bluuebunny/crossref_metadata_2025 huggingface dataset:
Focal seizures are organized by feedback between neural activity and ion concentration changes
Authors: Gentiletti Damiano , de Curtis Marco , Gnatkovsky Vadym , Suffczynski Piotr
Published: March 2021

Human and animal EEG data demonstrate that focal seizures start with low-voltage fast activity, evolve into rhythmic burst discharges and are followed by a period of suppressed background activity. This suggests that processes with dynamics in the range of tens of seconds govern focal seizure evolution. We investigate the processes associated with seizure dynamics by complementing the Hodgkin-Huxley mathematical model with the physical laws that dictate ion movement and maintain ionic gradients. Our biophysically realistic computational model closely replicates the electrographic pattern of a typical human focal seizure characterized by low voltage fast activity onset, tonic phase, clonic phase and postictal suppression. Our study demonstrates, for the first timein silico, the potential mechanism of seizure initiation by inhibitory interneurons via the initial build-up of extracellular K+due to intense interneuronal spiking. The model also identifies ionic mechanisms that may underlie a key feature in seizure dynamics, i.e., progressive slowing down of ictal discharges towards the end of seizure. Our model prediction of specific scaling of inter-burst intervals is confirmed by seizure data recorded in the whole guinea pig brain in vitro and in humans, suggesting that the observed termination pattern may hold across different species. Our results emphasize ionic dynamics as elementary processes behind seizure generation and indicate targets for new therapeutic strategies.
Insights into single hiPSC-derived cardiomyocyte phenotypes and maturation using ConTraX, an efficient pipeline for tracking contractile dynamics
Authors: Pardon Gaspard , Lewis Henry , Vander Roest Alison S. , Castillo Erica A. , Wilson Robin , Denisin Aleksandra K. , Blair Cheavar A. , Birnbaum Foster , Holbrook Colin , Koleckar Kassie , Chang Alex C-Y , Blau Helen M. , Pruitt Beth L.
Published: March 2021

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerfulin-vitromodels to study the mechanisms underlying cardiomyopathies and cardiotoxicity. To understand how cellular mechanisms affect the heart, it is crucial to quantify the contractile function in single hiPSC-CMs over time, however, such measurements remain demanding and low-throughput, and are too seldom considered.

We developed an open-access, versatile, streamlined, and highly automated pipeline to address these challenges and enable quantitativetrackingof thecontractiledynamics of single hiPSC- CMs over time:ConTraX. Three interlocking software modules enable: (i) parameter-based localization and selection of single hiPSC-CMs; (ii) automated video acquisition of >200 cells/hour; and (iii) streamlined measurements of the contractile parameters via traction force microscopy. UsingConTraX, we analyzed >2,753 hiPSC-CMs over time under orthogonal experimental conditions in terms of culture media and substrate stiffnesses. Using undirected high-dimensional clustering, we dissected the complex diversity of contractile phenotypes in hiPSC-CM populations and revealed converging maturation patterns.

Our modularConTraXpipeline empowers biologists with a potent quantitative analytic tool applicable to the development of cardiac therapies.
ODOR IDENTITY CAN BE EXTRACTED FROM THE RECIPROCAL CONNECTIVITY BETWEEN OLFACTORY BULB AND PIRIFORM CORTEX IN HUMANS
Authors: Iravani Behzad , Arshamian Artin , Lundqvist Mikael , Kay Leslie , Wilson Donald A. , Lundström Johan N.
Published: March 2021

Neuronal oscillations route external and internal information across brain regions. In the olfactory system, the two central nodes—the olfactory bulb (OB) and the piriform cortex (PC)—communicate with each other via neural oscillations to shape the olfactory percept. Communication between these nodes have been well characterized in non-human animals but less is known about their role in the human olfactory system. Using a recently developed and validated EEG-based method to extract signals from the OB and PC sources, we show in healthy human participants that there is a bottom-up information flow from the OB to the PC in the beta and gamma frequency bands, while top-down information from the PC to the OB is facilitated by delta and theta oscillations. Importantly, we demonstrate that there was enough information to decipher odor identity above chance from the low gamma in the OB-PC oscillatory circuit as early as 100ms after odor onset. These data further our understanding of the critical role of bidirectional information flow in human sensory systems to produce perception. However, future studies are needed to determine what specific odor information is extracted and communicated in the information exchange.
Diet-induced changes in titer support a threshold effect ofWolbachia-associated plastic recombination inDrosophila melanogaster
Authors: Mostoufi Sabrina L. , Singh Nadia D.
Published: March 2021

Plastic recombination inDrosophila melanogasterhas been associated with a variety of extrinsic and intrinsic factors such as temperature, starvation, and parasite infection. The bacterial endosymbiontWolbachia pipientishas also been associated with plastic recombination inD. melanogaster. Wolbachiainfection is pervasive in arthropods and this infection induces a variety of phenotypes in its hosts, the strength of which can depend on bacterial concentration, or titer. Here we test the hypothesis that the magnitude ofWolbachia-associated plastic recombination inD. melanogasterdepends on titer. To manipulate titer, we raisedWolbachia-infected and uninfected flies on diets that have previously been shown to increase or decreaseWolbachiatiter relative to controls. We measured recombination in treated and control individuals using a standard backcrossing scheme with two X-linked visible markers. Our results recapitulate previous findings thatWolbachiainfection is associated with increased recombination rate across theyellow-vermillioninterval of the X chromosome. Our data show no significant effect of diet or diet byWolbachiainteractions on recombination, suggesting that diet-induced changes inWolbachiatiter have no effect on the magnitude of plastic recombination. These findings represent the first step toward investigating the mechanisms behindWolbachia-associated plastic recombination and demonstrate that the effect may be threshold-based as opposed to dose-dependent.
Joint effects of genes underlying a temperature specialization tradeoff in yeast
Authors: AlZaben Faisal , Chuong Julie N. , Abrams Melanie B. , Brem Rachel B.
Published: March 2021

A central goal of evolutionary genetics is to understand, at the molecular level, how organisms adapt to their environments. For a given trait, the answer often involves the acquisition of variants at unlinked sites across the genome. Genomic methods have achieved landmark successes in pinpointing adaptive loci. To figure out how a suite of adaptive alleles work together, and to what extent they can reconstitute the phenotype of interest, requires their transfer into an exogenous background. We studied the joint effect of adaptive, gain-of-function thermotolerance alleles at eight unlinked genes fromSaccharomyces cerevisiae, when introduced into a thermosensitive sister species,S. paradoxus. Although the loci damped each other’s beneficial impact (that is, they were subject to negative epistasis), most boosted high-temperature growth alone and in combination, and none was deleterious. The complete set of eight genes was sufficient to confer ∼15% of theS. cerevisiaephenotype in theS. paradoxusbackground. The same loci also contributed to a heretofore unknown advantage in cold growth byS. paradoxus. Together, our data establish temperature resistance in yeasts as a model case of a genetically complex evolutionary tradeoff, which can be partly reconstituted from the sequential assembly of unlinked underlying loci.

Author summary

Organisms adapt to threats in the environment by acquiring DNA sequence variants that tweak traits to improve fitness. Experimental studies of this process have proven to be a particular challenge when they involve manipulation of a suite of genes, all on different chromosomes. We set out to understand how so many loci could work together to confer a trait. We used as a model system eight genes that govern the ability of the unicellular yeastSaccharomyces cerevisiaeto grow at high temperature. We introduced these variant loci stepwise into a non-thermotolerant sister species, and found that the moreS. cerevisiaealleles we added, the better the phenotype. We saw no evidence for toxic interactions between the genes as they were combined. We also used the eight-fold transgenic to dissect the biological mechanism of thermotolerance. And we discovered a tradeoff: the same alleles that boosted growth at high temperature eroded the organism’s ability to deal with cold conditions. These results serve as a case study of modular construction of a trait from nature, by assembling the genes together in one genome.
Inhibition of select actinobacteria by the organophosphate pesticide chlorpyrifos
Authors: McDonald Nathan D. , Love Courtney E. , Killens-Cade Rushyannah , Werth Jason , Gebert Matthew , Weber Carolyn F. , Nealon Christopher , Sweet Charles , Fierer Noah , Gibbons Henry S.
Published: March 2021

Organophosphorus compounds have an extensive history as both agricultural pesticides as well as chemical nerve agents. Decades of research have demonstrated numerous links between these chemicals and their direct and indirect effects on humans and other organisms. The inhibitory effects of organophosphate pesticides (OPPs) on metazoan physiology, are well-characterized; however, the effects of organophosphorus compounds on soil microbes - essential contributors to key agricultural processes - are poorly understood. Chlorpyrifos (CPF) is an OPP that is used globally for crop protection. Studies of CPF application to soils have shown transient effects on soil microbial communities with conflicting data. Here, we directly test the effect of CPF on a panel of 196 actinobacteria strains, examining the effects of CPF on their growth andin vitrophenotypes on solid media. Strains were grown and replica-plated onto media containing CPF or a vehicle control and grown at 28°C. CPF dramatically inhibited the growth of most strains and/or altered colony morphologies, with 13 strains completely inhibited by CPF. In disk diffusion assays with CPF, its degradation product 3,5,6-trichloropyridinol (TCP), malathion, parathion, monocrotophos and mevinphos, only CPF exhibited direct antimicrobial activity suggesting that the observed effects were due to CPF itself.

IMPORTANCE

Chlorpyrifos is a globally used pesticide with documented neurological effects on non-target organisms in the environment. Finding that chlorpyrifos can inhibit the growth of some soil microbesin vitromay have implications for the composition, stability, and health of the soil microbiome. Due to the importance of soil microbes to numerous biogeochemical processes in agricultural systems, additional investigations into the non-target effects of CPF on soil microbes are clearly needed.
Treatment and Cost -outcomes of a simplified antiretroviral treatment strategy for hepatitis C among HCV and HIV co-infected patients in Ukraine
Authors: Antoniak Sergie , Charles Chasela C , Freiman Morgan J , Stopolianska Yulia , Barnard Tetiana , Gandhi MM , Liulchuk Maria , Tsenilova Zhanna , Tretiakov V , Dible Jeri , Kinge Constance Wose , Minior T , Mohamed Sofiane , Marange Fadzai , Cavenaugh Clint , van der Horst Charles , Antonyak Svitlana , Xulu Thembisile , Chew Kara W , Sanne Ian , Rosen Sydney ,   for EQUIP Health
Published: March 2021

Background

We conducted a demonstration project of an integrated HIV and viral hepatitis testing and treatment strategy using generic ledipasvir/sofosbuvir (LDV/SOF).

Methods

Eligible HCV viraemic adults from two clinics in Kyiv were treated with LDV/SOF +/-weight-based ribavirin for 12 weeks. Clinical assessments were performed at screening and week 24 and as needed; treatment was dispensed every 4 weeks. The primary outcome was sustained virologic response (SVR)12 weeks after treatment. Program costs in 2018 USD were estimated per patient treated using observed resource utilization, local unit, and antiretroviral therapy (ART) costs over the 24-week period.

Results

868 participants initiated on treatment, 87% (755) were PWID and 55.5% (482) were HIV co-infected. The common genotypes were 1 (74.1%) and 3 (22%) and SVR was achieved in 831/868 (95.7%) by intention-to-treat analysis. The average cost per patient treated was $680, assuming generic LDV/SOF and ribavirin pricing and standard quantitative HCV viral load testing. Medications comprised 38% of the average cost/patient, laboratory tests 26%, events (clinic visits, counselling) 10%, and indirect costs 26%. ART accounted for 60% of all drug costs, with HCV medications just 40%.

Conclusion

Generic LDV/SOF +/- ribavirin provided produced exceptionally good outcomes including amongst patients with genotype 3 HCV and PWID at an average cost of <$700/patient year, including ART for those with HIV. Under the assumptions of generic drug pricing but higher laboratory costs, an average cost of $750/patient is likely a reasonable estimate for this intervention in Ukraine, excluding costs for scaling or maintaining the treatment program.
The effect of COVID-19 vaccination in Italy and perspectives for “living with the virus”
Authors: Marziano Valentina , Guzzetta Giorgio , Mammone Alessia , Riccardo Flavia , Poletti Piero , Trentini Filippo , Manica Mattia , Siddu Andrea , Bella Antonino , Stefanelli Paola , Pezzotti Patrizio , Ajelli Marco , Brusaferro Silvio , Rezza Giovanni , Merler Stefano
Published: March 2021

Vaccination campaigns against COVID-19 are allowing the progressive release of physical distancing restrictions in many countries. However, the global spread of the highly transmissible Delta variant has likely suppressed the residual chances of SARS-CoV-2 elimination through herd immunity alone. Here we assess the impact of the vaccination program in Italy since its start on December 27, 2020 and evaluate possible prospects for reopening the society while at the same time keeping COVID-19 under control. To this aim, we propose a mathematical modeling framework where levels of social activity are adjusted to match the time-series of the net reproduction number as estimated from surveillance data. We compared the estimated level of social contacts, number of deaths, and transmission potential with those of a counterfactual scenario where the same epidemic trajectory is obtained in absence of vaccination. We then evaluate the prospective impact of different scenarios of vaccination coverage and different social activity levels on SARS-CoV-2 reproduction number. We estimate that by June 30, 2021, the COVID-19 vaccination program allowed the resumption of about half the social contacts that were recorded in pre-pandemic times; in absence of vaccination, only about one third could have been resumed to obtain the same number of cases, with the added cost of about 12,100 (95%CI: 6,600-21,000) extra deaths (+27%; 95%CI: 15-47%) between December 27, 2020 and June 30, 2021. We show that the negative effect of the Delta variant diffusion in July was entirely offset by vaccination in the month of July and August 2021. Finally, we estimate that a complete return to the pre-pandemic life could be safely attained only if >90%, including children from 5 years on, will be vaccinated using mRNA vaccines developed in 2020. In any case, increasing the vaccination coverage will allow further margins for societal reopening even in absence of a pediatric vaccine. These results may support the definition of vaccination targets for countries that have already achieved a broad population coverage.
Statistical challenges of investigating a disease with a complex diagnosis
Authors: Malato João , Graça Luís , Nacul Luís , Lacerda Eliana , Sepúlveda Nuno
Published: March 2021

Given the absence of a disease-specific biomarker, there are more than 20 symptoms-based case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. As a consequence, the diagnosis for a given patient could vary from one case definition to another. In this context, we analyse data from a biobank dedicated to this disease in order to study the agreement between different case definitions, the similarity between symptom’s profile among all participants including healthy controls and patients with multiple sclerosis. We also investigate the impact of patients’ misclassification on a hypothetical association analysis using data simulation.
Arresting Vertical Transmission of Hepatitis B Virus (AVERT-HBV) in the Democratic Republic of the Congo
Authors: Thompson Peyton , Morgan Camille E. , Ngimbi Patrick , Mwandagalirwa Kashamuka , Ravelomanana Noro , Tabala Martine , Fathy Malongo , Kawende Bienvenu , Muwonga Jérémie , Misingi Pacifique , Mbendi Charles , Luhata Christophe , Jhaveri Ravi , Cloherty Gavin , Kaba Didine , Yotebieng Marcel , Parr Jonathan B.
Published: March 2021

Background

Hepatitis B virus (HBV) remains endemic throughout sub-Saharan Africa despite the widespread availability of effective vaccines. We evaluated the feasibility of adding HBV testing and treatment of pregnant women and birth-dose vaccination of HBV-exposed infants to the HIV prevention of MTCT (PMTCT) program infrastructure in the Democratic Republic of the Congo (DRC), where HBV treatment and birth-dose vaccination programs are not established.

Methods

As part of the HIV PMTCT program at two maternity centers in Kinshasa, DRC, pregnant women were screened for HBV at routine prenatal care registration. Pregnant women with high viral load and/or HBeAg positivity were offered tenofovir disoproxil fumarate (TDF). HBV-exposed infants received a birth-dose of HBV vaccine within 24 hours of life. The primary endpoint was the feasibility and acceptability of the study.

Findings

Of 4,016 women screened, 109 (2.7%) were HBsAg-positive. Ten of 91 (11.1%) women evaluated had high-risk disease. Of 88 infants, 60 (68.2%) received a birth-dose vaccine; of these, 46 (76.7%) received a timely birth-dose. No cases of HBV MTCT were observed in our cohort. There were no serious adverse events associated with TDF nor with birth-dose vaccine. The study procedures were highly acceptable (>80%) among mothers.

Interpretation

Adding HBV screening and treatment of pregnant women and infant birth-dose vaccination to existing HIV PMTCT platforms is feasible in countries like the DRC. Birth-dose vaccination against HBV integrated within the current Expanded Programme on Immunization (EPI) and HIV PMTCT program could accelerate progress toward HBV elimination in Africa.
Barriers to early initiation of breastfeeding in healthy neonates in an urban hospital setting
Authors: Rubagumya Davis , Abeid Muzdalfat , Aghan Eric , Noorani Mariam
Published: March 2021

Background

Breastfeeding is a key intervention to improve global targets on nutrition, health and survival. The World Health Organization (WHO) recommends early initiation of breastfeeding to prevent infections in the newborn and achieve targets of exclusive breastfeeding for the first six months of life. Early initiation of breastfeeding improves neonatal-maternal bonding, reduces jaundice and prevents gastrointestinal and respiratory tract infections. Global prevalence of early initiation of breastfeeding is 45% and 51% for Tanzania. The recommended prevalence is at least 80% by WHO guidelines.

Objective

To explore barriers to early initiation of breastfeeding in a hospital setting.

Methods

A descriptive exploratory qualitative study with semi-structured individual interviews was employed to explore the barriers to early initiation of breastfeeding in a hospital setting. Three midwives and six mothers were interviewed. The interview topic guide covered experiences and challenges of early initiation of breastfeeding. Data was analyzed using Systematic Text Condensation as described by Malterud.

Results

Participants perceived that inadequate breastfeeding information especially on ideal time to start breastfeeding contributed to delayed initiation. The practices and environment post-delivery such as perineal tear repair and dirty labor room prevented women from initiating breastfeeding immediately.

Conclusions

The barriers identified were related to gaps in knowledge, immediate postpartum practices and individual perceptions of a non-conducive environment.
Human lipoproteins comprise at least 12 different classes that are lognormally distributed
Authors: Konishi Tomokazu , Fujiwara Risako , Saito Tadaaki , Satou Nozomi , Crofts Naoko , Iwasaki Ikuko , Abe Yoshihisa , Kawata Shinpei , Ishikawa Tatsuya
Published: March 2021

Lipoproteins in medical samples have been measured by enzymatic methods that coincide with conventional ultracentrifugation. However, the high gravity and time required for ultracentrifugation can cause sample degradation. This study presents the results of HPLC, a gentler and rapid separation method, for 55 human serum samples. The elution patterns were analysed parametrically, and the attribute of each class was confirmed biochemically. Human samples contained 12 classes of lipoproteins, each of which may consist primarily of proteins. There are three classes of VLDLs. The level of each class was distributed lognormally, and the standard amount and the 95% range were estimated. Enzymatic methods measure the levels of several mixed classes. This lognormal character suggests that the levels are controlled by the synergy of multiple factors.
Development of a Video-based Evidence Synthesis Knowledge Translation Resource: Applying a User-Centred Approach
Authors: Deliv Cristian , Putnam El , Devane Declan , Healy Patricia , Hall Amanda , Rosenbaum Sarah , Toomey Elaine
Published: March 2021

Background

People of all ages and walks of life are bombarded with health claims from an array of sources. An understanding of evidence synthesis is important for people to make truly informed healthcare decisions. There is an increasing focus on the use of knowledge translation resources within healthcare; however, the development of these resources has often been poorly described or studied.

Objectives

This study employs a user-centred approach to develop a video animation resource to explain the purpose, use and importance of evidence synthesis to the general public regarding healthcare decision-making.

Methods

We employed a user-centred approach to developing a spoken animated video that could explain evidence synthesis to a public audience, conducting several cycles of idea generation, prototyping, user-testing, analysis and refinement. Six researchers with expertise in evidence synthesis and knowledge translation resource development gave input on the key messages of the video animation and informed the first draft of the storyboard and script. Seven members of the public provided feedback on this draft through Think-aloud interviews, which we used to develop a video animation prototype. Seven additional members of the public participated in Think-aloud interviews while watching the video prototype. In addition to interviews, participants completed a questionnaire that collected data on perceived usefulness, desirability, clarity and credibility. One experienced patient and public involvement (PPI) advocate also provided feedback on the script and prototype. At the end of each feedback cycle, we assimilated all data and made necessary changes, resulting in a final, rendered version of the animation video.

Results

Researchers identified the initial key messages for the SAV as 1) the importance of evidence synthesis, 2) what an evidence synthesis is and 3) how evidence synthesis can impact healthcare decision-making. Using guidance and feedback from members of the public, we produced a three-and-a-half-minute video animation that members of the public rated 9/10 for usefulness, 8/10 for desirability, 8/10 for clarity and 9/10 for credibility. The video was uploaded on YouTube (https://www.youtube.com/watch?v=nZR0xQmZVQg) and has been viewed over 5500 times to date.

Conclusions

Employing a user-centred approach, we developed a video animation knowledge translation resource to explain evidence synthesis to the general public that was assessed as useful, desirable and clear by its intended target audience. This study describes the structured and systematic development of this knowledge translation resource and how key stakeholders and end-users informed the final output.
Comparing the efficacy of anti□infectious drugs for the treatment of mild to severe COVID-19 patients: a protocol for a systematic review and network meta-analysis of randomized clinical trials
Authors: Debela Dejene Tolossa , Heraro Kidist Digamo
Published: March 2021

Background

COVID-19 is a viral infection spreading at a great speed and has quickly caused an extensive burden to individuals, families, countries, and the world. No intervention has yet been proven highly effective for the treatment of COVID-19. Different drugs were being evaluated and reported through randomized clinical trials, and more are currently under trial. This review aimed to compare the efficacy of anti-infectious drugs with a comparator of the standard of care or placebo in patients with COVID-19.

Methods and analysis

Two independent review authors will extract data and assess a risk of bias using RoB2. Randomized controlled trials (RCT) that evaluate single and/or combined antiviral drugs recommended by WHO latest guideline for the treatment of COVID-19 will be included. We will search for Pub Med, the Cochrane Center for Clinical Trial database (CENTRAL), clinicaltrials.gov, etc. databases for articles published in the English language between December 2019 to April 2021. We will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) involving Network Meta-analysis guidelines for the design and reporting of the results. The primary endpoints will be time to clinical recovery and time to RNA negativity. The certainty of evidence will be evaluated using the GRADE extension of NMA. Data analysis will be performed using the frequentist NMA approach with netmeta package implemented in R.

Ethics and dissemination

There are no ethical considerations associated with this study as we will use publicly available data from previously published studies. We plan to publish results in open access peer-reviewed journals.

PROSPERO registration number

ID=CRD42021230919.

Strengths and limitations of this study

This will be the first systematic review and network meta-analysis to assess the efficacy specific to anti-infectious drugs category for for mild to severe patients of COVID-19.

Its compliance with the Preferred Reporting Items for Systematic Review and Meta-Analysis for Protocols (PRISMA-P) involving network meta-analysis(NMA) will ensure the quality of reporting.

Doing both pairwise meta-analysis and network meta-analysis (NMA) can comprehensively analyse direct and indirect comparison results of different anti-infectious drugs for COVID 19 will give more reliable conclusions aswell as the rank of those drugs.

There is risk of heterogeneity and inconsistency, given the different anti-infectious drugs that will be included; however, we try to control intransitivity by carefully identifying the eligibility criteria depending on PICOS strategy and assess inconsistency using local as well as global approaches.

The limitation of this study is it will not explore the economic benefits of these drugs.
Within-country age-based prioritisation, global allocation, and public health impact of a vaccine against SARS-CoV-2: a mathematical modelling analysis
Authors: Hogan Alexandra B , Winskill Peter , Watson Oliver J , Walker Patrick G T , Whittaker Charles , Baguelin Marc , Brazeau Nicholas F , Charles Giovanni D , Gaythorpe Katy A M , Hamlet Arran , Knock Edward , Laydon Daniel J , Lees John A , Løchen Alessandra , Verity Robert , Whittles Lilith K , Muhib Farzana , Hauck Katharina , Ferguson Neil M , Ghani Azra C
Published: March 2021

The worldwide endeavour to develop safe and effective COVID-19 vaccines has been extraordinary, and vaccination is now underway in many countries. However, the doses available in 2021 are likely to be limited. We extended a mathematical model of SARS-CoV-2 transmission across different country settings to evaluate the public health impact of potential vaccines using WHO-developed target product profiles. We identified optimal vaccine allocation strategies within- and between-countries to maximise averted deaths under constraints on dose supply. We found that the health impact of SARS-CoV-2 vaccination depends on the cumulative population-level infection incidence when vaccination begins, the duration of natural immunity, the trajectory of the epidemic prior to vaccination, and the level of healthcare available to effectively treat those with disease. Within a country we find that for a limited supply (doses for <20% of the population) the optimal strategy is to target the elderly. However, with a larger supply, if vaccination can occur while other interventions are maintained, the optimal strategy switches to targeting key transmitters to indirectly protect the vulnerable. As supply increases, vaccines that reduce or block infection have a greater impact than those that prevent disease alone due to the indirect protection provided to high-risk groups. Given a 2 billion global dose supply in 2021, we find that a strategy in which doses are allocated to countries proportional to population size is close to optimal in averting deaths and aligns with the ethical principles agreed in pandemic preparedness planning.

Highlights

The global dose supply of COVID-19 vaccines will be constrained in 2021

Within a country, prioritising doses to protect those at highest mortality risk is efficient

For a 2 billion dose supply in 2021, allocating to countries according to population size is efficient and equitable
Novel blood test for early biomarkers of preeclampsia and Alzheimer’s disease
Authors: Cheng Shibin , Banerjee Sayani , Daiello Lori A. , Nakashima Akitoshi , Jash Sukanta , Huang Zheping , Drake Jonathan D. , Ernerudh Jan , Berg Goran , Padbury James , Saito Shigeru , Ott Brian R. , Sharma Surendra
Published: March 2021

Non-invasive and sensitive blood test has long been a goal for early stage disease diagnosis and treatment for Alzheimer’s disease (AD) and other proteinopathy diseases. However, a blood test based on a mechanistic link to pathologic protein aggregate complexes has not been yet elucidated. We previously reported that preeclampsia (PE), a severe pregnancy complication, is another proteinopathy disorder with impaired autophagy. We hypothesized that induced autophagy deficiency would promote accumulation of pathologic protein aggregates. Here, we describe a novel, sensitive assay that detects serum protein aggregates from patients with PE as well as AD in both dementia and prodromal mild cognitive impairment (MCI) stages. The assay employs exposure of genetically engineered, autophagy-deficient human trophoblasts (ADTs) to serum from patients. The aggregated protein complexes and their individual components, including transthyretin, amyloid β-42, α-synuclein, and phosphorylated tau231, can be detected and quantified by co-staining with ProteoStat, a rotor dye with affinity to aggregated proteins, and respective antibodies. Autophagy-proficient human trophoblasts failed to accumulate serum protein aggregates under similar culture conditions. Detection of protein aggregates in ADTs was not dependent on transcriptional upregulation of these biomarkers. The ROC curve analysis validated the robustness of the assay for its specificity and sensitivity. In conclusion, we have developed a novel noninvasive diagnostic and predictive assay for AD, MCI and PE.
Effect of information about COVID-19 vaccine effectiveness and side effects on behavioural intentions: two online experiments
Authors: Kerr John R. , Freeman Alexandra L. J. , Marteau Theresa M. , van der Linden Sander
Published: March 2021

The success of mass COVID-19 vaccination campaigns rests on widespread uptake. However, although vaccinations provide good protection, they do not offer full immunity and while they likely reduce transmission of the virus to others, the extent of this remains uncertain. This produces a dilemma for communicators who wish to be transparent about benefits and harms and encourage continued caution in vaccinated individuals but not undermine confidence in an important public health measure. In two large pre-registered experimental studies on quota-sampled UK public participants we investigate the effects of providing transparent communication—including uncertainty—about vaccination effectiveness on decision-making. In Study 1 (n= 2,097) we report that detailed information about COVID-19 vaccines, including results of clinical trials, does not have a significant impact on beliefs about the efficacy of such vaccines, concerns over side effects, or intentions to receive a vaccine. Study 2 (n= 2,217) addressed concerns that highlighting the need to maintain protective behaviours (e.g. social distancing) post-vaccination may lower perceptions of vaccine efficacy and willingness to receive a vaccine. We do not find evidence of this: transparent messages did not significantly reduce perceptions of vaccine efficacy, and in some cases increased perceptions of efficacy. We again report no main effect of messages on intentions to receive a vaccine. The results of both studies suggest that transparently informing people of the limitations of vaccinations does not reduce intentions to be vaccinated but neither does it increase intentions to engage in protective behaviours post-vaccination.
SARS-CoV-2 variants of concern are associated with lower RT-PCR amplification cycles between January and March 2021 in France
Authors: Roquebert Benedicte , Haim-Boukobza Stéphanie , Trombert-Paolantoni Sabine , Lecorche Emmanuel , Verdurme Laura , Foulongne Vincent , Burrel Sonia , Alizon Samuel , Sofonea Mircea T.
Published: March 2021

SARS-CoV-2 variants raise concern regarding the mortality caused by COVID-19 epidemics. We analyse 88,375 cycle amplification (Ct) values from variant-specific RT-PCR tests performed between January 26 and March 13, 2021. We estimate that on March 12, nearly 85% of the infections were caused by the V1 variant and that its transmission advantage over wild type strains was between 38 and 44%. We also find that tests positive for V1 and V2/V3 variants exhibit significantly lower cycle threshold (Ct) values.
Data-driven estimate of SARS-CoV-2 herd immunity threshold in populations with individual contact pattern variations
Authors: Lu Dan , Aleta Alberto , Ajelli Marco , Pastor-Satorras Romualdo , Vespignani Alessandro , Moreno Yamir
Published: March 2021

The development of efficacious vaccines has made it possible to envision mass vaccination programs aimed at suppressing SARS-CoV-2 transmission around the world. Here we use a data-driven age-structured multilayer representation of the population of 34 countries to estimate the disease induced immunity threshold, accounting for the contact variability across individuals. We show that the herd immunization threshold of random (un-prioritized) mass vaccination programs is generally larger than the disease induced immunity threshold. We use the model to test two additional vaccine prioritization strategies, transmission-focused and age-based, in which individuals are inoculated either according to their behavior (number of contacts) or infection fatality risk, respectively. Our results show that in the case of a sterilizing vaccine the behavioral strategy achieves herd-immunity at a coverage comparable to the disease-induced immunity threshold, but it appears to have inferior performance in averting deaths than the risk vaccination strategy. The presented results have potential use in defining the effects that the heterogeneity of social mixing and contact patterns has on herd immunity levels and the deployment of vaccine prioritization strategies.
Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design
Authors: Oelsner Elizabeth C , Allen Norrina Bai , Ali Tauqeer , Anugu Pramod , Andrews Howard , Asaro Alyssa , Balte Pallavi P , Barr R Graham , Bertoni Alain G , Bon Jessica , Boyle Rebekah , Chang Arunee A , Chen Grace , Cole Shelley A , Coresh Josef , Cornell Elaine , Correa Adolfo , Couper David , Cushman Mary , Demmer Ryan T , Elkind Mitchell S. V. , Folsom Aaron R , Fretts Amanda M , Gabriel Kelley Pettee , Gallo Linda , Gutierrez Jose , Han MeiLan K. , Henderson Joel M , Howard Virginia J , Isasi Carmen R , Jacobs David R , Judd Suzanne E , Mukaz Debora Kamin , Kanaya Alka M , Kandula Namratha R , Kaplan Robert , Krishnaswamy Akshaya , Kinney Gregory L , Kucharska-Newton Anna , Lee Joyce S. , Lewis Cora E , Levine Deborah A. , Levitan Emily B. , Levy Bruce , Make Barry , Malloy Kimberly , Manly Jennifer J , Meyer Katie A , Min Yuan-I , Moll Matthew , Moore Wendy C. , Mauger Dave , Ortega Victor E. , Palta Priya , Parker Monica M , Phipatanakul Wanda , Post Wendy , Psaty Bruce M , Regan Elizabeth A , Ring Kimberly , Roger Véronique L. , Rotter Jerome I , Rundek Tatjana , Sacco Ralph L. , Schembri Michael , Schwartz David A. , Seshadri Sudha , Shikany James M , Sims Mario , Hinckley Stukovsky Karen D , Talavera Gregory A , Tracy Russell P , Umans Jason G , Vasan Ramachandran S , Watson Karol , Wenzel Sally E. , Winters Karen , Woodruff Prescott G. , Xanthakis Vanessa , Zhang Ying , Zhang Yiyi ,   For the C4R Investigators
Published: March 2021

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
Validation of a NGS panel, with automated analysis, designed for detection of medically actionable tumor biomarkers for Latin America
Authors: Salvo Mauricio , González-Feliú Evelin , Toro Jessica , Gallegos Iván , Maureira Ignacio , González Nicolás Miranda , Barajas Olga , Bustamante Eva , Ahumada Mónica , Colombo Alicia , Armisén Ricardo , Villamán Camilo , Ibañez Carolina , Loreto Bravo María , Sanhueza Verónica , Spencer Loreto , Toro Gonzalo de , Morales Erik , Bizama Carolina , García Patricia , María Carrasco Ana , Gutiérrez Lorena , Lorenzo-Bermejo Justo , Verdugo Ricardo A. , Marcelain Katherine
Published: March 2021

The genomic characterization of solid tumors and a rapidly growing repertoire of target drugs are revolutionizing cancer treatment. Next-generation sequencing (NGS) panels are progressively used in clinical practice for target therapy in high-income countries. In contrast, limited access to tumor sequencing, among other barriers, precludes precision cancer treatment in low- and middle-income countries. To build towards the implementation of precision oncology in Chile and Latin America, we designed a 25-gene panel that contains predictive biomarkers for currently or near-future available therapies in Latin America. Library preparation was optimized to account for DNA integrity variability in Formalin-Fixed Paraffin-Embedded (FFPE) tissue. The bioinformatic pipeline removes FFPE-induced artifacts and known germline variants; while identifying possible discrepancies in somatic mutations due to Latin Americans’ underrepresentation in the reference genome databases. Analytic sensitivity and accuracy were assessed using commercial standard controls for FFPE DNA and for germline BRCA1 and BRCA2 mutations, which are biomarkers for PARP inhibitors. Our panel detects small insertions and deletions and single nucleotide variants (SNVs) with 100% sensitivity and specificity down to allelic frequencies of 0.05, and with 100% between-run and within-run reproducibility for non-synonymous variants. The workflow was validated in 265 clinical samples, including breast, colorectal, gastric, ovarian, and gallbladder tumors and blood, leading to identifying 131 actionable variants. Therefore, this NGS panel constitutes an accurate and sensitive method for routine tumor biopsies that could replace multiple non-NGS assays and costly large NGS panels in the Latin American clinical context. The proposed streamlined assay and automated analysis are expected to facilitate the implementation of precision medicine in Latin America.
Heterogeneous immunological recovery trajectories revealed in post-acute COVID-19
Authors: Su Yapeng , Yuan Dan , Chen Daniel G. , Wang Kai , Choi Jongchan , Dai Chengzhen L. , Hong Sunga , Zhang Rongyu , Xie Jingyi , Li Sarah , Scherler Kelsey , Pavlovitch-Bedzyk Ana Jimena , Dong Shen , Lausted Christopher , Ng Rachel H. , Lee Inyoul , Fallen Shannon , Kornilov Sergey A. , Baloni Priyanka , Duvvuri Venkata R. , Anderson Kristin G. , Li Jing , Yang Fan , Rostomily Clifford , Troisch Pamela , Smith Brett , Zhou Jing , Mackay Sean , Murray Kim , Edmark Rick , Jones Lesley , Zhou Yong , Rowen Lee , Liu Rachel , Chour William , Berrington William R. , Wallick Julie A , Algren Heather A ,   the ISB-Swedish COVID19 Biobanking Unit, Wrin Terri , Petropoulos Christos J. , Wei Wei , Price Nathan D. , Subramanian Naeha , Hadlock Jennifer , Magis Andrew T. , Ribas Antoni , Lanier Lewis L. , Boyd Scott D. , Bluestone Jeffrey A. , Hood Leroy , Gottardo Raphael , Greenberg Philip D. , Davis Mark M. , Goldman Jason D. , Heath James R.
Published: March 2021

The immunological picture of how different patients recover from COVID-19, and how those recovery trajectories are influenced by infection severity, remain unclear. We investigated 140 COVID-19 patients from diagnosis to convalescence using clinical data, viral load assessments, and multi-omic analyses of blood plasma and circulating immune cells. Immune-phenotype dynamics resolved four recovery trajectories. One trajectory signals a return to pre-infection healthy baseline, while the other three are characterized by differing fractions of persistent cytotoxic and proliferative T cells, distinct B cell maturation processes, and memory-like innate immunity. We resolve a small panel of plasma proteins that, when measured at diagnosis, can predict patient survival and recovery-trajectory commitment. Our study offers novel insights into post-acute immunological outcomes of COVID-19 that likely influence long-term adverse sequelae.
Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir
Authors: Pohl Marie O. , Busnadiego Idoia , Marrafino Francesco , Wiedmer Lars , Hunziker Annika , Fernbach Sonja , Glas Irina , Moroz-Omori Elena V. , Hale Benjamin G. , Caflisch Amedeo , Stertz Silke
Published: March 2021

Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we used high-throughput docking to screen 6000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3CL main protease, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallelin vitrofluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3CL main protease inhibitorin vitro(IC50 value of 29 µM) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3CL main protease inhibitorin vitro, but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication, albeit this was specific to Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our work shows that combining computational and cellular screening is a means to identify existing drugs with repurposing potential as antiviral compounds. Future studies could be aimed at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option.
Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers
Authors: Barton Amber , Hill Jennifer , Bibi Sagida , Chen Liye , Jones Claire , Jones Elizabeth , Camara Susana , Shrestha Sonu , Jin Celina , Gibani Malick M , Dobinson Hazel , Waddington Claire , Darton Thomas C , Blohmke Christoph J , Pollard Andrew J
Published: March 2021

Background

Infection withSalmonella entericaserovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility.

Methods

Human challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n=176) and/or transcriptionally profiled by RNA-sequencing (n=178).

Results

Two SNPs withinCAPN14andMIATNBwere identified with p<10−5for association with development of symptoms or bacteraemia following oralS. Typhi orS. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with non-typhoidalSalmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (p=0.012). Genes related to the unfolded protein response and heat shock were over-represented in HLA-B*27:05+participants following challenge (p=0.01). Furthermore, intracellular replication ofS. Typhi is higher in C1R cells transfected with HLA-B*27:05 (p=0.02).

Conclusion

These data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive toS. Typhi replication, increasing susceptibility to enteric fever.