bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidences of hypothyroidism and autoimmune thyroiditis are increased in patients with nonalcoholic fatty liver disease
Authors: Loosen Sven H. , Demir Münevver , Kostev Karel , Luedde Tom , Roderburg Christoph
Published: April 2021

Background & aims

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease, with about one in four people being affected in most areas of the world. Due to its strong association with metabolic syndrome, NAFLD is associated with high morbidity and mortality. Recent data have suggested a pathophysiological association between NAFLD and thyroid disease, but most studies are explorative and results remained conflicting. Here, we aimed at evaluating a potential association between NAFLD and hypothyroidism as well as autoimmune thyroiditis primary care patients in Germany.

Methods

Incidence rates of hypothyroidism and autoimmune thyroiditis were compared between a cohort of n = 40,583 patients with NAFLD and a cohort of equal size without NAFLD that was matched by sex, age, index year, obesity and diabetes within 10 years from the index date.

Results

Within the 10 years observation period, incidence of hypothyroidism was significantly higher among patients with NAFLD compared to patients without NAFLD [hazard ratio: 1.53 (95% confidence interval, 1.43–1.64), P < 0.001]. Importantly, regression analysis revealed that the association was significant in both men and women patients as well as in patients from all age groups. Moreover, NAFLD patients showed a significantly higher incidence rate of autoimmune thyroiditis compared to patients without NAFLD [hazard ratio: 1.55 (95% confidence interval, 1.34–1.79), P < 0.001]. This association was most pronounced in patients >70 years.

Conclusion

Our study provides strong evidence for a significant association between NAFLD and hypothyroidism as well as autoimmune thyroiditis in a large population-based cohort in Germany. This finding should trigger a particular awareness of thyroid diseases in this increasingly important patient group.
The semirecumbent position for high-resolution esophageal manometry. Results of a feasibility study
Authors: Siboni Stefano , Riva Carlo G , Ferrari Davide , Capuzzo Matteo , Asti Emanuele , Bonavina Luigi
Published: April 2021

Objective

Normative values for high-resolution manometry (HRM) have been obtained with the patient lying supine. The aim of the study was to compare supine, semirecumbent and sitting positions during HRM in terms of variation in normative metrics, diagnostic yield, and patient’s comfort.

Methods

A prospective, single-center feasibility study was planned in consecutive patients referred to the esophageal function laboratory. In each of the three positions, 10 consecutive 5 ml water swallows and three 10 ml multiple rapid swallows were administered. Validated reflux questionnaires were administered prior to the test, and a visual analogue scale (VAS) assessing the patient’s comfort after the test.

Results

Twenty patients presenting with gastroesophageal reflux symptoms completed the study protocol. The intra-abdominal segment of the lower esophageal sphincter was significantly longer in the sitting position (P = 0.013), and the multiple rapid swallow distal contractile integral was lowest in the supine position (P = 0.012). The VAS comfort score did not significantly differ in the three body positions (P = 0.295). The concordance in the final diagnosis was 80% for semirecumbent vs. sitting (kappa = 0.15; P = 0.001), 70% for supine vs. sitting and 65.0% for semirecumbent vs. supine.

Conclusion

Compared to the supine position, both the semirecumbent and sitting position seems to provide similar advantages. HRM metrics and the final manometric diagnosis may be affected by body position, but complementary maneuvers, such are the rapid drink challenge, can resolve diagnostic discrepancies and improve the overall accuracy of the test.
Optimizing a decision support system for damage-control resuscitation using mixed methods human factors analysis
Authors: Schmulevich Daniela , Cacchione Pamela Z. , Holland Sara , Quinlan Kristin , Hinkle Alyson , Meador Chris , Abella Benjamin S. , Cannon Jeremy W.
Published: April 2021

BACKGROUND

Damage-control resuscitation (DCR) improves trauma survival; however, consistent adherence to DCR principles through multiple phases of care has proven challenging. Clinical decision support may improve adherence to DCR principles. In this study, we designed and evaluated a DCR decision support system using an iterative development and human factors testing approach.

METHODS

The phases of analysis included initial needs assessment and prototype design (Phase 0), testing in a multidimensional simulation (Phase 1), and testing during initial clinical use (Phase 2). Phase 1 and Phase 2 included hands-on use of the decision support system in the trauma bay, operating room, and intensive care unit. Participants included trauma surgeons, trauma fellows, anesthesia providers, and trauma bay and intensive care unit nurses who provided both qualitative and quantitative feedback on the initial prototype and all subsequent iterations.

RESULTS

In Phase 0, 14 (87.5%) of 16 participants noted that they would use the decisions support system in a clinical setting. Twenty-four trauma team members then participated in simulated resuscitations with decision support where 178 (78.1%) of 228 of tasks were passed and 27 (11.8%) were passed with difficulty. Twenty-three (95.8%) completed a postsimulation survey. Following iterative improvements in system design, Phase 2 evaluation included 21 trauma team members during multiple real-world trauma resuscitations. Of these, 15 (71.4%) completed a formal postresuscitation survey. Device-level feedback on a Likert scale (range, 0–4) confirmed overall ease of use (median score, 4; interquartile range, 4–4) and indicated the system integrated well into their workflow (median score, 3; interquartile range, 2–4). Final refinements were then completed in preparation for a pilot clinical study using the decision support system.

CONCLUSIONS

An iterative development and human factors testing approach resulted in a clinically useable DCR decision support system. Further analysis will determine its applicability in military and civilian trauma care.

LEVEL OF EVIDENCE

Therapeutic/Care Management, Level V.
Preparations of Dutch emergency departments for the COVID-19 pandemic: a questionnaire-based study
Authors: O’Connor Rory D , Barten Dennis G , Latten Gideon HP
Published: April 2021

Background

The onset of the COVID-19 pandemic was characterized by rapidly increasing patient volumes, which necessitated a swift emergency department (ED) overhaul. Challenges mainly concerned surge capacity, frontline staff protection and the segregation of patients with suspected COVID-19. To date, only few studies have assessed nation-wide ED preparedness for the COVID-19 pandemic. This study aimed to form an overview of preparations that were taken in Dutch EDs during the initial phase of this public health crisis.

Methods

This study was designed as a nation-wide, cross-sectional, questionnaire-based study among Dutch hospital organizations with ≥1 ED. The questionnaire was conducted between the first and the second wave of the COVID-19 pandemic in the Netherlands and contained close-ended and open-ended questions on changes in ED infrastructure, ED workforce adaptions and the role of emergency physicians (EPs) in the hospital’s crisis organization.

Results

Overall response rate was 79.5%. All EDs had made preparations in anticipation of a possible COVID-19 surge. Treatment capacity was expanded in 69.7% of EDs, with a median increase of 49% (IQR 32.5–72.7%). COVID-19 suspected patients were segregated from non-COVID-19 patients in 86.4% of EDs. Non-COVID-19 patients were more often assessed at alternative locations than patients with suspected COVID-19 infection. In 81.8% of EDs the workforce was expanded, which mainly concerned expansion of nursing staff. A formal role of EPs in the hospital’s crisis organization was reported by 93.9% of EP staffed hospital organizations.

Conclusion

All Dutch EDs made preparations for COVID-19 in a short time span and with many uncertainties. Preparations predominantly concerned expansion of treatment capacity and segregation of COVID-19 ED care. EPs had a prominent role, both in direct patient COVID-19 ED care and in the hospitals’ crisis organizations. Although it is vital for EDs to be able to dynamically adapt to community needs, variability of pandemic ED preparedness was high.
Mutation bias shapes the spectrum of adaptive substitutions
Authors: Cano Alejandro V. , Rozhoňová Hana , Stoltzfus Arlin , McCandlish David M. , Payne Joshua L.
Published: April 2021

Evolutionary adaptation often occurs via the fixation of beneficial point mutations, but different types of mutation may differ in their relative frequencies within the collection of substitutions contributing to adaptation in any given species. Recent studies have established that this spectrum of adaptive substitutions is enriched for classes of mutations that occur at higher rates. Yet, little is known at a quantitative level about the precise extent of this enrichment, or its dependence on other factors such as the beneficial mutation supply or demographic conditions. Here we address the extent to which the mutation spectrum shapes the spectrum of adaptive amino acid substitutions by applying a codon-based negative binomial regression model to three large data sets that include thousands of amino acid changes identified in natural and experimental adaptation inS. cerevisiae,E. coli, andM. tuberculosis. We find that the mutation spectrum has a strong and roughly proportional influence on the spectrum of adaptive substitutions in all three species. In fact, we find that by inferring the mutation rates that best explain the spectrum of adaptive substitutions, we can accurately recover species-specific mutational spectra obtained via mutation accumulation experiments. We complement this empirical analysis with simulations to determine the factors that influence how closely the spectrum of adaptive substitutions mirrors the spectrum of amino acid variants introduced by mutation, and find that the predictive power of mutation depends on multiple factors including population size and the breadth of the mutational target for adaptation.

SIGNIFICANCE STATEMENT

How do mutational biases influence the process of adaptation? Classical neo-Darwinian thinking assumes that selection alone determines the course of adaptation from abundant pre-existing variation. Yet, theoretical work shows that under some circumstances the mutation rate to a given variant may have a strong impact on the probability of that variant contributing to adaptation. Here we introduce a statistical approach to analyzing how mutation shapes protein sequence adaptation, and show that the mutation spectrum has a proportional influence on the changes fixed in adaptation observed in three large data sets. We also show via computer simulations that a variety of factors can influence how closely the spectrum of adaptive substitutions mirrors the spectrum of variants introduced by mutation.
Diversity of vaccination-induced immune responses can prevent the spread of vaccine escape mutants
Authors: Bouman Judith A , Capelli Céline , Regoes Roland R
Published: April 2021

Pathogens that are resistant against drug treatment are widely observed. In contrast, pathogens that escape the immune response elicited upon vaccination are rare. Previous studies showed that the prophylactic character of vaccines, the multiplicity of epitopes to which the immune system responds within a host, and their diversity between hosts delay the evolution and emergence of escape mutants in a vaccinated population. By extending previous mathematical models, we find that, depending on the cost of the escape mutations, there even exist critical levels of immune response diversity that completely prevent vaccine escape. Furthermore, to quantify the potential for vaccine escape below these critical levels, we propose a concept ofescape depthwhich measures the fraction of escape mutants that can spread in a vaccinated population. Determining this escape depth for a vaccine could help to predict its sustainability in the face of pathogen evolution.
Beyond the fish-Daphniaparadigm: testing the potential forNeoplea striola(Hemiptera: Pleidae) to cause a trophic cascade in subtropical ponds
Authors: Rakowski Chase J. , Leibold Mathew A.
Published: April 2021

Trophic cascades, or indirect effects of predators on non-adjacent lower trophic levels, have become paradigmatic in ecology, though they are thought to be stronger in aquatic ecosystems. Most research on freshwater trophic cascades focused on temperate lakes, where fish are present and whereDaphniatend to dominate the zooplankton community. These studies identified thatDaphniaoften play a key role in facilitating trophic cascades by linking fish to algae with strong food web interactions. However,Daphniaare rare or absent in most tropical and subtropical lowland freshwaters, and fish are absent from small and temporary water bodies, where invertebrates fill the role of top predator. While invertebrate predators are ubiquitous in freshwater systems, most have received little attention in food web research. Therefore, we aimed to test whether trophic cascades are possible in small warmwater ponds where small invertebrates are the top predators andDaphniaare absent. We collected naturally occurring plankton communities from small fishless water bodies in central Texas and propagated them in replicate pond mesocosms. We removed zooplankton from some mesocosms, left the plankton community intact in others, and added one of two densities of the predaceous insectNeoplea striolato others. Following an incubation period we then compared biomasses of plankton groups to assess food web effects between the trophic levels including whetherNeopleacaused a trophic cascade by reducing zooplankton. The zooplankton community became dominated by copepods which prefer large phytoplankton and exhibit a fast escape response. Perhaps due to these qualities of the copepods and perhaps due to slow consumption rates byNeopleaon key grazers, no evidence for food web effects were found other than somewhat weak evidence for zooplankton reducing large phytoplankton. More research is needed to understand the behavior and ecology ofNeoplea, but trophic cascades may generally be weak or absent in fishless low-latitude lowland water bodies whereDaphniaare rare.
Human Leukocyte Antigen-C and Haplotypes: Associations with Resistance and Susceptibility to HIV-1 Infection among Serodiscordant Couples in Nigeria
Authors: Otuonye Ngozi Mirabel , Luo Ma , Enabulele Onaiwu Idahosa , James Ayorinde , Emele Felix , Ele Prince , Bielawny Thomas , Ojetunde Mercy Mayowa , Odunukwe Nkiruka Nnonyelum
Published: April 2021

INTRODUCTION

The Human Leucocyte Antigen (HLA) class-1 is known to play a significant role in mediating resistance or susceptibility to HIV infection in the clinical course of AIDS. Recent studies have identified HLA-C as a key molecule that affects HIV disease progression. However, the role of HLA class 1 in heterosexual HIV-1 susceptibility or resistance in serodiscordant couples is not known in Nigeria. Therefore, this study evaluated the association between HLA-C susceptibility and resistance in HIV-1 transmission amongst heterosexual serodiscordant couples in Nigeria.

METHODS

A total of 271 serodiscordant, concordant HIV positive and negative couples who gave informed consent were enrolled into this study. Extracted genomic DNA was sequenced for high resolution HLA-C class 1 genotypes using allele-specific primers (on exons 2 and 3) for HLA-C sequencing and typing.

RESULTS

The highest frequency distribution of high-resolution HLA-C alleles observed in the HIV positive subjects were: HLA-C*040101 178 (35.0%) followed by C*0701 124 (24.9%) compared with HIV negative subjects: C*040101 108(39.0%) followed by C*0701 64(24.7%). Alleles C*070201 (OR = 4.19, P<0.05) and C*0804 (OR = 3, P<0.045) were found to be independently associated with HIV-1 susceptibility in the cohort of serodiscordant couples. HLA-C*0802 (OR=0.5. P<0.005) and C*0304 (OR=0.34. P<0.002) were significantly associated with HIV-1 resistance to HIV-1 infection among the cohort.

CONCLUSION

The result has contributed to the importance of how host HLA-C genetic factors can influence HIV-1 disease susceptibility (HLA-C*070201; C*0804) and resistance (HLA-C*0802; C*0304) in serodiscordant couples. This information may contribute to the development of future effective HIV vaccine in Nigeria.
Alterations to the Gut Microbiota of a Wild Juvenile Passerine in an Urban Mosaic
Authors: Maraci Öncü , Corsini Michela , Antonatou-Papaioannou Anna , Jünemann Sebastian , Sudyka Joanna , Lecce Irene Di , Caspers Barbara A. , Szulkin Marta
Published: April 2021

Urbanisation is a major anthropogenic perturbation that progressively alters multiple environmental parameters, thereby presenting novel evolutionary challenges to wild populations. Symbiotic microorganisms residing in the gastrointestinal tracts (gut) of vertebrates have well-established mutual connections with the physiology of their hosts and respond quickly to environmental alterations. However, the impacts of anthropogenic changes and urbanisation on gut microbiota remain poorly understood, especially in early development. To address this knowledge gap, we investigated the gut microbiota in juvenile great tits (Parus major) in an urban mosaic. First, we compared the microbiota of nestlings reared in artificial nest boxes or natural cavities. Next, we analysed microbiota variations employing two distinct urbanisation frameworks, (i) the classical urban/rural dichotomy and (ii) gradual changes in the amount of impervious surface area (ISA) in the urban space and identified the environmental variables that predicted the changes in the microbial communities. Alpha diversity was influenced by cavity type and by the amount of impervious surface surrounding the breeding location. Alpha diversity was also positively correlated with the tree cover density. Beta diversity differed between urban and rural sites, and these alterations covaried with sound pollution, the distance to the city centre and the distance to the closest road. Overall, the microbial communities reflect and are possibly influenced by the heterogeneous environmental modifications that are typical of the urban space. Strikingly, the choice of framework used to define the urban space can influence the outcomes of studies investigating animal-microbe symbiosis. Our results open new perspectives from which the potential function of microbial symbionts in the adaptation of their hosts to anthropogenic stress can be investigated.
Two levels of selection of rhythmicity in gene expression: energy saving for rhythmic proteins and noise optimization for rhythmic transcripts
Authors: Laloum David , Robinson-Rechavi Marc
Published: April 2021

Many genes have nycthemeral rhythms of expression,i.e.a 24-hours periodic variation, at either mRNA or protein level or both, and, most rhythmic genes are tissue-specific. Here, we investigate and discuss the evolutionary origins of rhythms in gene expression. Our results suggest that thythmicity of protein expression has been favored by selection for low cost. Trends are consistent in bacteria, plants and animals, and are also supported in tissue-specific patterns in mouse. Cost cannot explain rhythm at the RNA level, and we suggest instead it allows to periodically and drastically reduce expression noise. Noise control had strongest support in mouse, with limited power in other species. Genes under stronger purifying selection are rhythmically expressed at the mRNA level, probably because they are noise sensitive genes. We also suggest that mRNA rhythmicity allows to switch between optimal precision and higher stochasticity. Higher precision allows to maximize the robustness of gene expression when the function is most needed, while higher stochasticity allows to maintain oscillations and to exhibit diverse molecular phenotypes, i.e. “blind anticipation” of cells. The ability to alternate between these two states, enabled by rhythmicity at the mRNA level, might be adaptive in fluctuating environments. Finally, the adaptive role of rhythmic expression is also supported by rhythmic genes being highly expressed yet tissue-specific genes. This provides a good evolutionary explanation for the observation that nycthemeral rhythms are often tissue-specific.
A shift from competition to facilitation amplifies the temperature-dependence of microbial community respiration
Authors: García Francisca C. , Clegg Tom , Barrios O’Neill Daniel , Warfield Ruth , Pawar Samraat , Yvon-Durocher Gabriel
Published: April 2021

The respiratory release of CO2by microbes is a dominant component of the global carbon cycle. However, large uncertainties exist about the effects of climatic warming on the respiration of microbial communities due to lack of mechanistic, empirically-tested theory that accounts for dynamic species interactions. We developed a general mathematical model which predicts that thermal sensitivity of microbial community respiration increases as species interactions become more positive, i.e., change from competition to facilitation. This is because facilitation disproportionately increases positive feedbacks between the thermal sensitivities of species-level metabolic and biomass accumulation rates at warmer temperatures. We experimentally validated this prediction in bacterial communities of 8 taxa, finding that a shift from competition to facilitation after a month of co-adaptation caused a 60% increase in the thermal sensitivity of their respiration relative tode novocommunities that had not co-adapted. Thus, rapid changes in species interactions can profoundly change the temperature-dependence of microbial community respiration and should be considered in climate change models.
Global mismatches between crop distributions and climate suitability
Authors: Mahaut Lucie , Pironon Samuel , Barnagaud Jean-Yves , Bretagnolle François , Khoury Colin K. , Mehrabi Zia , Milla Ruben , Phillips Charlotte , Renard Delphine , Rieseberg Loren H. , Violle Cyrille
Published: April 2021

The selection of new crops and the migration of crop areas are two key strategies for agriculture to cope with climate change and ensure food security in the coming years. However, both rely on the assumption that climate is a major factor determining crop distributions worldwide. Here, we show that the current global distributions of nine of twelve major crops strongly diverge from their modelled climatic suitability for yields, after controlling for technology, agricultural management and soil conditions. Comparing the climatic niches of crops and their wild progenitors reveals that climate suitability is higher outside the native climatic range for six of these nine crops while all of them are farmed predominantly in their native ranges. These results show that agricultural strategies coping with climate change will be unsuccessful unless they fully consider the social, cultural, and ecological factors underpinning crop distributions.
Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN
Authors: Li Yihang , Pazyra-Murphy Maria F. , Avizonis Daina , Russo Mariana de Sa Tavares , Tang Sophia , Bergholz Johann S. , Jiang Tao , Zhao Jean J. , Zhu Jian , Ko Kwang Woo , Milbrandt Jeffrey , DiAntonio Aaron , Segal Rosalind A.
Published: April 2021

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a “dying-back” axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating CIPN.

HIGHLIGHTS

Paclitaxel induces intra-axonal calcium flux

Sarm1-dependent cADPR production promotes axonal calcium elevation and degeneration

Antagonizing cADPR signaling pathway protects against paclitaxel-induced peripheral neuropathyin vitroandin vivo
Ambulacrarian insulin-related peptides and their putative receptors suggest how insulin and similar peptides may have evolved from Insulin-like Growth Factor
Authors: Veenstra Jan A.
Published: April 2021

Background

Some Insulin/IGF-related peptides (irps) stimulate a receptor tyrosine kinase (RTK) that transfers the extracellular hormonal signal into an intracellular response. Other irps, such as relaxin, do not use an RTK, but a G-protein coupled receptor (GPCR). This is unusual since evolutionarily related hormones typically either use the same or paralogous receptors. In arthropods three different irps,i.e. arthropod IGF, gonadulin andDrosophilainsulin-like peptide 7 (dilp7), likely evolved from a gene triplication, as in several species genes encoding these three peptides are located next to one another on the same chromosomal fragment. These arthropod irps have homologs in vertebrates, which suggests that the initial gene triplication was perhaps already present in the last common ancestor of deuterostomes and protostomes. It would be interesting to know whether this is indeed so and how insulin might be related to this trio of irps.

Methodology

Genes encoding irps as well as their putative receptors were identified in genomes and transcriptomes from echinoderms and hemichordates.

Results

A similar triplet of genes coding for irps is also found in some ambulacrarians. Two of these are orthologs of arthropod IGF and dilp7 and the third is likely a gonadulin ortholog. In echinoderms two novel irps emerged, gonad stimulating substance (GSS) and multinsulin, likely from gene duplications of the IGF and dilp7-like genes respectively. The structures of GSS diverged considerably from IGF, which would suggest they use different receptors than IGF, but no novel irp receptors evolved. If IGF and GSS use different receptors and the evolution of GSS from a gene duplication of IGF is not associated with the appearance of a novel receptor while irps are known to use two different types of receptors, it seems to suggest that the ancestor of GSS and IGF might have acted on both types of receptors while one or both of its descendants act on only one. There are three ambulacrarian GPCRs that have amino acid sequences suggestive of being irp GPCRs, two of these are orthologs of the gonadulin and dilp7 receptors. This suggests that the third might be an IGF receptor, and that by deduction GSS only acts on the RTK. The evolution of GSS from IGF may represent a pattern, where IGF gene duplications lead to novel genes coding for shorter peptides that activate an RTK. It is likely this is how insulin and the insect neuroendocrine irps evolved independently from IGF.

Conclusion

The local gene triplication described from arthropods that yielded three genes encoding irps was already present in the last common ancestor of protostomes and deuterostomes. It seems plausible that irps, such as those produced by neuroendocrine cells in the brain of insects and echinoderm GSS evolved independently from IGF and thus are not true orthologs, but the result of convergent evolution.
Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2
Authors: Shi Guoli , Chiramel Abhilash I. , Li Tiansheng , Lai Kin Kui , Kenney Adam D. , Zani Ashley , Eddy Adrian , Majdoul Saliha , Zhang Lizhi , Dempsey Tirhas , Beare Paul A. , Kar Swagata , Yewdell Jonathan W. , Best Sonja M. , Yount Jacob S. , Compton Alex A.
Published: April 2021

SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. Rapalog use is commonly associated with increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increases susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naive rodents by antagonizing the cell-intrinsic immune response. By identifying one rapalog (ridaforolimus) that is less potent in this regard, we demonstrate that rapalogs promote Spike-mediated entry into cells by triggering the degradation of antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increase virus entry inhibit the mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitates its nuclear translocation and triggers microautophagy. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity.

Significance

Rapamycin is an immunosuppressant used in humans to treat cancer, autoimmunity, and other disease states. Here, we show that rapamycin and related compounds promote the first step of the SARS-CoV-2 infection cycle—entry into cells—by disarming cell-intrinsic immune defenses. We outline the molecular basis for this effect by identifying a rapamycin derivative that is inactive, laying the foundation for improved mTOR inhibitors that do not suppress intrinsic immunity. We find that rapamycin analogs that promote SARS-CoV-2 entry are those that activate TFEB, a transcription factor that triggers the degradation of antiviral membrane proteins inside of cells. Finally, rapamycin administration to rodents prior to SARS-CoV-2 challenge results in enhanced viral disease, revealing that its use in humans may increase susceptibility to infection.
Software development for autologous skin substitute production
Authors: Mestrallet Guillaume
Published: April 2021

Objective

The gold-standard for the management of patients affected by large-surface third-degree burns is autologous skin graft. There is no way to accurately assess burned area size and predict the number of cells and the time necessary to produce a skin graft.

Materials and Methods

When burns affect <40% total body surface area (TBSA), meshed skin samples harvested from non-affected donor sites can be used as grafts. In cases corresponding to burns affecting >40% TBSA), the donor site surfaces are insufficient. The alternative grafting strategy uses bioengineered skin substitutes that are generated using the own keratinocytes of the patient after ex vivo expansion. We developed a software for severe burn diagnosis and autologous skin substitute production.

Results

We developed a software-assisted calculation of the required graft surface and keratinocyte numbers and the time to produce the graft needed, according to patient clinical characteristics. The software also offers assistance to estimate the Baux score, a method that links the severity of burn injuries and the prognosis for the patient.

Discussion

Optimal setup of the bioengineering process involved determination of the required graft surface, adjustment of cell quantities, and control of the timing necessary for production. This could be determined and automated by this software. Accordingly, tools to assist the design of personalized protocols will contribute to care quality and cost limitation.

Conclusion

This software provides a principle of assisted burned patient diagnose and skin substitute bioengineering process which development may facilitate the design of personalized protocols for skin regenerative cell therapies.
Persistent expression of interleukin‐17 and downstream effector cytokines in recalcitrant psoriatic lesions after ustekinumab treatment
Authors: Kim Bo Ri , Kim Minsu , Yang Seungkeol , Choi Chong Won , Lee Kyu Sang , Youn Sang Woong
Published: April 2021

The interleukin (IL)‐23/T‐helper (Th)17 axis is considered central to the pathogenesis of psoriasis, with IL‐36γ considered a marker for histological differential diagnosis. However, expression data regarding key cytokines in the pathogenesis of psoriasis, as well as data on the effects of IL‐23 inhibition on downstream cytokines in human psoriatic skin, are limited. We investigated the expression profile of key cytokines and the effect of ustekinumab (UST) on cytokine expression in human psoriatic tissue. Tumor necrosis factor (TNF)‐α, IL‐23, IL‐17A, and IL‐22 were highly expressed in the epidermis, dermal papillae, and upper dermis in patients with psoriasis compared with controls; IL‐36γ was strongly expressed in the upper epidermis. Compared with the untreated group, expression intensity and area of IL‐23 were significantly decreased in the UST group; expression areas of TNF‐α, IL‐17A, IL‐22, and IL‐36γ did not differ. This study identified the distribution and quantitative expression levels of key cytokines in psoriatic lesions and demonstrated that only IL‐23 was downregulated without blocking downstream effector cytokines in recalcitrant psoriatic lesions during UST treatment. Our results suggest that, although IL‐23 is inhibited, the persistent expression of IL‐17 through an alternative pathway maintains the vicious cycle of the TNF‐α/IL‐23/IL‐17 axis with IL‐36γ, inducing refractory psoriatic lesions in patients with well‐controlled psoriasis.
Effect of brousse tigrée on the dynamics of nurse–protégé interactions of a cactus in the Chihuahuan Desert
Authors: Aranda‐Pineda José A. , Valverde Pedro L. , Búrquez Alberto , Golubov Jordan , Mandujano María C.
Published: April 2021

A nurse–protégé relationship is a frequent facilitation interaction in deserts that allows the recruitment of new individuals of many species. Our aim was to evaluate the relationship of Echinocereus enneacanthus during its life cycle and its nurse plants in the brousse tigrée (tiger bush) vegetation of the Chihuahuan Desert. The population structure of the cactus is skewed toward adult stages, which are commonly found in the bare areas of the brousse tigrée, whereas juveniles are located in the vegetated bands. The vegetation structure and the nurse–protégé relationship were determined using censuses of 19 permanent plots monitored between 2008 and 2019. The differential association of E. enneacanthus with potential nurse plants was evaluated using an interaction network, under the hypothesis of strict association of the seedlings and juveniles with nurse species. In addition, χ2 tests and standardized residuals were fitted among likely nurse species, weighted by the cover of the nurse and of the areas without vegetation. The study species, as well as the nurse plants, had an aggregated distribution pattern. The interaction network showed that the frequency of the association with nurse plants decreased as the size of the protégé individuals increased. At the same time, there were differences in the establishment of E. enneacanthus under particular nurse plants; Prosopis glandulosa and Hilaria mutica were the most important. The nurse–protégé relationship for seeds and seedlings is integral to the vegetation bands of the brousse tigrée.
Intraspecific competition favors ant–plant protective mutualism
Authors: Yamawo Akira
Published: April 2021

The dependency of the anti‐herbivore defense on ant–plant protective mutualism often varies depending on abiotic and biotic conditions. Although intraspecific competition is a primary interaction between neighboring plants, its effects on ant–plant mutualisms have yet to be sufficiently elucidated. In order to determine the effects of intraspecific competition and competitor genotype on ant–plant mutualisms, I conducted competition and ant‐removal experiments and examined their effects on damage to the leaves of Urena lobata var. tomentosa plants. I found that larger numbers of worker ants visited the plants growing with non‐siblings than plants growing alone and that plants growing with non‐siblings had a higher shoot to root ratio and secreted greater volumes of extrafloral nectar than plants growing alone and/or with siblings. Under the presence of both sibling and non‐sibling competitors, I observed that when ants were removed from plants, those grown with conspecific neighbors were characterized by a higher percentage of damaged leaf area than plants harboring ants. The effect of ant exclusion on leaf damage was more pronounced in plants grown with non‐siblings than those grown near siblings. However, when the plants were grown alone, I detected no significant difference in percentage leaf damage between the ant‐excluded and ant‐harboring plants. The results indicate that neighboring plants can exert strong effects on ant–plant protective mutualisms, thereby highlighting the need to take into consideration plant–plant interactions in studies on these mutualistic associations.
Tie Strength Dispersion and Alliance Portfolio Performance: The Moderating Effects of CEOs’ Political and International Experience
Authors: Bi Jingyu , Xie En , Sheng Shibin
Published: April 2021

Many firms simultaneously develop multiple alliances with different partners and face the challenges of managing a complex alliance portfolio that contains both strong and weak ties. How does this dispersion of tie strength affect alliance portfolio performance? This study examines the effect of tie strength dispersion on alliance portfolio performance, as well as the contingent effects of CEOs’ experience. The empirical analyses, using a dataset consisting of 748 funds initiated by 62 fund management firms over a 10‐year period (2002–2011), reveal an inverted U‐shaped relationship between tie strength dispersion and alliance portfolio performance. The analyses also reveal that CEOs’ political experience weakens, while their international experience strengthens, this inverted U‐shaped relationship.
Characteristics, presentation and outcomes of music festival patrons with stimulant drug‐induced serotonin toxicity
Authors: Miles Lachlan F , Austin Kristy , Eade Alan , Anderson David , Graudins Andis , McGain Forbes , Maplesden Jacqueline , Greene Shaun , Rotella Joe‐Anthony , Dutch Martin
Published: April 2021

Objective

A large number of stimulant drug‐associated deaths at music festivals in Australia were reported during the southern hemisphere summer of 2018–2019. This led to the prehospital deployment of healthcare professional‐led critical care response teams. We aimed to describe the characteristics, clinical presentation, management and outcomes of music festival patrons with stimulant drug‐induced serotonin toxicity managed using this model during the study period.

Methods

We performed a retrospective observational study of patients presenting with stimulant drug‐induced serotonin toxicity and/or drug‐induced hyperthermia who presented between December 2017 and December 2019. Comprehensive follow‐up data were collected for those patients who required hospital admission. Data included demographics, clinical features, management and disposition, hospital outcomes and laboratory data, stratified by severity of presentation.

Results

Forty‐seven patients were included. Median age was 21.9 years (interquartile range 19.6–22.2). 3,4‐Methylenedioxymetamphetamine was the most frequently reported agent ingested (32/47). After stratification, 13 of 47 patients were classified as mild, 20 of 47 as moderate and 14 of 47 as severe. Median presenting temperature in this latter cohort was 41.1°C (40.5–42.0°C). All severely ill patients required intensive care unit admission, with a median hospital stay of 4.63 days (interquartile range 2.08–8.36). End‐organ complications were reported in 11 of 14 patients. No mortalities were reported. All patients (13/13) from the mild cohort and 15 of 20 patients from the moderate cohort were treated and discharged on‐site.

Conclusions

Severe illness was associated with a high incidence of end‐organ impairment. A high proportion of patients without severe disease were able to be successfully managed at the event without transport to hospital. No deaths are reported in this series.
Determinants and Consequences of Budget Reallocations*
Authors: Grabner Isabella , Moers Frank
Published: April 2021

We investigate the determinants and consequences of budget reallocations—that is, corrective changes to the budget made during the year. Using proprietary data from a large consumer goods manufacturer, we analyze the extent to which initial budgeting decisions drive reallocations. Examining this relationship is important because initial budget negotiations are often troubled by power struggles and politicking, which may give rise to the need for reallocations. We hypothesize that one important driver of reallocation decisions is the firm's aim to correct systematic deviations from the optimal initial budget that were driven by lobbying during the initial budgeting process. We find evidence that is consistent with this prediction. In a more exploratory analysis, we show that reallocations do not have the desired effects on market performance. In particular, budget cuts are negatively associated with a product's change in market share. More surprisingly, while budget increases do help product lines achieve their sales targets in the last quarter, they do not boost market share. Our results demonstrate that efficient investment planning is essential to achieve an improvement in market performance.
The root system of guar: Spatial and temporal analysis of root and nodule development
Authors: MacMillan Jennifer , Shrestha Rajan , Adams Curtis B. , Hinson Philip O. , Trostle Calvin
Published: April 2021

Guar (Cyamopsis tetragonoloba [L.] Taub.) is a leguminous crop plant produced in semi‐arid regions worldwide, primarily for industrial uses of guar gum. Little research has been conducted on critical belowground traits of the plant, particularly on spatial and temporal development of the root system, including nodules. Providing such analysis was the objective of this research. We observed root and nodule character traits at regular time intervals in 130‐cm‐tall soil columns sectioned by depth in 2 years. In this tap‐rooted plant, root weight was greatest at the soil surface (0–15 cm) and decreased with depth. Root length density (RLD) from 0 to 15 cm and 15 to 30 cm soil depths was similar. The RLD and root weight were generally minimal in deeper soil layers, although deeper roots seem to play an important role in water uptake for guar, especially in drought conditions. Compared to most crops, guar has fine rooting and a small root‐to‐shoot ratio. At all soil depths analysed, ≥86% of root length was comprised of roots <1 mm in diameter, although most were very fine roots <0.5 mm. The root‐to‐shoot ratio ranged from 0.055 to 0.17 g g−1 over the growing seasons. Significant accumulation of nodule weight occurred by 60 days, as did the first observations of nodule senescence, but nodule growth continued after this time. Most nodules and nodule weight were concentrated near the soil surface and the average weight per nodule decreased with depth, although smaller nodules were present at all depths. Because guar is typically grown in dryland conditions in hot semi‐arid regions, nodules near the soil surface may often be susceptible to shedding or loss of function due to dehydration and/or heat stress and the plant may rely on deeper nodules for N fixation. The basic biological information provided in this report is needed to hasten progress in guar genetic improvement and management.
History of healthcare use and disease burden in older adults with different levels of alcohol use. A register‐based cohort study
Authors: Mejldal Anna , Andersen Kjeld , Behrendt Silke , Bilberg Randi , Christensen Anne Illemann , Lau Cathrine Juel , Möller Sören , Nielsen Anette Søgaard
Published: April 2021

Background

Only a minority of individuals with problematic alcohol use ever seek alcohol treatment. Knowledge of general help‐seeking behavior in the healthcare system can identify possibilities for prevention and intervention.

Method

The current study describes healthcare use, burden of disease, and prior morbidities over a 15‐year period by current alcohol use behavior among Danish adults aged 60–70. The Danish National Health Survey 2013 and the baseline assessment of the Elderly Study (2014–2016) were linked to Danish national registers to collect annual information on healthcare use and morbidity for the 15 years prior to inclusion. Participants from the 3 largest Danish municipalities were divided into 4 groups with varying drinking patterns and no recent treatment [12‐month abstinent (n = 691), low‐risk drinkers (n = 1978), moderate‐risk drinkers (n = 602), and high‐risk drinkers (n = 467)], and a group of treatment‐seeking individuals with a 12‐month DSM‐5 alcohol use disorder (AUD; n=262). Negative binomial regression models were utilized to compare rates of healthcare use and logistic regressions were used to compare odds of diagnoses.

Results

Low‐, moderate‐, and high‐risk drinkers had similar rates of past healthcare utilization (low‐risk mean yearly number of contacts for primary care 7.50 (yearly range 6.25–8.45), outpatient care 0.80 (0.41–1.32) and inpatient care 0.13 (0.10–0.21)). Higher rates were observed for both the 12‐month abstinent group (adjusted RR = 1.16–1.26) and the group with AUD (ARR = 1.40–1.60) compared to the group with low‐risk alcohol consumption. Individuals with AUD had higher odds of previous liver disease (adjusted OR = 6.30), ulcer disease (AOR = 2.83), and peripheral vascular disease (AOR 2.71). Twelve‐month abstinence was associated with higher odds of diabetes (AOR = 1.97) and ulcer disease (AOR = 2.10).

Conclusions

Looking back in time, we found that older adults had regular healthcare contacts, with those who received treatment for AUD having had the highest contact frequency and prevalence of alcohol‐related diseases. Thus, healthcare settings are suitable locations for efforts at AUD prevention and intervention.