bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasmodium falciparum hrp2 and hrp3 gene deletion status in Africa and South America by highly sensitive and specific digital PCR
Authors: Vera-Arias Claudia A. , Holzschuh Aurel , Oduma Colins O. , Badu Kingsley , Abdul-Hakim Mutala , Yukich Joshua , Hetzel Manuel W. , Fakih Bakar S. , Ali Abdullah , Ferreira Marcelo U. , Ladeia-Andrade Simone , Sáenz Fabián E. , Afrane Yaw , Zemene Endalew , Yewhalaw Delenasaw , Kazura James W. , Yan Guiyun , Koepfli Cristian
Published: June 2021

Background

The most commonly used Plasmodium falciparum rapid diagnostic tests target the Histidine-Rich Proteins 2 and 3 (HRP2, HRP3). An increasing number of countries report parasites that carry hrp2 and/or hrp3 gene deletions, resulting in false negative test results. Molecular surveillance of hrp2 and hrp3 deletions is crucial but adequate protocols have been lacking.

Methods and Findings

We have developed novel assays for deletion typing based on droplet digital PCR (ddPCR), targeting hrp2 exon1, hrp2 exon 2, and hrp3. In the ddPCR assay, hrp2 or hrp3 and a control gene were quantified with very high accuracy in a single tube. The theoretical limit of detection of the ddPCR assay was 0.33 parasites/uL, and thus well suited for typing of low-density asymptomatic infections. The deletion was reliably detected in mixed infections with wild-type and hrp2-deleted parasites when the proportion of parasites carrying the deletion was >40%. For a side-by-side comparison with the conventional nested PCR (nPCR) assay, 248 samples from asymptomatic individuals from western Kenya were screened in triplicate by ddPCR and nPCR. No deletions were observed by ddPCR, while by nPCR no band for hrp2 was observed in 8% of samples. The ddPCR assay was applied to screen 830 samples from six countries in Africa and South America. No or very few deletions were observed in Kenya (n=241), Zanzibar/Tanzania (n=91), and Ghana (n=223). In southwestern Ethiopia, 1/47 (2.1%) samples carried hrp2 deletion, and 35/47 (74.5%) hrp3 deletions. In Brazil, 87/187 (46.5%) samples carried hrp2 deletions, and 116/187 (62%) hrp3 deletions. In Ecuador, no hrp2 deletions were observed, but 22/41 (53.7%) samples carried hrp3 deletions.

Conclusions

Compared to nPCR, the ddPCR assay minimizes the risk of false-negative results (i.e. hrp2 deletion observed when the sample is wild type), increases sensitivity, and greatly reduces the number of reactions that need to be run. Pronounced differences in the prevalence of deletion were observed among sites, with more hrp3 than hrp2 deletions.
Intra-individual reproducibility as essential determinant of clinical utility of smartphone-based neurological disability tests
Authors: Messan Komi S. , Pham Linh , Harris Thomas , Kim Yujin , Morgan Vanessa , Kosa Peter , Bielekova Bibiana
Published: June 2021

Technological advances, lack of medical professionals, high cost of face-to face encounters and disasters such as COVID19 pandemic, fuel the telemedicine revolution. Numerous smartphone apps have been developed to measure neurological functions. However, their psychometric properties are seldom determined. Lacking such data, it is unclear which designs underlie’ eventual clinical utility of the smartphone tests.

We have developed the smartphone Neurological Function Tests Suite (NeuFun-TS) and are systematically evaluating their psychometric properties against the gold-standard of complete neurological examination digitalized into NeurExTM App. This paper examines the fifth, and thus far the most complex NeuFun-TS test, the “Spiral tracing”. We generated 40 features in the training cohort (22 healthy donors [HD] and 105 multiple sclerosis [MS] patients) and compared their intraclass correlation coefficient, fold-change between HD and MS and correlations with relevant clinical and imaging outcomes. We assembled the best features into machine-learning models and examined their performance in the independent validation cohort (56 MS patients).

We show that by aggregating multiple neurological functions, complex tests such as spiral tracing are susceptible to intra-individual variations, decreasing their reproducibility and thus, clinical utility. Simple tests, reproducibly measuring single function(s) that can be aggregated to increase sensitivity are preferable in app design.
Rates of Glaucoma Progression Derived from Linear Mixed Models Using Varied Random Effect Distributions
Authors: Swaminathan Swarup S. , Berchuck Samuel I. , Jammal Alessandro A. , Rao J. Sunil , Medeiros Felipe A.
Published: June 2021

Purpose

To compare the ability of linear mixed models with different random effect distributions to estimate rates of visual field loss in glaucoma patients.

Methods

Eyes with ≥5 reliable standard automated perimetry (SAP) tests were identified from the Duke Glaucoma Registry. Mean deviation (MD) values from each visual field and associated timepoints were collected. These data were modeled using ordinary least square (OLS) regression and linear mixed models using the Gaussian, Student-t, or log-gamma (LG) distributions as the prior distribution for random effects. Model fit was compared using Watanabe-Akaike information criterion (WAIC). Simulated eyes of varying initial disease severity and rates of progression were created to assess the accuracy of each model in predicting the rate of change and likelihood of declaring progression.

Results

A total of 52,900 visual fields from 6,558 eyes of 3,981 subjects were included. Mean follow-up period was 8.7±4.0 years, with an average of 8.1±3.7 visual fields per eye. The LG model produced the lowest WAIC, demonstrating optimal model fit. In simulations, the LG model declared progression earlier than OLS (P<0.001) and had the greatest accuracy in predicted slopes (P<0.001). The Gaussian model significantly underestimated rates of progression among fast and catastrophic progressors.

Conclusions

Linear mixed models using the LG distribution outperformed conventional approaches for estimating rates of SAP MD loss in a population with glaucoma.

Translational Relevance

Use of the LG distribution in models estimating rates of change among glaucoma patients may improve their accuracy in rapidly identifying progressors at high risk for vision loss.
Antibody profiling reveals gender differences in response to SARS-COVID-2 infection
Authors: Tsverava Lia , Chitadze Nazibrola , Chanturia Gvantsa , Kekelidze Merab , Dzneladze David , Imnadze Paata , Gamkrelidze Amiran , Lagani Vincenzo , Khuchua Zaza , Solomonia Revaz
Published: June 2021

The recent emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an ongoing global COVID-19 pandemic and public health crisis. Detailed study of human immune response to SARS-COVIS-2 infection is the important topic for a successful treatment of this disease. Our study was aimed to characterize immune response on the level of antibody profiling in convalescent plasma of patients in Georgia. Antibodies against the following SARS-COV-2 proteins were studied: nucleocapsid and various regions of Spike (S) protein: S1, S2 and Receptor binding domain (RBD). Convalescent plasma of patients 6-8 weeks after initial confirmation of SARS-COV-2 infection were tested. Nearly 80% out of 154 patients studied showed presence of antibodies against nucleocapsid protein. The antibody response to three fragments of S protein was significantly less and varied in the range of 20-30%. Significantly more females as compared to males were producing antibodies against S1 fragment, whereas the difference between genders by the antibodies against nucleocapsid protein and RBD was statistically significant only by one-tailed Fisher exact test. There were no differences between the males and females by antibodies against S2 fragment. Thus, immune response against some viral antigens are stronger in females and we suggest that it could be one of the factors of less female fatality after SARS-COVID-2 infection.
Necessity of COVID-19 Vaccination in Persons who have Already had COVID-19
Authors: Shrestha Nabin K. , Burke Patrick C. , Nowacki Amy S. , Terpeluk Paul , Gordon Steven M.
Published: June 2021

Background

The purpose of this study was to evaluate the necessity of COVID-19 vaccination in persons with prior COVID-19.

Methods

Employees of Cleveland Clinic working in Ohio on Dec 16, 2020, the day COVID-19 vaccination was started, were included. Anyone who tested positive for COVID-19 at least once before the study start date was considered previously infected. One was considered vaccinated 14 days after receipt of the second dose of a COVID-19 mRNA vaccine. The cumulative incidence of COVID-19, symptomatic COVID-19, and hospitalizations for COVID-19, were examined over the next 10.5 months.

Results

Among the 52238 employees, 4718 (9%) had prior COVID-19 at the start of the study, and 35113 (67%) had received at least two doses of the vaccine by the end of the study. Of the 4284 COVID-19 infections during the study, 3476 (81.1%) occurred in persons who were unvaccinated, and 4263 (99.5%) occurred among those without prior COVID-19. In Cox proportional hazards regression, both prior COVID-19 and vaccination were independently associated with significantly lower risk of COVID-19. Vaccination was associated with lower risk of COVID-19 among those without prior COVID-19 (HR 0.24, 95% CI 0.22–0.26) but not among those with prior COVID-19 (HR 0.86, 95% CI 0.33–2.29).

Conclusions

Both previous infection and vaccination provide substantial protection against COVID-19. Vaccination reduces risk of COVID-19 among those without prior COVID-19 but not among those with prior COVID-19, at least not within one year following infection.

Cumulative incidence of COVID-19 over 10.5 months, including the Delta phase, was examined among 52238 employees at Cleveland Clinic. Vaccination was associated with significantly lower risk of COVID-19 among those without prior COVID-19 but not among those with prior COVID-19.
2020 SARS-CoV-2 diversification in the United States: Establishing a pre-vaccination baseline
Authors: Capoferri Adam A. , Shao Wei , Spindler Jon , Coffin John M. , Rausch Jason W. , Kearney Mary F.
Published: June 2021

In 2020, SARS-CoV-2 spread across the United States (U.S.) in three phases distinguished by peaks in the numbers of infections and shifting geographical distribution. We investigated the viral genetic diversity in each phase using sequences publicly available prior to December 15th, 2020, when vaccination was initiated in the U.S. In Phase 1 (winter/spring), sequences were already dominated by the D614G Spike mutation and by Phase 3 (fall), genetic diversity of the viral population had tripled and at least 54 new amino acid changes had emerged at frequencies above 5%, several of which were within known antibody epitopes. These findings highlight the need to track the evolution of SARS-CoV-2 variants in the U.S. to ensure continued efficacy of vaccines and antiviral treatments.

One Sentence Summary

SARS-CoV-2 genetic diversity in the U.S. increased 3-fold in 2020 and 54 emergent nonsynonymous mutations were detected.
Formation of oxidized gases and secondary organic aerosol from a commercial oxidant-generating electronic air cleaner
Authors: Joo Taekyu , Rivera-Rios Jean C. , Alvarado-Velez Daniel , Westgate Sabrina , Ng Nga Lee
Published: June 2021

Airborne virus transmission during the COVID-19 pandemic increased the demand for indoor air cleaners. While some commercial electronic air cleaners could be effective in reducing primary pollutants and inactivating bioaerosol, studies on the formation of secondary products from oxidation chemistry during their use are limited. Here, we measured oxygenated volatile organic compounds (OVOCs) and the chemical composition of particles generated from a hydroxyl radical generator in an office. During operation, enhancements in OVOCs, especially low-molecular-weight organic and inorganic acids, were detected. Rapid increases in particle number and volume concentrations were observed, corresponding to the formation of highly-oxidized secondary organic aerosol (SOA) (O:C ∼1.3). The organic mass spectra showed an enhanced signal at m/z 44 (CO2+) and the aerosol evolved with a slope of ∼ -1 in the Van Krevelen diagram. These results suggest that organic acids generated during VOC oxidation contributed to particle nucleation and SOA formation. Nitrate, sulfate, and chloride also increased during the oxidation without a corresponding increase in ammonium, suggesting organic nitrate, organic sulfate, and organic chloride formation. As secondary species are reported to have detrimental health effects, further studies are needed to evaluate potential OVOCs and SOA formation from electronic air cleaners in different indoor environments.

Synopsis

We observed formation of oxygenated volatile organic compounds and secondary organic aerosol from an electronic air cleaner.
The Impact of COVID-19 Vaccination on California’s Return to Normalcy
Authors: Daza–Torres Maria L. , García Yury E. , Schmidt Alec J. , Pollock Brad H , Sharpnack James , Nuño Miriam
Published: June 2021

SARS-CoV-2 has infected nearly 3.7 million and killed 61,722 Californians, as of May 22, 2021. Non-pharmaceutical interventions have been instrumental in mitigating the spread of the coronavirus. How- ever, as we ease restrictions, widespread implementation of COVID- 19 vaccines is essential to prevent its resurgence. In this work, we addressed the adequacy and deficiency of vaccine uptake within California and the possibility and severity of resurgence of COVID-19 as restrictions are lifted given the current vaccination rates. We implemented a real-time Bayesian data assimilation approach to provide projections of incident cases and deaths in California following the reopening of its economy on June 15, 2021. We implemented scenarios that vary vaccine uptake prior to reopening, and transmission rates and effective population sizes following the reopening. For comparison purposes, we adopted a baseline scenario using the current vaccination rates, which projects a total 11,429 cases and 429 deaths in a 15-day period after reopening. We used posterior estimates based on CA historical data to provide realistic model parameters after reopening. When the transmission rate is increased after reopening, we projected an increase in cases by 21.8% and deaths by 4.4% above the baseline after reopening. When the effective population is increased after reopening, we observed an increase in cases by 51.8% and deaths by 12.3% above baseline. A 30% reduction in vaccine uptake alone has the potential to increase cases and deaths by 35% and 21.6%, respectively. Conversely, increasing vaccine uptake by 30% could decrease cases and deaths by 26.1% and 17.9%, respectively. As California unfolds its plan to reopen its economy on June 15, 2021, it is critical that social distancing and public behavior changes continue to be promoted, particularly in communities with low vaccine uptake. The Centers of Disease Control’s (CDC) recommendation to ease mask- wearing for fully vaccinated individuals despite major inequities in vaccine uptake in counties across the state highlights some of the logistical challenges that society faces as we enthusiastically phase out of this pandemic.
Rapid and Sensitive Detection of SARS-CoV-2 Infection Using Quantitative Peptide Enrichment LC-MS Analysis
Authors: Hober Andreas , Hua Tran-Minh Khue , Foley Dominic , McDonald Thomas , Vissers Johannes P.C. , Pattison Rebecca , Ferries Samantha , Hermansson Sigurd , Betner Ingvar , Uhlen Mathias , Razavi Morteza , Yip Richard , Pope Matthew E. , Pearson Terry W. , Anderson N. Leigh , Bartlett Amy , Calton Lisa , Alm Jessica J. , Engstrand Lars , Edfors Fredrik
Published: June 2021

Reliable, robust, large-scale molecular testing for SARS-CoV-2 is essential for monitoring the ongoing Covid-19 pandemic. We have developed a scalable analytical approach to detect viral proteins based on peptide immunoaffinity enrichment combined with liquid chromatography - mass spectrometry (LC-MS). This is a multiplexed strategy, based on targeted proteomics analysis and read-out by LC-MS, capable of precisely quantifying and confirming the presence of SARS-CoV-2 in PBS swab media from combined throat/nasopharynx/saliva samples.

The results reveal that the levels of SARS-CoV-2 measured by LC-MS correlate well with their corresponding RT-PCR readout (r=0.79). The analytical workflow shows similar turnaround times as regular RT-PCR instrumentation with a quantitative readout of viral proteins corresponding to cycle thresholds (Ct) equivalents ranging from 21 to 34. Using RT-PCR as a reference, we demonstrate that the LC-MS-based method has 100% negative percent agreement (estimated specificity) and 95% positive percent agreement (estimated sensitivity) when analyzing clinical samples collected from asymptomatic individuals with a Ct within the limit of detection of the mass spectrometer (Ct ≤30). These results suggest that a scalable analytical method based on LC-MS has a place in future pandemic preparedness centers to complement current virus detection technologies.
Passively Sensing SARS-CoV-2 RNA in Public Transit Buses
Authors: Hoffman Jason , Hirano Matthew , Panpradist Nuttada , Breda Joseph , Ruth Parker , Xu Yuanyi , Lester Jonathan , Nguyen Bichlien , Ceze Luis , Patel Shwetak N.
Published: June 2021

Affordably tracking the transmission of respiratory infectious diseases in urban transport infrastructures can inform individuals about potential exposure to diseases and guide public policymakers to prepare timely responses based on geographical transmission in different areas in the city. Towards that end, we designed and tested a method to detect SARS-CoV-2 RNA in the air filters of public buses, revealing that air filters could be used as passive fabric sensors for the detection of viral presence. We placed and retrieved filters in the existing HVAC systems of public buses to test for the presence of trapped SARS-CoV-2 RNA using phenol-chloroform extraction and RT-qPCR. SARS-CoV-2 RNA was detected in 14% (5/37) of public bus filters tested in Seattle, Washington, from August 2020 to March 2021. These results indicate that this sensing system is feasible and that, if scaled, this method could provide a unique lens into the geographically relevant transmission of SARS-CoV-2 through public transit rider vectors, pooling samples of riders over time in a passive manner without installing any additional systems on transit vehicles.

Synopsis

Passive sensing of viral presence on urban transit infrastructure is proven, with forward-looking benefits for tracking pandemic spread.
Image-based computational hemodynamics analysis of systolic obstruction in hypertrophic cardiomyopathy
Authors: Fumagalli Ivan , Vitullo Piermario , Scrofani Roberto , Vergara Christian
Published: June 2021

Hypertrophic Cardiomyopathy (HCM) is a pathological condition characterized by an abnormal thickening of the myocardium. When it affects the medio-basal portion of the septum, it is named Hypertrophic Obstructive Cardiomyopathy because it induces a flow obstruction in the left ventricle outflow tract, which may compromise the cardiac function and possibly lead to cardiac death. In this work, we investigate the hemodynamics of different HCM patients by means of computational hemodynamics, aiming at quantifying the effects of this pathology on blood flow and pressure gradients and thus providing clinical indications that may help diagnosis and the design of surgical treatment (septal myectomy). To this aim, we employ an enhanced version of an image-based computational pipeline proposed in a previous work, integrating fluid dynamics simulations with geometrical and functional data reconstructed from standard cine-MRI acquisitions. Blood flow is modelled as an incompressible Newtonian fluid, The corresponding Navier-Stokes equations are solved in a moving domain obtained from cine-MRI, whereas the valve leaflets are accounted for by a resistive method.
Health care use up to 6 months after COVID-19 in 700.000 children and adolescents: a pre-post study
Authors: Magnusson Karin , Skyrud Katrine Damgaard , Suren Pål , Greve-Isdahl Margrethe , Størdal Ketil , Kristoffersen Doris Tove , Telle Kjetil
Published: June 2021

Objectives

To explore whether, and for how long COVID-19 among children gives an increase in use of health care services, when compared to children with no COVID-19.

Methods

Studying all Norwegian residents aged 1-5, 6-15 and 16-19 years from August 1st2020 to February 1st2021 (N= 768 560), we contrasted rates of monthly all-cause primary and specialist health care use before and after testing for SARS-CoV-2 (% relative change), for children testing positive (non-hospitalized in the acute phase) (N=10 306) vs children with no COVID-19 (N=758 254).

Results

We found a substantial elevation in short-term primary care use for children testing positive for SARS-CoV-2 during the first month following positive test when compared to children testing negative (relative elevation 1-5 years: 325%, 95%CI=296-354; 6-15 years: 434%, 95%CI=415-453; 16-19 years: 360%, 95%CI=342-379). There was still elevated primary care use at 2 months (1-5 years: 21%, 95%CI= 4-38; 6-15 years: 13%, 95%CI=2-25) and at 3 months (1-5 years: 26%, 95%CI=7-45, 6-15 years: 15%, 95%CI=3-26) for young children, but not at 2 or 3 months for the older children (16-19 years: 10%, 95%CI=-1-22 and 6%, 95%CI=-5-18, respectively). The 1-5-year-olds also had a long-term (up to 6 months) increase of primary care (14%, 95%CI=1-26) that was not observed for older age groups, when compared to same-aged children testing negative. We observed no elevated use of specialist care.

Conclusion

Children in pre-school age used health services for a longer time (3-6 months) after COVID-19 than children in primary and secondary school age (1-3 months).
Magnetic activated cell-sorting identifies a unique lung microbiome community associated with disease states
Authors: Dunlap Daniel G. , Yang Libing , Qin Shulin , Ries John , Li Kelvin , Fitch Adam , Huang Laurence , McVerry Bryan J. , Methé Barbara A. , Morris Alison
Published: June 2021

Rationale

The advent of culture-independent, next-generation DNA sequencing has led to discovery of distinct lung bacterial communities. Studies of lung microbiome taxonomy often reveal only subtle differences between health and disease, but microbial host response may distinguish members of similar communities in different populations.

Objectives

Magnetic-activated cell sorting (MACS) has been applied to the gut microbiome to identify numbers and types of bacteria eliciting a humoral response. We adapted this technique to examine populations of immunoglobulin-bound bacteria and investigate the lung microbiota in HIV as a representative disease.

Methods

42 people living with HIV (PLWH) and 22 HIV-uninfected individuals underwent bronchoalveolar lavage (BAL). We separated immunoglobulin G-bound bacteria using MACS and sequenced the 16S rRNA gene on the Illumina MiSeq platform. We analyzed sequences and quantified BAL cytokines and bacterial rRNA copy numbers.

Measurements and Main Results

Immunoglobulin G-bound bacteria were detectable in the healthy lung microbiota. Comparison of raw BAL by HIV status showed no significant taxonomic differences, but the immunoglobulin-bound lung microbiota differed by HIV status with greater abundance of Pseudomonas in PLWH. BAL cytokine levels were also higher in PLWH, which correlated with increased quantity of immunoglobulin G-bound bacteria.

Conclusions

We report a novel application of magnetic-activated cell sorting to identify immunoglobulin G-bound bacteria in the lung. This technique identified distinct bacterial communities which differed in composition from raw BAL, revealing differences in health and disease not detected by traditional analyses. Cytokine response was also associated with differential immunoglobulin binding of lung bacteria, suggesting functional importance of these communities.
Clinical cholera surveillance sensitivity in Bangladesh and implications for large-scale disease control
Authors: Hegde Sonia T. , Lee Elizabeth C. , Khan Ashraful Islam , Lauer Stephen A. , Islam Md. Taufiqul , Bhuiyan Taufiqur Rahman , Lessler Justin , Azman Andrew S. , Qadri Firdausi , Gurley Emily S.
Published: June 2021

Introduction

A surveillance system that is sensitive to detecting high burden areas is critical for achieving widespread disease control. In 2014, Bangladesh established a nationwide, facility-based cholera surveillance system for Vibrio cholerae infection. We sought to measure the sensitivity of this surveillance system to detect cases to assess whether cholera elimination targets outlined by the Bangladesh national control plan can be adequately measured.

Methods

We overlaid maps of nationally-representative annual V. cholerae seroincidence onto maps of the catchment areas of facilities where confirmatory laboratory testing for cholera was conducted, and identified its spatial complement as surveillance greyspots, areas where cases likely occur but go undetected. We assessed surveillance system sensitivity and changes to sensitivity given alternate surveillance site selection strategies.

Results

We estimated that 69% of Bangladeshis (111.7 million individuals) live in surveillance greyspots, and that 23% (25.5 million) of these individuals live in areas with the highest V. cholerae infection rates.

Conclusions

The cholera surveillance system in Bangladesh has the ability to monitor progress towards cholera elimination goals among 31% of the country’s population, which may be insufficient for accurately measuring progress. Increasing surveillance coverage, particularly in the highest risk areas, should be considered.
Reduced risk of placental parasitaemia associated with complement fixation on Plasmodium falciparum by antibodies among pregnant women
Authors: Opi D. Herbert , Boyle Michelle J. , McLean Alistair , Reiling Linda , Chan Jo-Anne , Stanisic Danielle I. , Ura Alice , Mueller Ivo , Fowkes Freya J. , Rogerson Stephen J. , Beeson James G.
Published: June 2021

Background

The pathogenesis of malaria in pregnancy (MiP) involves accumulation of P. falciparum-infected red blood cells (pRBCs) in the placenta, contributing to poor pregnancy outcomes. Parasite accumulation is primarily mediated by P. falciparum erythrocyte membrane 1 (PfEMP1). Magnitude of IgG to pRBCs has been associated with reduced risk of MiP in some studies, but associations have been inconsistent. Further, antibody effector mechanisms are poorly understood, and the role of antibody complement interactions is unknown.

Methods

Studying a longitudinal cohort of pregnant women (n=302) from a malaria-endemic province in Papua New Guinea (PNG), we measured the ability of antibodies to fix and activate complement using placental binding pRBCs and PfEMP1 recombinant domains. We determined antibody-mediated complement inhibition of pRBC binding to the placental receptor, chondroitin sulfate A (CSA) and associations with protection against placental parasitaemia.

Results

Some women acquired antibodies that effectively promoted complement fixation on placental-binding pRBCs. Complement fixation correlated with IgG1 and IgG3 antibodies, which dominated the response. There was, however, limited evidence for membrane attack complex activity or pRBC lysis or killing. Importantly, a higher magnitude of complement fixing antibodies was prospectively associated with reduced odds of placental infection at delivery. Using genetically-modified P. falciparum and recombinant PfEMP1 domains, we found that complement-fixing antibodies primarily targeted a specific variant of PfEMP1 (known as VAR2CSA). Furthermore, complement enhanced the ability of antibodies to inhibit pRBC binding to CSA, which was primarily mediated by complement C1q protein.

Conclusion

These findings provide new insights into mechanisms mediating immunity to MiP and reveal potential new strategies for developing malaria vaccines that harness antibody-complement interactions.
Taxon-specific shifts in bacterial and archaeal transcription of dissolved organic matter cycling genes in a stratified fjord
Authors: Pontiller Benjamin , Pérez-Martínez Clara , Bunse Carina , Osbeck Christofer M.G. , González José M. , Lundin Daniel , Pinhassi Jarone
Published: June 2021

A considerable fraction of organic matter derived from photosynthesis in the euphotic zone settles into the ocean’s interior, and under way is degraded by diverse microbial consortia that utilize a suite of extracellular enzymes and membrane transporters. Still, the molecular details that regulate carbon cycling across depths remain little explored. As stratification in fjords has made them attractive models to explore patterns in biological oceanography, we here analyzed bacterial and archaeal transcription in samples from five depth layers in the Gullmar Fjord, Sweden. Transcriptional variation over depth correlated with gradients in chlorophyllaand nutrient concentrations. Differences in transcription between sampling dates (summer and early autumn), were strongly correlated with ammonium concentrations, which potentially was linked with a stronger influence of (micro-)zooplankton grazing in summer. Transcriptional investment in carbohydrate-active enzymes (CAZymes) decreased with depth and shifted toward peptidases, partly a result of elevated CAZyme transcription by Flavobacteriales, Cellvibrionales and Synechococcales at 2-25 m and a dominance of peptidase transcription by Alteromonadales and Rhodobacterales from 50 m and down. In particular, CAZymes for chitin, laminarin, and glycogen were important. High levels of transcription of ammonium transporters by Thaumarchaeota at depth (up to 18% of total transcription), along with the genes for ammonia oxidation and CO2-fixation, indicated that chemolithoautotrophy contributed to the carbon flux in the fjord. The taxon-specific expression of functional genes for processing of the marine DOM pool and nutrients across depths emphasizes the importance of different microbial foraging mechanisms across spatiotemporal scales for shaping biogeochemical cycles.

IMPORTANCE

It is generally recognized that stratification in the ocean strongly influences both the community composition and the distribution of ecological functions of microbial communities, which in turn are expected to shape the biogeochemical cycling of essential elements over depth. Here we used metatranscriptomics analyses to infer molecular detail on the distribution of gene systems central to the utilization of organic matter in a stratified marine system. We thereby uncovered that pronounced shifts in transcription of genes encoding CAZymes, peptidases, and membrane transporters occurred over depth among key prokaryotic orders. This implies that sequential utilization and transformation of organic matter through the water column is a key feature that ultimately influences the efficiency of the biological carbon pump.
The African swine fever virus protease pS273R inhibits DNA sensing cGAS-STING pathway by targeting IKKε
Authors: Luo Jia , Ni Jinghua , Jiang Sen , Xia Nengwen , Guo Yiwen , Shao Qi , Zhang Jiajia , Cao Qi , Xu Zhenqi , Zheng Wanglong , Chen Nanhua , Zhang Quan , Chen Hongjun , Guo Xiaoyu , Zhu Hongfei , Meurens François , Zhu Jianzhong
Published: June 2021

African swine fever virus (ASFV), a large and complex cytoplasmic double-stranded DNA virus, has developed multiple strategies to evade the antiviral innate immune responses. Cytosolic DNA arising from invading ASFV is mainly detected by the cyclic GMP-AMP synthase (cGAS) and then triggers a series of innate immune responses to prevent virus invasion. However, the immune escape mechanism of ASFV remains to be fully clarified. The pS273R of ASFV is a member of the SUMO-1-specific protease family and is crucial for valid virus replication. In this study, we identified pS273R as a suppressor of cGAS-STING pathway mediated type I interferon (IFN) production by ASFV genomic open reading frame screening. The pS273R was further confirmed as an inhibitor of IFN production as well as its downstream antiviral genes in cGAS-STING pathway. Mechanistically, pS273R greatly decreased the cGAS-STING signaling by targeting IKKε but not TBK1 and pS273R was found to disturb the interaction between IKKε and STING through its interaction with IKKε. Further, mutational analyses revealed that pS273R antagonized the cGAS-STING pathway by enzyme catalytic activity, which may affect the IKKε sumoylation state required for the interaction with STING. In summary, our results revealed for the first time that pS273R acts as an obvious negative regulator of cGAS-STING pathway by targeting IKKε via its enzymatic activity, which shows a new immune evasion mechanism of ASFV.

Importance

African swine fever (ASF) is a devastating disease for domestic pigs and wild boar and the pathogen ASFV is a cytoplasmic double-stranded DNA virus. The innate immune cGAS-STING-IFN signaling pathway exerts a critical role in sensing ASFV infection. However, the functions of half ASFV encoded 150 plus proteins are still unknown and the evasion against the cGAS-STING pathway is not resolved. In our study, via ASFV genomic open reading frame (ORF) screening, we found that 29 ASFV proteins could inhibit cGAS-STING signaling pathway, with pS273R showing the most obvious inhibitory effect. Surprisingly, pS273R was found to antagonize the cGAS-STING signaling by targeting IKKε. Moreover, the pS273R enzyme activity is required for its ability to inhibit the cGAS-STING pathway. Our findings deepen the understanding of the immune evasion mechanism of ASFV, which will provide a support for the development of safe and effective ASFV vaccines.
Developing and testing an arts-based, digital knowledge translation tool for parents about childhood croup
Authors: Scott Shannon D. , Le Anne , Hartling Lisa
Published: June 2021

Croup is a common viral illness affecting 80,000 children annually in Canada. Between 7-31% of children seen in an ED for croup are admitted to hospital due to health care provider apprehension. However, over 60% of children with croup experience mild symptoms that can be safely managed at home. Emerging evidence suggests that initiatives targeting healthcare consumers (i.e., patients, parents, families) can inform decision making and shape treatment expectations. Previous research demonstrates that innovative media are superior to traditional standard health sheets for transferring information to consumers.

The purpose of this project was to develop, refine, and test the usability of a whiteboard animation video for parents about childhood croup. Parents rated the tools highly across all usability items, suggesting that creative tools developed using multi-method development processes can help facilitate the uptake of health information in parents.
Predictive targeting of mitochondrial metabolism in Acute Myeloid Leukemia patients with a lipoic acid analog
Authors: Reid Michael A. , Bose Shree , Pladna Kristin M , Anderson Rebecca , Mikhael Peter G. , Xiao Zhengtao , Dai Ziwei , Liu Shiyu , Liu Juan , Pardee Timothy S. , Locasale Jason W.
Published: June 2021

Targeting metabolism has long been a theory for cancer therapy, but clinical development has been limited by toxicities, compound availability, overall efficacy, and patient specificity1. CPI-613, a lipoic acid analogue that interferes with enzymes involved in mitochondrial metabolism, has demonstrated clinical activity in lethal malignancies including relapsed or therapy refractory Acute Myeloid Leukemias (AMLs)2,3 and Phase III trials are ongoing1. Using metabolomics, we investigated blood and bone marrow samples from a cohort of 29 relapsed or refractory AML patients involved in Phase I and II studies undergoing CPI-613 treatment (NCT01768897, NCT02484391) including 13 that achieved a complete response. We show that CPI-613 treatment in patients induced defined alterations related to the tricarboxylic acid (TCA) cycle and associated redox, anabolic and catabolic metabolism. These findings are consistent with targeting of several ketoacid dehydrogenase (KADH) enzymes that use lipoic acid as a cofactor and are related to mitochondrial metabolism. The alterations were observed systemically but were more pronounced within the leukemic bone marrow microenvironment consistent with its mechanistic target. Machine learning revealed that metabolic status and changes associated with mitochondrial metabolism were predictive of treatment response, indicating that mechanism-based metabolite biomarkers to a targeted metabolic cancer therapy may be feasible. Finally, we confirm using isotope tracing and flux analysis that these effects are due to disruptions to substrate utilization into the mitochondria. Our findings provide evidence that a tolerated, anti-cancer therapeutic can act by targeting mitochondrial metabolism in humans.
Comparing India’s second COVID wave with the first wave – a single-center experience
Authors: Kapoor Mayank , Singh Budha O , Panda Prasan Kumar , Dhanger Pathik , Kataria Anant
Published: June 2021

Background

The COVID-19 pandemic has resurfaced in India in the form of a hard-hitting second wave. This study aims to compare the clinical profile of the first wave (April-June 2020) and the second wave (March-May 2021) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a single tertiary care center of India. This will help prioritize the target population group and management strategies in the upcoming third wave if any.

Methods

In this retrospective observational study, we examined the demographic profile, symptoms at presentation, the severity of illness, baseline investigations, treatments received, underlying comorbidities, and outcomes of the COVID-19 patients belonging to the first (W1) and the second wave (W2) of the pandemic in India.

Findings

Among 106 patients in W1 and 104 patients in W2, the age group affected most was 37·1 (SD=16·9) years compared with 50.5 (SD=17.7) years respectively. The baseline oxygen saturation is lower in W2, being 84·0 (13·4) % compared with 91·9 (7·4) % in W1. 70.2 % of the cases belonged to the severe category in W2 compared to 37.5% in W1. W2 patients demonstrated higher transaminase levels [SGOT, 108.3 (99.3) v/s 54.6 (69.3); SGPT, 97.6 (82.3) v/s 58.7 (69.7)] with respect to W1. Similarly, the CT severity score for W2 [29.5 (6.7)] was higher than W1 [23·2 (11·5)][All P<0.05]. The proportion of patients requiring oxygen (81.8% v/s 11.2%), high flow nasal cannula (11.4% v/s 5.6%), non-invasive ventilation (41.2% v/s 1.5%), invasive ventilation (24.5% v/s 0.9%), as well as ICU/HDU admissions (56.4% v/s 12.0%) was higher for W2 as compared with W1. The measured case fatality rate varies from 29% for W2 to 9.6% for W1.

Interpretation

Higher age, oxygen requirement, ventilator requirement, ICU admission, and organ impairment are more prevalent in the admitted COVID-19 cases during the second wave that has hit India compared to the first wave and associated with more fatalities. Strategy for another wave should be planned accordingly.

Key points

Question

What are the differences between the clinical profile of the first wave (W1) and the second wave (W2) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a single tertiary care center of India?

Findings

In this observational study among 106 patients in W1 (April-June 2020) and 104 patients in W2 (March-May 2021), there were higher proportion of increased age, oxygen requirement, ventilator requirement, ICU admission, and organ impairment in the admitted COVID-19 cases during the second wave.

Meaning

The second wave hits India badly than the first wave and associated with more fatalities.
Novel scotoma detection method using time required for fixation to the random targets
Authors: Takahashi Nobuyuki , Saeki Shozo , Kawahara Minoru , Aman Hirohisa , Nakano Eri , Mori Yuki , Miyake Masahiro , Tamura Hiroshi , Tsujikawa Akitaka
Published: June 2021

We developed a novel scotoma detection system using time required for fixation to the random targets, or the” eye-guided scotoma detection method “. In order to verify the” eye-guided scotoma detection method “, we measured 78 eyes of 40 subjects, and examined the measurement results in comparison with the results of measurement by Humphrey perimetry. The results were as follows: (1) Mariotte scotomas were detected in 100% of the eyes tested; (2) The false-negative rate (the percentage of cases where a scotoma was evaluated as a non-scotoma) was less than 10%; (3) The positive point distribution in the low-sensitivity eyes was well matched. These findings suggested that the novel scotoma detection method in the current study will pave the way for the realization of mass screening to detect pathological scotoma earlier.

Author summary

Conventional perimeters, such as the Goldmann perimeter and Humphrey perimeter, require experienced examiners and space occupying. With either perimeter, subjects’ eye movements need to be strictly fixed to the fixation target of the device. Other perimeters can monitor fixation and automatically measure the visual field. With the eye-guided scotoma detection method proposed in the current study, subjects feel less burdened since they do not have to fixate on the fixation target of the device and can move their eyes freely. Subjects simply respond to visual targets on the display; then, scotomas can be automatically detected. The novel method yields highly accurate scotoma detection through an algorithm that separates scotomas from non-scotomas.
Aggregating probabilistic predictions of the safety, efficacy, and timing of a COVID-19 vaccine
Authors: McAndrew Thomas , Cambeiro Juan , Besiroglu Tamay
Published: June 2021

Safe, efficacious vaccines were developed to reduce the transmission of SARS-CoV-2 during the COVID-19 pandemic. But in the middle of 2020, vaccine effectiveness, safety, and the timeline for when a vaccine would be approved and distributed to the public was uncertain. To support public health decision making, we solicited trained forecasters and experts in vaccinology and infectious disease to provide monthly probabilistic predictions from July to September of 2020 of the efficacy, safety, timing, and delivery of a COVID-19 vaccine. We found, that despite sparse historical data, a consensus—a combination of human judgment probabilistic predictions—can quantify the uncertainty in clinical significance and timing of a potential vaccine. The consensus underestimated how fast a therapy would show a survival benefit and the high efficacy of approved COVID-19 vaccines. However, the consensus did make an accurate prediction for when a vaccine would be approved by the FDA. Compared to individual forecasters, the consensus was consistently above the 50thpercentile of the most accurate forecasts. A consensus is a fast and versatile method to build probabilistic predictions of a developing vaccine that is robust to poor individual predictions. Though experts and trained forecasters did underestimate the speed of development and the high efficacy of a SARS-CoV-2 vaccine, consensus predictions can improve situational awareness for public health officials and for the public make clearer the risks, rewards, and timing of a vaccine.
Estimating the impact of Angelman syndrome on parental productivity in Australia using productivity-adjusted life years
Authors: Hartmanis Sally L , Baker Emma K , Godler David E , Liew Danny
Published: June 2021

Background

Angelman syndrome (AS) is a rare genetic condition characterised by global developmental delay, including severe to profound intellectual disability. The parents of persons with AS experience increased stress, anxiety and depression. This impacts parents’ career choices and productivity.

Aims

To estimate, for the first time, the total productivity lost by the parents of persons with AS over a 10-year period in Australia and the corresponding cost to society.

Methods and procedures

A cost-of-illness model with simulated follow-up over a 10-year period was developed, with 2019 as the baseline year, facilitated by a Markov chain of life tables. The prevalence of persons with AS and their parents, the productivity-adjusted life years (PALYs) lost by parents, and the cost to society were estimated. Key data were obtained from a prospective cohort of AS families, peer-reviewed literature, and publicly available sources.

Outcomes and results

The base-case productivity burden borne by the estimated 330 living parents of the 428 prevalent-persons with AS totalled AUD$45.30 million, corresponding to a loss of 38.42% of PALYs per-parent.

Conclusions and implications

Caring for a child with AS has a significant impact on the productivity of affected parents, with a large associated impact on the broader Australian economy.

What this paper adds?

Persons with AS require lifelong care and support. Consequently, AS results in a significant socioeconomic impact, borne both by the healthcare system and affected families. This is the first known study to estimate the total impact of caring for a child with AS on parental productivity, as well as the first study known to estimate the PALYs lost by a parental or caregiver population. This study found that caring for a child with AS has a significant impact on the productivity of affected parents, with a large associated impact on the broader Australian economy. At present, the supports available to persons with AS and their families include sleep aids and behavioural therapy. In future, specific therapeutic treatments for AS may become available, with trials underway at present investigating the efficacy and effectiveness of gene therapies for AS. As such, evidence regarding the total socioeconomic impact, including the parental productivity burden, attributable to AS is needed to inform future funding decisions.
Reg4 defenses the intestine against Salmonella infection via binding the flagellin
Authors: Wang Weipeng , Lu Ying , Tian Xinbei , Chen Shanshan , Du Jun , Cai Wei , Xiao Yongtao
Published: June 2021

Salmonella Typhimurium is gram-negative flagellated bacteria that can cause food-borne gastroenteritis and diarrhea in humans and animals. The regenerating islet-derived family member 4 (Reg4) is overexpressed in the gastrointestinal tract during intestinal inflammation. However, the role of Reg4 in the intestinal inflammation induced by Salmonella Typhimurium is largely unknown. In this study, we reported for the first time that Reg4 has bactericidal activity against intestinal infection caused by Salmonella Typhimurium. In vivo, Reg4 could reduce the colonization of Salmonella Typhimurium and attenuate intestinal inflammation in the Salmonella Typhimurium-infected model. Additionally, the mice with the epithelial cell specific deletion of Reg4 (Reg4ΔIEC) exhibited more severe intestinal inflammation and more colonization of Salmonella Typhimurium. However, the administration of Reg4 could reverse these negative impacts. In vitro, Reg4 protein was showed to inhibit the growth of Salmonella Typhimurium. We further investigate the function motif of Reg4 and find that the “HDPQK” motif in Reg4 is essential to its bactericidal activity. Reg4 exerted the bactericidal effect by binding to the flagellin of Salmonella Typhimurium and suppressing its motility, adhesion, and invasion to the intestinal epithelia. In conclusion, our findings identify Reg4 as a novel antimicrobial peptide against infection by Salmonella Typhimurium and explore its possible mechanism, which may be of great significance for developing novel agents against flagellated micro pathogens.
Phenotypic and functional characterisation of circulating cytomegalovirus-specific T cells in healthy virus carriers and lung transplant candidates
Authors: Altaf Mohammed , Irfan Md Azhar , Naheed Nazneen , Aleemuddin NM
Published: June 2021

This manuscript has been withdrawn by the authors as it was submitted and made public without appropriate approval. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.