bluuebunny/crossref_metadata_2025 huggingface dataset:
Factorial design-assisted spectroscopic determination of oxybutynin hydrochloride
Authors: Yosrey Eman , Elmansi Heba , Sheribah Zeinab A. , El-Sayed Metwally Mohamed
Published: November 2021

In this study, we have developed two facile spectroscopic methods for quantifying oxybutynin (OBT) hydrochloride in its pure form and tablets using design of experiments (DOEs). The spectroscopic methods depended on the ion-pair complex formation between the tertiary amino group in the drug and eosin in 0.2 M acetate buffer of pH 4. Method I involves spectrophotometric measurement of the absorbance of the developed complex at 550 nm and showed linearity through 1.0–10.0 µg ml
−1
. Method II involves spectrofluorometric measurement of the quenching influence of OBT on the native fluorescence of eosin (λ excitation/λ emission of 304/548 nm) and showed linearity through 1.0–6.0 µg ml
−1
. Critical parameters were identified through preliminary trials and optimized using the DOE. Additionally, the quenching mechanism was investigated and the pathway of the reaction was postulated. The fluorescence quenching constant and thermodynamic parameters were explored using the Stern–Volmer plot and Van't Hoff graph, respectively. Assessments conducted via analytical ecoscale revealed the ‘excellent-greenness’ of the methodology. The two methods have the potentials of being green and fast compared with other reported methods.
A growth model for water distribution networks with loops
Authors: Sugishita Kashin , Abdel-Mottaleb Noha , Zhang Qiong , Masuda Naoki
Published: November 2021

Water distribution networks (WDNs) expand their service areas over time. These growth dynamics are poorly understood. One facet of WDNs is that they have loops in general, and closing loops may be a functionally important process for enhancing their robustness and efficiency. We propose a growth model for WDNs that generates networks with loops and is applicable to networks with multiple water sources. We apply the proposed model to four empirical WDNs to show that it produces networks whose structure is similar to that of the empirical WDNs. The comparison between the empirical and modelled WDNs suggests that the empirical WDNs may realize a reasonable balance between cost, efficiency and robustness in terms of the network structure. We also study the design of pipe diameters based on a biological positive feedback mechanism. Specifically, we apply a model inspired by
Physarum polycephalum
to find moderate positive correlations between the empirical and modelled pipe diameters. The difference between the empirical and modelled pipe diameters suggests that we may be able to improve the performance of WDNs by following organizing principles of biological flow networks.
Recent natural variability in global warming weakened phenological mismatch and selection on seasonal timing in great tits (Parus major)
Authors: Visser Marcel E. , Lindner Melanie , Gienapp Phillip , Long Matthew C. , Jenouvrier Stephanie
Published: November 2021

Climate change has led to phenological shifts in many species, but with large variation in magnitude among species and trophic levels. The poster child example of the resulting phenological mismatches between the phenology of predators and their prey is the great tit (Parus major), where this mismatch led to directional selection for earlier seasonal breeding. Natural climate variability can obscure the impacts of climate change over certain periods, weakening phenological mismatching and selection. Here, we show that selection on seasonal timing indeed weakened significantly over the past two decades as increases in late spring temperatures have slowed down. Consequently, there has been no further advancement in the date of peak caterpillar food abundance, while great tit phenology has continued to advance, thereby weakening the phenological mismatch. We thus show that the relationships between temperature, phenologies of prey and predator, and selection on predator phenology are robust, also in times of a slowdown of warming. Using projected temperatures from a large ensemble of climate simulations that take natural climate variability into account, we show that prey phenology is again projected to advance faster than great tit phenology in the coming decades, and therefore that long-term global warming will intensify phenological mismatches.
Growth of Neanderthal infants from Krapina (120–130 ka), Croatia
Authors: Mahoney Patrick , McFarlane Gina , Smith B. Holly , Miszkiewicz Justyna J. , Cerrito Paola , Liversidge Helen , Mancini Lucia , Dreossi Diego , Veneziano Alessio , Bernardini Federico , Cristiani Emanuela , Behie Alison , Coppa Alfredo , Bondioli Luca , Frayer David W. , Radovčić Davorka , Nava Alessia
Published: November 2021

Modern humans have a slow and extended period of childhood growth, but to what extent this ontogenetic pathway was present in Neanderthals is debated. Dental development, linked to the duration of somatic growth across modern primates, is the main source for information about growth and development in a variety of fossil primates, including humans. Studies of Neanderthal permanent teeth report a pace of development either similar to recent humans or relatively accelerated. Neanderthal milk teeth, which form and emerge before permanent teeth, provide an opportunity to determine which pattern was present at birth. Here we present a comparative study of the prenatal and early postnatal growth of five milk teeth from three Neanderthals (120 000–130 000 years ago) using virtual histology. Results reveal regions of their milk teeth formed quickly before birth and over a relatively short period of time after birth. Tooth emergence commenced towards the earliest end of the eruption schedules displayed by extant human children. Advanced dental development is consistent with expectations for Neanderthal infant feeding.
Environmental variability directly affects the prevalence of divorce in monogamous albatrosses
Authors: Ventura Francesco , Granadeiro José Pedro , Lukacs Paul M. , Kuepfer Amanda , Catry Paulo
Published: November 2021

In many socially monogamous species, divorce is a strategy used to correct for sub-optimal partnerships and is informed by measures of previous breeding performance. The environment affects the productivity and survival of populations, thus indirectly affecting divorce via changes in demographic rates. However, whether environmental fluctuations directly modulate the prevalence of divorce in a population remains poorly understood. Here, using a longitudinal dataset on the long-lived black-browed albatross (Thalassarche melanophris) as a model organism, we test the hypothesis that environmental variability directly affects divorce. We found that divorce rate varied across years (1% to 8%). Individuals were more likely to divorce after breeding failures. However, regardless of previous breeding performance, the probability of divorce was directly affected by the environment, increasing in years with warm sea surface temperature anomalies (SSTA). Furthermore, our state-space models show that warm SSTA increased the probability of switching mates in females in successful relationships. For the first time, to our knowledge, we document the disruptive effects of challenging environmental conditions on the breeding processes of a monogamous population, potentially mediated by higher reproductive costs, changes in phenology and physiological stress. Environmentally driven divorce may therefore represent an overlooked consequence of global change.
Beamforming seizures from the temporal lobe
Authors: Dominguez Luis Garcia , Tarazi Apameh , Valiante Taufik , Wennberg Richard
Published: November 2021

Background

Surgical treatment of drug-resistant temporal lobe epilepsy (TLE) depends on proper identification of the seizure onset zone (SOZ), and differentiation of mesial, temporolimbic seizure onsets from temporal neocortical seizure onsets. Non-invasive source imaging using electroencephalography (EEG) and magnetoencephalography (MEG) can provide accurate information on interictal spike localization; however, EEG and MEG have low sensitivity for epileptiform activity restricted to deep temporolimbic structures. Moreover, in mesial temporal lobe epilepsy (MTLE), interictal spikes frequently arise in neocortical foci distant from the SOZ, rendering interictal spike localization potentially misleading for presurgical planning.

Methods

In this study, we used two different beamformer techniques applied to the MEG signal of ictal events acquired during EEG-MEG recordings in six patients with TLE (three neocortical, three MTLE). The ictal source localization results were compared to the patients’ ground truth SOZ localizations determined from intracranial EEG and/or clinical, neuroimaging and postsurgical outcome evidence.

Results

Beamformer analysis proved to be highly accurate in all cases and able to reliably identify focal seizure onsets localized to mesial, temporolimbic structures. In three patients, interictal spikes were either absent, too complex for inverse dipole modeling, or localized to anterolateral temporal neocortex distant to a mesial temporal SOZ.

Conclusions

This report demonstrates the suitability of MEG beamformer analysis of ictal events in TLE, which can supersede or complement the traditional analysis of interictal spikes. The method outlined is applicable to any type of epileptiform event, greatly expanding the information value of MEG and broadening its utility for presurgical recording in epilepsy.
Surveillance of NK cell subsets and cytokine profile in patients with Rocky Mountain Spotted Fever
Authors: Maynez-Prieto Carolina , Adame-Gallegos Jaime R. , Ramírez-López Moisés , Quintana-Mendías Estefanía , Estrada-Aguirre Blanca E. , Baquera-Arteaga Maribel , Manzanera-Ornelas Diana , Guevara-Macías Enrique , Espino-Solís Gerardo P.
Published: November 2021

Introduction

The intracellular pathogen Rickettsia rickettsii causes tick-borne spotted fever (also called Rocky Mountain spotted fever (RMSF) and is increasingly recognized as an emerging cause of febrile illness in Mexico. However, little is known about the early immune responses to infection.

Methodology

Four RMSF pediatric patients on acute phase and eight healthy controls from Chihuahua, Mexico were recruited. The natural killer cell (NK) immunophenotype and the cytokine profile in peripheral blood were characterized by flow cytometry.

Results

There was a decrease in total NK (CD3-CD56+) and activation receptor (CD56+NKG2D+) in NK population in patients at day 3 after hospitalization, when compared to healthy controls. Regarding to the NK cytotoxic population (CD16brightCD56dim) there was an observed decrease in patients only, between day 3 and on hospital admission. Interleukin and chemokine levels measured were significantly increased in patients upon admission compared to controls (IL-6, IL-8, IL-10, IP-10, MCP-1 and MIG).

Conclusions

This study shows that circulating NK cells are numerically decreased, while cytokines induce a pro-inflammatory process in patients.
Sustained negative mental health outcomes among healthcare workers over the first year of the COVID-19 pandemic: a prospective cohort study
Authors: Mediavilla Roberto , Fernández-Jiménez Eduardo , Martinez-Morata Irene , Jaramillo Fabiola , Andreo-Jover Jorge , Morán-Sánchez Inés , Mascayano Franco , Moreno-Küstner Berta , Minué Sergio , Ayuso-Mateos José Luis , Bryant Richard A. , Bravo-Ortiz María-Fe , Martínez-Alés Gonzalo ,   the COVID-19 HEalth caRe wOrkErS – Spain (HEROES-SPA) Group
Published: November 2021

Objective

To characterize the evolution of healthcare workers’ mental health status over the 1-year period following the initial COVID-19 pandemic outbreak and to examine baseline characteristics associated with resolution or persistence of mental health problems over time.

Methods

We conducted an 8-month follow-up cohort study. Eligible participants were healthcare workers working in Spain. Baseline data were collected during the initial pandemic outbreak. Survey-based self-reported measures included COVID-19-related exposures, sociodemographic characteristics, and three mental health outcomes (psychological distress, depression symptoms, and posttraumatic stress disorder symptoms). We examined three longitudinal trajectories in mental health outcomes between baseline and follow-up assessments (namelyasymptomatic/stable, recovering, andpersistently symptomatic/worsening).

Results

We recruited 1,807 participants. Between baseline and follow-up assessments, the proportion of respondents screening positive for psychological distress and probable depression decreased, respectively, from 74% to 56% and from 28% to 21%. Two-thirds remained asymptomatic/stable in terms of depression symptoms and 56% remained symptomatic or worsened over time in terms of psychological distress.

Conclusions

Poor mental health outcomes among healthcare workers persisted over time. Occupational programs and mental health strategies should be put in place.
Behaviour, booster vaccines and waning immunity: modelling the medium-term dynamics of SARS-CoV-2 transmission in England in the Omicron era
Authors: Barnard Rosanna C. , Davies Nicholas G. ,   Centre for Mathematical Modelling of Infectious Diseases COVID-19 working group, Jit Mark , Edmunds W. John
Published: November 2021

England has experienced a heavy burden of COVID-19, with multiple waves of SARS-CoV-2 transmission since early 2020 and high infection levels following the emergence and spread of Omicron variants since late 2021. In response to rising Omicron cases, booster vaccinations were accelerated and offered to all adults in England. Using a model fitted to more than 2 years of epidemiological data, we project potential dynamics of SARS-CoV-2 infections, hospital admissions and deaths in England to December 2022. We consider key uncertainties including future behavioural change and waning immunity, and assess the effectiveness of booster vaccinations in mitigating SARS-CoV-2 disease burden between October 2021 and December 2022. If no new variants emerge, SARS-CoV-2 transmission is expected to decline, with low levels remaining in the coming months. The extent to which projected SARS-CoV-2 transmission resurges later in 2022 depends largely on assumptions around waning immunity and to some extent, behaviour and seasonality.
In vitro, classical complement activation differs by disease severity and between SARS-CoV-2 antigens
Authors: Lamerton Rachel E , Marcial Juarez Edith , Faustini Sian E , Perez-Toledo Marisol E , Goodall Margaret , Jossi Sian E , Newby Maddy L , Chapple Iain , Dietrich Thomas , Veenith Tonny , Shields Adrian M , Harper Lorraine , Henderson Ian R , Rayes Julie , Wraith David C , Watson Steve P , Crispin Max , Drayson Mark T , Richter Alex G , Cunningham Adam F
Published: November 2021

Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of anti-SARS-CoV-2 antibodies from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the antigen and subjects studied. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending on the specific antigen targeted and the disease status of the subject.
Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial
Authors: Holubar Marisa , Subramanian Aruna , Purington Natasha , Hedlin Haley , Bunning Bryan , Walter Katharine S. , Bonilla Hector , Boumis Athanasia , Chen Michael , Clinton Kimberly , Dewhurst Liisa , Epstein Carol , Jagannathan Prasanna , Kaszynski Richard H. , Panu Lori , Parsonnet Julie , Ponder Elizabeth L. , Quintero Orlando , Sefton Elizabeth , Singh Upinder , Soberanis Luke , Truong Henry , Andrews Jason R. , Desai Manisha , Khosla Chaitan , Maldonado Yvonne
Published: November 2021

Background

Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries.

Methods

We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1:1 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 deep sequencing, we assessed favipiravir’s impact on mutagenesis.

Results

From July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants’ mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48 – 1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54 – 1.29; sustained: HR 0.87, 95% CI 0.52 – 1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment.

Conclusions

Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

Trial registration number

NCT04346628

In this phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or uncomplicated patients with COVID-19, we found no difference in time to shedding cessation or time to symptom resolution by treatment arm.
Whole Genome Sequencing Illuminates the Developmental Signatures of Human Language Ability
Authors: Koomar Tanner , Casten Lucas G , Thomas Taylor R , Koh Jin-Young , Hofamman Dabney , Thenuwara Savantha , Momany Allison , O’Brien Marlea , Murray Jeffrey , Tomblin J Bruce , Michaelson Jacob J
Published: November 2021

1

Language is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis — and how it compares to that of more general cognitive functioning— remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals who were characterized with seven latent language phenotypes. We conducted region, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few “language genes”.
Human phospho-signaling networks of SARS-CoV-2 infection are rewired by population genetic variants
Authors: Pellegrina Diogo , Bahcheli Alexander T. , Krassowski Michal , Reimand Jüri
Published: November 2021

SARS-CoV-2 infection hijacks signaling pathways and induces protein-protein interactions between human and viral proteins. Human genetic variation may impact SARS-CoV-2 infection and COVID-19 pathology; however, the role of genetic variation in these signaling networks remains uncharacterized. We studied human single nucleotide variants (SNVs) affecting phosphorylation sites modulated by SARS-CoV-2 infection, using machine learning to identify amino acid changes altering kinase-bound sequence motifs. We found 2033 infrequent phosphorylation-associated SNVs (pSNVs) that are enriched in sequence motif alterations, potentially reflecting the evolution of signaling networks regulating host defenses. Proteins with pSNVs are involved in viral life cycle processes and host responses, including regulators of RNA splicing and interferon response, as well as glucose homeostasis pathways with potential associations with COVID-19 co-morbidities. Certain pSNVs disrupt CDK and MAPK substrate motifs and replace these with motifs recognized by Tank Binding Kinase 1 (TBK1) involved in innate immune responses, indicating consistent rewiring of infection signaling networks. Our analysis highlights potential genetic factors contributing to the variation of SARS-CoV-2 infection and COVID-19 and suggests leads for mechanistic and translational studies.
Development and Performance verification of colloidal gold labeled SARS-CoV-2 antigen detection method for routine popular screening of COVID-19 with clinical samples in Poland and China
Authors: Guo Chuanxiang , Yao Li , Chen Fengling , Zhang Chao , Chen Wei
Published: November 2021

In this research, we have constructed and optimized the colloidal gold labeled lateral flow strip (LFS) for rapid detection of antigen of SARS-CoV-2 and rapid screening of COVID-19. Based on the constructed and optimized colloidal gold lateral flow strip, the parameters of the LFS have been well evaluated with the clinical samples in the professional labs. The screening performance have also been evaluated from the aspects including the CT values, age distribution and onset of symptoms. Finally, based on the detection results of 420 clinical samples, the LFS can achieve the screening of COVID-19 with the positive percentage agreement (PPA, sensitivity), negative percent agreement (NPA, specificity), the positive predictive value (PPV) and the negative predictive value (NPV) of 96.8%, 100%, 100% and 96.6%, respectively, indicating the powerful potential for practical screening applications in pandemic control. Of great significance, this developed SARS-CoV-2 antigen detection method has also been successfully utilized for screening of delta-variant of SARS-CoV-2.
Simulating the impact of vaccination rates on the initial stages of a COVID-19 outbreak in New Zealand (Aotearoa) with a stochastic model
Authors: Watson Leighton M.
Published: November 2021

Aim

The August 2021 COVID-19 outbreak in Auckland has caused the New Zealand government to transition from an elimination strategy to suppression, which relies heavily on high vaccination rates in the population. As restrictions are eased and as COVID-19 leaks through the Auckland boundary, there is a need to understand how different levels of vaccination will impact the initial stages of COVID-19 outbreaks that are seeded around the country.

Method

A stochastic branching process model is used to simulate the initial spread of a COVID-19 outbreak for different vaccination rates.

Results

High vaccination rates are effective at minimizing the number of infections and hospitalizations. Increasing vaccination rates from 20% (approximate value at the start of the August 2021 outbreak) to 80% (approximate proposed target) of the total population can reduce the median number of infections that occur within the first four weeks of an outbreak from 1011 to 14 (25thand 75thquantiles of 545-1602 and 2-32 for V=20% and V=80%, respectively). As the vaccination rate increases, the number of breakthrough infections (infections in fully vaccinated individuals) and hospitalizations of vaccinated individuals increases. Unvaccinated individuals, however, are 3.3x more likely to be infected with COVID-19 and 25x more likely to be hospitalized.

Conclusion

This work demonstrates the importance of vaccination in protecting individuals from COVID-19, preventing high caseloads, and minimizing the number of hospitalizations and hence limiting the pressure on the healthcare system.
Establishing and characterising large COVID-19 cohorts after mapping the Information System for Research in Primary Care in Catalonia to the OMOP Common Data Model
Authors: Burn Edward , Fernández-Bertolín Sergio , Voss Erica A , Blacketer Clair , Aragón Maria , Recalde Martina , Roel Elena , Pistillo Andrea , Raventós Berta , Reyes Carlen , van Sandijk Sebastiaan , Halvorsen Lars , Rijnbeek Peter R , Duarte-Salles Talita
Published: November 2021

Background

Few datasets have been established that capture the full breadth of COVID-19 patient interactions with a health system. Our first objective was to create a COVID-19 dataset that linked primary care data to COVID-19 testing, hospitalisation, and mortality data at a patient level. Our second objective was to provide a descriptive analysis of COVID-19 outcomes among the general population and describe the characteristics of the affected individuals.

Methods

We mapped patient-level data from Catalonia, Spain, to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). More than 3,000 data quality checks were performed to assess the readiness of the database for research. Subsequently, to summarise the COVID-19 population captured, we established a general population cohort as of the 1st March 2020 and identified outpatient COVID-19 diagnoses or positive test results for SARS-CoV-2, hospitalisations with COVID-19, and COVID-19 deaths during follow-up, which went up until 30th June 2021.

Findings

Mapping data to the OMOP CDM was performed and high data quality was observed. The mapped database was used to identify a total of 5,870,274 individuals, who were included in the general population cohort as of 1st March 2020. Over follow up, 604,472 had either an outpatient COVID-19 diagnosis or positive test result, 58,991 had a hospitalisation with COVID-19, 5,642 had an ICU admission with COVID-19, and 11,233 had a COVID-19 death. People who were hospitalised or died were more commonly older, male, and with more comorbidities. Those admitted to ICU with COVID-19 were generally younger and more often male than those hospitalised in general and those who died.

Interpretation

We have established a comprehensive dataset that captures COVID-19 diagnoses, test results, hospitalisations, and deaths in Catalonia, Spain. Extensive data checks have shown the data to be fit for use. From this dataset, a general population cohort of 5.9 million individuals was identified and their COVID-19 outcomes over time were described.

Funding

Generalitat de Catalunya and European Health Data and Evidence Network (EHDEN).
The experiences of 33 national COVID-19 dashboard teams during the first year of the pandemic in the WHO European Region: a qualitative study
Authors: Barbazza Erica , Ivanković Damir , Davtyan Karapet , Poldrugovac Mircha , Yelgezekova Zhamin , Willmington Claire , Meza-Torres Bernardo , Bos Véronique L.L.C. , Fernandes Óscar Brito , Rotar Alexandru , Nuti Sabina , Vainieri Milena , Carinci Fabrizio , Azzopardi-Muscat Natasha , Groene Oliver , Novillo-Ortiz David , Klazinga Niek , Kringos Dionne
Published: November 2021

Background

Governments across the WHO European Region prioritized dashboards for reporting COVID-19 data. The ubiquitous use of dashboards for public reporting is novel. This study explores the development of COVID-19 dashboards during the pandemic’s first year and common barriers, enablers and lessons from the experiences of teams responsible for their development.

Methods

Multiple methods were applied to identify and recruit COVID-19 dashboard teams using a purposive, quota sampling approach. Semi-structured group interviews were conducted between April– June 2021. Using elaborative coding and thematic analysis, descriptive and explanatory themes were derived from interview data. A validation workshop with study participants was held in June 2021.

Results

Eighty informants, representing 33 national COVID-19 dashboard teams across the WHO European Region participated. Most dashboards were launched swiftly in the first months of the pandemic, between February–May 2020. The urgency, intense workload, limited human resources, data and privacy constraints, and public scrutiny were common to the initial development stage. Themes related to barriers or enablers were identified pertaining to the pre-pandemic context, pandemic itself, people and processes, software, data, and users. Lessons emerged around the themes of simplicity, trust, partnership, software and data, and change.

Conclusions

COVID-19 dashboards were developed in a learning-by-doing approach. The experiences of teams signal initial under-preparedness was compensated by high-level political endorsement, the professionalism of teams, accelerated data improvements, and immediate support of commercial software solutions. To leverage the full potential of dashboards, investments are needed at team-, national- and pan-European-level.
Higher Limbic and Basal Ganglia volumes in surviving COVID-negative patients and the relations to fatigue
Authors: Hafiz Rakibul , Gandhi Tapan Kumar , Mishra Sapna , Prasad Alok , Mahajan Vidur , Di Xin , Natelson Benjamin H. , Biswal Bharat B.
Published: November 2021

Background

Among systemic abnormalities caused by the novel coronavirus, little is known about the critical attack on the central nervous system (CNS). Few studies have shown cerebrovascular pathologies that indicate CNS involvement in acute patients. However, replication studies are necessary to verify if these effects persist in COVID-19 survivors more conclusively. Furthermore, recent studies indicate fatigue is highly prevalent among ‘long-COVID’ patients. How morphometry in each group relate to work-related fatigue need to be investigated.

Method

COVID survivors were MRI scanned two weeks after hospital discharge. We hypothesized, these survivors will demonstrate altered gray matter volume (GMV) and experience higher fatigue levels when compared to healthy controls, leading to stronger correlation of GMV with fatigue. Voxel-based morphometry was performed on T1-weighted MRI images between 46 survivors and 30 controls. Unpaired two-sample t-test and multiple linear regression were performed to observe group differences and correlation of fatigue with GMV.

Results

The COVID group experienced significantly higher fatigue levels and GMV of this group was significantly higher within the Limbic System and Basal Ganglia when compared to healthy controls. Moreover, while a significant positive correlation was observed across the whole group between GMV and self-reported fatigue, COVID subjects showed stronger effects within the Posterior Cingulate, Precuneus and Superior Parietal Lobule.

Conclusion

Brain regions with GMV alterations in our analysis align with both single case acute patient reports and current group level neuroimaging findings. We also newly report a stronger positive correlation of GMV with fatigue among COVID survivors within brain regions associated with fatigue, indicating a link between structural abnormality and brain function in this cohort.
A RANDOMIZED CLINICAL TRIAL OF 2-WEEK METHOTREXATE DISCONTINUATION IN RHEUMATOID ARTHRITIS PATIENTS VACCINATED WITH INACTIVATED SARS-COV-2 VACCINE
Authors: Araujo Carlo S R , Medeiros-Ribeiro Ana C , Saad Carla G S , Bonfiglioli Karina R , Domiciano Diogo S , Shimabuco Andrea Y , Silva Matheus R , Yuki Emily F N , Pasoto Sandra G , Pedrosa Tatiana N , Kupa Leonard , Zou Gioanna , Pereira Rosa M R , Silva Clovis A , Aikawa Nadia E , Bonfa Eloisa
Published: November 2021

Objectives

To evaluate the effect on immunogenicity and safety of 2-week methotrexate(MTX) discontinuation after each dose of the Sinovac-CoronaVac vaccine versus MTX maintenance in rheumatoid arthritis(RA) patients.

Methods

This was a single-center, prospective, randomized, investigator-blinded, intervention study (#NCT04754698, CoronavRheum), including adult RA patients(stable CDAI<10, prednisone<7.5mg/day), randomized(1:1) to withdraw MTX(MTX-hold) for 2 weeks after each vaccine dose or maintain MTX(MTX-maintain), evaluated at D0, D28 and D69. Co-primary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion(SC) and neutralizing antibody(NAb) positivity at D69. Secondary outcomes were GMT and changes in disease activity scores. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and, for safety reasons, those unable to hold MTX twice(CDAI>10 at D28).

Results

Randomization included 138 patients with 9 exclusions(5 COVID-19, 4 protocol violations). Safety evaluation included 60(MTX-hold) and 69(MTX-maintain) patients. Further exclusions consisted of 27 patients[13(21.7%) vs. 14(20.3%),p=0.848] with positive baseline IgG/NAb and 10 patients(21.3%) in MTX-hold with CDAI>10 at D28. At D69, a higher increase in SC[29(78.4%) vs 30(54.5%),p=0.019] was observed in MTX-hold(n=37) in comparison to MTX-maintain(n=55), with parallel augmentation in GMT[34.2(25.2-46.4) vs 16.8(11.9-23.6),p=0.006]. No differences were observed for NAb positivity[23(62.2%) vs 27(49.1%),p=0.217]. Longitudinal variations in disease activity scores were alike in both groups(CDAI,p=0.144; DAS28-CRP,p=0.718).

Conclusion

We provided novel data that 2-week MTX withdrawal after each vaccine dose improves anti-SARS-CoV-2 immunogenicity. The comparable longitudinal variations of disease activity in both groups suggest that discontinuation is a feasible and efficient strategy in well-controlled RA patients, and may be even safer for vaccines with longer interval between doses or single dose schedules.

Funding

FAPESP/CNPq/B3-Bolsa de Valores-Brasil.
Haplotype-resolved powdery mildew resistance loci reveal the impact of heterozygous structural variation on NLR genes inMuscadinia rotundifolia
Authors: Massonnet Mélanie , Vondras Amanda M. , Cochetel Noé , Riaz Summaira , Pap Dániel , Minio Andrea , Figueroa-Balderas Rosa , Walker M. Andrew , Cantu Dario
Published: November 2021

Muscadinia rotundifoliacv. Trayshed is a valuable source of resistance to grape powdery mildew. It carries two powdery mildew resistance-associated genetic loci,Run1.2on chromosome 12 andRun2.2on chromosome 18. In this study, we identified, phased, and reconstructed the two haplotypes of each resistance-associated locus. Haplotype phasing allowed the identification of several structural variation events between haplotypes of both loci. Combined with manual refinement of the gene models, we found that the heterozygous structural variants affected the gene content, with some resulting in duplicated or hemizygous nucleotide-binding leucine-rich repeat (NLR) genes. Structural variations also impacted the domain composition of some NLRs. These findings emphasize the need of generating haplotype-resolved sequences instead of using consensus sequences for identifying haplotype-specific candidate genes. Comparison of the NLRs in theRun1.2andRun2.2loci indicated that the two loci are composed of a different number and classes of NLR genes. We provide a list of candidate NLR genes from theRun1.2bandRun2.2loci, whose expression suggests a role in powdery mildew resistance in Trayshed. These first complete and haplotype-resolved resistance-associated loci, and their candidate NLR genes, represent new resources to develop powdery mildew-resistant grape cultivars.
Resting state functional connectivity in relapsing remitting multiple sclerosis with mild disability – a data driven, whole brain multi-voxel pattern analysis study
Authors: Nair Gowthami , Nair Sruthi S. , Arun K. M. , Camacho Paul , Bava Elshal , Ajayaghosh Priya , Menon Ramshekhar N. , Nair Muralidharan , Kesavadas Chandrasekharan , Anteraper Sheeba Arnold
Published: November 2021

Background

Multivoxel pattern analysis (MVPA) has emerged as a powerful unbiased approach for generating seed regions of interest (ROIs) in resting-state functional connectivity (RSFC) analysis in a data-driven manner. Studies exploring RSFC in multiple sclerosis have produced diverse and often incongruent results.

Objectives

The aim of the present study was to investigate RSFC differences between persons with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HC).

Methods

We performed a whole-brain connectome-wide MVPA in 50 RRMS patients with expanded disability status scale ≤4 and 50 age and gender-matched HCs.

Results

Significant group differences were noted in RSFC in three clusters distributed in the following regions; anterior cingulate gyrus, right middle frontal gyrus, and frontal medial cortex. Whole-brain seed-to-voxel RSFC characterization of these clusters as seed ROIs revealed network-specific abnormalities, specifically in the anterior cingulate cortex and the default mode network.

Conclusions

The network-wide RSFC abnormalities we report agree with the previous findings in RRMS, the cognitive and clinical implications of which are discussed herein.

IMPACT STATEMENT

This study investigated resting state functional connectivity (RSFC) in relapsing remitting multiple sclerosis (RRMS) persons with mild disability (expanded disability status scale ≤4). Whole-brain connectome-wide multivoxel pattern analysis (MVPA) was used for assessing RSFC. Compared to healthy controls (HC), we were able to identify three regions of interest for significant differences in connectivity patterns, which were then extracted as a mask for whole-brain seed-to-voxel analysis. A reduced connectivity was noted in the RRMS group, particularly in the anterior cingulate cortex and the default mode network regions, providing insights into the RSFC abnormalities in RRMS.
Chemo-mechanical Diffusion Waves Orchestrate Collective Dynamics of Immune Cell Podosomes
Authors: Gong Ze , van den Dries Koen , Cambi Alessandra , Shenoy Vivek B.
Published: November 2021

Immune cells, such as macrophages and dendritic cells, can utilize podosomes, actin-rich protrusions, to generate forces, migrate, and patrol for foreign antigens. In these cells, individual podosomes exhibit periodic protrusion and retraction cycles (vertical oscillations) to probe their microenvironment, while multiple podosomes arranged in clusters demonstrate coordinated wave-like spatiotemporal dynamics. However, the mechanisms governing both the individual vertical oscillations and the coordinated oscillation waves in clusters remain unclear. By integrating actin polymerization, myosin contractility, actin diffusion, and mechanosensitive signaling, we develop a chemo-mechanical model for both the oscillatory growth of individual podosomes and wave-like dynamics in clusters. Our model reveals that podosomes show oscillatory growth when the actin polymerization-associated protrusion and the signaling-associated myosin contraction occur at similar rates, while the diffusion of actin monomers within the cluster drives mesoscale coordination of individual podosome oscillations in an apparent wave-like fashion. Our model predicts the influence of different pharmacological treatments targeting myosin activity, actin polymerization, and mechanosensitive pathways, as well as the impact of the microenvironment stiffness on the wavelengths, frequencies, and speeds of the chemo-mechanical waves. Overall, our integrated theoretical and experimental approach reveals how collective wave dynamics arise due to the coupling between chemo-mechanical signaling and actin diffusion, shedding light on the role of podosomes in immune cell mechanosensing within the context of wound healing and cancer immunotherapy.
A family of cell wall transglutaminases is essential for appressorium development and pathogenicity in Phytophthora infestans
Authors: Brus-Szkalej Maja , Andersen Christian B. , Vetukuri Ramesh R. , Grenville-Briggs Laura J.
Published: November 2021

Transglutaminases (TGases) are enzymes highly conserved among prokaryotic and eukaryotic organisms, where their role is to catalyse protein cross-linking. One of the putative TGases of Phytophthora infestans has previously been shown to be localised to the cell wall. Based on sequence similarity we were able to identify six more genes annotated as putative TGases and show that these seven genes group together in phylogenetic analysis. All of the seven proteins are predicted to contain transmembrane helices and both a TGase domain and a MANSC domain, the latter of which was previously shown to play a role in protein stability. Chemical inhibition of transglutaminase activity and silencing of the entire family of the putative cell wall TGases are both lethal to P. infestans indicating the importance of these proteins in cell wall formation and stability. The intermediate phenotype obtained with lower drug concentrations and less efficient silencing displays a number of deformations to germ tubes and appressoria. Both chemically treated and silenced lines show lower pathogenicity than the wild type in leaf infection assays. Finally, we show that appressoria of P. infestans possess the ability to build up turgor pressure and that this ability is decreased by chemical inhibition of TGases.
Alpha oscillations and stimulus-evoked activity dissociate metacognitive reports of attention, visibility and confidence in a rapid visual detection task
Authors: Davidson Matthew J , Macdonald James S.P. , Yeung Nick
Published: November 2021

Variability in the detection and discrimination of weak visual stimuli has been linked to oscillatory neural activity. In particular, the amplitude of activity in the alpha-band (8-12 Hz) has been shown to impact upon the objective likelihood of stimulus detection, as well as measures of subjective visibility, attention, and decision confidence. We aimed to clarify how preparatory alpha influences performance and phenomenology, by recording simultaneous subjective measures of attention and confidence (Experiment 1), or attention and visibility (Experiment 2) on a trial-by-trial basis in a visual detection task. Across both experiments, alpha amplitude was negatively and linearly correlated with the intensity of subjective attention. In contrast to this linear relationship, we observed a quadratic relationship between the strength of alpha oscillations and subjective ratings of confidence and visibility. We find that this same quadratic relationship links alpha amplitude to the strength of stimulus evoked responses. Visibility and confidence judgements corresponded to the strength of evoked responses, but confidence, uniquely, incorporated information about attentional state. As such, our findings reveal distinct psychological and neural correlates of metacognitive judgements of attentional state, stimulus visibility, and decision confidence.
Transection injury differentially alters the proteome of the human sural nerve
Authors: Chau Monica J. , Quintero Jorge E. , Blalock Eric , Samaan Christopher , Gerhardt Greg , van Horne Craig
Published: November 2021

Regeneration after severe peripheral nerve injury is often poor. Knowledge of human nerve regeneration and the growth microenvironment is greatly lacking. We aimed to identify the regenerative proteins in human peripheral nerve by comparing the proteome before and after a transection injury. In a unique study design, we collected from the same participants, samples from naïve and degenerating sural nerve. Naïve and degenerating (two weeks after injury) samples were analyzed using mass spectrometry and immunoassays. Using a correlation matrix, we found significantly altered levels following the nerve injury. Mass spectrometry revealed that post-injury samples had 672 proteins significantly upregulated and 661 significantly downregulated compared to naïve samples (q < 0.05, |FC| > 2). We used Gene Ontology pathways to highlight groups of proteins that were significantly upregulated or downregulated with injury-induced degeneration and regeneration. Significant protein changes in key pathways were identified including growth factor levels, Schwann cell de-differentiation, myelination downregulation, epithelial-mesenchymal transition, and axonal regeneration pathways. Having proteome signatures of human peripheral nerves of both the uninjured and the degenerating/regenerating state may serve as biomarkers to aid in the future development of repair strategies and in monitoring neural tissue regeneration.
Tom70-based transcriptional regulation of mitochondrial biogenesis and aging
Authors: Liu Qingqing , Chang Catherine E. , Wooldredge Alexandra C. , Fong Benjamin , Kennedy Brian K. , Zhou Chuankai
Published: November 2021

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70’s transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.