bluuebunny/crossref_metadata_2025 huggingface dataset:
Complement-dependent mpox virus-neutralizing antibodies in infected and vaccinated individuals
Authors: Hubert Mathieu , Guivel-Benhassine Florence , Bruel Timothée , Porrot Françoise , Planas Delphine , Vanhomwegen Jessica , Wiedemann Aurélie , Burrel Sonia , Marot Stéphane , Palich Romain , Monsel Gentiane , Diombera Harouna , Gallien Sébastien , Lopez-Zaragoza Jose Luis , Vindrios William , Taieb Fabien , Fernandes-Pellerin Sandrine , Delhaye Maurine , Laude Hélène , Arowas Laurence , Ungeheuer Marie-Noelle , Hocqueloux Laurent , Pourcher Valérie , Prazuck Thierry , Marcelin Anne-Geneviève , Lelièvre Jean-Daniel , Batéjat Christophe , Lévy Yves , Manuguerra Jean-Claude , Schwartz Olivier
Published: April 2023

Mpox virus (MPXV) caused a multi-country outbreak in non-endemic areas in 2022. The Modified Vaccinia Ankara (MVA)-based vaccine was used as prophylaxis, but its effectiveness remains poorly characterized. Here, we developed two assays for quantification of neutralizing antibodies (NAbs), using MVA-GFP or a recently isolated MPXV. We measured NAb levels in 470 sera from control, MPXV-infected or MVA-vaccinated individuals. Various levels of MVA NAbs were detected after infection, historic smallpox or MVA vaccination. MPXV was barely sensitive to neutralization. Addition of complement enhanced detection of responsive individuals and NAb levels. Anti-MVA and -MPXV NAbs were observed in 94% and 82% of infected individuals, respectively, and 92% and 56% of MVA vaccinees, respectively. NAb titers were higher in individuals born before 1980, highlighting the impact of historic smallpox vaccination on humoral immunity. Altogether, our results indicate that MPXV neutralization is complement-dependent and help uncover the mechanisms underlying vaccine effectiveness.

In 2022, mpox virus (MPXV) caused an unprecedented pandemic outbreak in non-endemic areas. The efficacy of currently available third generation MVA-based vaccines and the nature of the humoral response generated after MPXV infection remain poorly characterized. We established cell-based assays to measure neutralizing antibodies (NAbs) targeting MVA or MPXV. We analyzed 470 sera and detected robust levels of MVA NAbs after infection, historic smallpox vaccination or administration of MVA-based vaccines. Efficient MPXV neutralization required addition of complement. High NAb titers were measured in ancient smallpox-vaccinated MPXV-infected patients, suggesting a potential cross-protection mediated by hybrid immunity.
Multimodal imaging of microstructural cerebral changes and loss of synaptic density in Alzheimer’s disease
Authors: Moallemian Soodeh , Salmon Eric , Bahri Mohamed Ali , Beliy Nikita , Delhaye Emma , Balteau Evelyne , Phillips Christophe , Bastin Christine
Published: April 2023

Multiple neuropathological changes are involved in Alzheimer’s disease (AD). The current study investigated the concurrence of neurodegeneration, increased iron content, atrophy, and demyelination in AD.

Quantitative multiparameter MRI maps providing neuroimaging biomarkers for myelination and iron content along with synaptic density measurements using [18F] UCB-H PET were acquired in 24 AD and 19 Healthy controls (19 males).

The whole brain voxel-wise group comparison revealed demyelination in the right hippocampus, while no significant iron content difference was detected. Bilateral atrophy and synaptic density loss was observed in the hippocampus and amygdala. The multivariate GLM (mGLM) analysis shows a bilateral difference in the hippocampus and amygdala, right pallidum, left fusiform and temporal lobe suggesting that these regions are the most affected despite the diverse changes in brain tissue properties in AD. Demyelination was identified as the most affecting factor in the observed differences.

Here, the mGLM is introduced as an alternative for multiple comparisons between different modalities, reducing the risk of false positives while informing about the co-occurrence of neuropathological processes in AD.
Sleep Regularity and Mortality: A Prospective Analysis in the UK Biobank
Authors: Cribb Lachlan , Sha Ramon , Yiallourou Stephanie , Grima Natalie A , Cavuoto Marina , Baril Andree-Ann , Pase Matthew P.
Published: April 2023

Background

Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort.

Methods

The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hours apart, averaged over 7-days of accelerometry (range 0-100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models.

Findings

The mean sample age was 62 years (SD, 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard (p[global test of spline term] < 0·001). Hazard Ratios, relative to the median SRI, were 1·53 (95% confidence interval [CI]: 1·41, 1·66) for participants with SRI at the 5thpercentile (SRI = 41) and 0·90 (95% CI: 0·81, 1·00) for those with SRI at the 95thpercentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern.

Conclusions

Irregular sleep-wake patterns are associated with higher mortality risk.

Funding

National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer’s Association (2018-AARG-591358), and the Banting Fellowship Program (#454104).
Impaired flexible reward learning is associated with blunted reinforcement sensitivity and attenuated learning and choice signals in ventral striatum and parietal cortex of ADHD patients
Authors: Aster Hans-Christoph , Waltmann Maria , Busch Anika , Romanos Marcel , Gamer Matthias , van Noort Betteke Maria , Beck Anne , Kappel Viola , Deserno Lorenz
Published: April 2023

Reward-based learning and decision-making are prime candidates to understand symptoms of attention deficit hyperactivity disorder (ADHD). However, only limited evidence is available regarding the neurocomputational underpinnings of the alterations seen in ADHD. This particularly concerns the flexible behavioral adaption in dynamically changing environments, which is challenging for individuals with ADHD. One previous study points to elevated choice switching in adolescent ADHD, which was accompanied by disrupted learning signals in medial prefrontal cortex.

In the present study, we investigated young adults with ADHD (n=17, 18-32 years) and age and sex matched controls (n=17, 18-30 years) using a probabilistic reversal learning experiment during functional magnetic resonance imaging (fMRI). The task requires continuous learning to guide flexible behavioral adaptation to changing reward contingencies. To disentangle the neurocomputational underpinnings of the behavioral data, we used detailed reinforcement learning (RL) models, which informed the analysis of fMRI data.

ADHD patients performed worse than controls particularly in trials before reversals, i.e., when reward contingencies were stable. This pattern resulted from ‘noisy’ choice switching regardless of previous feedback. RL modelling showed decreased reinforcement sensitivity and enhanced learning rates for negative feedback in ADHD patients. At the neural level, this was reflected in diminished representation of choice probability in the left posterior parietal cortex in ADHD. Moreover, modelling showed a marginal reduction of learning about the unchosen option, which was paralleled by an equally marginal reduction in learning signals incorporating the unchosen option in the left ventral striatum.

Taken together, we show that flexible behavioral adaptation in the context of dynamically changing reward contingencies is impaired in ADHD. This is due to excessive choice switching (‘hyper-flexibility’), which can be detrimental or beneficial depending on the learning environment. Computationally, this results from blunted sensitivity to reinforcement. We detected neural correlates of this blunted sensitivity to reinforcement in the attention-control network, specifically in the parietal cortex. These neurocomputational findings are promising but remain preliminary due to the relatively small sample size.
Recognizing Activities of Daily Living using Multi-sensor Smart Glasses
Authors: Stankoski Simon , Sazdov Borjan , Broulidakis John , Kiprijanovska Ivana , Sofronievski Bojan , Cox Sophia , Gjoreski Martin , Archer James , Nduka Charles , Gjoreski Hristijan
Published: April 2023

Continuous and automatic monitoring of an individual’s physical activity using wearable devices provides valuable insights into their daily habits and patterns. This information can be used to promote healthier lifestyles, prevent chronic diseases, and improve overall well-being. Smart glasses are an emerging technology that can be worn comfortably and continuously. Their wearable nature and hands-free operation make them well suited for long-term monitoring of physical activity and other real-world applications. To this end, we investigated the ability of the multi-sensor OCOsense™ smart glasses to recognize everyday activities. We evaluated three end-to-end deep learning architectures that showed promising results when working with IMU (accelerometer, gyroscope, and magnetometer) data in the past. The data used in the experiments was collected from 18 participants who performed pre-defined activities while wearing the glasses. The best architecture achieved an F1 score of 0.81, demonstrating its ability to effectively recognize activities, with the most problematic categories being standing vs. sitting.
Impaired Proactive Cognitive Control in Parkinson’s disease
Authors: Kricheldorff Julius , Ficke Julia , Debener Stefan , Witt Karsten
Published: April 2023

Adaptive control has been studied in Parkinson’s disease (PD) mainly in the context of proactive control and with mixed results. We compared reactive- and proactive control in 30 participants with Parkinson’s disease (PD) to 30 age matched healthy control participants (HC). The electroencephalographic (EEG) activity of the participants was recorded over 128 channels while they performed a numerical Stroop task, in which we controlled for confounding stimulus-response learning. We assessed effects of reactive- and proactive control on reaction time-, accuracy- and EEG time-frequency data. Behavioral results show distinct impairments of proactive-reactive control in participants with PD, when tested on their usual medication. Participants with PD were unable to adapt cognitive control proactively and were less effective to resolve conflict using reactive control. Successful reactive and proactive control in the HC group was accompanied by a reduced conflict effect between congruent and incongruent items in midline-frontal theta power. Our findings provide evidence for a general impairment of proactive control in PD and suggest that the same may be the case for reactive control.
Thiamine alone rather than in combination with ascorbic acid is associated with improved survival in septic shock
Authors: Legouis David , Ourahmoune Aimad , Sgardello Sebastian , Sangla Frederic , Criton Gilles
Published: April 2023

Background

Sepsis and septic shock are common causes of ICU admission with devastating outcomes. Adjunctive therapies are urgently needed, and the use of high dose of vitamin B1 and C have recently gained interest. However, on the basis of a perceived possible synergic effect, most trials have never tested the combination of thiamine and ascorbic acid, with a separate assessment of the effect of each individual component. In this context, while the association of thiamine and ascorbic acid was not found to improve survival rates, potentially harmful effects were found when administering ascorbic acid alone. We have conducted a retrospective cohort study, comparing ICU mortality of septic shock patients receiving standard treatment, thiamine alone or a combination of thiamine and ascorbic acid.

Results

A total of 1800 patients were included, 1260 receiving standard care, 436 receiving only thiamine and 104 patients receiving a thiamine / ascorbic acid combination. Using doubly robust estimation of the treatment effect, combining propensity score weighting and variables adjustment, we found thiamine alone to be associated with a decrease in ICU mortality compared to the use of a thiamine / ascorbic acid combination (Hazar Ratio equal to 0.60, 95% Confidence Interval [0.36;0.99], p=0.048).

Conclusions

In septic shock patients, administration of thiamine is associated with improved ICU mortality when used alone rather than when associated with ascorbic acid. This result strengthens the evidence showing a lack of effectiveness of the ascorbic acid / thiamine combination reported in recent randomized controlled trials. Furthermore, it argues in favor of the need for further trials investigating the effect of thiamine in septic ICU patients as an adjunctive therapy.
Research Letter: Application of GPT-4 to select next-step antidepressant treatment in major depression
Authors: Perlis Roy H.
Published: April 2023

Introduction

Large language models perform well on a range of academic tasks including medical examinations. The performance of this class of models in psychopharmacology has not been explored.

Method

Chat GPT-plus, implementing the GPT-4 large language model, was presented with each of 10 previously-studied antidepressant prescribing vignettes in randomized order, with results regenerated 5 times to evaluate stability of responses. Results were compared to expert consensus.

Results

At least one of the optimal medication choices was included among the best choices in 38/50 (76%) vignettes: 5/5 for 7 vignettes, 3/5 for 1, and 0/5 for 2. At least one of the poor choice or contraindicated medications was included among the choices considered optimal or good in 24/50 (48%) of vignettes. The model provided as rationale for treatment selection multiple heuristics including avoiding prior unsuccessful medications, avoiding adverse effects based on comorbidities, and generalizing within medication class.

Conclusion

The model appeared to identify and apply a number of heuristics commonly applied in psychopharmacologic clinical practice. However, the inclusion of less optimal recommendations indicates that large language models may pose a substantial risk if routinely applied to guide psychopharmacologic treatment without further monitoring.
Understanding the Impact of Comorbidity-Interaction in Patients Undergoing Transcatheter Edge-to-Edge Mitral Valve Repair on Outcomes
Authors: Agrawal Ankit , Ramu Shivabalan Kathavarayan , Shekhar Shashank , Isogai Toshiaki , Bansal Agam , Yun James , Reed Grant W. , Puri Rishi , Krishnaswamy Amar , Kapadia Samir R.
Published: April 2023

BACKGROUND

Transcatheter Edge-to-Edge Mitral Valve Repair (M-TEER) is an accepted procedure for high-risk surgical patients with degenerative and functional mitral regurgitation. Non-cardiovascular comorbidities (NCCs) are highly prevalent in patients undergoing M-TEER. Although the impact of mitral valve anatomy and cardiac comorbidities in determination of M-TEER outcomes has been studied, precise understanding of the effect of the burden of NCCs on patients undergoing M-TEER remains unclear for acute outcomes. Our objective was to identify the association of NCC comorbidity-interaction patterns in patients undergoing M-TEER on length of stay (LOS), cost of care, and in-hospital major adverse cardiovascular events (MACE).

METHODS

9 245 admissions from the Nationwide Readmission Database that underwent M-TEER between 2015 and 2018 were included in the study. Patients were categorized by the overall burden of non-cardiovascular comorbidities (0, 1, 2, and ≥ 3). NCC included chronic liver disease, chronic lung disease, obesity, diabetes mellitus, dementia, major depressive disorder, chronic anemia, chronic kidney disease including end-stage renal disease (ESRD) on dialysis, and malignancy. Logistic Regression and Machine Learning (ML) algorithms were used to assess associations between comorbidity burden and in-hospital MACE.

RESULTS

Out of 9 245 index admissions, in-hospital MACE was recorded in a total of 504 (5.3 %). Of these, the majority (30.4%) had one NCC (n = 2 861). Patients with at least three NCCs had the longest median LOS [3.0, IQR (1.0 – 11.0)] and highest median cost of hospital care [$47 275, IQR (34 175.8 – 71 149.4)]. The Gradient Boosting (GB) classifier performed the best in predicting MACE with an AUROC of 96 % (95% CI: 0.95 – 0.97). The top features of importance that predicted in-hospital MACE were admission type, number of NCCs, and age in descending order.

CONCLUSIONS

Calibrated GB classifier identified patients with three NCCs as the subset of admission having the highest probability of a positive MACE outcome.
A Tool for Low-Cost, Quantitative Assessment of Shoulder Function Using Machine Learning
Authors: Darevsky David M. , Hu Daniel A. , Gomez Francisco A. , Davies Michael R. , Liu Xuhui , Feeley Brian T.
Published: April 2023

Tears within the stabilizing muscles of the shoulder, known as the rotator cuff (RC), are the most common cause of shoulder pain—often presenting in older patients and requiring expensive, advanced imaging for diagnosis1–4. Despite the high prevalence of RC tears within the elderly population, there are no accessible and low-cost methods to assess shoulder function which can eschew the barrier of an in-person physical exam or imaging study. Here we show that a simple string pulling behavior task, where subjects pull a string using hand-over-hand motions, provides a reliable readout of shoulder health across animals and humans. We find that both mice and humans with RC tears exhibit decreased movement amplitude, prolonged movement time, and quantitative changes in waveform shape during string pulling task performance. In rodents, we further note the degradation of low dimensional, temporally coordinated movements after injury. Furthermore, a predictive model built on our biomarker ensemble succeeds in classifying human patients as having a RC tear with >90% accuracy. Our results demonstrate how a combined framework bridging task kinematics, machine learning, and algorithmic assessment of movement quality enables future development of smartphone-based, at-home diagnostic tests for shoulder injury.
Fluid restrictive resuscitation with high molecular weight hyaluronan infusion in early peritonitis-sepsis
Authors: Barrueta Tenhunen Annelie , van der Heijden Jaap , Skorup Paul , Maccarana Marco , Larsson Anders , Larsson Anders , Perchiazzi Gaetano , Tenhunen Jyrki
Published: April 2023

Sepsis is a condition with high morbidity and mortality. Prompt recognition and initiation of treatment is essential. Despite forming an integral part of sepsis management, fluid resuscitation may also lead to volume overload, which in turn is associated with increased mortality. The optimal fluid strategy in sepsis resuscitation is yet to be defined. Hyaluronan, an endogenous glycosaminoglycan with high affinity to water is an important constituent of the endothelial glycocalyx. We hypothesized that exogenously administered hyaluronan would contribute to endothelial glycocalyx integrity and counteract intravascular volume depletion in a fluid restrictive model of peritonitis. In a prospective, blinded model of porcine peritonitis-sepsis, we randomized animals to intervention with hyaluronan (n=8) or 0.9% saline (n=8). The animals received an infusion of 0.1% hyaluronan 6 ml/kg/h, or the same volume of saline, during the first two hours of peritonitis. Stroke volume variation and hemoconcentration were comparable in the two groups throughout the experiment. Cardiac output (p=0.008 and p=0.017) and diastolic blood pressure (p=0.015 and p=0.019) were higher in the intervention group during the infusion of hyaluronan, but these effects disappeared as the experiment proceeded. The increase in lactate was more pronounced in the intervention group (p=0.041) throughout the experiment, while concentrations of surrogate markers of glycocalyx damage; syndecan 1 (0.6 ± 0.2 ng/ml vs 0.5 ± 0.2 ng/ml, p=0.292), heparan sulphate (1.23 ± 0.2 vs 1.4 ± 0.3 ng/ml, p=0.211) and vascular adhesion protein 1 (7.0 ± 4.1 vs 8.2 ± 2.3 ng/ml, p=0.492) were comparable in the two groups at the end of the experiment. In conclusion, hyaluronan did not counteract intravascular volume depletion in early peritonitis sepsis. The intervention was associated with higher cardiac output and diastolic blood pressure, than placebo, during the infusion. However, the increase in lactate throughout the experiment was more pronounced in the intervention group.
Precision Gestational Diabetes Treatment: Systematic review and Meta-analyses
Authors: Benham Jamie L , Gingras Véronique , McLennan Niamh-Maire , Most Jasper , Yamamoto Jennifer M , Aiken Catherine E , Ozanne Susan E , Reynolds RM
Published: April 2023

We hypothesized that a precision medicine approach could be a tool for risk-stratification of women to streamline successful GDM management. With the relatively short timeframe available to treat GDM, commencing effective therapy earlier, with more rapid normalization of hyperglycaemia, could have benefits for both mother and fetus. We conducted two systematic reviews, to identify precision markers that may predict effective lifestyle and pharmacological interventions. There were a paucity of studies examining precision lifestyle-based interventions for GDM highlighting the pressing need for further research in this area. We found a number of precision markers identified from routine clinical measures that may enable earlier identification of those requiring escalation of pharmacological therapy. Whether there are other sensitive markers that could be identified using more complex individual-level data, such as ‘omics’, and if these can be implemented in clinical practice remains unknown. These will be important to consider in future studies.
Enhanced Peer-Group strategies to support prevention of Mother-to-Child HIV transmission leads to increased retention in care in Uganda: A Randomized controlled trial
Authors: Amone Alexander , Gabagaya Grace , Wavamunno Priscilla , Rukundo Gordon , Namale-Matovu Joyce , Malamba Samuel S. , Lubega Irene , Homsy Jaco , King Rachel , Nakabiito Clemensia , Namukwaya Zikulah , Fowler Mary Glenn , Musoke Philippa
Published: April 2023

Introduction:Despite scale up of Option B+, long-term retention of women in HIV care during pregnancy and the postpartum period remains an important challenge. We compared adherence to clinic appointments and antiretroviral therapy (ART) at different follow-up time points between enrolment and 24 months postpartum among pregnant women living with HIV and initiating Option B+ randomized to a peer group support, community-based drug distribution and income-generating intervention called “Friends for Life Circles” (FLCs) versus the standard of care (SOC).

Methods:Between 16 May 2016 and 12 September 2017, 540 ART-naïve pregnant women living with HIV at urban and rural health facilities in Uganda were enrolled in the study. Participants were randomized 1:1 to the FLC intervention or SOC and assessed for adherence to prevention of mother to child HIV transmission (PMTCT) clinic appointments at 6 weeks, 12 and 24 months postpartum, self-reported adherence to ART at 6 weeks, 6 and 24 months postpartum validated by plasma HIV-1 RNA viral load (VL) measured at the same time points, and HIV status and HIV-free survival of infants at 18 months postpartum. We used Log-rank and Chi-Square p-values to test the equality of Kaplan-Meier survival probabilities and hazard rates (HR) for failure to retain in care for any reason by study arm.

Results:There was no significant difference in adherence to PMTCT clinic visits or to ART or in median viral loads between FLC and SOC arms at any follow-up time points. Retention in care through the end of study was high in both arms but significantly higher among participants randomized to FLC (86.7%) compared to SOC (79.3%), p=0.022. The adjusted HR of visit dropout was 2.5 times greater among participants randomized to SOC compared to FLC (aHR=2.498, 95% CI: 1.417 – 4.406, p=0.002). Median VL remained < 400 copies/ml in both arms at 6 weeks, 6 and 24 months postpartum.

Conclusions:Our findings suggest that programmatic interventions that provide group support, community based ART distribution and income-generation activities may contribute to retention in PMTCT care, HIV-free survival of children born to women living with HIV, and to the elimination of mother to child HIV transmission (MTCT).
Effect of nasal carriage ofBacillusspecies on COVID-19 severity: A cross-sectional study
Authors: Fowora Muinah A. , Aiyedogbon Adenike , Omolopo Ibilola , Tajudeen Ahmed O. , Olanlege Abdul-Lateef , Abioye Adefunke , Akintunde Grace B. , Folayan Morenike O. , Salako Babatunde L.
Published: April 2023

Intranasal sprays containingBacillusspecies are being researched for treating viral respiratory tract infections. The aim of this study was to assess the relationship between the nasal carriage ofBacillusand COVID-19 severity. This was a cross-sectional study that collected nasopharyngeal samples from adults 18 years and above visiting two COVID-19 testing centers in Lagos, Nigeria between September 2020 and September 2021.Bacillusspecies were cultured from the respiratory samples and confirmed using molecular methods. The dependent variable was COVID-19 status classified as negative, asymptomatic, mild, or severe. The independent variable was the nasal carriage ofBacillusspecies. Multinomial regression analysis was done to determine the association between nasal carriage ofBacillusand COVID-19 severity after adjusting for age, sex, and co-morbidity status. About 388 participants were included in the study with a mean (standard deviation) age of 40.05 (13.563) years. The majority (61.1%) of the participants were male, 100 (25.8%) had severe COVID-19, 130 (33.5%) had pre-existing comorbidity, and 76 (19.6%) hadBacilluscultured from their nasopharyngeal specimen. Bacillus species presence was significantly associated with higher odds of severe COVID-19 compared to having a negative COVID-19 status. However, the presence ofBacillusspecies was significantly associated with lower odds of severe COVID-19 compared to having a mild COVID-19 status. The study suggests that nasal carriage ofBacillusspecies may substantially impact the clinical course of COVID-19. This study supports the exploration ofBacillusspecies in the prevention and management of viral respiratory tract infections.

IMPORTANCE

With the introduction of intranasal spray containingBacillusspecies for the treatment of viral respiratory tract infections, such as COVID-19 and respiratory syncytial virus, identifying the association between the nasal carriage ofBacillusspecies and COVID-19 susceptibility and severity will help further substantiate the investigation of these bacteria for COVID-19 prevention and treatment. This study evaluated the association between the carriage ofBacillusspecies in the nasopharyngeal tract and COVID-19 severity and found that the presence ofBacillusspecies in the nasopharynx may significantly impact the clinical course of COVID-19.
Symptom persistence and biomarkers in post-COVID-19/chronic fatigue syndrome – results from a prospective observational cohort
Authors: Legler A. F. , Meyer-Arndt L. , Mödl L. , Kedor C. , Freitag H. , Stein E. , Hoppmann U. , Rust R. , Konietschke Frank , Thiel A. , Paul F. , Scheibenbogen C. , Bellmann-Strobl J.
Published: April 2023

Introduction

Post-COVID-19 syndrome (PCS) is characterized by a wide range of symptoms, predominantly fatigue and exertional intolerance. While disease courses during the first year post infection have been repeatedly described, little is known about long-term health consequences.

Methods

We assessed symptom severity and various biomarkers at three time points post infection (3-8 months (mo), 9-16mo, 17-20mo) in 106 PCS patients with moderate to severe fatigue and exertional intolerance. A subset of patients fulfilled diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (PCS-ME/CFS) based on the Canadian Consensus Criteria.

Results

While PCS-ME/CFS patients showed persisting symptom severity and disability up to 20mo post infection, PCS patients reported an overall health improvement. Inflammatory biomarkers equally decreased in both groups. Lower hand grip force at onset correlated with symptom persistence especially in PCS-ME/CFS.

Discussion

Debilitating PCS may persist beyond 20mo post infection, particularly in patients fulfilling diagnostic criteria for ME/CFS.
Human airway ex vivo models: new tools to study the airway epithelial cell response to SARS-CoV-2 infection
Authors: Assou Said , Ahmed Engi , Morichon Lisa , Nasri Amel , Foisset Florent , Bourdais Carine , Gros Nathalie , Wong Sonia , Petit Aurelie , Vachier Isabelle , Muriaux Delphine , Bourdin Arnaud , De Vos John
Published: April 2023

Airway-liquid interface cultures of primary epithelial cells and of induced pluripotent stem cell-derived airway epithelial cells (ALI and iALI, respectively) are physiologically relevant models for respiratory virus infection studies because they can mimic thein vivohuman bronchial epithelium. Here, we investigated gene expression profiles in human airway cultures (ALI and iALI models) infected or not with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using publicly available and our own bulk and single-cell transcriptome datasets. SARS-CoV-2 infection significantly increased the expression of interferon-stimulated genes (IFI44,IFIT1,IFIT3,IFI35,IRF9,MX1,OAS1,OAS3andISG15) and inflammatory genes (NFKBIA,CSF1,FOSL1,IL32andCXCL10) at day 4 post-infection, indicating activation of the interferon and immune responses to the virus. Extracellular matrix genes (ITGB6,ITGB1andGJA1) also were altered in infected cells. Single-cell RNA sequencing data revealed that SARS-CoV-2 infection damaged the respiratory epithelium, particularly mature ciliated cells. The expression of genes encoding intercellular communication and adhesion proteins also was deregulated, suggesting a mechanism to promote shedding of infected epithelial cells. These data demonstrate that ALI/iALI models help to understand the airway epithelium response to SARS-CoV-2 infection and are a key tool for developing COVID-19 treatments.
SARS-CoV-2 shifts transcription of host gene to increase Spike acylation and boost infectivity
Authors: Mesquita Francisco S. , Abrami Laurence , Bracq Lucie , Panyain Nattawadee , Mercier Vincent , Kunz Béatrice , Chuat Audrey , Carlevaro-Fita Joana , Trono Didier , van der Goot F. Gisou
Published: April 2023

SARS-CoV-2 infection requires Spike protein mediating fusion between the viral and cellular membranes. The fusogenic activity of Spike requires its post-translational lipid modification by host S-acyltransferases, predominantly ZDHHC20. Previous observations indicate that SARS-CoV-2 infection augments the S-acylation of Spike when compared to transfection. Here, we find that SARS-CoV-2 infection triggers a change in the transcriptional start site of thezddhc20gene, both in cells and in anin vivoinfection model, resulting in a 67-amino–acid-long N-terminally extended protein with 37-times higher Spike acylating activity, leading to enhanced viral infectivity. Furthermore, we observed the same induced transcriptional change in response to other challenges, such as chemically induced colitis, indicating that SARS-CoV-2 hijacks an existing cell damage response pathway to generate more infectious viruses.
Rapid epidemic expansion of chikungunya virus-ECSA lineage in Paraguay
Authors: Giovanetti Marta , Vazquez Cynthia , Lima Mauricio , Castro Emerson , Rojas Analia , de la Fuente Andrea Gomez , Aquino Carolina , Cantero Cesar , Fleitas Fatima , Torales Juan , Barrios Julio , Ortega Maria Jose , Gamarra Maria Liz , Villalba Shirley , Alfonzo Tania , Xavier Joilson , Adelino Talita , Fritsch Hegger , Iani Felipe C. M. , Pereira Glauco Carvalho , de Oliveira Carla , Schuab Gabriel , Rodrigues Evandra Strazza , Kashima Simone , Leite Juliana , Gresh Lionel , Franco Leticia , Tegally Houriiyah , Van Voorhis Wesley C. , Lessels Richard , de Filippis Ana Maria Bispo , Ojeda Andrea , Sequera Guillermo , Montoya Romeo , Holmes Edward C. , de Oliveira Tulio , Rico Jairo Mendez , Lourenço José , Fonseca Vagner , Junior Alcantara Luiz Carlos
Published: April 2023

The spread of vector-borne viruses, such as CHIKV, is a significant public health concern in the Americas, with over 120,000 cases and 51 deaths in 2023, of which 46 occurred in Paraguay. Using a suite of genomic, phylodynamic, and epidemiological techniques, we characterized the ongoing large CHIKV epidemic in Paraguay.

Article Summary Line

Genomic and epidemiological characterization of the ongoing Chikungunya virus epidemic in Paraguay
Epidemiology of Syphilis infections among pregnant women in Tanzania: Analysis of the 2020 national representative sentinel surveillance
Authors: Sunguya Bruno , Mboya Erick , Mizinduko Mucho , Balandya Belinda , Sabasaba Amon , Amani Davis Elias , Kamori Doreen , Ruhago George , Mkumbwa Rebecca , Faustine Prosper , Maokola Werner , Sambu Veryeh , Mushi Jeremiah , Nyamuhagata Mukome , Jullu Boniphace S. , Juya Amiri , Rugemalila Joan , Mgomella George , Asiimwe Sarah , Pembe Andrea B.
Published: April 2023

Background

Syphilis has detrimental effects on the health of the mother and that of the child when pregnant. Understanding its local epidemiology is essential for policies, planning, and implementation of targeted preventive interventions. Using data from the 2020 National Sentinel Surveillance of pregnant women attending antenatal clinics (ANCs) in Tanzania we determined the prevalence and determinants of Syphilis among pregnant women in Tanzania mainland.

Methodology

The ANC surveillance was conducted in 159 ANC sites from all 26 regions of Tanzania’s mainland from September to December 2020. It included all pregnant women older than 14 years on their first ANC visit in the current pregnancy during the survey period. Counselling for Syphilis was done using standard guidelines at the ANC and testing was done using rapid SD Bioline HIV/Syphilis Duo test kits. Analysis was done using both descriptive statistics to determine the prevalence and characteristics of syphilis, whereas, logistic regressions were used to examine the independent association between syphilis and dependent variables.

Results

A total of 38,783 women [median age (Interquartile range (IQR)) =25 (21-30) years] participated in the surveillance. Of them, 582 (1.4%) tested positive for Syphilis. A wide regional variation was observed with the highest burden in Kagera (4.5%) to the lowest burden in Kigoma (0.3%). The odds of Syphilis infections were higher among older women and those with no formal education. Compared with primigravids, women with 1-2, those with 3-4 and those with more than four previous pregnancies had 1.8 (aOR=1.8, 95% CI: 1.2-2.5), 2.1 (aOR=2.1, 95% CI: 1.4-3.1) and 2.6 (aOR=2.6, 95% CI: 1.7-3.9) higher odds of syphilis infection respectively.

Conclusion

Syphilis is still prevalent among pregnant women in Tanzania with a wide regional disparity. Efforts to prevent new infections, screen pregnant women, and treat those infected should be strategized to include all regions and renewed emphasis in regions with high burden, and importantly among women who are multipara, with the low level of education, and advanced age.
Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain
Authors: Liu Hanqing , Zeng Qiurui , Zhou Jingtian , Bartlett Anna , Wang Bang-An , Berube Peter , Tian Wei , Kenworthy Mia , Altshul Jordan , Nery Joseph R. , Chen Huaming , Castanon Rosa G. , Zu Songpeng , Li Yang Eric , Lucero Jacinta , Osteen Julia K. , Pinto-Duarte Antonio , Lee Jasper , Rink Jon , Cho Silvia , Emerson Nora , Nunn Michael , O’Connor Carolyn , Yao Zizhen , Smith Kimberly A. , Tasic Bosiljka , Zeng Hongkui , Luo Chongyuan , Dixon Jesse R. , Ren Bing , Behrens M. Margarita , Ecker Joseph R
Published: April 2023

Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brain’s 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq1) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH2) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq3dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brain’s cellular-spatial and regulatory genome diversity.
mitoSplitter: A mitochondrial variants-based method for efficient demultiplexing of pooled single-cell RNA-seq
Authors: Lin Xinrui , Chen Yingwen , Lin Li , Yin Kun , Cheng Rui , Wang Xiaoyu , Guo Ye , Wu Zhaorun , Zhang Yingkun , Li Jin , Yang Chaoyong , Song Jia
Published: April 2023

Single-cell RNA-seq (scRNA-seq) analysis of multiple samples separately can be costly and lead to batch effects. Exogenous barcodes or genome-wide RNA mutations can be used to demultiplex pooled scRNA-seq data, but they are experimentally or computationally challenging and limited in scope. Mitochondrial genomes are small but diverse, providing concise genotype information. We developed “mitoSplitter”, an algorithm that demultiplexes samples using mitochondrial RNA (mtRNA) variants, and demonstrated that mtRNA variants can be used to demultiplex large-scale scRNA-seq data. Using affordable computational resources, mitoSplitter can accurately analyze 10 samples and 60,000 cells in 6 hours. To avoid the batch effects from separated experiments, we applied mitoSplitter to analyze the responses of five non-small cell lung cancer (NSCLC) cell lines to BET chemical degradation in a multiplexed fashion. We found the synthetic lethality ofTOP2Ainhibition and BET chemical degradation in BET inhibitor-resistant cells. The result indicates that mitoSplitter can accelerate the application of scRNA-seq assays in biomedical research.
An open and lightweight method to analyze the vertical distribution of pelagic organisms using echogram screenshots
Authors: Bahlburg Dominik , Böhrer Thomas , Hüppe Lukas
Published: April 2023

Multifrequency echosounders are versatile devices commonly used in commercial fisheries, fisheries science and biological oceanography for the detection, quantification and even identification of organisms suspended in the underlying water column. They produce data that is rich in information, but can be tedious to process, often relying on expensive commercial software. The aim of our overarching research project was to analyze the vertical distribution of Antarctic krill swarms (Euphausia superba) in different seasons and regions in order to learn more about their behavioral ecology and ecophysiological adaptation. Therefore, we only required visual information on the distribution of krill swarms as well as metrics that characterize their vertical position. Instead of using storageintensive raw acoustic data, we developed a simple method to extract the relevant information from screenshots taken automatically on board a commercial krill fishing vessel during its operations. Using screenshots instead of raw data reduced the amount of data by a factor of >1000 (3 TB of raw data vs. 2.8 GB of screenshots for 8 months of observations) while preserving the information needed to carry out our seasonal behavioral analyses. In this study, we present the workflow and demonstrate that our method produces qualitatively and quantitatively similar results to using raw data, while being much less demanding in terms of computation and data storage. The code for the data processing is written in the open source programming language R, publicly accessible and therefore, provides a useful resource for other scientists interested in the dynamics of vertical biomass distributions from echosounder data.
Inter-generational nuclear crosstalk links the control of gene expression to programmed genome rearrangements during theParameciumsexual cycle
Authors: Bazin-Gélis Mélanie , Eleftheriou Evangelia , Zangarelli Coralie , Lelandais Gaëlle , Sperling Linda , Arnaiz Olivier , Bétermier Mireille
Published: April 2023

Multinucleate cells are found in many eukaryotes, but how multiple nuclei coordinate their functions is still poorly understood. In the cytoplasm of the ciliateParamecium tetraurelia, two micronuclei (MIC) serving sexual reproduction coexist with a somatic macronucleus (MAC) dedicated to gene expression. During sexual processes, the MAC is progressively destroyed while still ensuring transcription and new MACs develop from copies of the zygotic MIC. Several gene clusters are successively induced and switched off before vegetative growth resumes. Concomitantly, programmed genome rearrangements (PGR) remove transposons and their relics from the new MACs. Development of the new MACs is controlled by the old MAC, since the latter expresses genes involved in PGR, including thePGMgene encoding the essential PiggyMac endonuclease that cleaves the ends of eliminated sequences. Using RNA deep sequencing and transcriptome analysis, we show that impairing PGR up-deregulates key PGR genes, together with ∼600 other genes possibly also involved in PGR. Among these genes, 42% are no longer induced when no new MACs are formed, including 180 genes that are co-expressed withPGMunder all tested conditions. We propose that bi-directional crosstalk between the two coexisting generations of MACs links gene expression to the progression of MAC development.
Phenotype prediction using biologically interpretable neural networks on multi-cohort multi-omics data
Authors: van Hilten Arno , van Rooij Jeroen ,   BIOS consortium, Ikram M. Arfan , Niessen Wiro. J. , van Meurs Joyce. B.J. , Roshchupkin Gennady V.
Published: April 2023

Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability, and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA-expression and CpG methylation data from blood of the BIOS consortium(4 population cohorts, N_total=2940). In a cohort-wise cross validation setting, the consistency of the diagnostic performance and interpretation was assessed.

Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI, 0.90 - 1.00) and interpretation revealed the involvement of well-replicated genes such asAHRR, GPR15andLRRN3. LDL-level predictions only generalized in a single cohort with an R2of 0.07 (95% CI, 0.05 - 0.08). Age was infered with a mean error of 5.16 (95% CI, 3.97 - 6.35) years with the genesCOL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2andCD34consistently predictive. In general, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks.

We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts.
Topographical analysis of immune cell interactions reveals a biomechanical signature for immune cytolysis
Authors: de Jesus Miguel , Settle Alexander H. , Vorselen Daan , Gaetjens Thomas K. , Galiano Michael , Wong Yung Yu , Fu Tian-Ming , Santosa Endi , Winer Benjamin Y. , Tamzalit Fella , Wang Mitchell S. , Bao Zhirong , Sun Joseph C. , Shah Pavak , Theriot Julie A. , Abel Steven M. , Huse Morgan
Published: April 2023

Immune cells live intensely physical lifestyles characterized by structural plasticity, mechanosensitivity, and force exertion. Whether specific immune functions require stereotyped patterns of mechanical output, however, is largely unknown. To address this question, we used super-resolution traction force microscopy to compare cytotoxic T cell immune synapses with contacts formed by other T cell subsets and macrophages. T cell synapses were globally and locally protrusive, which was fundamentally different from the coupled pinching and pulling of macrophage phagocytosis. By spectrally decomposing the force exertion patterns of each cell type, we associated cytotoxicity with compressive strength, local protrusiveness, and the induction of complex, asymmetric interfacial topographies. These features were further validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, direct imaging of synaptic secretory events, andin silicoanalysis of interfacial distortion. We conclude that T cell-mediated killing and, by implication, other effector responses are supported by specialized patterns of efferent force.