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Objective: Axonal excitability reflects ion channel function, and it is proposed that this may be a biomarker in painful (vs painless) polyneuropathy. Our objective was to investigate the relationship between axonal excitability parameters and chronic neuropathic pain in deeply phenotyped cohorts with diabetic or chemotherapy-induced distal symmetrical polyneuropathy. Methods: Two hundred thirty-nine participants with diabetic polyneuropathy were recruited from sites in the UK and Denmark, and 39 participants who developed chemotherapy-induced polyneuropathy were recruited from Denmark. Participants were separated into those with probable or definite neuropathic pain and those without neuropathic pain. Axonal excitability of large myelinated fibers was measured with the threshold tracking technique. The stimulus site was the median nerve, and the recording sites were the index finger (sensory studies) and abductor pollicis brevis muscle (motor studies). Results: Participants with painless and painful polyneuropathy were well matched across clinical variables. Sensory and motor axonal excitability measures, including recovery cycle, threshold electrotonus, strength–duration time constant, and current–threshold relationship, did not show differences between participants with painful and painless diabetic polyneuropathy, and there were only minor changes for chemotherapy-induced polyneuropathy. Interpretation: Axonal excitability did not significantly differ between painful and painless diabetic or chemotherapy-induced polyneuropathy in a multicenter observational study. Threshold tracking assesses the excitability of myelinated axons; the majority of nociceptors are unmyelinated, and although there is some overlap of the "channelome" between these axonal populations, our results suggest that alternative measures such as microneurography are required to understand the relationship between sensory neuron excitability and neuropathic pain. ANN NEUROL 2022;91:506–520.

OBJECTIVE: It is estimated that childhood ADHD remits by adulthood in approximately 50% of cases; however, this conclusion is typically based on single endpoints, failing to consider longitudinal patterns of ADHD expression. We investigated the extent to which children with ADHD experience recovery and variable patterns of remission by adulthood. METHOD: Children with ADHD (N=558) in the Multimodal Treatment Study of ADHD (MTA) were administered eight assessments from 2-year (M age=10.44) to 16-year follow-up (M age=25.12). We identified participants with fully remitted, partially remitted, and persistent ADHD at each timepoint based on parent, teacher, and self-reports of ADHD symptoms and impairment, treatment utilization, and substance use and mental disorders. Longitudinal patterns of remission and persistence were identified that considered context and timing. RESULTS: Approximately 30% of children with ADHD experienced full remission at some point during the 14-year follow-up period; however, a majority (60% of these) experienced recurrence of ADHD after the initial period of remission. Only 9.1% of the sample demonstrated recovery (sustained remission) by study endpoint and only 10.8% demonstrated stable ADHD persistence across study timepoints. Instead, most participants with ADHD (63.8%) had fluctuating periods of remission and recurrence over time. CONCLUSIONS: The MTA findings challenge the notion that approximately 50% of children with ADHD outgrow the disorder by adulthood. Most cases demonstrated fluctuating symptoms between childhood and young adulthood. Although intermittent periods of remission can be expected in most cases, 90% of children with ADHD continued to struggle with residual ADHD through young adulthood. Clinical Trial Number: NCT00000388, Multimodal Treatment Study of Children with Attention Deficit and Hyperactivity Disorder (MTA). https://clinicaltrials.gov/ct2/show/NCT00000388

Here, we describe molecular engineering of monovalent ultra-long acting two-chain insulin-Fc conjugates. Insulin-Fc conjugates were synthesized using trifunctional linkers with one amino reactive group for reaction with a lysine residue of insulin and two thiol reactive groups used for re-bridging of a disulfide bond within the Fc molecule. The ultra-long pharmacokinetic profile of the insulin-Fc conjugates was the result of concertedly slowing insulin receptor-mediated clearance by (1) introduction of amino acid substitutions that lowered the insulin receptor affinity and (2) conjugating insulin to the Fc element. Fc conjugation leads to recycling by the neonatal Fc receptor and increase in the molecular size, both contributing to the ultra-long pharmacokinetic and pharmacodynamic profiles.

Background Mycoplasma genitalium (MG) infection is challenging to cure because of rising antimicrobial resistance and limited treatment options. Methods This was a prospective evaluation of the efficacy and tolerability of resistance-guided combination antimicrobial therapy for MG treatment at Melbourne Sexual Health Centre (August 2019–December 2020). All patients received 7 days of doxycycline before combination therapy based on the macrolide-resistant profile. Macrolide-susceptible infections received combination doxycycline + azithromycin (1 g, day 1; 500 mg, days 2–4) and macrolide-resistant infections combination doxycycline + moxifloxacin (400 mg daily for 7 days). Adherence and adverse effects were recorded at test-of-cure, recommended 14–28 days after antimicrobial completion. Sequencing was performed to determine the prevalence of single nucleotide polymorphisms (SNPs) in the parC gene and their association with moxifloxacin treatment outcomes in macrolide-resistant infections. Results Of 100 patients with macrolide-susceptible MG treated with doxycycline + azithromycin, 93 were cured (93.0%; 95% confidence interval [CI], 86.1–97.1). Of 247 patients with macrolide-resistant MG receiving doxycycline + moxifloxacin, 210 were cured (85.0%; 95% CI, 80.0–89.2). parC sequencing was available for 164 (66%) macrolide-resistant infections; 29% had SNPs at parC S83 or D87 (23% S83I). The absence of SNPs at parC S83/D87 was associated with 98.3% cure (95% CI, 93.9–99.8) following doxycycline + moxifloxacin. The presence of the parC S83I-SNP was associated with failure in 62.5% (95% CI, 45.8–77.3). Side effects were common (40%–46%) and predominantly mild and gastrointestinal. Conclusions Combination doxycycline + azithromycin achieved high cure for macrolide-susceptible infections. However, in the context of a high prevalence of the parC S83I mutation (23%) in macrolide-resistant infections, doxycycline + moxifloxacin cured only 85%. Infections that were wild-type for S83/D87 experienced high cure following doxycycline + moxifloxacin, supporting the use of a parC-resistance/susceptibility testing strategy in clinical care.

In Spatial crowdsourcing, mobile users perform spatio-temporal tasks that involve travel to specified locations. Spatial crowdsourcing (SC) is enabled by SC platforms that support mobile worker recruitment and retention, as well as task assignment, which is essential to maximize profits that are accrued from serving task requests. Specifically, how to best achieve task assignment in a cost-effective manner while contending with spatio-temporal constraints is a key challenge in SC. To address this challenge, we formalize and study a novel Profit-driven Task Assignment problem. We first establish a task reward pricing model that takes into account the temporal constraints (i.e., expected completion time and deadline) of tasks. Then we adopt an optimal algorithm based on tree decomposition to achieve an optimal task assignment and propose greedy algorithms based on Random Tuning Optimization to improve the computational efficiency. To balance effectiveness and efficiency, we also provide a heuristic task assignment algorithm based on Ant Colony Optimization that assigns tasks by simulating behavior of ant colonies foraging for food. Finally, we conduct extensive experiments using real and synthetic data, offering detailed insight into effectiveness and efficiency of the proposed methods.

Background: The demand for estimates of biological nitrogen (N) fixation inputs in agricultural systems is driven by the need to effectively manage the global N cycle. Scope: We present a methodology for quantifying N2 fixation by the grain legume-rhizobia symbioses that can be used for any year or sequence of years for which area and production statistics for legume oilseed and pulse crops were available and at country-to-global scales. The coefficients used in the templates – harvest index, N harvest index, %N shoots, %N grain and a factor to account for below-ground N – were aggregated from 224 reports containing > 4,000 observations. Values for the % total crop N derived from atmospheric N2 (%Ndfa) for specific grain legumes and regions were determined in a companion paper. The grain legumes were estimated to fix a global total of 35.5 Tg N in the year 2018 - 25.0 Tg for soybean (Glycine max), 7.2 Tg for the pulses and 3.3 Tg for groundnut (Arachis hypogaea). Soybean dominated global grain legume N2 fixation, with 38 % of total N fixed associated with soybean in South and Central America and a further 22 % by soybean in North America. Conclusions: The updated estimates of N2 fixation by the grain legumes inform us of a substantial and increasing role that biological N2 fixation plays in global agricultural systems. The challenge remains to reliably estimate N inputs from other N2-fixing organisms that are active in these systems.

Telomerase reverse transcriptase (TERT) is expressed by quiescent adult stem cells (ASC) in numerous adult murine and human tissues, but has never been explored in the adult brain. Here, we demonstrate that TERT+ cells in the adult mouse brain represent a novel population of multipotent ASCs that are localized to numerous classical neuro/gliogenic niches (including the ventricular-subventricular zone, hypothalamus, and olfactory bulb), as well as more recently described regions of adult brain plasticity such as the meninges and choroid plexus. Using a direct-reporter mouse line, we found that TERT+ cells expressed known neural stem cell markers such as Nestin and Sox2, but not markers of committed stem/progenitor cells, nor markers of mature neuronal or glial cells. TERT+ ASCs rarely expressed the proliferation marker Ki67, andin vitroTERT+ cells lost TERT expression when activated by growth factors, together indicating a quiescent phenotype similar to what has been observed in other tissues. When cultured, TERT+ cells behaved like neural stem cells by forming neurospheres, which could proliferate and become more metabolically active once stimulated by growth factors. TERT+ cells were observed in numerous brain niches, particularly near the ventricles and cerebrospinal fluid barriers, but notably, TERT+ cells were never observed in the hippocampus. Lineage tracing of TERT+ cells in adult transgenic mice (mTERTrtTA::oTET-Cre::RosamTmG) revealed large-scale expansion of TERT+ progeny and differentiation to diverse cell types in multiple brain regions. For example, lineage-traced cells expressed markers of mature neurons, oligodendrocytes, astrocytes, ependymal cells, and choroid epithelial cells, thus demonstrating the striking multipotency of this stem cell population in basal tissue turnover of the adult brain. Together, these data demonstrate that TERT+ cells represent a novel population of multipotent stem cells that contribute to basal plasticity and regeneration in the adult mouse brain.Graphical Abstract

SummaryA key phenomenon in cancer is the establishment of a highly immunosuppressive tumor microenvironment (TME). Despite advances in immunotherapy, where the purpose is to induce tumor recognition and hence hereof tumor eradication, the majority of patients applicable for such treatment still fail to respond. It has been suggested that high immunological activity in the tumor is essential for achieving effective response to immunotherapy, which therefore have led to exploration of strategies that triggers inflammatory pathways. Here activation of the stimulator of interferon genes (STING) signaling pathway has been considered an attractive target, as it is a potent trigger of pro-inflammatory cytokines and type I and III interferons. However, immunotherapy combined with targeted STING agonists has not yielded sustained clinical remission in humans. This suggest a need for exploring novel adjuvants to improve the innate immunological efficacy. Here, we demonstrate that extracellular vesicles (EVs), derived from activated CD4+T cells (T-EVs), sensitizes macrophages to elevate STING activation, mediated by IFNγ carried on the T-EVs. Our work support that T-EVs can disrupt the immune suppressive environment in the tumor by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.

The world has seen numerous infectious disease outbreaks in the past decade. In many cases these outbreaks have had considerable perinatal health consequences including increased risk of preterm delivery (e.g., influenza, measles, and COVID-19), and the delivery of low birth weight or small for gestational age babies (e.g., influenza, COVID-19). Furthermore, severe perinatal outcomes including perinatal and infant death are a known consequence of multiple infectious diseases (e.g., Ebola virus disease, Zika virus disease, pertussis, and measles). In addition to vaccination during pregnancy (where possible), pregnant women, are provided some level of protection from the adverse effects of infection through community-level application of evidence-based transmission-control methods. This review demonstrates that it takes almost 2 years for the perinatal impacts of an infectious disease outbreak to be reported. However, many infectious disease outbreaks between 2010 and 2020 have no associated pregnancy data reported in the scientific literature, or pregnancy data is reported in the form of case-studies only. This lack of systematic data collection and reporting has a negative impact on our understanding of these diseases and the implications they may have for pregnant women and their unborn infants. Monitoring perinatal health is an essential aspect of national and global healthcare strategies as perinatal life has a critical impact on early life mortality as well as possible effects on later life health. The unpredictable nature of emerging infections and the potential for adverse perinatal outcomes necessitate that we thoroughly assess pregnancy and perinatal health implications of disease outbreaks and their public health interventions in tandem with outbreak response efforts. Disease surveillance programs should incorporate perinatal health monitoring and health systems around the world should endeavor to continuously collect perinatal health data in order to quickly update pregnancy care protocols as needed.

The purpose of this paper is to show that, by combining Feshbach resonances with external confining potentials, the energy scale factor of neighboring Efimov states can be tremendously reduced. The Efimov conditions can be reached for systems made of three different particles. For the case of two identical light particles and a heavy particle the energy factor can be reduced by many orders of magnitude, and the Efimov states are in this way more easily reachable experimentally. The equivalence between external potentials and the formulation in terms of non-integer dimensions, $d$, is exploited. The technically simpler $d$-method is used to derive analytic expressions for two-component relative wave functions describing two short-range square-well interacting particles. The two components express one open and one closed channel. The scattering length is obtained after phase shift expansion, providing an analytic form for the Efimov condition. We illustrate the results by means of systems made of $^7$Li, $^{39}$K, and $^{87}$Rb, with realistic parameters. The related pairs of dimension and magnetic field are shown and discussed. The results are universal as they only rely on large-distance properties., Comment: To be published in the European Physical Journal D

Contains fulltext : 291067.pdf (Publisher’s version ) (Open Access) BACKGROUND: Capsid virus-like particles (cVLP) have proven safe and immunogenic and can be a versatile platform to counter pandemics. We aimed to clinically test a modular cVLP COVID-19 vaccine in individuals who were naive to SARS-CoV-2. METHODS: In this phase 1, single-centre, dose-escalation, adjuvant-selection, open-label clinical trial, we recruited participants at the Radboud University Medical Center in Nijmegen, Netherlands, and sequentially assigned them to seven groups. Eligible participants were healthy, aged 18-55 years, and tested negative for SARS-CoV-2 and anti-SARS-CoV-2 antibodies. Participants were vaccinated intramuscularly on days 0 and 28 with 6 μg, 12 μg, 25 μg, 50 μg, or 70 μg of the cVLP-based COVID-19 vaccine (ABNCoV2). A subgroup received MF59-adjuvanted ABNCoV2. Follow-up was for 24 weeks after second vaccination. The primary objectives were to assess the safety and tolerability of ABNCoV2 and to identify a dose that optimises the tolerability-immunogenicity ratio 14 days after the first vaccination. The primary safety endpoint was the number of related grade 3 adverse events and serious adverse events in the intention-to-treat population. The primary immunogenicity endpoint was the concentration of ABNCoV2-specific antibodies. The trial is registered with ClinicalTrials.gov, NCT04839146. FINDINGS: 45 participants (six to nine per group) were enrolled between March 15 and July 15, 2021. Participants had a total of 249 at least possibly related solicited adverse events (185 grade 1, 63 grade 2, and one grade 3) within a week after vaccination. Two serious adverse events occurred; one was classified as a possible adverse reaction. Antibody titres were dose-dependent with levels plateauing at a vaccination dose of 25-70 μg ABNCoV2. After second vaccination, live virus neutralisation activity against major SARS-CoV-2 variants was high but was lower with an omicron (BA.1) variant. Vaccine-specific IFNγ(+) CD4(+) T cells were induced. INTERPRETATION: Immunisation with ABNCoV2 was well tolerated, safe, and resulted in a functional immune response. The data support the need for additional clinical development of ABNCoV2 as a second-generation SARS-CoV-2 vaccine. The modular cVLP platform will accelerate vaccine development, beyond SARS-CoV-2. FUNDING: EU, Carlsberg Foundation, and the Novo Nordisk Foundation.

MHD models and the observation of accretion streamers confirmed that protostars can undergo late accretion events after the initial collapse phase. To provide better constraints, we study the evolution of stellar masses in MHD simulations of a (4 pc)^3 molecular cloud. Tracer particles allow us to accurately follow the trajectory of accreting material for all protostars and thereby constrain the accretion reservoir of the stars. The diversity of the accretion process implies that stars in the solar mass regime can have vastly different accretion histories. Some stars accrete most of their mass during the initial collapse phase, while others gain >50 % of their final mass from late infall. The angular momentum budget of stars that experience substantial infall, so-called late accretors, is significantly higher than for stars without or with only little late accretion. As the probability of late infall increases with increasing final stellar mass, the specific angular momentum budget of higher mass stars is on average higher. The hypothetical centrifugal radius computed from the accreting particles at the time of formation is orders of magnitude higher than observed disk sizes, which emphasizes the importance of angular momentum transport during disk formation. Nevertheless, we find a correlation that the centrifugal radius is highest for stars with substantial infall, which suggests that very large disks are the result of recent infall events. There are also indications for a subtle trend of increasing centrifugal radius with increasing final stellar mass, which is in agreement with an observed marginal correlation of disk size and stellar mass. Finally, we show that late accretors become embedded again during infall. As a consequence, late accretors are (apparently) rejuvenated and would be classified as Class 0 objects according to their bolometric temperature despite being 1 Myr old., 18 pages, 7 figures, accepted invited paper for EpJ Plus Focus Point on Environmental and multiplicity effects on planet formation

With the continued digitization of societal processes, we are seeing an explosion in available data. This is referred to as big data. In a research setting, three aspects of the data are often viewed as the main sources of challenges when attempting to enable value creation from big data: volume, velocity, and variety. Many studies address volume or velocity, while fewer studies concern the variety. Metric spaces are ideal for addressing variety because they can accommodate any data as long as it can be equipped with a distance notion that satisfies the triangle inequality. To accelerate search in metric spaces, a collection of indexing techniques for metric data have been proposed. However, existing surveys offer limited coverage, and a comprehensive empirical study exists has yet to be reported. We offer a comprehensive survey of existing metric indexes that support exact similarity search: we summarize existing partitioning, pruning, and validation techniques used by metric indexes to support exact similarity search; we provide the time and space complexity analyses of index construction; and we offer an empirical comparison of their query processing performance. Empirical studies are important when evaluating metric indexing performance, because performance can depend highly on the effectiveness of available pruning and validation as well as on the data distribution, which means that complexity analyses often offer limited insights. This article aims at revealing strengths and weaknesses of different indexing techniques to offer guidance on selecting an appropriate indexing technique for a given setting, and to provide directions for future research on metric indexing.

Low serum levels of magnesium, phosphate, and zinc are observed in many intensive care unit (ICU) patients, but clinical equipoise exists regarding supplementation strategies. We aimed to assess the desirable and undesirable effects of supplementation with magnesium, phosphate, or zinc in adult ICU patients.We conducted a systematic review with meta-analysis of randomised clinical trials assessing the effects of supplementation with magnesium, phosphate, or zinc in adult ICU patients. Primary outcomes were mortality and duration of mechanical ventilation. We registered the protocol, followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, used the Cochrane risk of bias 2 tool, and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for assessing the certainty of the evidence.We identified no low risk of bias trials. For magnesium supplementation, we included three trials (n=235); the relative risk (RR) for mortality was 0.54, 95% confidence interval (CI) 0.30 to 0.96 compared to no supplementation (very low certainty of evidence). For zinc supplementation, two trials were included (n=168); the RR for mortality was 0.73, 95% CI 0.41 to 1.28 compared to control. No trials assessed the effects of phosphate supplementation on mortality. For outcomes other than mortality, only zero or one trial was available.In adult ICU patients, the certainty of evidence for the effects of supplementation with magnesium, phosphate, or zinc was very low. High quality trials are needed to assess the value of supplementation strategies in these patients. This article is protected by copyright. All rights reserved.