bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards a framework to unify the relationship between numerical abundance, biomass, and quantitative eDNA
Authors: Yates M.C , Wilcox T. M. , Kay S. , Heath D.D.
Published: December 2022

Does environmental DNA (eDNA) correlate more closely with numerical abundance (N) or biomass in aquatic organisms? We hypothesize that the answer is ‘neither’: eDNA production likely scales allometrically, reflecting key physiological rates and surface area-to-body mass relationships. Building on individual-level frameworks developed from the Metabolic Theory of Ecology, we derive a framework through which quantitative eDNA data can be transformed to simultaneously reflect both population-level N and biomass. We then validated our framework using data from two previously published studies: (i) a marine eDNA metabarcoding dataset; and (ii) a freshwater single-species qPCR dataset. Using a Bayesian modeling approach, we estimated the value of the allometric scaling coefficient that jointly optimized the relationship between N, biomass, and ‘corrected’ eDNA data to be 0.82 and 0.77 in Case Studies (i) and (ii), respectively. These estimates closely match expected scaling coefficients estimated in previous work on Teleost fish metabolic rates. We also demonstrate that correcting quantitative eDNA can significantly improve correspondence between eDNA- and traditionally-derived quantitative community biodiversity metrics (e.g., Shannon index and Bray-Curtis dissimilarity) under some circumstances. Collectively, we show that quantitative eDNA data is unlikely to correspond exactly to either N or biomass, but can be ‘corrected’ to reflect both through our unifying joint modelling framework. This framework can also be further expanded to include other variables that might impact eDNA pseudo-steady-state concentrations in natural ecosystems (e.g., temperature, pH, and phenology), and is flexible enough to model these relationships across trophic levels.

Significance Statement

Aquatic animals release DNA (from shed cells, mucous, faeces, etc.) into water, which can be detected via environmental DNA (eDNA) sampling. What is less clear is whether we can estimate numerical abundance (N) or biomass from eDNA concentrations. We hypothesize that eDNA production scales allometrically; that is, large animals release less DNA per unit mass than smaller animals. Building from the Metabolic Theory of Ecology, we derived a framework through which eDNA data can be transformed to simultaneously reflect bothNand biomass. We then validated the framework using two case studies in marine and freshwater systems. This framework unifies discrepancies between eDNA,N, and biomass data, unlocking the potential of eDNA to monitor population abundance/biomass and quantify biodiversity.
Genomic signatures of local adaptation in recent invasiveAedes aegyptipopulations in California
Authors: Soudi Shaghayegh , Crepeau Marc , Collier Travis C. , Lee Yoosook , Cornel Anthony J. , Lanzaro Gregory C.
Published: December 2022

Background

Rapid adaptation to new environments can facilitate species invasions and range expansions. Understanding the mechanisms of adaptation used by invasive disease vectors in new regions has key implications for mitigating the prevalence and spread of vector-borne disease, although they remain relatively unexplored.

Results

Here, we use whole-genome sequencing data from 103Aedes aegyptimosquitoes collected from various sites in southern and central California to infer the genetic structure of invasive populations. We integrate genome data with 25 topo-climate variables to investigate genome-wide signals of local adaptation among populations. Patterns of population structure, as inferred using principle components and admixture analysis, were consistent with three genetic clusters, likely resulting from multiple independent introductions. Using various landscape genomics approaches, which all remove the confounding effects of shared ancestry on correlations between genetic and environmental variation, we identified 112 genes showing strong signals of local environmental adaptation associated with one or more topo-climate factors. Some of them have known effects in climate adaptation, such as heat-shock proteins, which shows selective sweep and recent positive selection acting on these genomic regions.

Conclusions

Our results provide a genome wide perspective on the distribution of adaptive loci and lay the foundation for future work to understand how environmental adaptation inAe. aegyptiimpacts the arboviral disease landscape and how such adaptation could help or hinder efforts at population control.
Fetal cannabidiol (CBD) exposure alters thermal pain sensitivity, cognition, and prefrontal cortex excitability
Authors: Swenson Karli S. , Wulschner Luis E. Gomez , Hoelscher Victoria M. , Folts Lillian , Korth Kamryn M. , Oh Won Chan , Bates Emily Anne
Published: December 2022

Thousands of people suffer from nausea with pregnancy each year. Nausea can be alleviated with cannabidiol (CBD), a primary component of cannabis that is widely available. However, is it unknown how fetal CBD exposure affects embryonic development and postnatal outcomes. CBD binds and activates receptors that are important for fetal development and are expressed in the fetal brain, including serotonin receptors (5HT1A), voltage-gated potassium (Kv)7 receptors, and the transient potential vanilloid 1 receptor (TRPV1). Excessive activation of each of these receptors during fetal development can disrupt neurodevelopment. Here, we test the hypothesis that intrauterine CBD exposure alters offspring neurodevelopment and postnatal behavior. We show that fetal CBD exposure sensitizes male offspring to thermal pain in a TRPV1 dependent manner. We show that fetal CBD exposure decreases cognitive function in female CBD-exposed offspring. We demonstrate that fetal CBD exposure increases the minimum current required to elicit action potentials and decreases the number of action potentials in female offspring layer 2/3 prefrontal cortex (PFC) pyramidal neurons. Fetal CBD exposure reduces the amplitude of glutamate uncaging-evoked excitatory post-synaptic currents. Combined, these data show that fetal CBD exposure disrupts neurodevelopment and postnatal behavior in a sex-dependent manner.

One Sentence Summary

Cannabidiol (CBD) consumption during pregnancy alters offspring behavior and neuronal excitability in a sex dependent manner in mice.
Defining the role of host biomarkers in the diagnosis and prognosis of childhood pneumonia – a prospective cohort study
Authors: Chandna Arjun , Lubell Yoel , Mwandigha Lazaro , Tanunchai Phattaranit , Vinitsorn Asama , Richard-Greenblatt Melissa , Koshiaris Constantinos , Limmathurotsakul Direk , Nosten Francois , Abdad Mohammad Yazid , Perera-Salazar Rafael , Turner Claudia , Turner Paul
Published: December 2022

Background

Reliable tools to inform outpatient management of childhood pneumonia in resource-limited settings are needed. We investigated the value added by biomarkers of host infection response to the performance of the Liverpool quick Sequential Organ Failure Assessment score (LqSOFA), for triage of children presenting with pneumonia to a primary care clinic in a refugee camp on the Thailand-Myanmar border.

Methods

900 presentations of children aged ≤ 24 months meeting WHO pneumonia criteria were included. The primary outcome was receipt of supplemental oxygen. We compared discrimination of a clinical risk score (LqSOFA) to markers of endothelial injury (Ang-1, Ang-2, sFlt-1), immune activation (CHI3L1, IP-10, IL-1ra, IL-6, IL-8, IL-10, sTNFR-1, sTREM-1), and inflammation (CRP, PCT), and quantified the net-benefit of including biomarkers alongside LqSOFA. We evaluated the differential contribution of LqSOFA and host biomarkers to the diagnosis and prognosis of severe pneumonia.

Results

49/900 (5.4%) presentations met the primary outcome. Discrimination of LqSOFA and Ang-2, the best performing biomarker, were comparable (AUC 0.82 [95% CI 0.76-0.88] and 0.81 [95% CI 0.74-0.87] respectively). Combining Ang-2 with LqSOFA improved discrimination (AUC 0.91; 95% CI 0.87-0.94; p < 0.001), and resulted in greater net-benefit, with 10-30% fewer children requiring oxygen supplementation incorrectly identified as safe for community-based management. Ang-2 had greater prognostic utility than LqSOFA to identify children requiring supplemental oxygen later in their illness course.

Conclusions

Combining Ang-2 and LqSOFA could guide referrals of childhood pneumonia from resource-limited community settings. Further work on integration into patient triage is required.
Compositional coding of individual finger movements in human posterior parietal cortex and motor cortex enables ten-finger decoding
Authors: Guan Charles , Aflalo Tyson , Kadlec Kelly , Gámez de Leon Jorge , Rosario Emily R. , Bari Ausaf , Pouratian Nader , Andersen Richard A.
Published: December 2022

Abstract

Objective

Enable neural control of individual prosthetic fingers for participants with upper-limb paralysis.

Approach

Two tetraplegic participants were each implanted with a 96-channel array in the left posterior parietal cortex (PPC). One of the participants was additionally implanted with a 96-channel array near the hand knob of the left motor cortex (MC). Across tens of sessions, we recorded neural activity while the participants attempted to move individual fingers of the right hand. Offline, we classified finger movements from neural firing rates using linear discriminant analysis (LDA) with cross-validation. The participants then used the neural classifier online to control individual fingers of a brain-machine interface (BMI). Finally, we characterized the neural representational geometry during individual finger movements of both hands.

Main Results

The two participants achieved 86% and 92% online accuracy during BMI control of the contralateral fingers (chance = 17%). Offline, a linear decoder achieved ten-finger decoding accuracies of 70% and 66% using respective PPC recordings and 75% using MC recordings (chance = 10%). A compositional code linked corresponding finger movements of the contralateral and ipsilateral hands.

Significance

This is the first study to decode both contralateral and ipsilateral finger movements from PPC. Online BMI control of contralateral fingers exceeded that of previous finger BMIs. PPC and MC signals can be used to control individual prosthetic fingers, which may contribute to a hand restoration strategy for people with tetraplegia.
Healthy behaviors and circadian patterns determined by actigraphy in researchers and administrative personnel as protective factors against metabolic disease and obesity
Authors: Espitia-Bautista Estefania , Morales-Bautista Francisco , Rizo-Pastrana Ivette , Escobar Carolina , Stephens Christopher R.
Published: December 2022

Objectives

Three important, directly-causal, behavioral risk factors for obesity and its metabolic consequences are: food consumption, sedentary lifestyle and circadian disruption, such as social jet-lag, which should also partially explain the relevance of known, indirectly-causal, such as educational level, socio-economic status and/or type of job and its conditions. In this study we use actigraphy as a means to quantify and understand those differences in behaviors or conducts, related to 1) physical activity and 2) circadian disruption, which can explain observed differences in metabolic health in two different populations.

Methods

Metabolic and anthropometric data were taken from a population of university workers segmented by educational level – administrative workers (bachelor’s degree) and researchers (Masters or PhD degree) – Actigraphs collected temperature, acceleration, luxes and time in movement; participants use them for at least 1 week. Actigraphy data were divided in weekdays and weekends for analysis.

Results

We show that body mass index and metabolic syndrome criteria were significantly worse for the lower educational level group. Correspondingly, significant differences were found between administrative personnel and researchers across all measured actigraphy parameters – activity level, acceleration, light exposure and temperature. The most relevant differences are that researchers presented significantly more/less time in high/low-activity conducts, less differences in activity level between weekdays and weekends, and less social jet-lag than administrative personnel.

Conclusions

Researchers have healthier habits both in terms of voluntary physical activity and less circadian disruption, showing how work environment can be an important determinant of the degree to which healthy habits can be adopted.

Highlights

Educational level and work environment are relevant factors to contribute to the development of metabolic syndrome and obesity.

Administrative personnel showed worse metabolic health than Researchers, and also Administrative workers showed less healthy behaviors in actigraphy.

Differences between weekdays and weekends are a good parameter to measure social jet lag, but also for habits.

Administrative personnel presented more Social jet lag than researchers, and more differences between weekdays and weekends in activity and temperature.
Developing and validating a multi-criteria decision analytic tool to assess the value of cancer clinical trials
Authors: Gillett Piers , Mahar Robert K , Tran Nancy R , Rosenthal Mark , IJzerman Maarten
Published: December 2022

Background

Demonstrating safety and efficacy of new medical treatments requires clinical trials. But clinical trials are costly and may not provide value proportionate to their costs. In health systems with limited resources, it is important to identify the trials with the highest value. Tools exist to assess elements of a clinical trial such as statistical validity but are not wholistic in their valuation of a clinical trial. This study aims to develop a measure of clinical trials value and provide an online tool for clinical trial prioritisation.

Methods

A search of the academic and grey literature and expert consultation was undertaken to identify a set of metrics to aid clinical trial valuation using multi-criteria decision analysis. Swing weighting and ranking exercises were used to calculate appropriate weights of each of the included metrics and to estimate the partial-value function for each underlying metric. The set of metrics and their respective weights were applied to the results of six different clinical trials to calculate their value.

Results

Seven metrics were identified: ‘unmet need’, ‘size of target population’, ‘eligible participants can access the trial’, ‘patient outcomes’, ‘total trial cost’, ‘academic impact’ and ‘use of trial results’. The survey had 80 complete sets of responses (51% response rate). A trial designed to address an ‘Unmet Need’ was most commonly ranked as the most important with a weight of 24.4%, followed by trials demonstrating improved ‘Patient Outcomes’ with a weight of 21.2%. The value calculated for each trial allowed for their clear delineation and thus a final value ranking for each of the six trials.

Conclusion

We confirmed that the use of the decision tool for valuing clinical trials is feasible and that the results are face valid based on the evaluation of six trials. A proof-of-concept applying this tool to a larger set of trials with an external validation is currently underway.
Multiscale modelling of invasive species control: the cane toad in Australia
Authors: Pham Anh D. , Baker Christopher M. , Geard Nicholas
Published: December 2022

The cane toad (Bufo marinus) is an invasive species in Australia that has a negative impact on native species. Control methods such as trapping, fencing, and water exclusion have been devised to contain the spread of cane toads and reduce their ecological impact. However, implementing these interventions is expensive, and estimating the likely impact of a proposed intervention on spread at a large spatial scale, comprising one or more control methods, is challenging due to the lack of large-scale data and the computational cost of modelling a large number of toads.

To address this challenge, we developed a multiscale model which uses individual-level data on cane toad behaviour to estimate the impact of trapping, fencing, and water exclusion when applied at scale in the Pilbara region in north-western Australia. Compared to previous work, our model allows us to explore more complex combinations and tradeoffs of control methods by utilising data sources at different scales.

Our results suggest that exclusion of toads from water points is the most effective method for containing the spread of cane toads, and that trapping and fencing alone are unlikely to be sufficient. However, trapping and fencing are still useful supplementary measures in scenarios where exclusion cannot be broadly applied to a large number of water points.

Synthesis and applications. Our analyses highlight the importance of limiting access to sheltering and breeding sites in invasive species control. Furthermore, this study illustrates the value of multiscale computational models for exploring scenarios where parameters and calibration data are available at the scale of individuals and small groups, but management questions are framed at a much larger scale.
A unified classification system for HIV-1 5’ long terminal repeats
Authors: Guo Xing , Yu Dan , Liu Mengying , Li Hanping , Chen Mingyue , Wang Xinyu , Zhai Xiuli , Zhang Bohan , Wang Yanglan , Yang Caiqing , Wang Chunlei , Liu Yongjian , Han Jingwan , Wang Xiaolin , Li Tianyi , Li Jingyun , Jia Lei , Li Lin
Published: December 2022

The HIV-1 provirus mainly consists of internal coding region flanked by the 2 same long terminal repeats (LTRs) at each terminus. The LTRs play important roles in HIV-1 reverse transcription, integration, and transcription by the association with host factors. However, despite of the significant study advances of the internal coding regions of HIV-1 by using definite reference classification, there are no systematic classifications for HIV-1 5’ LTRs, which hinders our elaboration on 5’ LTR and a better understanding of the viral origin, spread and therapy. Here, by analyzing all available resources of 5’ LTR sequences in public databases following 4 recognized principles for the reference classification, 83 representatives and 14 consensus sequences were identified as representatives of 2 groups, 6 subtypes, 6 sub-subtypes, and 9 CRFs. To test the reliability of our established classification system, the constructed references were applied to identify the 5’ LTR assignment of the 22 clinical isolates in China. The results revealed that 16 out of 22 tested strains showed a consistent subtype classification with the previous LTR-independent classification system. However, 6 strains, for which recombination events within 5’ LTR were demonstrated, unexpectedly showed a different subtype classification, leading a significant change of binding sites for important transcription factors including SP1, p53, and NF-κB. The binding change of these transcriptional factors would probably affect the transcriptional activity of 5’ LTR. This study established a unified classification system for HIV-1 5’ LTRs, which will facilitate HIV-1 characterization and be helpful for both basic and clinical research fields.

IMPORTANCE

Here, a scientific, reliable, and usable classification system based on the 5’ LTR sequences was established, which will allow us to effectively facilitate the precise typing of HIV-1 strains. This classification system was applied to 22 HIV-1 strains circulating in China, we found that 6 out of 22 strains analyzed, belonged to a different subtype when our results were compared to those obtained with the previous LTR-independent classification system. Thus, these data demonstrated that our classification method could greatly improve the HIV-1 subtype classification. We found that 6 5’ LTR sequences showed recombination events, leading to a significant exchange of the binding sites of transcriptional factors. Thus, this work established a comprehensive HIV-1 5’ LTR classification system, which will help the scientific community to precisely characterize HIV-1 variants, and better understand the origin and spread of HIV-1 strains, and it also may be helpful for pathogenicity and transmissibility evaluation studies.
Quantitative proteomics of cerebrospinal fluid from African Americans and Caucasians reveals shared and divergent changes in Alzheimer’s disease
Authors: Modeste Erica , Ping Lingyan , Watson Caroline M. , Duong Duc M. , Dammer Eric B. , Johnson Erik C.B. , Roberts Blaine R. , Lah James J. , Levey Allan I. , Seyfried Nicholas T.
Published: December 2022

Despite being twice as likely to get Alzheimer’s disease (AD), African Americans have been grossly underrepresented in AD research. While emerging evidence indicates that African Americans with AD have lower cerebrospinal fluid (CSF) levels of Tau compared to Caucasians, other differences in AD CSF biomarkers have not been fully elucidated. Here, we performed unbiased proteomic profiling of CSF from African Americans and Caucasians with and without AD to identify both common and divergent AD CSF biomarkers. Multiplex tandem mass tag-based mass spectrometry (TMT-MS) quantified 1,840 proteins from 105 control and 98 AD patients of which 100 identified as Caucasian while 103 identified as African American. Consistent with previous findings, the increase of Tau levels in AD was greater in Caucasians than in African Americans by both immunoassay and TMT-MS measurements. Network analysis organized the CSF proteome into 14 modules associated with brain cell-types and biological pathways. CSF modules which included 14-3-3 proteins (YWHAZ and YWHAG), demonstrated equivalent disease-related elevations in both African Americans and Caucasians with AD, whereas other modules demonstrated more profound disease changes within race. Modules enriched with proteins involved with glycolysis and neuronal/cytoskeletal proteins, including Tau, were more increased in Caucasians than in African Americans with AD. In contrast, a module enriched with synaptic proteins including VGF, SCG2, and NPTX2 was significantly lower in African Americans than Caucasians with AD. Using a targeted proteomic approach (selected reaction monitoring) followed by a receiver operating characteristic curve (ROC) analysis we measured levels of VGF, SCG2, and NPTX2, which were significantly better at classifying African Americans than Caucasians with AD. Collectively, our findings provide insight into additional protein biomarkers and pathways reflecting underlying brain pathology that are shared or differ by race.
Interior pH Sensing Residue of Human Voltage-Gated Proton Channel Hv1 is Histidine 168
Authors: Shen Mingzhe , Huang Yandong , Cai Zhitao , Cherny Vladimir V. , DeCoursey Thomas E. , Shen Jana
Published: December 2022

The molecular mechanisms governing the human voltage-gated proton channel hHv1 remain elusive. Here we used membrane-enabled hybrid-solvent continuous constant pH molecular dynamics (CpHMD) simulations with pH replica exchange to further evaluate the recently obtained structural models of hHv1 in hyperpolarized (closed channel) and depolarized (open channel) states (Geragotelis, Tobias et al., Proc. Natl. Acad. Sci. USA 2020) and explore potential pH-sensing residues. The CpHMD titration at a set of symmetric pH conditions revealed three residues that can gain or lose protons upon channel depolarization. Among them residue H168 at the intracellular end of the S3 helix switches from the deprotonated to the protonated state and its protonation is correlated with the increased tilting of the S3 helix during the transition from the hyper-to the depolarized state. Thus, the simulation data suggest H168 as an interior pH sensor, in support of a recent finding based on electrophysiological experiments of Hv1 mutants (Cherny, DeCoursey et al., J. Gen. Physiol. 2018). Our work represents an important step towards deciphering the pH-dependent gating mechanism of hHv1.

SIGNIFICANCE

The human voltage-gated proton channel hHv1 is comprised of a proton-selective voltage sensing domain and responsible for cellular pH homeostasis. Despite intense experimental and theoretical investigations, its pH-dependent gating mechanism is not understood. Our simulation data offer strong evidence supporting the role of H168 as a pHisensor (Cherny, DeCoursey et al., J. Gen. Physiol. 2018). Deciphering the interior pH sensor moves us a step closer to elucidating the structure-function relationship of hHv1.
Alteration of pro-carcinogenic gut microbiota is associated with clear cell renal cell carcinoma tumorigenesis
Authors: Yang Bo-Yu , Zhao Fang-Zhou , Li Xuan-Hao , Zhao Mei-Shan , Lv Jing-Cheng , Shi Ming-Jun , Li Jun , Zhou Zhi-Yuan , Wang Jing-Jing , Song Jian
Published: December 2022

Increasing evidence suggests that gut microbiota is involved in the occurrence and progression of urinary system diseases such as clear cell renal cell carcinoma (ccRCC). However, the mechanism of how alteration of gut metagenome promotes ccRCC remains unclear. Here we aim to elucidate the association of specific gut bacteria and their metabolites with ccRCC. In a pilot case-control study among 30 ccRCC patients and 30 healthy controls, 16S ribosomal RNA (rRNA) gene sequencing were analyzed from fecal samples collected prior to surgery or hospitalization. Alpha diversity and beta diversity analysis of the gut microbiota were performed, and differential taxa were identified by multivariate statistics. Meanwhile, serum metabolism was measured by UHPLC-MS, and differential genes were identified based on theTCGAdatabase. Random Forests revealed the relative abundances of 20 species differed significantly between the RCC group and the Control group, among which 9 species, such asDesulfovibrionaceae,were enriched in the RCC group, and 11 species, such as four kinds ofLactobacillus,were less abundant. Concomitantly, serum level of taurine, which was considered to be consumed byDesulfovibrionaceaeand released byLactobacillus, has decreased in the RCC group. In addition, macrophage-related genes such asGabbr1was upregulated in ccRCC patients from our results.

IMPORTANCE

To our knowledge, few studies investigate the correlation of gut microbiota and ccRCC tumorigenesis. Overall, our sequencing data suggest that changes in the composition of specific gut microbiota, especiallyLactobacillusandDesulfovibrionaceae,may be involved in ccRCC. Numerous serum metabolites, for example, taurine, which were modified in concert with dysregulation of gut microbiota, were associated with metabolic status during ccRCC development. Furthermore, through comparative analysis of clinical indicators, we found that gut dysbiosis could potentially reshape systemic inflammation, which participated in ccRCC tumorigenesis and we performed bioinformatics analysis to draw this conclusion. In Summary, it could be concluded from our study that the reduction of protective bacteriaLactobacillus, proliferation of sulfide-degrading bacteriaDesulfovibrionaceae, reduction of taurine, and enrichment of macrophage related genes might be the risk predictors of ccRCC.
Multiple sites on glycoprotein H (gH) functionally interact with the gB fusion protein to promote fusion during herpes simplex virus (HSV) entry
Authors: Fan Qing , Hippler Daniel P. , Yang Yueqi , Longnecker Richard , Connolly Sarah A.
Published: December 2022

Enveloped virus entry requires fusion of the viral envelope with a host cell membrane. Herpes simplex virus type 1 (HSV-1) entry is mediated by a set of glycoproteins that interact to trigger the viral fusion protein glycoprotein B (gB). In the current model, receptor-binding by gD signals a gH/gL heterodimer to trigger a refolding event in gB that fuses the membranes. To explore functional interactions between gB and gH/gL, we used a bacterial artificial chromosome (BAC) to generate two HSV-1 mutants that show a small plaque phenotype due to changes in gB. We passaged the viruses to select for restoration of plaque size and analyzed second-site mutations that arose in gH. HSV-1 gB was replaced either by gB from saimiriine herpesvirus type 1 (SaHV-1) or by a mutant form of HSV-1 gB with three alanine substitutions in domain V (gB3A). To shift the selective pressure away from gB, the gB3A virus was passaged in cells expressing gB3A. Sequencing of passaged viruses identified two interesting mutations in gH, including gH-H789 in domain IV and gH-S830N in the cytoplasmic tail (CT). Characterization of these gH mutations indicated they are responsible for the enhanced plaque size. Rather than being globally hyperfusogenic, both gH mutations partially rescued function of the specific gB version present during their selection. These sites may represent functional interaction sites on gH/gL for gB. gH-H789 may alter the positioning of a membrane-proximal flap in the gH ectodomain, whereas gH-S830 may contribute to an interaction between the gB and gH CTs.

IMPORTANCE

Enveloped viruses enter cells by fusing their envelope with the host cell membrane. Herpes simplex virus type 1 (HSV-1) entry requires the coordinated interaction of several viral glycoproteins, including gH/gL and gB. gH/gL and gB are essential for virus replication and both proteins are targets of neutralizing antibodies. gB fuses the membranes after being activated by gH/gL, but the details of how gH/gL activates gB are not known. This study examined the gH/gL-gB interaction using HSV-1 mutants that displayed reduced virus entry due to changes in gB. The mutant viruses were grown over time to select for additional mutations that could partially restore entry. Two mutations in gH (H789Y and S830N) were identified. The positions of the mutations in gH/gL may represent sites that contribute to gB activation during virus entry.
Capillary angiopathy and aquaporin-4 after Aβ immunisation in Alzheimer’s disease – potential relevance to Amyloid-Related Imaging Abnormalities
Authors: Harrison Charlotte H. , Sakai Kenji , Johnston David A. , Holmes Clive , Boche Delphine , Nicoll James AR
Published: December 2022

Aims

Amyloid-related imaging abnormalities (ARIA) have hampered clinical trials and therapeutic use of amyloid-β (Aβ) immunotherapy for Alzheimer’s disease (AD), with the cause of the white matter oedema (ARIA-E) unknown. Aquaporin 4 (AQP4), present in astrocyte endfeet, controls water flow across the blood-brain barrier. Experimental studies suggest that as Aβ plaques are cleared following immunotherapy, capillary angiopathy (capCAA) increases, displacing astrocyte endfeet allowing influx of extracellular water (oedema). We sought neuropathological evidence for this mechanism in immunised AD patients.

Methods

Brains of 16 Alzheimer’s patients immunised against Aβ42 (iAD, AN1792, Elan Pharmaceuticals) and 28 unimmunized Alzheimer’s (cAD) cases were immunolabelled and quantified for Aβ42 and AQP4.

Results

CapCAA was 3.5 times higher in iAD (p=0.009). No difference between the groups was identified in the proportion of capillaries wrapped by AQP4 or AQP4 protein load. However, capCAA in iAD negatively correlated with AQP4 load (r = -0.498, p<0.001), suggesting disturbance of AQP4 in presence of capCAA.

Conclusions

After Aβ immunotherapy, capCAA was increased, likely reflecting the drainage of soluble Aβ towards the vasculature and providing a potential mechanism to disrupt AQP4-containing astrocyte endfeet, resulting in ARIA-E. We did not identify alterations in AQP4, potentially because of limitations in the timing of the post-mortem analysis. Given the recent licencing of Aβ immunotherapy, the field must prioritise obtaining neuropathological correlates of ARIA to explore its mechanisms further.
Th17.1 cell driven sarcoidosis-like inflammation after anti-BCMA CAR T cells in multiple myeloma
Authors: Leipold Alexander M. , Werner Rudolf A. , Düll Johannes , Jung Pius , John Mara , Stanojkovska Emilia , Zhou Xiang , Hornburger Hannah , Ruckdeschel Anna , Dietrich Oliver , Imdahl Fabian , Krammer Tobias , Knop Stefan , Rosenwald Andreas , Buck Andreas , Sander Leif Erik , Einsele Hermann , Kortüm K. Martin , Saliba Antoine-Emmanuel , Rasche Leo
Published: December 2022

Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.
Comparable Efficacy of Curcumin and Proton Pump Inhibitor for Functional Dyspepsia: A Randomized Double-blind Controlled Trial
Authors: Kongkam Pradermchai , Khongkha Wichittra , Lopimpisuth Chawin , Chumsri Chisanucha , Kosarussawadee Prach , Phutrakool Phanupong , Khamsai Sittichai , Sawanyawisuth Kittisak , Sura Thanyachai , Phisalprapa Pochamana , Buamahakul Thanwa , Siwamogsatham Sarawut , Angsusing Jaenjira , Poonniam Pratchayanan , Wanaratna Kulthanit , Teerachaisakul Monthaka , Pongpirul Krit
Published: December 2022

Objectives

Curcumin has been claimed to have gastrointestinal benefits, including dyspepsia, a common disorder that could be managed in a primary care setting with behavioral and dietary modifications as well as over-the-counter medications. This study aimed to compare the efficacy of curcumin versus omeprazole in improving patient-reported outcomes.

Design

Patients with functional dyspepsia were randomized to curcumin alone (C), omeprazole alone (O), or curcumin plus omeprazole (C+O). Patients in the combination group received 2 capsules of 250 mg curcumin 4 times daily and 1 capsule of 20 mg omeprazole once daily for 28 days. The primary outcomes were functional dyspepsia symptoms on days 28 and 56 assessed using the Severity of Dyspepsia Assessment (SODA) scores. Secondary outcomes were the occurrence of adverse events (AEs) and serious adverse events (SAEs).

Results

A total of 206 enrolled patients were randomly assigned to the three groups, of which 151 completed the study. Demographic data (age 49.7±11.9 years; female 73.4%), clinical characteristics, and baseline dyspepsia scores were comparable between the three groups. SODA scores in each group showed significant improvement on day 28 and day 56 in the pain, non-pain, and satisfaction categories. No significant differences were observed among the three groups and no serious adverse events occurred.

Conclusion

Curcumin and omeprazole have comparable efficacy for functional dyspepsia with no obvious synergistic effect.

Key Messages

What is already known

Dyspepsia is one of the most common disorders in which patients usually try behavioral and diet modifications, and over-the-counter drugs before seeing a physician.

Proton pump inhibitors have been established as an effective treatment for functional dyspepsia.

Curcumin, an active ingredient in turmeric, is currently used for the treatment of dyspepsia in countries in Southeast Asia.

However, there is no clinical trial evidence to support the use of curcumin as a first-line treatment.

What this study adds

Based on this double-blind, placebo-controlled clinical trial, oral curcumin is safe and well tolerated.

Patients with functional dyspepsia were treated with curcumin, curcumin plus omeprazole, and omeprazole, which showed a similar significant symptomatic improvement.

There was no synergistic effect detected between omeprazole and curcumin.

How this study might affect research, practice, or policy

This study provides a possible additional drug option for patients with functional dyspepsia.

More clinical trials are required to assess long-term outcomes and adverse events.
Statistical Assessment of Biomarker Replicability using MAJAR Method
Authors: Xie Yuhan , Zhai Song , Jiang Wei , Zhao Hongyu , Mehrotra Devan V. , Shen Judong
Published: December 2022

In the era of precision medicine, many biomarkers have been discovered to be associated with drug efficacy and safety responses, which can be used for patient stratification and drug response prediction. Due to small sample size and limited power of randomized clinical studies, meta-analysis is usually conducted to aggregate all available studies to maximize the power for identifying prognostic and predictive biomarkers. Since all available data are already aggregated, it is often challenging to find an independent study to replicate the discoveries from the meta-analysis (e.g., in meta-analysis of pharmacogenomics genome-wide association studies (PGx GWAS)), which seriously limits the potential impacts of the discovered biomarkers. To overcome this challenge, we develop a novel statistical framework, MAJAR (Meta-Analysis of Joint effect Associations for biomarker Replicability assessment), to jointly test prognostic and predictive effects and assess the replicability of identified biomarkers by implementing an enhanced Expectation–Maximization algorithm and calculating their posterior-probability-of-replicabilities (PPR) and Bayesian false discovery rates (Fdr). Extensive simulation studies were conducted to compare the performance of MAJAR and existing methods in terms of Fdr, power, and computational efficiency. The simulation results showed improved statistical power with well-controlled Fdr of MAJAR over existing methods and robustness to outliers under different data generation processes while considering both prognostic and predictive effects in the model. We further demonstrated the advantages of MAJAR over existing methods by applying MAJAR to the PGx GWAS summary statistics data from a large cardiovascular randomized clinical trial (IMPROVE-IT). Compared to testing main effects only, MAJAR identified 12 novel variants associated with the treatment-related LDL cholesterol (LDL-C) reduction from baseline.
Liver disease is a significant risk factor for cardiovascular outcomes - a UK Biobank study
Authors: Roca-Fernandez Adriana , Banerjee Rajarshi , Thomaides-Brears Helena , Telford Alison , Sanyal Arun , Neubauer Stefan , Nichols Thomas E , Raman Betty , McCracken Celeste , Petersen Steffen E , Ntusi Ntobeko AB , Cuthbertson Daniel J , Lai Michele , Dennis Andrea , Banerjee Amitava
Published: December 2022

Background

Chronic liver disease (CLD) and cardiovascular diseases (CVD) share common risk factors; the former is associated with a two-fold greater incidence of CVD. With most CLD being preventable/modifiable, early identification of at high-risk individuals is crucial. Using data from the UK Biobank imaging sub-study, we tested the hypothesis that early signs of liver disease (measured by iron corrected T1-mapping (cT1)) is associated with an increased risk of major cardiovascular events.

Methods

Liver disease activity (cT1) and fat (PDFF) were measured using LiverMultiScan® from images acquired between January-2016 and February-2020 in the UK Biobank imaging sub-study. Multivariable Cox regression was used to explore associations between liver cT1 (MRI) andprimary CVD outcomes(coronary artery disease, atrial fibrillation, embolism/vascular events, heart failure and stroke), as well as CVDhospitalisationandall-cause mortality. Other liver blood biomarkers (AST, ALT, AST/ALT ratio, FIB4), general metabolism biomarkers (CRP, HbA1c, systolic blood pressure (SBP), total cholesterol), and demographics were also included. Subgroup analysis was conducted in those without metabolic syndrome (MetS= at least 3 of these traits: a large waist, high triglycerides, low HDL cholesterol, increased SBP, or elevated HbA1c)

Results

33,616 participants in the UK Biobank imaging sub-study (65 years, mean BMI 26kg/m2, mean HbA1c 35mmol/mol) had complete MRI liver data with linked clinical outcomes [median time to major CVD event onset: 1.4 years (range:0.002-5.1); follow-up: 2.5 years (range:1.1-5.2)]. Liver disease activity (cT1), but not liver fat (PDFF), was associated with a higher risk of any major CVD event [HR(CI) 1.14(1.03-1.26), p=0.008], AF [1.30 (1.12-1.5), p<0.001]; HF [1.30 (1.08 - 1.58), p=0.004]; CVD hospitalisation [1.27(1.18-1.387, p<0.001] and all-cause mortality [1.19(1.02-1.38), p=0.026]. FIB4 index, was associated with HF [1.06 (1.01 - 1.10)), p=0.007]. The risk of CVD hospitalisation was also independently associated with cT1 in individuals without MetS [1.26(1.13-1.4), p<0.001].

Conclusion

Liver disease activity, as measured with MRI-derived biomarker cT1, was independently associated with a higher risk of new onset CVD events and all-cause mortality. This association occurred even without pre-existing impairment of metabolic health and was independent of FIB4 or liver fat content. cT1 was identified as a major predictor of adverse CVD outcomes.
The effect of free school fruit on academic performance: a nationwide quasi-experiment
Authors: Halkjelsvik Torleif , Bere Elling
Published: December 2022

In past research, higher intake of fruit has been associated with better academic achievement. Can the provision of one piece of fruit every school day improve children’s academic performance? In Norway, the government required all lower secondary schools to provide fruit to their pupils from 2007 to 2014. The policy also covered schools with combined elementary and lower secondary education (1st to 10thgrade), but not ordinary elementary schools (1stto 7thgrade). This differentiation, in combination with administrative data on test scores before, during, and after the law was enforced, created a nationwide quasi-experiment. Population register data on parents’ sociodemographic characteristics allowed for targeted analyses of a subsample with lower grades and lower fruit intake (boys of low socioeconomic status). In pre-registered analyses, we found no evidence that exposure to the free school fruit policy improved academic performance in the subsample or the entire population of Norwegian pupils. The free fruit policy coincided with a slight decline in performance among pupils covered by the policy. In a Western country with low levels of food insecurity, a policy that required schools to provide free fruit to pupils did not improve learning and may even have interfered with learning.

Significance Statement

The intake of fruit is believed to be beneficial for children’s concentration, and research has linked a higher intake of fruit to better academic performance. During a national policy that made it mandatory for some types of elementary schools to provide one daily piece of fruit to every pupil, we did not observe any beneficial effects on learning. On the contrary, the policy coincided with a slight performance decline. Even for low-socioeconomic boys, who have lower-than-average grades and a lower intake of fruit, there was no improvement in academic results associated with the policy. We speculate that the policy may have required resources that otherwise would be used for teaching or teaching-related administration.
Determinants for detection of infection with SARS-CoV-2 Omicron variants of concern in health care workers by rapid antigen tests
Authors: Wettengel Jochen M. , Strehle Katharina , von Lucke Catharina , Roggendorf Hedwig , Jeske Samuel D. , Christa Catharina , Zelger Otto , Haller Bernhard , Protzer Ulrike , Knolle Percy A.
Published: December 2022

IMPORTANCE

The rapid genetic evolution of SARS-CoV-2 and in particular the highly contagious Omicron variant of concern (VoC) may pose problems for rapid and accurate diagnosis of infection.

OBJECTIVE

Determine the diagnostic accuracy and robustness of a second generation rapid antigen tests compared to gold-standard, PCR-based diagnostics, for detection of infection with different SARS-CoV-2 Omicron VoC sub lineages in health care workers.

DESIGN, SETTING, AND PARTICIPANTS

The study included 428 health care workers from the University Hospital Munich Rechts der Isar of the Technical University of Munich who either reported recent onset of COVID-19 associated symptoms or completed routine diagnostic testing between 24thof May and 22ndof September 2022. All participants gave written informed consent to participate in this study and completed a questionnaire on infection-associated symptoms, prior SARS-CoV-2 infections and vaccination status.

INTERVENTIONS

During the first visit, two nasal swabs and one oropharyngeal swab were taken to perform two rapid antigen tests and a SARS-CoV-2 PCR-assay, respectively. A second set of nasal swabs was taken by the participants themselves two days later to repeat the two rapid antigen tests.

MAIN OUTCOMES AND MEASURES

The accuracy for detection of infection with different SARS-CoV-2 Omicron VoCs with two rapid antigen tests (Test IandTest II) was determined and compared to quantitative SARS-CoV-2 RNA levels detected by PCR.

RESULTS

In a side-by-side comparison, we found thatTest Idetected viral nucleocapsids from Omicron VoC (BA.5.2.3) at higher dilutions compared toTest II. In the 428 health care workers,Test Iand Test II detected PCR-confirmed SARS-CoV-2 infection with different Omicron VoCs (BA.2, BA.4, BA.5) with a sensitivity of 89.4% (95% CI 81.9% - 94.6%) and 83.7% (95% CI 75.12% - 90.18%), respectively. Increased sensitivity ofTest Iwas also reflected by earlier detection of SARS-CoV-2 infection. The lower test sensitivity ofTest IIcould be compensated for by a repeated test performed two days later.

CONCLUSIONS AND RELEVANCE

Our study demonstrates that rapid antigen tests are suited to detect infection with the SARS-CoV-2 Omicron VoC and reveal an advantage of a lower detection limit for earlier detection of infection in health care workers.
Mental health self-care during the COVID-19 pandemic: A prospective cohort study in Australia
Authors: Griffiths Daniel , Dhira Pradipta Vinsensia Maharani Kanya , Collie Alex
Published: December 2022

Pandemic public health measures have affected mental health for many people, resulting in varied approaches to mental health self-care. During 27 April – 26 July 2020, we surveyed a cohort of 1646 Australians, who were in paid employment prior to the pandemic, on changes in work, health, and managing their mental health concerns. Lifestyle changes were most the most frequently reported action to manage mental health concerns (78%), and were more common for women (OR=2.33, 95%CI=[1.82, 3.03]), and people experiencing recent work loss (OR=1.54, 95%CI=[1.04, 2.28]). Mental health self-care was more common for people experiencing psychological distress, or with pre-exisiting mental health conditions. Talking to friends about mental health, exercise and dietary changes, were more common for women and younger adults. Findings highlight potential benefits of reducing barriers to formal mental health services and supports during crises, particularly for people who less commonly seek help, and those experiencing psychological distress.