bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of COVID-19 on NO2 and PM2.5 Levels and Their Associations with Human Mobility Patterns in Singapore
Authors: Li Yangyang , Zhu Yihan , Tan Jia Yu Karen , Teo Hoong Chen , Law Andrea , Qu Dezhan , Luo Wei
Published: December 2021

The decline in NO2 and PM2.5 pollutant levels were observed during COVID-19 around the world, especially during lockdowns. Previous studies explained such observed decline with the decrease in human mobility, whilst overlooking the meteorological changes (e.g., rainfall, wind speed) that could mediate air pollution level simultaneously. This pitfall could potentially lead to over-or under-estimation of the effect of COVID-19 on air pollution. Consequently, this study aims to re-evaluate the impact of COVID-19 on NO2 and PM2.5 pollutant level in Singapore, by incorporating the effect of meteorological parameters in predicting NO2 and PM2.5 baseline in 2020 using machine learning methods. The results found that NO2 and PM2.5 declined by a maximum of 38% and 36%, respectively, during lockdown period. As two proxies for change in human mobility, taxi availability and carpark availability were found to increase and decrease by a maximum of 12.6% and 9.8%, respectively, in 2020 from 2019 during lockdown. To investigate how human mobility influenced air pollutant level, two correlation analyses were conducted: one between PM2.5 and carpark availability changes at regional scale and the other between NO2 and taxi availability changes at a spatial resolution of 0.01°. The NO2 variation was found to be more associated with the change in human mobility, with the correlation coefficients vary spatially across Singapore. A cluster of stronger correlations were found in the South and East Coast of Singapore. Contrarily, PM2.5 and carpark availability had a weak correlation, which could be due to the limit of regional analyses. Drawing to the wider context, the high association between human mobility and NO2 in the South and East Coast area can provide insights into future NO2 reduction policy in Singapore.

Graphical Abstract
The rise and spread of the SARS-CoV-2 AY.122 lineage in Russia
Authors: Klink Galya V. , Safina Ksenia , Nabieva Elena , Shvyrev Nikita , Garushyants Sofya , Alekseeva Evgeniia , Komissarov Andrey B. , Danilenko Daria M. , Pochtovyi Andrei A. , Divisenko Elizaveta V. , Vasilchenko Lyudmila A. , Shidlovskaya Elena V. , Kuznetsova Nadezhda A. ,   The Coronavirus Russian Genetics Initiative (CoRGI) Consortium, Samoilov Andrei E. , Neverov Alexey D. , Popova Anfisa V. , Fedonin Gennady G. ,   The CRIE Consortium, Akimkin Vasiliy G. , Lioznov Dmitry , Gushchin Vladimir A. , Shchur Vladimir , Bazykin Georgii A.
Published: December 2021

Background

Delta has outcompeted most preexisting variants of SARS-CoV-2, becoming the globally predominant lineage by mid-2021. Its subsequent evolution has led to emergence of multiple sublineages, many of which are well-mixed between countries.

Aim

Here, we aim to study the emergence and spread of the Delta lineage in Russia.

Methods

We use a phylogeographic approach to infer imports of Delta sublineages into Russia, and phylodynamic models to assess the rate of their spread.

Results

We show that nearly the entire Delta epidemic in Russia has probably descended from a single import event despite genetic evidence of multiple Delta imports. Indeed, over 90% of Delta samples in Russia are characterized by the nsp2:K81N+ORF7a:P45L pair of mutations which is rare outside Russia, putting them in the AY.122 sublineage. The AY.122 lineage was frequent in Russia among Delta samples from the start, and has not increased in frequency in other countries where it has been observed, suggesting that its high prevalence in Russia has probably resulted from a random founder effect.

Conclusion

The apartness of the genetic composition of the Delta epidemic in Russia makes Russia somewhat unusual, although not exceptional, among other countries.
Early detection of pancreatic ductal adenocarcinomas with an ensemble learning model based on a panel of protein serum biomarkers
Authors: Nené Nuno R. , Ney Alexander , Nazarenko Tatiana , Blyuss Oleg , Johnston Harvey E. , Whitwell Harry J. , Sedlak Eva , Gentry-Maharaj Aleksandra , Costello Eithne , Greenhalf William , Jacobs Ian , Menon Usha , Hsuan Justin , Pereira Stephen P. , Zaikin Alexey , Timms John F.
Published: December 2021

Earlier detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes, as it is mostly detected at advanced stages which are associated with poor survival. Developing non-invasive blood tests for early detection would be an important breakthrough. The primary objective of the work presented here was to use a unique dataset, that is both large and prospectively collected, to quantify a set of 96 cancer-associated proteins and construct multi-marker models with the capacity to accurately predict PDAC years before diagnosis. The data is part of a nested case control study within UK Collaborative Trial of Ovarian Cancer Screening and is comprised of 219 samples, collected from a total of 143 post-menopausal women who were diagnosed with pancreatic cancer within 70 months after sample collection, and 248 matched non-cancer controls. We developed a stacked ensemble modelling technique to achieve robustness in predictions and, therefore, improve performance in newly collected datasets. With a pool of 10 base-learners and a Bayesian averaging meta-learner, we can predict PDAC status with an AUC of 0.91 (95% CI 0.75 - 1.0), sensitivity of 92% (95% CI 0.54 - 1.0) at 90% specificity, up to 1 year to diagnosis, and at an AUC of 0.85 (95% CI 0.74 - 0.93) up to 2 years to diagnosis (sensitivity of 61%, 95 % CI 0.17 - 0.83, at 90% specificity). These models also use clinical covariates such as hormone replacement therapy use (at randomization), oral contraceptive pill use (ever) and diabetes and outperform biomarker combinations cited in the literature.
EpiLPS: a fast and flexible Bayesian tool for near real-time estimation of the time-varying reproduction number
Authors: Gressani Oswaldo , Wallinga Jacco , Althaus Christian , Hens Niel , Faes Christel
Published: December 2021

In infectious disease epidemiology, the instantaneous reproduction numberR(t) is a timevarying metric defined as the average number of secondary infections generated by individuals who are infectious at timet. It is therefore a crucial epidemiological parameter that assists public health decision makers in the management of an epidemic. We present a new Bayesian tool for robust estimation of the time-varying reproduction number. The proposed methodology smooths the epidemic curve and allows to obtain (approximate) point estimates and credible envelopes ofR(t) by employing the renewal equation, using Bayesian P-splines coupled with Laplace approximations of the conditional posterior of the spline vector. Two alternative approaches for inference are presented: (1) an approach based on a maximum a posteriori argument for the model hyperparameters, delivering estimates ofR(t) in only a few seconds; and (2) an approach based on a MCMC scheme with underlying Langevin dynamics for efficient sampling of the posterior target distribution. Case counts per unit of time are assumed to follow a Negative Binomial distribution to account for potential excess variability in the data that would not be captured by a classic Poisson model. Furthermore, after smoothing the epidemic curve, a “plug-in” estimate of the reproduction number can be obtained from the renewal equation yielding a closed form expression ofR(t) as a function of the spline parameters. The approach is extremely fast and free of arbitrary smoothing assumptions. EpiLPS is applied on data of SARS-CoV-1 in Hong-Kong (2003), influenza A H1N1 (2009) in the USA and current SARS-CoV-2 pandemic (2020-2021) for Belgium, Portugal, Denmark and France.

Author summary

The instantaneous reproduction numberR(t) is a key metric that provides important insights into an epidemic outbreak. We present a flexible Bayesian approach called EpiLPS (Epidemiological modeling with Laplacian-P-splines) for smooth estimation of the epidemic curve andR(t). Computational speed and absence of arbitrary assumptions on smoothing makes EpiLPS an interesting tool for near real-time estimation of the reproduction number. An R software package is available (https://github.com/oswaldogressani).
Healthcare worker risk of COVID-19: A 20-month analysis of protective measures from vaccination and beyond
Authors: Yassi Annalee , Barker Stephen , Lockhart Karen , Grant Jennifer M. , Okpani Arnold Ikedichi , Sprague Stacy , Zungu Muzimkhulu , Lubin Stan , Kim Sing Chad
Published: December 2021

Background: As the COVID-19 pandemic continues and new variants such as Omicron emerge, we aimed to re-evaluate vaccine effectiveness as well as impacts of rigorously implemented infection control, public health and occupational health measures in protecting healthcare workers (HCWs).
Methods: Following a cohort of 21,242 HCWs in Vancouver, British Columbia, Canada, for 20 months since the pandemic started, we used Cox regression and test-negative design to examine differences in SARS-COV-2 infection rates compared to community counterparts, and within the HCW workforce, assessing the role of occupation, testing accessibility, vaccination rates, and vaccine effectiveness over time.
Results: Nurses, allied health professionals and medical staff in this jurisdiction had a significantly lower rate of infection compared to their age-group community counterparts, at 47.4, 41.8, and 55.3% reduction respectively; controlling for vaccine-attributable reductions, the protective impact was still substantial, at 33.4, 28.0, and 36.5% respectively. Licensed practical nurses and care aides had the highest risk of infection among HCWs, more than double that of medical staff. However, even considering differences in vaccination rates, no increase in SARS-CoV-2 infection was found compared to community rates, with combined protective measures beyond vaccination associated with a 17.7% reduced SARS-COV-2 rate in the VCH workforce overall. There was also no evidence of waning immunity within at least 200 days after second dose.
Conclusion: Rigorously implemented occupational health, public health and infection control measures results in a well-protected healthcare workforce with infection rates at or below rates in community counterparts. Greater accessibility of vaccination worldwide is essential; however, as implementing measures to protect this workforce globally also requires considerable health system strengthening in many jurisdictions, we caution against overly focusing on vaccination to the exclusion of other crucial elements for wider protection of HCWs, especially in facing ongoing mutations which may escape current vaccines.
Prevalence of SARS-CoV-2 infection among COVID-19 RT-PCR laboratory workers in Bangladesh
Authors: Khan Mohammad Jahidur Rahman , Shumu Samshad Jahan , Raihan Ruksana , Mannan Nusrat , Reza Md. Selim , Khan Nazia Hasan , Bhuiyan Amirul Huda , Deb Paroma , Mim Farzana , Akram Arifa
Published: December 2021

Background

Health care workers (HCWs) at the frontline are confronting a substantial risk of infection during the coronavirus disease 2019 (COVID-19) pandemic. This emerging virus created specific hazards to researchers and laboratory staff in a clinical setting, underlined by rapid and extensive worldwide transmission. This study aimed to investigate the prevalence of SARS-CoV-2 infection among COVID-19 RT-PCR laboratory health workers in Bangladesh.

Materials & Methods

This retrospective study was conducted between October 2 to December 2, 2020. A total of 508 participants, including doctors, scientific officers, medical technologists, and cleaners working in several COVID-19 RT-PCR laboratories, were included in this study. Data were collected from each participant using a semi-structured questionnaire prepared in the format of an anonymous Google form. All participants provided informed consent. The Ethical clearance was obtained from the Institutional Ethics Review Committee of Shaheed Suhrawardy Medical College, Dhaka, Bangladesh. All statistical analyses were performed using SPSS (Statistical Package for the Social Sciences) version 25.0 software (SPSS, Inc).

Results

Out of the 508 participants, 295 tested positive for SARS CoV-2 RT-PCR. Among the positive cases, 202 were men, 93 were women, with the median age of 30 years. The most positive cases were medical technologists (53.22%) followed by doctors (28.8%). Out of the 271 symptomatic positive cases, the most typical symptoms were fever (78.5%), fatigue (70%), loss of smell and taste (65%), cough (64%), and others. Hypertension, obesity, and diabetes were found in 8.8%, 8.8%, and 7.1% positive cases. A + blood group was present in 37% of the positive cases, followed by the B+ blood group (27%) and O+ blood group (25%). Inadequate supply of personal protection equipment (PPE), absence of negative pressure ventilation, laboratory contamination, and no training on molecular test methods were found in 13.8%, 67.8%, 44.7%, and 40.6% of positive cases, respectively.

Conclusion

Evaluating the infection status of laboratory health workers is crucial for drawing attention from the public, providing practical suggestions for government agencies, and increasing protective measures for laboratory health workers.
Facial basal cell carcinoma: a clinicopathological analysis of incomplete excision
Authors: Layton Thomas
Published: December 2021

Basal cell carcinoma (BCC) is the most common malignancy in humans. Incomplete excision following conventional surgical excision requires careful consideration given the potential for disease recurrence. We performed a retrospective study analyzing facial BCC treated by conventional surgical excision to investigate factors influencing the likelihood of tumour clearance. In total, 456 cases of facial BCC were reviewed to collect a dataset of 50 tumours with involved margins and these compared to 50 completely excised tumours from the same cohort. Statistical comparison between incomplete and complete excision cases was performed using several metrics including tumour location, histology, grade, surgeon experience and method of wound reconstruction. Interestingly, our results demonstrated that only tumour location and histological type had a statistically significant impact on the completeness of resection. Infiltrative, morphoeic and mixed tumours had a higher chance of incomplete excision, as did tumours located on the inner canthus and ala nasi. In addition, the overall incomplete excision rate was 10.96% in line with previous studies. Our results help inform surgical practice and support consideration of extending the recommended macroscopic surgical margin for higher risk tumours. More research is needed to further categorize facial BCC to optimize surgical management.
Heterogeneity in statin responses explained by variation in the human gut microbiome
Authors: Wilmanski Tomasz , Kornilov Sergey A. , Diener Christian , Conomos Mathew , Lovejoy Jennifer C. , Sebastiani Paola , Orwoll Eric S. , Hood Leroy , Price Nathan D. , Rappaport Noa , Magis Andrew T. , Gibbons Sean M.
Published: December 2021

Statins remain one of the most prescribed medications worldwide. While effective in decreasing atherosclerotic cardiovascular disease risk, statin use is associated with several side effects for a subset of patients, including disrupted metabolic control and increased risk of type II diabetes. We investigated the potential role of the gut microbiome in modifying patient response to statin therapy. In a cohort of >1840 individuals, we find that the hydrolyzed substrate for 3-hydroxy-3-methylglutarate-CoA (HMG-CoA) reductase, HMG, may serve as a reliable marker for statin on-target effects. Through exploring gut microbiome associations between blood-derived measures of statin effectiveness and metabolic health parameters among statin users and non-users, we find that heterogeneity in statin response is associated with variation in the gut microbiome. A Bacteroides rich, α-diversity depleted, microbiome composition corresponds to the strongest statin on-target response, but also greatest disruption to glucose homeostasis, indicating lower treatment doses and/or complementary therapies may be beneficial in those individuals. Our findings suggest a potential path towards personalizing statin treatment through gut microbiome monitoring.
Homologous and Heterologous Vaccine Boost Strategies for Humoral and Cellular Immunologic Coverage of the SARS-CoV-2 Omicron Variant
Authors: Tan C. Sabrina , Collier Ai-ris Y. , Liu Jinyan , Yu Jingyou , Chandrashekar Abishek , McMahan Katherine , Wan Huahua , He Xuan , Jacob-Dolan Catherine , Sellers Daniel , Ventura John D. , Bartsch Yannic , Hauser Blake M. , Munt Jennifer E. , Mattocks Melissa , Stephenson Kathryn E. , Vidal Samuel J. , Jaegle Kate , Rowe Marjorie , Hemond Rachel , Rivera Lorraine Bermudez , Anioke Tochi , Barrett Julia , Chung Benjamin , Gardner Sarah , Gebre Makda S. , Hachmann Nicole , Lifton Michelle , Miller Jessica , Nampanya Felix , Powers Olivia , Sciacca Michaela , Siamatu Mazuba , Surve Nehalee , Tostanoski Lisa H. , VanWyk Haley , Wu Cindy , Baric Ralph S. , Schmidt Aaron G. , Alter Galit , Barouch Dan H.
Published: December 2021

The rapid spread of the highly mutated SARS-CoV-2 Omicron variant has raised substantial concerns about the protective efficacy of currently available vaccines. We assessed Omicron-specific humoral and cellular immune responses in 65 individuals who were vaccinated with two immunizations of BNT162b2 and were boosted after at least 6 months with either Ad26.COV2.S (Johnson & Johnson; N=41) or BNT162b2 (Pfizer; N=24) (Table S1).
Time trends in social contacts of individuals according to comorbidity and vaccination status, before and during the COVID-19 pandemic
Authors: Godbout Aurélie , Drolet Mélanie , Mondor Myrto , Simard Marc , Sauvageau Chantal , De Serres Gaston , Brisson Marc
Published: December 2021

Background

As we are confronted with more transmissible/severe variants with immune escape and the waning of vaccine efficacy, it is particularly relevant to understand how the social contacts of individuals at greater risk of COVID-19 complications evolved over time. We described time trends in social contacts of individuals according to comorbidity and vaccination status before and during the first three waves of the COVID-19 pandemic in Quebec, Canada.

Methods

We used data from CONNECT, a repeated cross-sectional population-based survey of social contacts conducted before (2018/2019) and during the pandemic (April 2020 to July 2021). We recruited non-institutionalized adults from Quebec, Canada, by random digit dialling. We used a self-administered web-based questionnaire to measure the number of social contacts of participants (two-way conversation at a distance ≤2 meters or a physical contact, irrespective of masking). We compared the mean number of contacts/day according to the comorbidity status of participants (pre-existing medical conditions with symptoms/medication in the past 12 months) and 1-dose vaccination status during the third wave. All analyses were performed using weighted generalized linear models with a Poisson distribution and robust variance.

Results

A total of 1441 and 5185 participants with and without comorbidities, respectively, were included in the analyses. Contacts significantly decreased from a mean of 6.1 (95%CI 4.9–7.3) before the pandemic to 3.2 (95%CI 2.5–3.9) during the first wave among individuals with comorbidities, and from 8.1 (95%CI 7.3–9.0) to 2.7 (95%CI 2.2–3.2) among individuals without comorbidities. Individuals with comorbidities maintained fewer contacts than those without comorbidities in the second wave, with a significant difference before the Christmas 2020/2021 holidays (2.9 (95%CI 2.5–3.2) v 3.9 (95%CI 3.5–4.3); P<0.001). During the third wave, contacts were similar for individuals with (4.1, 95%CI 3.4– 4.7) and without comorbidities (4.5, 95%CI 4.1–4.9; P=0.27). This could be partly explained by individuals with comorbidities vaccinated with their first dose who increased their contacts to the level of those without comorbidities.

Conclusions

It will be important to closely monitor COVID-19-related outcomes and social contacts by comorbidity and vaccination status to inform targeted or population-based interventions (e.g., booster doses of the vaccine).
Quantifying the impact of individual and collective compliance with infection control measures for ethical public health policy
Authors: Roberts Daniel , Jamrozik Euzebiusz , Heriot George S. , Slim Anja C. , Selgelid Michael J. , Miller Joel C.
Published: December 2021

Infectious disease control measures often require collective compliance of large numbers of individuals to benefit public health. This raises ethical questions regarding the value of the public health benefit created by individual and collective compliance. Answering these requires estimating the extent to which individual actions prevent infection of others. We develop mathematical techniques enabling quantification of the impacts of individuals or groups complying with three public health measures: border quarantine, isolation of infected individuals, and prevention via vaccination/prophylaxis. The results suggest that (i) these interventions exhibit synergy: they become more effective on a per-individual basis as compliance increases and (ii) There is often significant “overdetermination” of transmission: if a susceptible person contacts multiple infectious individuals, an intervention preventing one transmission may not change the ultimate outcome (thus risk imposed by some individuals may erode the benefits of others’ compliance). These results have implications for public health policy during epidemics.
A systematic review of anaesthetic agents used in Drug Induced Sedation Endoscopy (DISE) and a description of a new DISE technique
Authors: Sanders Oliver , Kotecha Bhik , Veer Vik
Published: December 2021

Objectives

Drug induced sleep endoscopy (DISE) is a standardly used investigation for surgical planning in obstructive sleep apnoea management once conservative treatments have proven inadequate. There are a variety of anaesthetic agents used to obtain sedation necessary for DISE. These agents may have different effect on the upper airway and other parameters important in the diagnosis of the site of collapse during sleep. We aimed to review the commonly agents and evaluate the significance of their impact on the the diagnosis.

Methods

A search was conducted through PubMed looking for studies on commonly used anaesthetic agents and their effect on the upper airway and cardiopulmonary parameters. Results: Of the 109 studies yielded by the search, 19 were deemed relevant to the review and met all inclusion criteria. The agents reviewed were: propofol, dexmedetomidine, remifentanil, isoflurane, sevoflurane, midazolam and topical lidocaine. A meta-analysis was not conducted due to the limited number of relevant studies and the heterogeneity of outcomes measured. All agents examined gave some element of airway collapse and impact on cardiopulmonary measures. Most of these effects were shown to be dose-dependent. Of the agents considered dexmedetomidine and propofol gave the most consistently reliable and physiologically safe representations of upper airway collapse seen in OSA patients.

Conclusion

There is limited information and no industry standard for the sedative regimen used for DISE. Of the agents reviewed those that caused least cardiopulmonary instability, respiratory depression and exaggerated upper airway collapse were deemed the most appropriate for DISE. The agent that best meet these criteria is dexmedetomidine followed by propofol.
Post-traumatic Stress Risk among COVID-19 Survivors in Colombia
Authors: Campo-Arias Adalberto , Pedrozo-Pupo John Carlos , Herazo Edwin
Published: December 2021

The study’s objective was to establish the prevalence and variables associated with post-traumatic stress disorder risk (PTSD-R) in a sample of COVID-19 survivors in Santa Marta, Colombia. A cross-sectional study was designed with a non-probabilistic sample of adult COVID-19 survivors. Participants were demographically characterized and completed scales for depression risk, insomnia risk, and PTSD-R. Three hundred and thirty COVID-19 survivors between 18 and 89 years participated; 61.52% were women. The frequency of depression risk was 49.70%; insomnia risk, 60.61%; and PTSD-R, 13.33%. Depression risk (OR = 41.43, 95% CI 5.54 – 311.63), insomnia risk (OR = 5.25, 95% CI 1.77 – 18.71), low income (OR = 3.46, 95% CI 1.38 – 8.67) and being married or free union (OR = 2.65, 95% CI 1.13 – 6.22) were associated with PTSD-R. In conclusion, two out of every fifteen COVID-19 survivors are in PTSD-R. Depression and insomnia risk are strongly associated with PTSD-R in COVID-19 survivors.
Fusion of Imaging and Non-Imaging Data for Disease Trajectory Prediction for COVID-19 Patients
Authors: Tariq Amara , Tang Siyi , Sakhi Hifza , Celi Leo Anthony , Newsome Janice M. , Rubin Daniel L. , Trivedi Hari , Gichoya Judy Wawira , Banerjee Imon
Published: December 2021

ABSTRCAT

Purpose

This study investigates whether graph-based fusion of imaging data with non-imaging EHR data can improve the prediction of disease trajectory for COVID-19 patients, beyond the prediction performance of only imaging or non-imaging EHR data.

Materials and Methods

We present a novel graph-based framework for fine-grained clinical outcome prediction (discharge, ICU admission, or death) that fuses imaging and non-imaging information using a similarity-based graph structure. Node features are represented by image embedding and edges are encoded with clinical or demographic similarity.

Results

Our experiments on data collected from Emory Healthcare network indicate that our fusion modeling scheme performs consistently better than predictive models using only imaging or non-imaging features, with f1-scores of 0.73, 0.77, and 0.66 for discharge from hospital, mortality, and ICU admission, respectively. External validation was performed on data collected from Mayo Clinic. Our scheme highlights known biases in the model prediction such as bias against patients with alcohol abuse history and bias based on insurance status.

Conclusion

The study signifies the importance of fusion of multiple data modalities for accurate prediction of clinical trajectory. Proposed graph structure can model relationships between patients based on non-imaging EHR data and graph convolutional networks can fuse this relationship information with imaging data to effectively predict future disease trajectory more effectively than models employing only imaging or non-imaging data. Forecasting clinical events can enable intelligent resource allocation in hospitals. Our graph-based fusion modeling frameworks can be easily extended to other prediction tasks to efficiently combine imaging data with non-imaging clinical data.
Premature white matter microstructure in female children with a history of concussion
Authors: Nishat Eman , Stojanovski Sonja , Scratch Shannon E , Ameis Stephanie H , Wheeler Anne L
Published: December 2021

As maturation of the brain continues throughout development, there is a risk of interference from concussions which are common in childhood. A concussion can cause widespread disruption to axons and inflammation in the brain and may influence emerging cognitive abilities. Females are more likely to experience persistent problems after a concussion, yet the sex-specific impact of concussions on brain microstructure in childhood is not well understood.

In children from a large population sample, this study (1) investigated differences in white matter and cortical microstructure between children with and without a history of concussion, and (2) examined relationships between altered brain microstructure and cognitive performance.

Neurite density measures from diffusion weighted magnetic resonance imaging were examined in 9-to 10-year-old children in the Adolescent Brain Cognitive Development Study with (n= 336) and without (n= 7368) a history of concussion. (1) Multivariate regression models were used to investigate the relationships between concussion history, sex, and age in the deep white matter, superficial white matter, subcortical structures, and cortex. (2) Principal component analysis was performed on neurite density, and components were examined in relation to performance on the Flanker Inhibitory Control and Attention Task and the Pattern Comparison Processing Speed Task to investigate the relationship between altered neurite density and cognitive performance.

Neurite density in all tissue types demonstrated robust positive relationships with age reflecting maturation of brain microstructure. (1) Comparisons between children with and without a history of concussion revealed higher neurite density in deep and superficial white matter in females with concussion. No group differences were observed in subcortical or cortical neurite density. (2) Higher neurite density in superficial white matter beneath the frontal and temporal cortices was associated with lower scores on the processing speed test in females with concussion, and higher scores on the processing speed test in males with concussion.

These findings suggest that concussion in childhood leads to premature white matter maturation in females and that this may be associated with slower processing speed. These sex-specific effects on the developing brain may contribute to the enhanced vulnerability to persistent symptoms after concussion in females.
New Phylogenetic Models Incorporating Interval-Specific Dispersal Dynamics Improve Inference of Disease Spread
Authors: Gao Jiansi , May Michael R. , Rannala Bruce , Moore Brian R.
Published: December 2021

Phylodynamic methods reveal the spatial and temporal dynamics of viral geographic spread, and have featured prominently in studies of the COVID-19 pandemic. Virtually all such studies are based on phylodynamic models that assume—despite direct and compelling evidence to the contrary—that rates of viral geographic dispersal are constant through time. Here, we: (1) extend phylodynamic models to allow both the average and relative rates of viral dispersal to vary independently between pre-specified time intervals; (2) implement methods to infer the number and timing of viral dispersal events between areas; and (3) develop statistics to assess the absolute fit of discrete-geographic phylodynamic models to empirical datasets. We first validate our new methods using simulations, and then apply them to a SARS-CoV-2 dataset from the early phase of the COVID-19 pandemic. We show that: (1) under simulation, failure to accommodate interval-specific variation in the study data will severely bias parameter estimates; (2) in practice, our interval-specific discrete-geographic phylodynamic models can significantly improve the relative and absolute fit to empirical data; and (3) the increased realism of our interval-specific models provides qualitatively different inferences regarding key aspects of the COVID-19 pandemic—revealing significant temporal variation in global viral dispersal rates, viral dispersal routes, and the number of viral dispersal events between areas—and alters interpretations regarding the efficacy of intervention measures to mitigate the pandemic.
Brain Injury in COVID-19 is Associated with Autoinflammation and Autoimmunity
Authors: Needham EJ , Ren AL , Digby RJ , Outtrim JG , Chatfield DA , Manktelow AE , Newcombe VFJ , Doffinger R , Barcenas-Morales G , Fonseca C , Taussig MJ , Burnstein RM , Dunai C , Sithole N , Ashton NJ , Zetterberg H , Gisslen M , Edén A , Marklund E , Griffiths MJ , Cavanagh J , Breen G , Irani SR , Elmer A , Kingston N , Bradley JR , Taams LS , Michael BD , Bullmore ET , Smith KGC , Lyons PA , Coles AJC , Menon DK ,   the Cambridge NeuroCOVID Group,   the NIHR COVID-19 BioResource,   Cambridge NIHR Clinical Research Facility
Published: December 2021

COVID-19 has been associated with many neurological complications including stroke, delirium and encephalitis. Furthermore, many individuals experience a protracted post-viral syndrome which is dominated by neuropsychiatric symptoms, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of severe COVID-19 more broadly.

We sought to investigate the dynamics of, and relationship between, serum markers of brain injury (neurofilament light [NfL], Glial Fibrillary Acidic Protein [GFAP] and total Tau) and markers of dysregulated host response including measures of autoinflammation (proinflammatory cytokines) and autoimmunity. Brain injury biomarkers were measured using the Quanterix Simoa HDx platform, cytokine profiling by Luminex (R&D) and autoantibodies by a custom protein microarray.

During hospitalisation, patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependant manner, and there was evidence of ongoing active brain injury at follow-up 4 months later. Raised NfL and GFAP were associated with both elevations of pro-inflammatory cytokines and the presence of autoantibodies; autoantibodies were commonly seen against lung surfactant proteins as well as brain proteins such as myelin associated glycoprotein, but reactivity was seen to a large number of different antigens.

Furthermore, a distinct process characterised by elevation of serum total Tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses in the same manner as NfL and GFAP.
Guillain-Barré Syndrome after COVID-19 Vaccination in the Vaccine Safety Datalink
Authors: Hanson Kayla E. , Goddard Kristin , Lewis Ned , Fireman Bruce , Myers Tanya R. , Bakshi Nandini , Weintraub Eric , Donahue James G. , Nelson Jennifer C. , Xu Stan , Glanz Jason M. , Williams Joshua T.B. , Alpern Jonathan D. , Klein Nicola P.
Published: December 2021

Importance

Post-authorization monitoring of vaccines in a large population can detect rare adverse events not identified in clinical trials including Guillain-Barré syndrome (GBS). GBS has a background rate of 1-2 per 100,000 person-years.

Objective

To 1) describe cases and incidence of GBS following COVID-19 vaccination, and 2) assess the risk of GBS after vaccination for Ad.26.COV2.S (Janssen) and mRNA vaccines.

Design

Interim analysis of surveillance data from the Vaccine Safety Datalink.

Setting

Eight participating integrated healthcare systems in the United States.

Participants

10,158,003 individuals aged ≥12 years.

Exposures

Receipt of Ad.26.COV2.S, BNT162b2 (Pfizer-BioNTech), or mRNA-1273 (Moderna) COVID-19 vaccine.

Main Outcomes and Measures

GBS with symptom onset in the 1-84 days after vaccination as confirmed by medical record review and adjudication. Descriptive characteristics of confirmed cases, GBS incidence rates during postvaccination risk intervals after each type of vaccine compared to the background rate, rate ratios (RRs) comparing GBS incidence in the 1-21 vs. 22-42 days postvaccination, and RRs directly comparing risk of GBS after Ad.26.COV2.S vs. mRNA vaccination, using Poisson regression adjusted for age, sex, race/ethnicity, site, and calendar day.

Results

From December 13, 2020 through November 13, 2021, 14,723,318 doses of COVID-19 vaccines were administered, including 467,126 Ad.26.COV2.S, 8,573,823 BNT162b2, and 5,682,369 mRNA-1273 doses. Eleven cases of GBS after Ad.26.COV2.S were confirmed. The unadjusted incidence rate of confirmed cases of GBS per 100,000 person-years in the 1-21 days after Ad.26.COV2.S was 34.6 (95% confidence interval [CI]: 15.8-65.7), significantly higher than the background rate, and the adjusted RR in the 1-21 vs. 22-42 days following Ad.26.COV2.S was 6.03 (95% CI: 0.79-147.79). Thirty-four cases of GBS after mRNA vaccines were confirmed. The unadjusted incidence rate of confirmed cases per 100,000 person-years in the 1-21 days after mRNA vaccines was 1.4 (95% CI: 0.7-2.5) and the adjusted RR in the 1-21 vs. 22-42 days following mRNA vaccines was 0.56 (95% CI: 0.21-1.48). In a head-to-head comparison of Ad.26.COV2.S vs. mRNA vaccines, the adjusted RR was 20.56 (95% CI: 6.94-64.66).

Conclusions and Relevance

In this interim analysis of surveillance data of COVID-19 vaccines, the incidence of GBS was elevated after Ad.26.COV2.S. Surveillance is ongoing.
Introduction and community transmission of SARS-CoV-2 lineage A.2.5 in Florida with novel spike INDELS
Authors: Schmedes Sarah E. , Azarian Taj , Cella Eleonora , Motes Jessy , Tekin Omer , Weiss James , Miller Nancimae , Blanton Jason
Published: December 2021

SARS-CoV-2 (SC2) variants of concern (VOC) continue to emerge and spread globally, threatening the use of monoclonal antibody therapies and vaccine effectiveness. Several mutations in the SC2 spike glycoprotein have been associated with reduction in antibody neutralization. Genomic surveillance of SC2 variants has been imperative to inform the public health response regarding the use of clinical therapies in specific jurisdictions based on the proportion of particular variants (e.g., Gamma (P.1)) in a region. Florida Department of Health Bureau of Public Health Laboratories (BPHL) performs tiled-amplicon whole genome sequencing for baseline and targeted surveillance of SC2 isolates in Florida from clinical specimens collected from county health departments and hospitals throughout the state. Here, we describe the introduction of SC2 lineage A.2.5 in Florida, which contains S:L452R (a substitution of therapeutic concern) and two novel Spike INDELS, the deletion of 141-143 and ins215AGY, with unknown implications on immune response. The A.2.5 lineage was first detected in Florida among an outbreak at a healthcare facility in January 2021, and subsequent A.2.5 isolates were detected across all geographical regions throughout the state. A time-scaled maximum clade credibility phylogeny determined there were at least eight separate introductions of A.2.5 in the state. The time of introduction of a monophyletic Florida clade was established to be December 2020. The Spike INDELS were determined to reside in the N-terminal domain, a region associated with antibody neutralization. As community transmission of SARS-CoV-2 in Florida continues, genomic surveillance of circulating variants in Florida and the detection of emerging variants are critical for informing public health response to COVID-19.
Compartment-specific total RNA profile of Hippocampal and Cortical cells from Mesial Temporal Lobe Epilepsy tissue
Authors: Vangoor Vamshidhar R. , Giuliani Giuliano , de Wit Marina , Venø Morten T. , Puhakka Noora , Gomes-Duarte Andreia , van Rijen Peter C. , Gosselaar Peter H. , van Eijsden Pieter , Kjems Jørgen , de Graan Pierre N.E. , Pasterkamp R. Jeroen
Published: December 2021

Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disease characterized by recurrent seizures. The pathogenic mechanisms underlying mTLE involve defects in post-transcriptional regulation of gene expression. So far, transcriptome profiles from epileptic tissue have been generated using whole cells, thereby lacking information on RNA localization and function at a subcellular level. In line with this, we have previously observed by in situ hybridization that a few microRNAs (miRNAs) display subcellular mis-localization with aberrant enrichment in the nucleus in human hippocampal mTLE tissue samples (Kan et al., 2012). To further investigate the possible mechanisms leading to the mis-localization of miRNAs, we set out to understand the compartment-specific total RNA (coding and non-coding) profile of human mTLE tissue samples. For this, we have successfully established a protocol to isolate cytoplasmic and nuclear compartments from human hippocampal tissue. After confirming the purity of the isolated cell compartments, we performed total RNA-sequencing (RNA-seq) on five resected hippocampal (HC) mTLE (no hippocampal sclerosis (non-HS)) samples and five HC postmortem control samples. Similarly, six neo-cortical (Cx) tissue samples from mTLE non-HS and HS International League Against Epilepsy (ILAE) Type 1, or mTLE+HS, samples were compared with six Cx postmortem controls. Our dataset provides a comprehensive overview of compartment-specific transcriptomic profiles of pharmacoresistant mTLE patient HC and Cx tissue, which in further studies can be used to investigate disease mechanisms.
A randomized clinical trial to stimulate the cholinergic anti-inflammatory pathway in patients with moderate COVID-19-pneumonia using a slow-paced breathing technique
Authors: Balint Elisabeth Maria , Grüner Beate , Haase Sophia , Kaw-Geppert Mandakini , Thayer Julian F. , Gündel Harald , Jarczok Marc N.
Published: December 2021

Importance

Vagus nerve stimulation via slow-paced breathing could serve as an adjuvant therapeutic approach to reduce excessive inflammation in coronavirus disease 2019 (COVID-19) pneumonia.

Objective

Does a slow-paced breathing technique increasing vagal activity reduce Interleukin-6 (IL-6) in patients hospitalized with moderate COVID-19 pneumonia compared to standard care?

Design

Single-center randomized controlled clinical trial with enrolment from February 23rd 2021 through June 17th 2021 and follow-up until July 22nd 2021.

Setting

Ward for infectious diseases and temporary COVID-19 ward, Ulm University Hospital, Germany

Participants

Consecutive sample of patients hospitalized with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (primary diagnosis). Of 131 patients screened, 48 patients were randomized and 46 patients analyzed (N=23 per group).

Interventions

Slow-paced 20-minute breathing exercise three times a day with six breaths per minute (inhalation-to-exhalation ratio 4:6).

Main outcomes and measures

Differences between intervention and control group in IL-6 calculated using multilevel mixed-effect linear regression models with random slope including the covariates relevant comorbidities, COVID-19 medication, and age.

Results

Mean age 57 years±13 years, N= 28 (60%) male, N=30 (65%) with relevant comorbidities.

The model including group by time interaction revealed a significantly lower trajectory of IL-6 in the intervention group compared to the control group (effect size Cohens f2=0.11, LR-test p=.040) in the intention-to-treat sample, confirmed by treatment-per-protocol analysis (f2=0.15, LR-test p=.022). Exploratory analysis using the median split of practice time to predict IL-6 of the next morning indicated a dose-response relationship with beneficial effects of practice time above 45 minutes a day.

Three patients in each group were admitted to ICU, one died. Oxygen saturation increased during slow-paced breathing (from 95.1%±2.1% to 95.4%±1.6%, p=0.006).

Conclusion and relevance

Patients practicing slow-paced breathing had significantly lower IL-6 values than controls with a small to medium effect size and without relevant side effects. Further trials should evaluate clinical outcomes as well as an earlier start of the intervention, i.e., at symptom onset. This would offer an access to a therapy option not only for high-income, but also for low- and middle-income countries.

Trial registration

German register of clinical trials (ID: DRKS00023971) https://www.drks.de, Universal Trial Number (UTN) U1111-1263-8658;
Spike-specific T cells are enriched in breastmilk following SARS-CoV-2 mRNA vaccination
Authors: Armistead Blair , Jiang Yonghou , Carlson Marc , Ford Emily S , Jani Saumya , Houck John , Wu Xia , Jing Lichen , Pecor Tiffany , Kachikis Alisa , Yeung Winnie , Nguyen Tina , Minkah Nana , Larsen Sasha E , Coler Rhea N , Koelle David M , Harrington Whitney E
Published: December 2021

Human breastmilk is rich in T cells; however, their specificity and function are largely unknown. We compared the phenotype, diversity, and antigen specificity of T cells in the breastmilk and peripheral blood of lactating individuals who received SARS-CoV-2 mRNA vaccination. Relative to blood, breastmilk contained higher frequencies of T effector and central memory populations that expressed mucosal-homing markers. T cell receptor (TCR) sequence overlap was limited between blood and breastmilk. Overabundan t breastmilk clones were observed in all individuals, were diverse, and contained CDR3 sequences with known epitope specificity including to SARS-CoV-2 Spike. Spike-specific TCRs were more frequent in breastmilk compared to blood and expanded in breastmilk following a third mRNA vaccine dose. Our observations indicate that the lactating breast contains a distinct T cell population that can be modulated by maternal vaccination with potential implications for infant passive protection.

One-Sentence Summary

The breastmilk T cell repertoire is distinct and enriched for SARS-CoV-2 Spike-specificity after maternal mRNA vaccination.
RNA Sequencing-Based Single Sample Predictors of Molecular Subtype and Risk of Recurrence for Clinical Assessment of Early-Stage Breast Cancer
Authors: Staaf Johan , Häkkinen Jari , Hegardt Cecilia , Saal Lao H , Kimbung Siker , Hedenfalk Ingrid , Lien Tonje , Sørlie Therese , Naume Bjørn , Russnes Hege , Marcone Rachel , Ayyanan Ayyakkannu , Brisken Cathrin , Malterling Rebecka R. , Asking Bengt , Olofsson Helena , Lindman Henrik , Bendahl Pär-Ola , Ehinger Anna , Larsson Christer , Loman Niklas , Rydén Lisa , Malmberg Martin , Borg Åke , Vallon-Christersson Johan
Published: December 2021

Background

Multigene expression assays for molecular subtypes and biomarkers can aid clinical management of early invasive breast cancer (IBC). Based on RNA-sequencing we aimed to develop robust single-sample predictor (SSP) models for conventional clinical markers as well as molecular intrinsic subtype and risk of recurrence (ROR) that provide clinically relevant prognostic stratification.

Methods

A uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set (n=5250) and a reserved test set (n=2412). We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) methods and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna in two external cohorts (ABiM, n=100 and OSLO2-EMIT0, n=103). Prognostic value was assessed using distant recurrence-free interval (DRFi).

Results

In the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC classification was assessed as equivalent and added clinically relevant prognostic information. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade, respectively. SSP concordance with Prosigna was high for subtype (OSLO 83% and ABiM 80%, Kappa=0.73 and 0.72, respectively) and moderate and high for ROR risk category (68% and 84%, Kappa=0.50 and 0.70, weighted Kappa=0.70 and 0.78). In pooled analysis, concordance between SSP and Prosigna for emulated treatment recommendation dichotomized for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of chemotherapy.

Conclusions

Robust SSP models, mimicking histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and DRFi analyses suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level. Retrospective evaluation in ER+/HER2-/N0 IBC suggested that molecular testing could lead to a changed therapy recommendation for almost one-fifth of patients.