave velocity (PWV) and aortic structure evaluated by immunohistochemistry were investigated in a second set of rats treated under the same conditions. Continuous treatment with valsartan reduced systolic BP (SBP) and reversed the aortic structural alterations observed in placebo treated SHR (decrease of medial cross-sectional area). Discontinuous treatment with valsartan decreased SBP to a similar extent but increased the day-to-day blood pressure variability, short term BPV, diastolic blood pressure (DBP) and PWV as compared with continuous treatment. Despite no modifications in the elastin/collagen ratio and aortic thickness, an increase in PWV was observed following discontinuous treatment and was associated with a specific accumulation of fibronectin and its av-integrin receptor compared with both groups of rats. Taken together the present results indicate that a discontinuous treatment with valsartan is able to induce a significant increase in day-to-day blood pressure variability coupled to an aortic phenotype close to that observed in hypertension. This experimental model should pave the way for future experimental and clinical studies aimed at assessing how long-term BPV increases aortic stiffness.

We have recently identified a neuroprotective role for omega-3 polyunsaturated fatty acids (n-3 PUFAs) in a toxin-induced mouse model of Parkinson's disease (PD). Combined with epidemiological data, these observations suggest that low n-3 PUFA intake is a modifiable environmental risk factor for PD. In order to strengthen these preclinical findings as prerequisite to clinical trials, we further investigated the neuroprotective role of n-3 PUFAs in Fat-1 mice, a transgenic model expressing an n-3 fatty acid desaturase converting n-6 PUFAs into n-3 PUFAs. Here, we report that the expression of the fat-1 transgene increased cortical n-3:n-6 PUFA ratio (+28%), but to a lesser extent than dietary supplementation (92%). Such a limited endogenous production of n-3 PUFAs in the Fat-1 mouse was insufficient to confer neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity as assessed by dopamine levels, tyrosine hydroxylase (TH)-positive neurons and fibers, as well as nigral Nurr1 and dopamine transporter (DAT) mRNA expression. Nevertheless, higher cortical docosahexaenoic acid (DHA) concentrations were positively correlated with markers of nigral dopaminergic neurons such as the number of TH-positive cells, in addition to Nurr1 and DAT mRNA levels. These associations are consistent with the protective role of DHA in a mouse model of PD. Taken together, these data suggest that dietary intake of a preformed DHA supplement is more effective in reaching the brain and achieving neuroprotection in an animal model of PD.

We sought to characterize the relationship between integrity of the white matter underlying the ventral anterior cingulate (vAC) and depressive symptoms in older adults with atherosclerotic vascular disease (AVD), a condition associated with preferential degeneration of the white matter. The ventral anterior cingulate was defined as including white matter underlying ventral Brodmann Area 24 and Brodmann Area 25, corresponding with the subcallosal and subgenual cingulate respectively. This region of interest was chosen based on the preponderance of evidence that the white matter in the region plays a critical role in the manifestation of depressive symptoms. Participants had current unequivocal diagnoses of AVD and were between 55 and 90 years old. Fractional anisotropy (FA) was used as an index of white matter integrity and organization. Whole-brain mean diffusivity (MD) was used as an index of global white matter lesion burden. Depressive symptoms were measured using the Symptom Checklist-90-Revised (SCL-90-R) Depression Scale. Depressive symptoms were significantly related to low FA in the right vAC (r=-.356, DF=30, p=.045) but not the left vAC (r=.024, DF=30, p=.896) after controlling for total brain MD (a statistical control for global white matter lesion burden). Further, depressive symptoms were significantly related to low FA in the right vAC (r=-0.361, DF=31, p=.039), but not the left vAC (r=.259, DF=31, p=.145) when controlled for the contralateral vAC FA. The correlation coefficients for this follow-up analysis were found to be significantly different between left and right vAC (Z=2.310, p=.021).Poor white matter health in the vAC may be a biological mechanism for depressive symptoms in older adults with vascular disease. Further studies may corroborate that the right vAC plays a unique role in depressive symptom manifestation in cases where the white matter is preferentially affected, as is the case in AVD. This could lead to future targeting of

Nonequilibrium irreversible thermodynamics constitute a meaningful point of view suitable to explore life with a rich paradigm. This analytical framework can be used to span the gap from molecular processes to plant function and shows great promise to create a holistic description of life. Since living organisms dissipate energy, exchange entropy and matter with their environment, they can be assimilated to dissipative structures. This concept inherited from nonequilibrium thermodynamics has four properties which defines a scale independent framework suitable to provide a simpler and more comprehensive view of the highly complex plant biology. According to this approach, a biological process is modeled as an avalanche of dissipative structures. Each dissipative structure, corresponds to an unitary biological process, which is initiated by the amplification of a fluctuation. Evolution of the process leads to the breakage of the system symmetry and to the export of entropy. Exporting entropy to the surrounding environment corresponds to collecting information about it. Biological actors which break the symmetry of the system and which store information are by consequence, key actors on which experiments and data analysis focus most. This paper aims at illustrating properties of dissipative structure through familiar examples and thus initiating the dialogue between nonequilibrium thermodynamics and plant biology.

During the last decades, many studies reported that male reproductive disorders are increasing among humans. It is currently acknowledged that these abnormalities can result from fetal exposure to environmental chemicals that are progressively becoming more concentrated and widespread in our environment. Among the chemicals present in the environment (air, water, food and many consumer products), several can act as endocrine disrupting compounds (EDCs), thus interfering with the endocrine system. Phthalates, bisphenol A (BPA) and diethylstilbestrol (DES) have been largely incriminated, particularly during the fetal and neonatal period, due to their estrogenic and/or anti-androgenic properties. Indeed, many epidemiological and experimental studies have highlighted their deleterious impact on fetal and neonatal testis development. As EDCs can affect many different genomic and non-genomic pathways, the mechanisms underlying the adverse effects of EDC exposure are difficult to elucidate. Using literature data and results from our laboratory, in the present review we discuss the role of classical nuclear receptors (genomic pathway) in the fetal and neonatal testis response to EDC exposure, particularly to phthalates, BPA and DES. Among the nuclear receptors we focused on some of the most likely candidates, such as peroxisome-proliferator activated receptor (PPAR), androgen receptor (AR), estrogen receptors (ERα and β), liver X receptors (LXR) and small heterodimer partner (SHP). First, we describe the expression and potential functions (based on data from studies using receptor agonists and mouse knockout models) of these nuclear receptors in the developing testis. Then, for each EDC studied, we summarize the main evidences indicating that the reprotoxic effect of each EDC under study is mediated through a specific nuclear receptor(s). We also point-out the involvement of other receptors and nuclear receptor-independent pathways.

With the recent interest on the theranostic approach, there has been a renewed interest for alternative radionuclides in nuclear medicine. They can be produced using common production routes i.e. using protons accelerated by biomedical cyclotrons or neutrons produced in research reactors. However, in some cases, it can be more valuable to use deuterons as projectiles. In the case of Cu-64, smaller quantities of the expensive target material, Ni-64, are used with deuterons as compared with protons for the same produced activity. For the Sc-44m/Sc-44g generator, deuterons afford a higher Sc-44m production yield than with protons. Finally, in the case of Re-186g, deuterons lead to a production yield five times higher than protons. These three examples show that it is of interest to consider not only protons or neutrons but also deuterons to produce alternative radionuclides.

Study Objectives: Sleep disturbances are common in military personnel and are associated with increased risk for psychiatric morbidity, including posttraumatic stress disorder and depression, as well as inflammation. Improved sleep quality is linked to reductions in inflammatory bio-markers; however, the underlying mechanisms remain elusive. Methods: In this study we examine whole genome expression changes related to improved sleep in 68 military personnel diagnosed with insomnia. Subjects were classified into the following groups and then compared: improved sleep (n=46), or non-improved sleep (n=22) following three months of standard of care treatment for insomnia. Within subject differential expression was determined from microarray data using the Partek Genomics Suite analysis program and the interactive pathway analysis was used to determine key regulators of observed expression changes. Changes in symptoms of depression and posttraumatic stress disorder were also compared. Results: At baseline both groups were similar in demographics, clinical characteristics, and gene-expression profiles. The microarray data revealed that 217 coding genes were differentially expressed at the follow-up-period compared to baseline in the participants with improved sleep. Expression of inflammatory cytokines were reduced including IL-1β, IL-6, IL-8 and IL-13, with fold changes ranging from -3.19 to -2.1, and there were increases in the expression of inflammatory regulatory genes including toll-like receptors 1, 4, 7, and 8 in the improved sleep group. Interactive pathway analysis revealed 6 gene networks, including ubiquitin which was a major regulator in these gene-expression changes. The improved sleep group also had a significant reduction in the severity of depressive symptoms.Conclusions: Interventions that restore sleep likely reduce the expression of inflammatory genes, which relate to ubiquitin genes and relate to reductions in depressive symptoms.

Six weather types (WTs) are computed across the Maritime Continent during austral summer (September--April) using cluster analysis of unfiltered, daily, low-level winds at 850 hPa, by a k-means algorithm. This approach is shown to provide a unified view of the interactions across scales, from island-scale diurnal circulations to large-scale interannual ones. The WTs are interpreted either as snapshots of the intraseasonal Madden-Julian Oscillation (MJO); or as seasonal features, such as the transition between boreal- and austral-summer monsoons; or as slow variations associated with the El Nio--Southern Oscillation (ENSO). Scaleinteractions are analyzed in terms of the different phenomena that modulate regional-scale wind speed and direction, or the diurnal-cycle strength of rainfall. Decomposing atmospheric anomalies, relative to the mean annual cycle, into interannual and sub-seasonal components yields similar WT structures on both of these time scales for most of the WTs (4 out of 6). This result suggests that slow (viz. ENSO) and fast (viz. MJO) oscillatory variations superimposed on the mean annual cycle modulate the occurrence rate of WTs, without modifying radically their mean patterns. The latter pattern invariance holds especially true forMJO-type, propagating variations, while the quasi-stationary, planetary-scale ENSO variations have more impact on WT structure.These findings are interpreted with the help of dynamical systems theory. Interannual modulation of WT frequency is strongest for the ``transitional WTs between the boreal- and austral-summer monsoons, as well as for the ``quiescent WT, for which low-level winds are reduced over the whole of monsoonal Indonesia. The WT that characterizes NW monsoon surges, and peaks during the austral-summer monsoon in January-February, does not appear to be strongly modulated at the interannual time scale.The diurnal cycle is shown to play an important role in determining the rainfall over islands.

Objective: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated.Methods: To investigate the mechanisms of persistent blast related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n=19) were compared to control participants without TBI (n=17). Controls were matched to cases on demographic factors including age, gender and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate; FDR

Studies in HIV-1-infected infants and HIV-1-exposed, uninfected infants link early cytomegalovirus (CMV) acquisition with growth delay and cognitive impairment. We investigated maternal valacyclovir to delay infant acquisition of CMV.Pregnant women with HIV-1, HSV-2 and CD4 count >250 cells/µl were randomized at 34 weeks gestation to 500 mg twice-daily valacyclovir or placebo for 12 months. Maternal CMV DNA was measured in plasma at 34 weeks gestation, in cervical secretions at 34 and 38 weeks gestation, and in breast milk at 7 postpartum timepoints; infant CMV DNA was measured in dried blood spots at 8 timepoints including birth.Among 148 women, 141 infants were compared in intent-to-treat analyses. Maternal and infant characteristics were similar between study arms. Infant CMV acquisition did not differ between study arms, with 46/70 infants (66%) in placebo arm and 47/71 infants (66%) in the valacyclovir arm acquiring CMV; median time to CMV detection did not differ. CMV DNA was detected in 92% of 542 breast milk specimens with no difference in CMV level between study arms. Change in cervical shedding of CMV DNA between baseline and 38 weeks was 0.40-log greater in the placebo arm than the valacyclovir arm (p = 0.05).In this cohort of HIV-1-seropositive mothers, two-thirds of infants acquired CMV by one year. Maternal valacyclovir had no effect on timing of infant CMV acquisition or breast milk CMV viral loads, although it modestly reduced cervical CMV shedding. Maternal prophylaxis to reduce infant CMV acquisition warrants further evaluation in trials with antiviral agents.ClinicalTrials.gov NCT00530777.

The current study involved conducting a pilot test of a culturally sensitive support group program developed to assist Iraqi women in the year following the birth of their baby (CSSG-B) in Perth, Western Australia. The aim of this study was to evaluate the social validity of the program. It was hypothesised that women involved in the program would find the program to be socially valid and culturally appropriate, and will also report lower levels of depressive symptomatology and higher levels of social support, following the group intervention. Participants were twelve Iraqi Arabic speaking women, who had a child less than 12 months of age. The program was based on Iraqi women's explanatory models (Kleinman, 1978; Di Ciano, Rooney, Wright, Hay, & Robinson, 2010) of the birth and motherhood experience. Social validity ratings were obtained during the implementation of the program in order to assess the level of acceptability of the intervention. A one-group pretest-posttest design was used to determine if depressive symptoms had decreased during the course of the intervention and social support had increased. Results indicated that Iraqi Arabic speaking women found the support group intervention acceptable and relevant and there was a significant decrease in scores on the Edinburgh Postnatal Depression scale from pretest to posttest. These results that the culturally sensitive group intervention was culturally acceptable and was associated with decreased levels of depressive symptomatology.

The Aussie Optimism: Positive Thinking Skills Program (AOPTP) is a school-based prevention program aimed at addressing anxious and depressive symptoms in children aged 9-10 years. Nine-hundred and ten students from 22 Australian primary schools situated in low socio-economic areas were randomly assigned to either an intervention or control group, and assessed at a 30-month follow up. Those in the intervention group received the AOPTP program, where the control group continued to receive the regular health education course. Students completed self-report measures regarding their levels of depression, anxiety, and attribution style. Parents also reported on their children’s externalising and internalising problems outside of school. There were no significant differences between groups in regard to anxiety or depression, as well as no significant differences in attributional styles. Parents reported significantly less hyperactive behaviours from children in the intervention group. This finding suggests that AOP-PTS has the capacity to treat externalising problems at a medium term effect. The decrease in the externalising problems provides evidence of a partial medium term intervention effect. Future studies should continue to evaluate the program at a long term follow up.

Pathway-based association methods have been proposed to be an effective approach in identifying disease genes, when single-marker association tests do not have sufficient power. The analysis of quantitative traits may be benefited from these approaches, by sampling from two extreme tails of the distribution. Here we tested a pathway association approach on a small genome-wide association study (GWAS) on 653 subjects with extremely high high-density lipoprotein cholesterol (HDL-C) levels and 784 subjects with low HDL-C levels. We identified 102 genes in the sterol transport and metabolism pathways that collectively associate with HDL-C levels, and replicated these association signals in an independent GWAS. Interestingly, the pathways include 18 genes implicated in previous GWAS on lipid traits, suggesting that genuine HDL-C genes are highly enriched in these pathways. Additionally, multiple biologically relevant loci in the pathways were not detected by previous GWAS, including genes implicated in previous candidate gene association studies (such as LEPR, APOA2, HDLBP, SOAT2), genes that cause Mendelian forms of lipid disorders (such as DHCR24), and genes expressing dyslipidemia phenotypes in knockout mice (such as SOAT1, PON1). Our study suggests that sampling from two extreme tails of a quantitative trait and examining genetic pathways may yield biological insights from smaller samples than are generally required using single-marker analysis in large-scale GWAS. Our results also implicates that functionally related genes work together to regulate complex quantitative traits, and that future large-scale studies may benefit from pathway-association approaches to identify novel pathways regulating HDL-C levels.

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system.

The current study examines COVID-19 prevention behaviors and vaccine intentions among 83 youth at high risk for HIV. Most youth self-identified as Latinx (52%), cisgender men (84%), and homosexual (66%). Youth self-reported COVID-19 prevention behaviors and intentions to vaccinate. Participants reported wearing face masks, washing hands, and staying six feet apart, but fewer reported leaving home only for essential needs. About one-third reported that they would not get a vaccine, and lack of trust in their doctors and the government were significantly associated with non-intention. To improve efforts towards herd immunity, interventions to improve health messaging from trusted sources for at-risk youth may be necessary to achieve higher vaccine uptake., Competing Interests: The authors have declared that no competing interests exist.

We juxtapose 386 prominent contrarians with 386 expert scientists by tracking their digital footprints across ∼200,000 research publications and ∼100,000 English-language digital and print media articles on climate change. Projecting these individuals across the same backdrop facilitates quantifying disparities in media visibility and scientific authority, and identifying organization patterns within their association networks. Here we show via direct comparison that contrarians are featured in 49% more media articles than scientists. Yet when comparing visibility in mainstream media sources only, we observe just a 1% excess visibility, which objectively demonstrates the crowding out of professional mainstream sources by the proliferation of new media sources, many of which contribute to the production and consumption of climate change disinformation at scale. These results demonstrate why climate scientists should increasingly exert their authority in scientific and public discourse, and why professional journalists and editors should adjust the disproportionate attention given to contrarians.

The porcine gastric mucin binding magnetic bead (PGM-MB) assay was used to evaluate the ability of chlorine, chlorine dioxide, peroxyacetic acid, hydrogen peroxide, and trisodium phosphate to inactivate human norovirus within 10% stool filtrate. One-minute free chlorine treatments at concentrations of 33 and 189 ppm reduced virus binding in the PGM-MB assay by 1.48 and 4.14 log₁₀, respectively, suggesting that chlorine is an efficient sanitizer for inactivation of human norovirus (HuNoV). Five minute treatments with 5% trisodium phosphate (pH~12) reduced HuNoV binding by 1.6 log₁₀, suggesting that TSP, or some other high pH buffer, could be used to treat food and food contact surfaces to reduce HuNoV. One minute treatments with 350 ppm chlorine dioxide dissolved in water did not reduce PGM-MB binding, suggesting that the sanitizer may not be suitable for HuNoV inactivation in liquid form. However a 60-min treatment with 350 ppm chlorine dioxide did reduce human norovirus by 2.8 log₁₀, indicating that chlorine dioxide had some, albeit limited, activity against HuNoV. Results also suggest that peroxyacetic acid has limited effectiveness against human norovirus, since 1-min treatments with up to 195 ppm reduced human norovirus binding by <1 log₁₀. Hydrogen peroxide (4%) treatment of up to 60 min resulted in minimal binding reduction (~0.1 log₁₀) suggesting that H₂O₂ is not a good liquid sanitizer for HuNoV. Overall this study suggests that HuNoV is remarkably resistant to several commonly used disinfectants and advocates for the use of chlorine (sodium hypochlorite) as a HuNoV disinfectant wherever possible., (Copyright © 2013. Published by Elsevier B.V.)

The South Pacific convergence zone (SPCZ) is the Southern Hemisphere's most expansive and persistent rain band, extending from the equatorial western Pacific Ocean southeastward towards French Polynesia. Owing to its strong rainfall gradient, a small displacement in the position of the SPCZ causes drastic changes to hydroclimatic conditions and the frequency of extreme weather events--such as droughts, floods and tropical cyclones--experienced by vulnerable island countries in the region. The SPCZ position varies from its climatological mean location with the El Niño/Southern Oscillation (ENSO), moving a few degrees northward during moderate El Niño events and southward during La Niña events. During strong El Niño events, however, the SPCZ undergoes an extreme swing--by up to ten degrees of latitude toward the Equator--and collapses to a more zonally oriented structure with commensurately severe weather impacts. Understanding changes in the characteristics of the SPCZ in a changing climate is therefore of broad scientific and socioeconomic interest. Here we present climate modelling evidence for a near doubling in the occurrences of zonal SPCZ events between the periods 1891-1990 and 1991-2090 in response to greenhouse warming, even in the absence of a consensus on how ENSO will change. We estimate the increase in zonal SPCZ events from an aggregation of the climate models in the Coupled Model Intercomparison Project phases 3 and 5 (CMIP3 and CMIP5) multi-model database that are able to simulate such events. The change is caused by a projected enhanced equatorial warming in the Pacific and may lead to more frequent occurrences of extreme events across the Pacific island nations most affected by zonal SPCZ events.

Group and individual ability profiles of 89 English 4-year-olds on the McCarthy scales of children's abilities (MSCA) are presented. The results suggest that at this age, there is a high expectation of obtaining at least one significant difference between a child's mean ability score and the individual ability of index scores. The direction of these significant differences in ability suggested that, in this age group, abilities measured by the MSCA verbal and perceptual performance indexes tend to be more advanced than abilities measured by the quantitative and memory indexes. Motor development is relatively retarded compared to these other abilities. (The results are at variance with the often accepted concept of a "flat' ability profile in normal children). The use of the MSCA on English children could result in over referral of normal children, especially boys, who appear delayed on the motor index, and under referral of children who were regarded as normal on the verbal and perceptual indexes.