bluuebunny/crossref_metadata_2025 huggingface dataset:
IMPROVING IMAGE QUALITY BY INCREASING THE AMOUNT OF LIGHT IN THE READING ROOM
Authors: Sund Patrik
Published: March 2021

Many standards and guidelines related to the use of medical displays require viewers to be in dark rooms. The purpose of this theoretical study was to examine the validity of some commonly used requirements in terms of image contrast and contrast stability in rooms with fluctuating illuminance. By using the grayscale standard display function (Dicom part 14), contrast was calculated for several combinations of display minimum and maximum luminance as well as the possible range of illuminance fluctuations that will not exceed given contrast tolerance levels. The results show that some requirements are only valid in dark viewing rooms, which are also usually recommended or enforced. However, image contrast, contrast stability, ergonomics and fatigue would improve by using brighter displays in brighter rooms. With a better set of requirements, it would also be possible for displays in brighter rooms, like dentist departments and operating rooms, to conform to the requirements.
Identification of Colletotrichum Species Associated with Anthracnose Disease of Strawberry in Sichuan Province, China
Authors: Jian Yunqing , Li Ying , Tang Guiting , Zheng Xiaojuan , Khaskheli Muhammad Ibrahim , Gong Guoshu
Published: March 2021

Strawberry anthracnose, caused by Colletotrichum species, is a major fungal disease threatening the strawberry industry in Sichuan Province of southwestern China. However, research on identification of Colletotrichum species associated with strawberry anthracnose in Sichuan remains scarce. In this study, 73 representative Colletotrichum strains were isolated from diseased leaves, stolons, petioles, and crowns of 11 major strawberry-planting localities in Sichuan Province. Based on morphological characteristics and multiloci phylogenetic analysis, the Colletotrichum strains were identified as three distinct species: Colletotrichum fructicola (53 strains, 72.60%), Colletotrichum siamense (17 strains, 23.29%), and Colletotrichum gloeosporioides sensu stricto (3 strains, 4.11%). Among them, C. fructicola was the most ubiquitous and dominant species, whereas C. gloeosporioides sensu stricto was restricted to Chongzhou. Importantly, our pathogenicity tests showed that C. fructicola and C. siamense can infect both leaves and stolons, whereas C. gloeosporioides sensu stricto was only pathogenic to leaves. Interestingly, although the sexual stage of C. siamense was not observed in this study, it still exhibited the strongest virulence to strawberry compared with C. gloeosporioides sensu stricto and C. fructicola. This is the first study to characterize Colletotrichum species causing strawberry anthracnose and evaluate their pathogenicity in Sichuan Province of southwestern China, which will provide a better strategy for accurate diagnosis and management of anthracnose disease in strawberry.
Local anesthetic systemic toxicity
Authors: Schneider Melissa A. , Howard Katrina A.
Published: March 2021

Local or regional anesthetics are becoming more common pain management options for patients, especially considering concerns regarding opioid use disorders. Though mostly safe, these interventions may carry serious risks such as local anesthetic systemic toxicity (LAST). This article discusses LAST and the importance of recognizing its signs and symptoms.
BILATERAL SEROUS RETINAL DETACHMENTS IN A PATIENT WITH PREECLAMPSIA WITHOUT HYPERTENSION
Authors: Santoro Jarod M. , Jeng-Miller Karen W. , Liang Michelle C.
Published: March 2021

Purpose:

To report a case of bilateral serous retinal detachments in a patient with preeclampsia without hypertension using multimodal ophthalmic imaging.

Methods:

Case report.

Results:

This case demonstrates the rare presentation of bilateral serous retinal detachment in a patient with preeclampsia without hypertension. Characteristic subretinal fluid was seen on examination and optical coherence tomography. No leakage was noted on fluorescein angiography. Treatment was deferred, and the subretinal fluid resolved within 3 weeks.

Conclusion:

Practitioners should be aware of the rare presentation of serous retinal detachments in preeclampsia, even in the absence of hypertension. Long-term sequelae are uncommon and usually only seen in severe disease. Delivery should be considered once serous retinal detachment develops.
Patient-Reported Outcomes After Corneal Transplantation
Authors: Dunbar Grace E. , Titus Michael , Stein Joshua D. , Meijome Tomas E. , Mian Shahzad I. , Woodward Maria A.
Published: March 2021

Purpose:

To characterize vision-related quality of life after penetrating keratoplasty (PKP), deep anterior lamellar keratoplasty (DALK), Descemet stripping automated endothelial keratoplasty (DSAEK), and Descemet membrane endothelial keratoplasty (DMEK) using the National Eye Institute Visual Function Questionnaire (NEI-VFQ 9).

Methods:

Using the Sight Outcomes Research Collaborative ophthalmology electronic health record repository, questionnaire responses were obtained from 103 PKP patients, 24 DALK patients, 42 DSAEK patients, and 50 DMEK patients undergoing postoperative examination. No exclusions were made based on preoperative diagnosis, age, complications, or comorbidities. Associations between clinical characteristics and vision-related quality of life were analyzed using nonparametric and linear regression methods.

Results:

Patients were surveyed an average of 1.5 years postoperatively (range 24 d to 4.4 yrs). Participants who had undergone DALK, DMEK, DSAEK, and PKP had median composite VFQ scores of 77.8, 84.2, 76.1, and 70.6, respectively (P= 0.002). There were no significant differences in VFQ scores between patients treated with DMEK versus DSAEK (P = 0.440) or between patients treated with PKP versus DALK (P = 1.000). Higher postoperative acuities in the operative and fellow eyes were associated with higher VFQ scores (P < 0.001 and P < 0.001). When controlling for postoperative acuity by regression modeling, surgery type was not associated with patient-reported composite VFQ scores.

Conclusions:

In this study, patient-reported vision-related quality of life was similar among DMEK and DSAEK participants and also among DALK and PKP participants. When controlling for postoperative acuity, vision-related quality of life was similar among all study participants, irrespective of the keratoplasty technique.
Association Between Attending Physicians’ Rates of Referral to Palliative Care and Location of Death in Hospitalized Adults With Serious Illness
Authors: Quinn Kieran L. , Stukel Thérèse , Huang Anjie , Goldman Russell , Cram Peter , Detsky Allan S. , Bell Chaim M.
Published: March 2021

Background:

Patients who receive palliative care are less likely to die in hospital.

Objective:

To measure the association between physician rates of referral to palliative care and location of death in hospitalized adults with serious illness.

Research Design:

Population-based decedent cohort study using linked health administrative data in Ontario, Canada.

Subjects:

A total of 7866 physicians paired with 130,862 hospitalized adults in their last year of life who died of serious illness between 2010 and 2016.

Exposure:

Physician annual rate of referral to palliative care (high, average, low).

Measures:

Odds of death in hospital versus home, adjusted for patient characteristics.

Results:

There was nearly 4-fold variation in the proportion of patients receiving palliative care during follow-up based on attending physician referral rates: high 42.4% (n=24,433), average 24.7% (n=10,772), low 10.7% (n=6721). Referral to palliative care was also associated with being referred by palliative care specialists and in urban teaching hospitals. The proportion of patients who died in hospital according to physician referral rate were 47.7% (high), 50.1% (average), and 52.8% (low). Hospitalized patients cared for by a physician who referred to palliative care at a high rate had lower risk of dying in hospital than at home compared with patients who were referred by a physician with an average rate of referral [adjusted odds ratio 0.91; 95% confidence interval, 0.86–0.95; number needed to treat=57 (interquartile range 41–92)] and by a physician with a low rate of referral [adjusted odds ratio 0.81; 95% confidence interval, 0.77–0.84; number needed to treat =28 patients (interquartile range 23–44)].

Conclusions and Relevance:

An attending physicians’ rates of referral to palliative care is associated with a lower risk of dying in hospital. Therefore, patients who are cared for by physicians with higher rates of referral to palliative care are less likely to die in hospital and more likely to die at home. Standardizing referral to palliative care may help reduce physician-level variation as a barrier to access.
Differential roles of two isoforms of dopamine D2 receptors in l-dopa-induced abnormal involuntary movements in mice
Authors: Li Luke , Cheng Lei , Wang YanYan
Published: March 2021

l-dopa and dopamine D2 receptor (D2R) agonists are commonly used to relieve the motor deficits of Parkinson’s disease. However, long-term treatment with l-dopa or D2R agonists can induce adverse effects such as abnormal involuntary movements (AIMs), which are major limiting factors in achieving long-term control of parkinsonian syndromes. The pathophysiological mechanisms involved in the development of dopaminergic agonist-induced adverse effects are not well understood. Here, we examined the role of two D2R isoforms, D2S and D2L, in l-dopa-induced AIMs using dopamine D2L knockout (D2L KO) mice (expressing purely D2S) and wild-type mice (expressing predominantly D2L). We found that D2L KO mice displayed markedly enhanced AIMs in response to chronic treatment of l-dopa compared to wild-type mice. The l-dopa-induced enhancement of AIMs in D2L KO mice was significantly reduced by the D2R antagonist eticlopride. D2L KO mice also displayed markedly enhanced AIMs in response to chronic treatment with quinpirole, a preferential D2R agonist. These results suggest that D2S contributes more than D2L to dopaminergic agonist-induced AIMs. Our findings may uncover a new factor that contributes to the pathophysiology of dopaminergic drug-induced AIMs, a characteristic manifestation of dyskinesia and also present in psychosis. There is a possibility that the increased ratio of D2S to D2L in the brain plays a significant role in the development of AIM side effects induced by l-dopa or D2R agonists.

See Video Abstract, http://links.lww.com/WNR/A622.
Comparing activated brain regions between noisy and conventional galvanic vestibular stimulation using functional magnetic resonance imaging
Authors: Mitsutake Tsubasa , Sakamoto Maiko , Horikawa Etsuo
Published: March 2021

Objective

Galvanic vestibular stimulation (GVS) enhances vestibular sensory inputs in vestibular afferents. However, it is unclear whether noisy and conventional GVS activate different regions of the brain. The purpose of this study was to investigate the differences in activated brain regions between those two interventions using functional MRI (fMRI).

Methods

Twenty-four healthy volunteers who met the inclusion/exclusion criteria were randomly assigned to the noisy GVS or conventional GVS groups. Brain activity was measured during stimulation and compared with that during resting fMRI. This study used a blocked design comprising four task-rest blocks, each consisting of a 30-s period of vestibular stimulation followed by a 30-s period of rest. We evaluated the differences in contrast images between the noisy and conventional GVS groups.

Results

The noisy GVS group showed significantly increased activation in the vestibular system-related brain regions, including the insula and central operculum. The conventional GVS group showed significant activity in multisensory areas, including the supramarginal gyrus, central operculum and opercular part of the inferior frontal gyrus. Thus, the noisy GVS group showed significantly increased activity in the insula, putamen and central operculum compared with the conventional GVS group.

Conclusions

Noisy GVS could increase brain activity in the insular peripheral region compared to conventional GVS. Our results extend the literature about the importance of the stochastic resonance of noise addition for the vestibular system.
Speed and strength of an epidemic intervention
Authors: Dushoff Jonathan , Park Sang Woo
Published: March 2021

An epidemic can be characterized by its strength (i.e., the reproductive numberR) and speed (i.e., the exponential growth rater). Disease modellers have historically placed much more emphasis on strength, in part because the effectiveness of an intervention strategy is typically evaluated on this scale. Here, we develop a mathematical framework for the classic, strength-based paradigm and show that there is a dual speed-based paradigm which can provide complementary insights. In particular, we note thatr= 0 is a threshold for disease spread, just likeR=1[1], and show that we can measure the strength and speed of an intervention on the same scale as the strength and speed of an epidemic, respectively. We argue that, while the strength-based paradigm provides the clearest insight into certain questions, the speed-based paradigm provides the clearest view in other cases. As an example, we show that evaluating the prospects of ‘test-and-treat’ interventions against the human immunodeficiency virus (HIV) can be done more clearly on the speed than strength scale, given uncertainty in the proportion of HIV spread that happens early in the course of infection. We also discuss evaluating the effects of the importance of pre-symptomatic transmission of the SARS-CoV-2 virus. We suggest that disease modellers should avoid over-emphasizing the reproductive number at the expense of the exponential growth rate, but instead look at these as complementary measures.
Species-area and network-area relationships in host–helminth interactions
Authors: Dallas Tad A. , Jordano Pedro
Published: March 2021

The scaling relationship observed between species richness and the geographical area sampled (i.e. the species-area relationship (SAR)) is a widely recognized macroecological relationship. Recently, this theory has been extended to trophic interactions, suggesting that geographical area may influence the structure of species interaction networks (i.e. network-area relationships (NARs)). Here, we use a global dataset of host–helminth parasite interactions to test existing predictions from macroecological theory. Scaling between single locations to the global host–helminth network by sequentially adding networks together, we find support that geographical area influences species richness and the number of species interactions in host–helminth networks. However, species-area slopes were larger for host species relative to their helminth parasites, counter to theoretical predictions. Lastly, host–helminth network modularity—capturing the tendency of the network to form into separate subcommunities—decreased with increasing area, also counter to theoretical predictions. Reconciling this disconnect between existing theory and observed SAR and NAR will provide insight into the spatial structuring of ecological networks, and help to refine theory to highlight the effects of network type, species distributional overlap, and the specificity of trophic interactions on NARs.
A reversal in sensory processing accompanies ongoing ecological divergence and speciation in
Rhagoletis pomonella
Authors: Tait Cheyenne , Kharva Hinal , Schubert Marco , Kritsch Daniel , Sombke Andy , Rybak Jürgen , Feder Jeffrey L. , Olsson Shannon B.
Published: March 2021

Changes in behaviour often drive rapid adaptive evolution and speciation. However, the mechanistic basis for behavioural shifts is largely unknown. The tephritid fruit fly
Rhagoletis pomonella
is an example of ecological specialization and speciation in action via a recent host plant shift from hawthorn to apple. These flies primarily use specific odours to locate fruit, and because they mate only on or near host fruit, changes in odour preference for apples versus hawthorns translate directly to prezygotic reproductive isolation, initiating speciation. Using a variety of techniques, we found a reversal between apple and hawthorn flies in the sensory processing of key odours associated with host fruit preference at the first olfactory synapse, linking changes in the antennal lobe of the brain with ongoing ecological divergence. Indeed, changes to specific neural pathways of any sensory modality may be a broad mechanism for changes in animal behaviour, catalysing the genesis of new biodiversity.
Identifying Patterns of Association and Transition in the Use of Addictive Substances over Five Decades in the United States
Authors: Ray Sumanta , Aruru Meghana , Pyne Saumyadipta
Published: March 2021

Objectives

To conduct weighted itemset analysis to identify patterns of polysubstance use from National Survey on Drug Use and Health (NSDUH) data.

Methods

We computed weighted support for every combination of one or more substances, termed as a drugset, used by individuals in the nationally representative NSDUH data over 5 decades (1965-2014). A computational framework for efficient representation and search of patterns of association between drugsets and demographics of user groups over time was developed. A new method for mining rules of transition between pairs of substances used within a time-interval was given.

Results

We identified the frequent drugsets from individual substance use data, and determined their representation among different demographic groups at different intervals. An interesting pattern of use of pain relievers and tranquilizers was detected for the age-group of 26-34 years. Transition rules for heroin use in the last decade (2004-2015) of data were mined.

Conclusions

Computation of weighted supports over time for every possible drugset in the data and their association with specific user groups produced a framework for generation and testing new and interesting hypotheses. The framework is useful to explore different combinations of substances used among diverse demographic groups including those that have received less attention in this problem.
The effect of International Monetary Fund programmes on population health
Authors: Nosrati Elias , Marmot Michael , King Lawrence P.
Published: March 2021

Background

As one of the world’s most powerful international financial organisations, the International Monetary Fund (IMF) is uniquely positioned to shape global developmental trajectories by influencing domestic policy arrangements. However, its role in shaping population health is understudied.

Methods

We use previously unavailable cross-national time-series data and an instrumental-variables method to examine the causal impact of the IMF’s structural adjustment programmes on age-standardised all-cause mortality rates and disability-adjusted life years (DALYs) in 187 countries between 1990 and 2017. For this purpose, we specify two-way fixed-effects regression models.

Findings

According to our baseline models, IMF programmes cause 392 excess all-cause deaths (95% CI: 176–608; p = 0.0004) and 4,205 excess DALYs (95% CI: 2,429–5,981; p = 0.000004) per 100,000 population. This aggregate effect appears to be driven by IMF-mandated privatisation reforms, which lead to 562 excess all-cause deaths (95% CI: 267–857; p = 0.0002) and 5,285 excess DALYs (95% CI: 2,749–7,822; p = 0.00004) per 100,000 population.

Interpretation

Structural adjustment programmes play a significant role in perpetuating preventable disability and death in developing contexts. The IMF’s policy reforms, especially those pertaining to the privatisation of state-owned enterprises, increase excess mortality rates and disease burdens in the world’s most vulnerable regions.

Funding

None.
Structural adjustment programmes and infectious disease mortality
Authors: Nosrati Elias , Dowd Jennifer B. , Marmot Michael , King Lawrence P.
Published: March 2021

International financial organisations like the International Monetary Fund (IMF) play a central role in shaping the developmental trajectories of fiscally distressed countries through their conditional lending schemes, known as ‘structural adjustment programmes’. These programmes entail wide-ranging domestic policy reforms that influence local health and welfare systems. Using novel panel data from 187 countries between 1990 and 2017 and an instrumental variable technique, we find that IMF programmes lead to over 70 excess deaths from respiratory diseases and tuberculosis per 100,000 population and that IMF-mandated privatisation reforms lead to over 90 excess deaths per 100,000 population. Thus structural adjustment programmes, as currently designed and implemented, are harmful to population health and increase global infectious disease burdens.
Comparison between one and two dose SARS-CoV-2 vaccine prioritisation for a fixed number of vaccine doses
Authors: Hill Edward M. , Keeling Matt J.
Published: March 2021

The swift development of SARS-CoV-2 vaccines has been met with worldwide commendation. How-ever, in the context of an ongoing pandemic there is an interplay between infection and vaccination. Whilst infection can grow exponentially, vaccination rates are generally limited by supply and logistics. With the first SARS-CoV-2 vaccines receiving medical approval requiring two doses, there has been scrutiny on the spacing between doses; an elongated period between doses allows more of the population to receive a first vaccine dose in the short-term generating wide-spread partial immunity. Focusing on data from England, we investigated prioritisation of a one dose or two dose vaccination schedule given a fixed number of vaccine doses and with respect to a measure of maximising averted deaths. We optimised outcomes for two different estimates of population size and relative risk of mortality for at-risk groups within the Phase 1 vaccine priority order. Vaccines offering relatively high protection from the first dose favour strategies that prioritise giving more people one dose, although with increasing vaccine supply eventually those eligible and accepting vaccination will receive two doses. Whilst optimal dose timing can substantially reduce the overall mortality risk, there needs to be careful consideration of the logistics of vaccine delivery.
A digitization theory of the Weber–Fechner law
Authors: Choe Haengjin
Published: March 2021

Ever since the publication of Shannon’s article about information theory, there have been many attempts to apply information theory to the neuroscience field. Meanwhile, the Weber– Fechner law of psychophysics states that the magnitude of a subjective sensation of a person increases in proportion to the logarithm of the intensity of the external physical-stimulus. It is hardly surprising that we assign the amount of information to the response in the Weber– Fechner law. But, to date no one has succeeded in applying information theory directly to that law: the direct links between information theory and that response in the Weber–Fechner law have not yet been found. The proposed theory unveils a link between information theory and that response, and differs subtly from the field such as neural coding that involves complicated calculations and models. Because my theory targets the Weber–Fechner law which is a macroscopic phenomenon, this theory does not involve complicated calculations. My theory is expected to mark a new era in the fields of sensory perception research. My theory must be studied in parallel with the fields of microscopic scale such as neural coding. This article ultimately aims to provide the fundamental concepts and their applications so that a new field of research on stimuli and responses can be created.
Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV
Authors: Misko Albert , Weinstock Laura , Sankar Sitara , Furness Amanda , Grishchuk Yulia , Wood Levi B.
Published: March 2021

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. We thus hypothesized that peripheral blood cytokines would reflect inflammatory changes in the brain and would be linked to motor dysfunction. To test this, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scores. We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, IL-17, IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Like MLIV patients, IL-17 and IP-10 were up-regulated in blood of symptomatic mice. Together, our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting an importance for interferon signaling in MLIV.
Axes of Prognosis: Identifying Subtypes of COVID-19 Outcomes
Authors: Whitfield Emma , Coffey Claire , Zhang Huayu , Shi Ting , Wu Xiaodong , Li Qiang , Wu Honghan
Published: March 2021

COVID-19 is a disease with vast impact, yet much remains unclear about patient outcomes. Most approaches to risk prediction of COVID-19 focus on binary or tertiary severity outcomes, despite the heterogeneity of the disease. In this work, we identify heterogeneous subtypes of COVID-19 outcomes by considering ‘axes’ of prognosis. We propose two innovative clustering approaches − ‘Layered Axes’ and ‘Prognosis Space’ – to apply on patients’ outcome data. We then show how these clusters can help predict a patient’s deterioration pathway on their hospital admission, using random forest classification. We illustrate this methodology on a cohort from Wuhan in early 2020. We discover interesting subgroups of poor prognosis, particularly within respiratory patients, and predict respiratory subgroup membership with high accuracy. This work could assist clinicians in identifying appropriate treatments at patients’ hospital admission. Moreover, our method could be used to explore subtypes of ‘long COVID’ and other diseases with heterogeneous outcomes.
Long lockdowns and rainy days: Modeling the interactive roles of weather, behavior, and restrictions in COVID-19 transmission in the Netherlands
Authors: Mitas Ondrej , Kokkinou Alinda
Published: March 2021

Extant research on the role of weather in COVID-19 has produced ambiguous results and much methodological debate. Following advice emerging from this methodological debate, we take a step further in modeling effects of weather on COVID-19 spread by including interactions between weather, behavior, baseline cases, and restrictions in our model. Our model was based on secondary infection, hospitalization, restriction, weather, and mobility data per day nested with safety region in the Netherlands. Our findings show significant but inconsistent interactions. The robust effects of weather on COVID-19 spread persisted over and above these interactions, highlighting the need to account for weather with nuance and caution in public policy, communication, and forecasting.
Homophily in risk and behavior complicate understanding the COVID-19 epidemic curve
Authors: Fefferman Nina H. , Silk Matthew J. , Pasquale Dana K. , Moody James
Published: March 2021

New COVID-19 diagnoses have dropped faster than expected in the United States. Interpretations of the decrease have focused on changing factors (e.g. mask-wearing, vaccines, etc.), but predictive models largely ignore heterogeneity in behaviorally-driven exposure risks among distinct groups. We present a simplified compartmental model with differential mixing in two behaviorally distinct groups. We show how homophily in behavior, risk, and exposure can lead to early peaks and rapid declines that critically do not signal the end of the outbreak. Instead, higher exposure risk groups may more rapidly exhaust available susceptibles while the lower risk group are still in a (slower) growth phase of their outbreak curve. This simplified model demonstrates that complex incidence curves, such as those currently seen in the US, can be generated without changes to fundamental drivers of disease dynamics. Correct interpretation of incidence curves will be critical for policy decisions to effectively manage the pandemic.
Persistence and detection of anti-SARS-CoV-2 antibodies: immunoassay heterogeneity and implications for serosurveillance
Authors: Perez-Saez Javier , Zaballa María-Eugenia , Yerly Sabine , Andrey Diego O. , Meyer Benjamin , Eckerle Isabella , Balavoine Jean-François , Chappuis François , Pittet Didier , Trono Didier , Kherad Omar , Vuilleumier Nicolas , Kaiser Laurent , Guessous Idris , Stringhini Silvia , Azman Andrew S ,   for the Specchio-COVID19 Study Group
Published: March 2021

Serologic studies have been critical in tracking the evolution of the COVID-19 pandemic. The reliability of serologic studies for quantifying the proportion of the population that have been infected depends on the extent of antibody decay as well as on assay performance in detecting both recent and older infections. Data on anti-SARS-CoV-2 antibodies persistence remain sparse, especially from infected individuals with few to no symptoms. In a cohort of mostly mild/asymptomatic SARS-CoV-2-infected individuals tested with three widely-used immunoassays, antibodies persisted for at least 8 months after infection, although detection depended on immunoassay choice, with one of them missing up to 40% of past infections. Simulations reveal that without appropriate adjustment for time-varying assay sensitivity, seroprevalence surveys may underestimate infection rates. As the immune landscape becomes more complex with naturally-infected and vaccinated individuals, assay choice and appropriate assay-performance-adjustment will become even more important for the interpretation of serologic studies.
Epitope-resolved serology test differentiates the clinical outcome of COVID-19 and identifies defects in antibody response in SARS-CoV-2 variants
Authors: Voss Courtney , Esmail Sally , Liu Xuguang , Knauer Michael J. , Ackloo Suzanne , Kaneko Tomonori , Lowes Lori , Stogios Peter , Seitova Almagul , Hutchinson Ashley , Yusifov Farhad , Skarina Tatiana , Evdokimova Elena , Loppnau Peter , Ghiabi Pegah , Haijian Taraneh , Zhong Shanshan , Abdoh Husam , Hedley Benjamin D. , Bhayana Vipin , Martin Claudio M. , Slessarev Marat , Chin-Yee Benjamin , Fraser Douglas D. , Chin-Yee Ian , Li Shawn S-C.
Published: March 2021

BACKGROUND

The role of humoral immunity in the coronavirus disease 2019 (COVID-19) is not fully understood owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome.

METHODS

Using SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution.

RESULTS

We identified 54 linear epitopes from the Spike (S) and Nucleocapsid (N) protein and showed that epitopes enabled higher resolution antibody profiling than protein antigens. Specifically, we found that antibody responses to the S(811-825), S(881-895) and N(156-170) epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant B.1.1.7 altered the specificity of the corresponding epitopes.

CONCLUSIONS

Epitope-resolved antibody testing not only offers a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, it may also be used as predictor of clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants in both the peptide array and latex agglutination formats.

FUNDING

Ontario Research Fund (ORF)-COVID-19 Rapid Research Fund, the Toronto COVID-19 Action Fund, Western University, the Lawson Health Research Institute, the London Health Sciences Foundation, and the AMOSO Innovation Fund.
DNA methylomes derived from alveolar macrophages display distinct patterns in latent tuberculosis - implication for interferon gamma release assay status determination
Authors: Pehrson Isabelle , Das Jyotirmoy , Idh Nina , Karlsson Lovisa , Rylander Helena , af Segerstad Hilma Hård , Reuterswärd Elsa , Marttala Emma , Paues Jakob , Méndez-Aranda Melissa , Ugarte-Gil César , Lerm Maria
Published: March 2021

Host innate immune cells, including alveolar macrophages, have been identified as key players in the early eradication of Mycobacterium tuberculosis and in the maintenance of an anti-mycobacterial immune memory, which is believed to be induced through epigenetic changes. The aim of the study was to elucidate whether exposure to M. tuberculosis induced a different DNA methylation pattern of alveolar macrophages and pulmonary T lymphocytes.

Alveolar macrophages and T lymphocytes were isolated from induced sputum obtained from individuals living in Lima, which is an area high endemic for tuberculosis. To determine the latent tuberculosis infection status of the subjects, an interferon-γ release assay was performed. We evaluated the DNA methylomes of the alveolar macrophages and T lymphocytes using the Illumina Infinium Human Methylation 450K Bead Chip array, revealing a distinct DNA methylation pattern in alveolar macrophages allowing the discrimination of asymptomatic individuals with latent tuberculosis infection from non-infected individuals. Pathway analysis revealed that cell signalling of inflammation and chemokines in alveolar macrophages play a role in latent tuberculosis infection. In conclusion, we demonstrated that DNA methylation in alveolar macrophages can be used to determine the tuberculosis infection status of individuals in a high endemic setting.
A Differential DNA Methylome Signature of Pulmonary Immune Cells from Individuals Converting to Latent Tuberculosis Infection
Authors: Karlsson Lovisa , Das Jyotirmoy , Nilsson Moa , Tyrén Amanda , Pehrson Isabelle , Idh Nina , Paues Jakob , Ugarte-Gil Cesar , Méndez-Aranda Melissa , Lerm Maria
Published: March 2021

Tuberculosis (TB), caused byMycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary resident immune cells. The role of epigenetic regulations through DNA methylation in the immune cells is emerging. We have previously shown that capacity to killM. tuberculosisis reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in the pulmonary immune cells in a cohort of medical students with a previously documented increased risk of TB exposure, longitudinally. Sputum samples containing alveolar macrophages (AMs) and T cells were collected before and after study subjects worked in hospital departments with a high-risk of TB exposure. DNA methylome analysis revealed that a unique DNA methylation profile was present already at inclusion in subjects who developed latent TB during the study. The profile was both reflected in different overall DNA methylation distribution as well as more profound alterations in the methylation status of a unique set of CpG-sites. Over-representation analysis of the DMGs showed enrichment in pathways related to metabolic reprograming of macrophages and T cell migration and IFN-γ production. In conclusion, we identified a unique DNA methylation signature in individuals, while still IGRA-negative and who later developed latent TB. Epigenetic regulation was found in pathways that have previously been reported to be important in TB. Together the study suggests that DNA methylation status of pulmonary immune cells can predict IGRA conversion.
The Spike-specific IgA in milk commonly-elicited after SARS-Cov-2 infection is concurrent with a robust secretory antibody response, exhibits neutralization potency strongly correlated with IgA binding, and is highly durable over time
Authors: Fox Alisa , Marino Jessica , Amanat Fatima , Oguntuyo Kasopefoluwa , Hahn-Holbrook Jennifer , Lee Benhur , Krammer Florian , Zolla-Pazner Susan , Powell Rebecca L.
Published: March 2021

Approximately 10% of infants will experience COVID-19 illness requiring advanced care (1). A potential mechanism to protect this population could be provided by passive immunity through the milk of a previously infected mother. We and others have reported on the presence of SARS-CoV-2-specific antibodies in human milk (2-5). We now report the prevalence of SARS-CoV-2 IgA in the milk of 75 COVID-19-recovered participants, and find that 88% of samples are positive for Spike-specific IgA. In a subset of these samples, 95% exhibited robust IgA activity as determined by endpoint binding titer, with 50% considered high-titer. These IgA positive specimens were also positive for Spike-specific antibodies bearing the secretory component. Levels of IgA antibodies and antibodies bearing secretory component were shown to be strongly positively correlated. The secretory IgA response was dominant among the milk samples tested compared to the IgG response, which was present in 75% of samples and found to be of high-titer in only 13% of cases. Our IgA durability analysis using 28 paired samples, obtained 4-6 weeks and 4-10 months after infection, found that all samples exhibited persistently significant Spike-specific IgA, with 43% of donors exhibiting increasing IgA titers over time. Finally, COVID-19 and pre-pandemic control milk samples were tested for the presence of neutralizing antibodies; 6 of 8 COVID-19 samples exhibited neutralization of Spike-pseudotyped VSV (IC50 range, 2.39 – 89.4ug/mL) compared to 1 of 8 controls. IgA binding and neutralization capacities were found to be strongly positively correlated. These data are highly relevant to public health, not only in terms of the protective capacity of these antibodies for breastfed infants, but also for the potential use of such antibodies as a COVID-19 therapeutic, given that secretory IgA is highly stable not only in milk and the infant mouth and gut, but in all mucosa including the gastrointestinal tract, upper airway, and lungs (6).
A DNA methylome biosignature in alveolar macrophages from TB-exposed individuals predicts exposure to mycobacteria
Authors: Das Jyotirmoy , Idh Nina , Pehrson Isabelle , Paues Jakob , Lerm Maria
Published: March 2021

Several studies have identified biomarkers for tuberculosis (TB) diagnosis based on blood cell transcriptomics. Here, we instead studied epigenomics in the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to data from published work on protective heterologous immunity to TB. Taken together, our results demonstrate that epigenetic changes related to trained immunity occurs in the pulmonary immune cells of TB-exposed individuals and that a DNA methylation signature can be derived from the DNA methylome. Such a signature can be further developed for clinical use as a marker of TB exposure.
The indirect health impacts of COVID19 restrictions: a strong debate informed by weak evidence
Authors: Ouakrim Driss Ait , Katar Ameera , Abraham Patrick , Grills Nathan , Blakely Tony
Published: March 2021

KEY MESSAGES

There has been concern, and much heated debate, on the possible negative effects of restrictions, stay-at-home orders and lockdowns during the COVID-19 pandemic.

Most published studies on health impacts of restrictions and lockdowns are low quality and often severely biased.

Focusing on the few studies that approximate a change in restrictions alone (i.e. not the impact of the pandemic per se), we see clear adverse impacts of lockdowns on intimate partner violence and physical activity. Regarding diseases, road traffic crashes decrease, and anxiety increases.

A discussion driven by science (not politics) is urgently needed on what lockdowns can deliver, their limitations and how to optimally deploy them – along other public health strategies – in the fight against COVID-19.
Evidence for antibody as a protective correlate for COVID-19 vaccines
Authors: Earle Kristen A. , Ambrosino Donna M. , Fiore-Gartland Andrew , Goldblatt David , Gilbert Peter B. , Siber George R. , Dull Peter , Plotkin Stanley A.
Published: March 2021

Though eleven novel COVID-19 vaccines have demonstrated efficacy, additional affordable, scalable, and deliverable vaccines are needed to meet unprecedented global demand. With placebo-controlled efficacy trials becoming infeasible due to the roll out of licensed vaccines, a correlate of protection is urgently needed to provide a path for regulatory approval of novel vaccines. To assess whether antibody titers may reasonably predict efficacy, we evaluated the relationship between efficacy and in vitro neutralizing and binding antibodies of 7 vaccines for which sufficient data have been generated. Once calibrated to titers of human convalescent sera reported in each study, a robust correlation was seen between neutralizing titer and efficacy (ρ= 0.79) and binding antibody titer and efficacy (ρ = 0.93), despite geographically diverse study populations subject to different forces of infection and circulating variants, and use of different endpoints, assays, convalescent sera panels and manufacturing platforms. This correlation is strengthened by substituting post-hoc analyses for efficacy against the ancestral strain (D614G), where available. Together with an accumulating body of evidence from natural history studies and animal models, these results support the use of post-immunization antibody titers as the basis for establishing a correlate of protection for COVID-19 vaccines.
The effect of in-person primary and secondary school instruction on county-level SARS-CoV-2 spread in Indiana
Authors: Bosslet Gabriel T. , Pollak Micah , Jang Jeong Hoon , Roll Rebekah , Sperling Mark , Khan Babar
Published: March 2021

Background

To determine the county-level effect of in-person primary and secondary school reopening on daily cases of SARS-CoV-2 in Indiana.

Methods

This is a county-level population-based study using a panel data regression analysis of the proportion of in-person learning to evaluate an association with community-wide daily new SARS-CoV-2 cases. The study period was July 12-October 6, 2020. We included 73 out of 92 (79.3%) Indiana counties in the analysis, accounting for 85.7% of school corporations and 90.6% of student enrollement statewide. The primary exposure was the proportion of students returning to in-person instruction. The primary outcome was the daily new SARS-CoV-2 cases per 100,000 residents at the county level.

Results

There is a statistically significant relationship between the proportion of students attending K-12 schools in-person and the county level daily cases of SARS-CoV-2 28 days later. For all ages, the coefficient of interest (β) is estimated at 3.36 (95% CI: 1.91—4.81; p < 0.001). This coefficient represents the effect of a change the proportion of students attending in-person on new daily cases 28 days later. For example, a 10 percentage point increase in K-12 students attending school in-person is associated with a daily increase in SARS-CoV-2 cases in the county equal to 0.336 cases/100,000 residents of all ages.

Conclusion

In-person primary and secondary school is associated with a statistically significant but proportionally small increase in the spread of SARS-CoV-2 cases.
Detecting SARS-CoV-2 lineages and mutational load in municipal wastewater; a use-case in the metropolitan area of Thessaloniki, Greece
Authors: Pechlivanis Nikolaos , Tsagiopoulou Maria , Maniou Maria Christina , Togkousidis Anastasis , Mouchtaropoulou Evangelia , Chassalevris Taxiarchis , Chaintoutis Serafeim , Dovas Chrysostomos , Petala Maria , Kostoglou Margaritis , Karapantsios Thodoris , Laidou Stamatia , Vlachonikola Elisavet , Chatzidimitriou Anastasia , Papadopoulos Agis , Papaioannou Nikolaos , Argiriou Anagnostis , Psomopoulos Fotis
Published: March 2021

The SARS-CoV-2 pandemic represents an unprecedented global crisis necessitating novel approaches for, amongst others, early detection of emerging variants relating to the evolution and spread of the virus. Recently, the detection of SARS-CoV-2 RNA in wastewater has emerged as a useful tool to monitor the prevalence of the virus in the community. Here, we propose a novel methodology, called lineagespot, for the detection of SARS-CoV-2 lineages in wastewater samples using next-generation sequencing. Our proposed method was tested and evaluated using NGS data produced by the sequencing of three wastewater samples from the municipality of Thessaloniki, Greece, covering three distinct time periods. The results showed a clear identification of trends in the presence of SARS-CoV-2 mutations in sewage data, and allowed for a robust inference between the variants evident through our approach and the variants observed in patients from the same area time periods. Lineagespot is an open-source tool, implemented in R, and is freely available on GitHub.