bluuebunny/crossref_metadata_2025 huggingface dataset:
Successive epidemic waves of cholera in South Sudan, 2014 - 2017
Authors: Jones Forrest K , Wamala Joseph F , Rumunu John , Mawien Pinyi Nyimol , Tut Kol Mathew , Wohl Shirlee , Deng Lul , Pezzoli Lorenzo , Omar Linda Haj , Lessler Justin , Quilici Marie-Laure , Luquero Francisco J , Azman Andrew S
Published: October 2020

Background

Between 2014 and 2017, successive cholera epidemics occurred in South Sudan within the context of civil war, population displacement, flooding, and drought. Understanding the determinants of cholera spread in complex settings like this can provide valuable insights for mitigating future cholera risk.

Methods

We analyzed cholera linelist and molecular data to describe the spatio-temporal progression of the epidemics. We explored the role of rainfall, population movement and vaccination campaigns in shaping the explaining incidence and the spatial distribution of reported cases.

Findings

South Sudan experienced three distinct cholera epidemic waves of cholera ranging from 6-18 months with more than 28,000 cases reported and more than 2 million cholera vaccine doses delivered to curb transmission. The 2014 and 2015 epidemics remained spatially limited while the 2016/17 epidemic exploded along the Nile river. Initial cases of each epidemic were reported in or around Juba soon after the start of the rainy season, but we found no evidence that rainfall modulated transmission during each epidemic. All isolates analyzed had similar genotypic and phenotypic characteristics, closely related to sequences from Uganda and Democratic Republic of Congo. The direction of large-scale population movements between counties with cholera outbreaks was consistent with the spatial distribution of outbreaks. As of September 2020, zero cholera cases have been confirmed within South Sudan since 2017.

Interpretation

The three epidemic waves were caused byV. choleraeof the same clonal origin despite the periods of no reported cases between waves. While the complex emergency likely shaped some of the observed spatial and temporal patterns of reported cases, the full scope of transmission determinants remains unclear. Timely and well targeted use of cholera vaccine can avert cases and deaths, however, most of the vaccine campaigns occurred after the epidemic peak highlighting the challenges of delivering vaccines quickly in response to an outbreak in settings like South Sudan. These analyses provide a multi-faceted template for examining cholera dynamics through epidemiological, microbiological, climatic, and behavioral lenses.

Funding

TheBill and Melinda Gates Foundation
The role of masks, testing and contact tracing in preventing COVID-19 resurgences: a case study from New South Wales, Australia
Authors: Stuart RM , Abeysuriya Romesh G. , Kerr Cliff C. , Mistry Dina , Klein Daniel J. , Gray Richard , Hellard Margaret , Scott Nick
Published: October 2020

Objectives

The early stages of the COVID-19 pandemic illustrated that SARS-CoV-2, the virus that causes the disease, has the potential to spread exponentially. Therefore, as long as a substantial proportion of the population remains susceptible to infection, the potential for new epidemic waves persists even in settings with low numbers of active COVID-19 infections, unless sufficient countermeasures are in place. We aim to quantify vulnerability to resurgences in COVID-19 transmission under variations in the levels of testing, tracing, and mask usage.

Setting

The Australian state of New South Wales, a setting with prolonged low transmission, high mobility, non-universal mask usage, and a well-functioning test-and-trace system.

Participants

None (simulation study)

Results

We find that the relative impact of masks is greatest when testing and tracing rates are lower (and vice versa). Scenarios with very high testing rates (90% of people with symptoms, plus 90% of people with a known history of contact with a confirmed case) were estimated to lead to a robustly controlled epidemic, with a median of ∼180 infections in total over October 1 – December 31 under high mask uptake scenarios, or 260–1,200 without masks, depending on the efficacy of community contact tracing. However, across comparable levels of mask uptake and contact tracing, the number of infections over this period were projected to be 2-3 times higher if the testing rate was 80% instead of 90%, 8-12 times higher if the testing rate was 65%, or 30-50 times higher with a 50% testing rate. In reality, NSW diagnosed 254 locally-acquired cases over this period, an outcome that had a low probability in the model (4-7%) under the best-case scenarios of extremely high testing (90%), near-perfect community contact tracing (75-100%), and high mask usage (50-75%), but a far higher probability if any of these were at lower levels.

Conclusions

Our work suggests that testing, tracing and masks can all be effective means of controlling transmission. A multifaceted strategy that combines all three, alongside continued hygiene and distancing protocols, is likely to be the most robust means of controlling transmission of SARS-CoV-2.

Strengths and limitations of this study

A key methodological strength of this study is the level of detail in the model that we use, which allows us to capture many of the finer details of the extent to which controlling COVID-19 transmission relies on the balance between testing, contact tracing, and mask usage.

Another key strength is that our model is stochastic, so we are able to quantify the probability of different epidemiological outcomes under different policy settings.

A key limitation is the shortage of publicly-available data on the efficacy of contact tracing programs, including data on how many people were contacted for each confirmed index case of COVID-19.
Large-scale Testing for SARS-CoV-2 using Tapestry Pooling
Authors: Chakravarthy Anirudh , Krishna Srikar , Ghosh Sumana , Tomar Ajay , Varahan Sriram , Rajwade Ajit , Ghosh Sabyasachi , Gupta Nimay , Agarwal Rishi , Payal Himanshu , Chakraborty Prantik , Vemula Krishna Vishal , Vyas Akanksha , Goru Ritesh , Krishna Sandeep , Palakodeti Dasaradhi , Gopalkrishnan Manoj
Published: October 2020

We have previously described Tapestry Pooling, a scheme to enhance the capacity of RT-qPCR testing, and provided experimental evidence with spiked synthetic RNA to show that it can help to scale testing and restart the economy. Here we report on validation studies with Covid19 patient samples for the Tapestry Pooling scheme with prevalence in the range of 1% to 2%. We pooled RNA extracted from patient samples that were previously tested for Covid19, sending each sample to three pools. Following three different pooling schemes, we pipetted 320 samples into 48 pools with pool size of 20 at prevalence rate of 1.6%, 500 samples into 60 pools with pool size of 25 at prevalence rate of 2%, and 961 samples into 93 pools with pool size of 31 at prevalence rate of 1%. Of the 191 RT-qPCR experiments that we performed, only one pool was incorrect (false negative). Our recovery algorithm correctly called results for the individual samples, with a 100% sensitivity and a 99.9% specificity, with only one false positive across all the 1,781 blinded results required to be called. We show up to 10X savings in number of tests required at a range of prevalence rates and pool sizes. These experiments establish that Tapestry Pooling is robust enough to handle the diversity of sample constitutions and viral loads seen in real-world samples.
Occurrence of Four Dengue Virus Serotypes and Chikungunya Virus in Kilombero, Tanzania during Dengue Outbreak in 2018
Authors: Chipwaza Beatrice , Sumaye Robert David , Weisser Maja , Gingo Winfrid , Yeo Nicholas Kim-Wah , Amrun Siti Naqiah , Okumu Fredros O. , Ng Lisa F.P.
Published: October 2020

Background

Dengue and Chikungunya viruses can cause large-scale epidemics with attack rates exceeding 80%. In Tanzania, there have been repeated outbreaks of dengue fever, the most recent one in 2018 and 2019 mostly reported in coastal areas. Despite its importance, there is limited knowledge on epidemiology of dengue (DENV) and chikungunya (CHIKV) in Tanzania. This study was conducted to investigate the prevalence of DENV and CHIKV in Kilombero district, South-Eastern Tanzania.

Methods

A cross-sectional study was conducted at Kibaoni Health Center, in Kilombero district, in the rainy and dry seasons of 2018. Febrile patients of any age and gender were enrolled. Blood samples were taken and screened for DENV and CHIKV viral RNA by real-time RT-PCR assays.

Results

A total of 294 patients were recruited. Most were females (65%), and aged between 14⍰25 years (33%). DENV and CHIKV were detected in 29 (9.9%) and 3 (1.0%) patients, respectively. DENV was detected across all age groups and during both dry and rainy seasons. Although all four DENV serotypes were detected, serotypes 1 and 3 dominated and were present in 14 patients (42.4%) each. Additionally, the study showed DENV-1 and DENV-3 co-infections.

Conclusion

This study reveals the co-circulation of all four DENV serotypes and CHIKV in Kilombero district. Importantly, we report the first occurrence of DENV-4 in Tanzania. Unlike previous DENV outbreaks caused by DENV-2, the 2018 outbreak was dominated by DENV-1 and DENV-3. Occurrence of all serotypes suggests the possibility of having severe clinical outcomes in future DENV epidemics in Tanzania.
Migration, Infectious Diseases and Drug Addiction in Russia
Authors: Lifshits Marina , Neklyudova Natalia
Published: October 2020

The aim of the paper is to analyze the possible impact of various aspects of internal and external migration in Russia’s regions on the prevalence of the following social dangerous diseases: HIV, active tuberculosis, syphilis, drug addiction, acute and chronic viral hepatitis B and C. We analyzed the papers that concern the impact of migration on the health of the host territory population. The main research methods are econometric and correlation analysis. We constructed panel models for each disease. The models tested various socioeconomic indicators (including education level, cash income, housing improvements and the incidence of alcoholism), as well as climatic, geographical and demographic indicators. Influence of disease incidence in the neighbouring regions is also considered. Five various indicators of migration were tested. They characterize labour immigration, internal and external migration inflows to the regions and share of people born outside the region. We tried to track changes of factors that influence spread of diseases over time. It allowed us to correct the conclusions drawn earlier. In the course of the research, positive significant statistical correlation of the following indicators of migration and disease incidence was established:

foreign citizens employment and incidence of syphilis in 2005;

share of internal migrants and incidence of drug addiction in 2005;

foreign citizens employment and incidence of drug addiction in 2006-2016;

foreign citizens inflow and detection of chronic viral hepatitis in 2010;

foreign citizens inflow and detection of acute hepatitis C in 2011-2016.

JEL F22; I1; R23
Development and evaluation of a new IgM/IgG rapid diagnostic test for SARS-CoV-2
Authors: Ducrest P.J.
Published: October 2020

There is an urgent need in rapid diagnostic test (RDT) to detect antibodies against SARS-CoV-2. We have developed a rapid and simple point-of-care lateral flow immunoassay (LFIA) detecting IgM and IgG against SARS-CoV-2 in 10 minutes. The aim of this study is to evaluate the diagnostic performance of this RDT. RT-PCR positive plasma samples (n=35) for SARS-CoV-2 and 97 negative control samples were studied. Diagnostic performance of IgG/IgM RDT was assessed using both gold standard RT-PCR and Electro-chemiluminescence immunoassay (ECLIA) Elecsys®Anti-SARS-CoV-2 total Ig. Overall, RDT sensitivity was 100% (95% confidence interval [95%CI]: 88-100%) and specificity 93% (95% CI: 85-97%). This IgG/IgM RDT done in plasma displays a high diagnostic accuracy for SARS-CoV-2 IgG/IgM in high COVID-19 prevalence settings. Its use could be considered in the absence of routine diagnostic serology facilities for samples collected between 10 and 180 days after symptoms onset.
Analysis of the potential for a malaria vaccine to reduce gaps in malaria intervention coverage
Authors: Unwin H. Juliette T. , Mwandigha Lazaro , Winskill Peter , Ghani Azra C. , Hogan Alexandra B.
Published: October 2020

Background

The RTS,S/AS01 malaria vaccine is currently being piloted in three African countries. We sought to identify whether vaccination could reach additional children who are at risk from malaria but do not currently have access to, or use, core malaria interventions.

Methods

Using data from household surveys we calculated the overlap between malaria intervention coverage and childhood vaccination (diphtheria-tetanus-pertussis dose 3, DTP3) uptake in 20 African countries with at least one first administrative level unit withPlasmodium falciparumparasite prevalence greater than 10%. We used multilevel logistic regression to explore patterns of overlap by demographic and socioeconomic variables. We also estimated the public health impact of delivering RTS,S/AS01 to those children who do not use an insecticide-treated net (ITN) but who received the DTP3 vaccine.

Results

Uptake of DTP3 was higher than malaria intervention coverage in most countries. Overall, 34% of children did not use ITNs and received DTP3, while 35% of children used ITNs and received DTP3, although this breakdown varied by country. We estimated that there are 33 million children in these 20 countries who do not use an ITN. Of these, 23 million (70%) received the DTP3 vaccine. Vaccinating those 23 million children who receive DTP3 but do not use an ITN could avert an estimated 9.7 million clinical malaria cases each year. An additional 10.8 million cases could be averted by vaccinating those 24 million children who receive the vaccine and use an ITN. Children who had access to or used an ITN were 9 to 13% more likely to reside in rural areas compared to those who had neither intervention regardless of vaccination status. Mothers’ education status was a strong predictor of intervention uptake and was positively associated with use of ITNs and vaccination uptake and negatively associated with having access to an ITN but not using it. Wealth was also a strong predictor of intervention coverage.

Conclusions

Childhood vaccination to prevent malaria has the potential to reduce inequity in access to existing malaria interventions and could substantially reduce the childhood malaria burden in sub-Saharan Africa, even in regions with lower existing DTP3 coverage.
The risk for a new COVID-19 wave – and how it depends on R0, the current immunity level and current restrictions
Authors: Britton Tom , Trapman Pieter , Ball Frank
Published: October 2020

The COVID-19 pandemic has hit different parts of the world differently: some regions are still in the rise of the first wave, other regions are now facing a decline after a first wave, and yet other regions have started to see a second wave. The current immunity level î in a region is closely related to the cumulative fraction infected, which primarily depends on two factors: a) the initial potential for COVID-19 in the region (often quantified by the basic reproduction number R0), and b) the timing, amount and effectiveness of preventive measures put in place. By means of a mathematical model including heterogeneities owing to age, social activity and susceptibility, and allowing for time-varying preventive measures, the risk for a new epidemic wave and its doubling time, and how they depend on R0, î and the overall effect of the current preventive measures, are investigated. Focus lies on quantifying the minimal overall effect of preventive measures pMin needed to prevent a future outbreak. The first result shows that the current immunity level î plays a more influential roll than when immunity is obtained from vaccination. Secondly, by comparing regions with different R0 and î it is shown that regions with lower R0 and low î may now need higher preventive measures (pMin) compared with other regions having higher R0 but also higher î, even when such immunity levels are far from herd immunity.
Multi-type branching and graph product theory of infectious disease outbreaks
Authors: Vazquez Alexei
Published: October 2020

The heterogeneity of human populations is a challenge to mathematical descriptions of epidemic outbreaks. Numerical simulations are deployed to account for the many factors influencing the spreading dynamics. Yet, the results from numerical simulations are often as complicated as the reality, leaving us with a sense of confusion about how the different factors account for the simulation results. Here, using a multi-type branching together with a graph tensor product approach, I derive a single equation for the effective reproductive number of an infectious disease outbreak. Using this equation I deconvolute the impact of crowd management, targeted testing, contact heterogeneity, stratified vaccination, mask use and smartphone tracing app use. This equation can be used to gain a basic understanding of infectious disease outbreaks and their simulations.
Antimicrobial Resistance, Evidences on Irrational Anti-microbial Prescribing and Consumption during COVID-19 Pandemic and Possible Mitigation Strategies: A Bangladesh Perspective
Authors: Parveen Monira , Yeasmin Mahmuda , Molla Md. Maruf Ahmed
Published: October 2020

There are evidences that show increased antimicrobial consumption among COVID-19 patients. This has increased the burden on worsening situation of antimicrobial resistance (AMR) throughout the world. Bangladesh, one of the countries with highest numbers of COVID-19 cases, without effective regulation of antimicrobial prescription may suffer in future with study results showing a significant proportion of participants taking antimicrobial without proper indication and prescription from physicians. Suggested mitigation strategies include – strict regulation of over the counter (OTC) antimicrobial prescription, testing biochemical marker such as procalcitonin prior to initiation of antimicrobial therapy, introduction of color coded and tightly sealed bottled antimicrobial drugs, massive campaigning on social media, effective utilization of telemedicine and finally, raising awareness among physicians and patients regarding judicial use of antimicrobial.
Host transcriptional analysis to improve the diagnosis of group A streptococcal pharyngitis
Authors: Yu Jinsheng , Tycksen Eric , Yang Wei , Mariani Thomas J. , Bhattacharya Soumyaroop , Falsey Ann R. , Topham David J. , Storch Gregory A.
Published: October 2020

Current diagnostic methods used to evaluate patients with pharyngitis for the presence of group AStreptococcus(GAS) do not discriminate between acute infection and asymptomatic carriage, potentially resulting in overuse of antibiotics. We hypothesized that host response as measured by the transcriptomic profile of peripheral blood leukocytes could make this distinction, and could also distinguish between GAS and viral infection. We used RNA sequencing to generate whole blood transcriptomes from 37 children, including 10 with acute GAS pharyngitis, 5 with asymptomatic GAS carriage, 3 with adenoviral pharyngitis, 3 with pharyngitis of unknown etiology, and 16 asymptomatic children negative for GAS. Transcriptional profiles from children with symptomatic GAS, GAS carriage, symptomatic adenoviral pharyngitis, and controls were each distinct. Of 15,185 genes with analyzable sequence, 1357 (8.9%) were differentially expressed in the children with symptomatic GAS compared to those with asymptomatic carriage, and 1336 (8.8%) compared to symptomatic adenovirus infection. A panel of 13 genes distinguished between children with acute GAS and all others with 91% accuracy. The gene encoding CD177, a marker of neutrophil activation, had a 152-fold increase in expression in children with acute GAS, and is a potential diagnostic biomarker. We conclude that measurement of host response is highly promising to improve the diagnosis of GAS pharyngitis and could help limit unnecessary antibiotic use.

One Sentence Summary

This study demonstrates that analysis of host gene expression can improve the diagnosis of group A streptococcal pharyngitis, which will limit unnecessary antibiotic therapy.
Mathematical Modeling of COVID-19 Pandemic in the African Continent
Authors: Aries Nawel , Ounis Houdayfa
Published: October 2020

The present work aims to give a contribution to the understanding of the highly infectious pandemic caused by the COVID-19 in the African continent. The study focuses on the modelling and the forecasting of COVID-19 spread in the most affected African continent, namely: Morocco, Algeria, Tunisia, Egypt and South Africa and for the sake of comparison two of the most affected European country are also considered, namely: France and Italy. To this end, an epidemiological SEIQRDP model is presented, which is an adaptation of the classic SIR model widely used in mathematical epidemiology. In order to better coincide with the preventive measures taken by the governments to deal with the spread of COVID-19, this model considers the quarantine. For the identification of the model’s parameters, official data of the pandemic up to August 1st, 2020 are considered. The results show that the number of infections due to the use of quarantine is expected to be very low provided the isolation is effective. However, it is increasing in some countries with the early lifting of containment. Finally, the information provided by the SEIQRDP model could help to establish a realistic assessment of the short-term pandemic situation. Moreover, this will help maintain the most appropriate and necessary public health measures after the lockdown lifting.
Electroconvulsive Therapy with a Memory Reactivation Intervention for Post-Traumatic Stress Disorder: A Randomized Controlled Trial
Authors: Tang Victor M. , Trought Kathleen , Gicas Kristina M. , Kozak Mari , Josselyn Sheena A. , Daskalakis Zafiris J. , Blumberger Daniel M. , Voineskos Daphne , Knyahnytska Yuliya , Chung Yuan , Zhou Young , Isserles Moshe , Wong Albert H.C.
Published: October 2020

Introduction

Post-traumatic Stress Disorder (PTSD) often does not respond to available treatments. Memories are vulnerable to disruption during reconsolidation, and electroconvulsive therapy (ECT) has amnestic effects. We sought to exploit this phenomenon as a potential treatment for PTSD with a clinical trial of patients with PTSD receiving ECT.

Methods

Twenty-eight participants with severe depression with comorbid PTSD referred for ECT treatment were randomly assigned to reactivation of a traumatic or non-traumatic memory using script driven imagery prior to each ECT treatment. Primary outcomes were change in scores on the Modified PTSD Symptom Scale - Self Report (MPSS-SR) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Assessments were completed by blinded raters. Secondary outcomes included a comparison of the change in heart rate while listening to the script.

Results

Twenty-five patients who completed a post-ECT assessment were included in the analysis. No significant group differences were found in the MPSS-SR or CAPS-5 scores from pre-ECT to post-ECT or 3-month follow-ups. However, both groups improved at post-ECT and 3-month follow up. Partial eta squared estimates of effect size showed large effect sizes for all outcomes (η2 > 0.13). Changes in heart rate were not significantly different between groups or over time.

Conclusions

In this RCT, ECT paired with pre-treatment traumatic memory reactivation was not more effective for treating PTSD symptoms than ECT alone. While our primary hypothesis was not supported, our data provides further support for the efficacy of ECT for improving symptoms of PTSD with comorbid depression.

ClinicalTrials.gov

https://clinicaltrials.gov/ct2/show/NCT04027452

Identifier: NCT04027452
An Overview of Retraction Status and Reasons of Non-Cochrane Systematic Reviews in Medicine
Authors: Shi Qianling , Wang Zijun , Zhou Qi , Hou Ruizhen , Gao Xia , He Shaoe , Zhao Siya , Ma Yanfang , Zhang Xianzhuo , Guan Quanlin , Chen Yaolong
Published: October 2020

Background

Many previous studies have analyzed the status of retracted publications from different perspectives, but so far no study has focused on systematic reviews (SRs). The purpose of this study is to analyze the retraction status and reasons of non-Cochrane SRs in the field of medicine.

Methods

We searched MEDLINE and Embase from their inception to April 18, 2020, as well as Retraction Watch Database and Google Scholar with no language restriction to find non-Cochrane SRs that were retracted for any reason. Two reviewers independently screened and extracted data. We describe the characteristic and reasons of retraction and the duration from publication to retraction.

Results

We identified 150 non-Cochrane SRs in medicine retracted between 2004 and 2020. The majority of retracted SRs were led by authors from China and affiliated with hospitals. Most SRs were published in journals with an impact factor ≤3, and in journal ranked in the third quarter. The largest proportion of retraction notices were issued by the publisher and editor(s) jointly; seven did not report this information. Fraudulent peer-review was the most common reason for retraction, followed by unreliable data meaning errors in study selection or data analysis. The median time between publication and retraction was 14.0 months. SRs retracted due to research misconduct took longer to retract than SRs retracted because of honest error.

Conclusions

The situation with retracted SRs is critical globally, and in particular in China. The most common reasons for retraction are fraudulent peer-review and unreliable data, and in most cases the study is retracted more than a year after publication. Efforts should be made to improve the process of peer review and adherence to the COPE retraction guidance, while at the same time authors should strengthen their skills in SR methodology.
Outcomes of COVID-19: disparities by ethnicity
Authors: Ali Hamad , Alshukry Abdullah , Marafie Sulaiman K , AlRukhayes Monera , Ali Yaseen , Abbas Mohammad Bu , Al-Taweel Abdullah , Bukhamseen Yousef , Dashti Mohammad H , Al-Shammari Abdullah , Abu-Farha Mohammad , AbuBaker Jehad , Al-Mulla Fahd
Published: October 2020

Objectives

To investigate the role of ethnicity in COVID-19 outcome disparities in a cohort in Kuwait.

Methods

This is a retrospective analysis of 405 individuals infected with SARS-CoV-2 in Kuwait. Outcomes such as symptoms severity and mortality were considered. Multivariate logistic regression models were used to report the odds ratios (OR) for ICU admission and dying from COVID-19.

Results

The cohort included 290 Arabs and 115 South Asians. South Asians recorded significantly higher COVID-19 death rates compared to Arabs (33% vs. 7.6%, P value<0.001). When compared to Arabs, South Asians also had higher odds of being admitted to the ICU (OR = 6.28, 95% CI: 3.34 – 11.80, p < 0.001). South Asian patients showed 7.62 (95% CI: 3.62 – 16.02, p < 0.001) times the odds of dying from COVID-19.

Conclusion

COVID-19 patients with South Asians ethnicity are more likely to have worse prognosis and outcome when compared to patients with Arab ethnicity. This suggest a possible role for ethnicity in COVID-19 outcome disparities and this role is likely to be multifactorial.
Forecasting combination of hierarchical time series: A novel method with an application to COVID-19
Authors: Fenga Livio
Published: October 2020

Multiple, hierarchically organized time series are routinely submitted to the forecaster upon request to provide estimates of their future values, regardless the level occupied in the hierarchy. In this paper, a novel method for the prediction of hierarchically structured time series will be presented. The idea is to enhance the quality of the predictions obtained using a technique of the type forecast reconciliation, by applying this procedure to a set of optimally combined predictions, generated by different statistical models. The goodness of the proposed method will be evaluated using the official time series related to the number of people tested positive to the SARS-CoV-2 in each of the Italian regions, between February 24th 2020 and August 31th 2020.
A combination of metagenomic and cultivation approaches reveals hypermutator phenotypes withinVibrio choleraeinfected patients
Authors: Levade Inès , Khan Ashraful I. , Chowdhury Fahima , Calderwood Stephen B. , Ryan Edward T. , Harris Jason B. , LaRocque Regina C. , Bhuiyan Taufiqur R. , Qadri Firdausi , Weil Ana A. , Shapiro B. Jesse
Published: October 2020

Vibrio choleraecan cause a range of symptoms, ranging from severe diarrhea to asymptomatic infection. Previous studies using whole genome sequencing (WGS) of multiple bacterial isolates per patient showed thatV. choleraecan evolve modest genetic diversity during symptomatic infection. To further explore the extent ofV. choleraewithin-host diversity, we applied culture-based WGS and metagenomics to a cohort of both symptomatic and asymptomatic cholera patients from Bangladesh. While metagenomics allowed us to detect more mutations in symptomatic patients, WGS of cultured isolates was necessary to detectV. choleraediversity in asymptomatic carriers, likely due to their lowV. choleraeload. Using both metagenomics and isolate WGS, we report three lines of evidence thatV. choleraehypermutators evolve within patients. First, we identified nonsynonymous inV. choleraeDNA repair genes in five out of 11 patient metagenomes sequenced with sufficient coverage of theV. choleraegenome, and in one of three patients with isolate genomes sequenced. Second, mutations in DNA repair genes tended to be accompanied by an excess of intrahost single nucleotide variants (iSNVs). Third, these iSNVs were enriched in transversion mutations, a known hallmark of hypermutator phenotypes. While hypermutators appeared to generate mostly selectively neutral mutations, non-mutators showed signs of convergent mutation across multiple patients, suggestingV. choleraeadaptation within hosts. Our results highlight the power and limitations of metagenomics combined with isolate sequencing to characterize within-patient diversity in acuteV. choleraeinfections, while providing evidence for hypermutator phenotypes within cholera patients.

IMPORTANCE

Pathogen evolution within patients can impact phenotypes such as drug resistance and virulence, potentially affecting clinical outcomes.V. choleraeinfection can result in life-threatening diarrheal disease, or asymptomatic infection. Here we describe whole-genome sequencing ofV. choleraeisolates and culture-free metagenomic sequencing from stool of symptomatic cholera patients and asymptomatic carriers. Despite the typically short duration of cholera, we found evidence for adaptive mutations in theV. choleraegenome that occur independently and repeatedly within multiple symptomatic patients. We also identifiedV. choleraehypermutator phenotypes within several patients, which appear to generate mainly neutral or deleterious mutations. Our work sets the stage for future studies of the role of hypermutators and within-patient evolution in explaining the variation from asymptomatic carriage to symptomatic cholera.
D614G mutation alters SARS-CoV-2 spike conformational dynamics and protease cleavage susceptibility at the S1/S2 junction
Authors: Gobeil Sophie M-C. , Janowska Katarzyna , McDowell Shana , Mansouri Katayoun , Parks Robert , Manne Kartik , Stalls Victoria , Kopp Megan , Henderson Rory , Edwards Robert J , Haynes Barton F. , Acharya Priyamvada
Published: October 2020

The SARS-CoV-2 spike (S) protein is the target of vaccine design efforts to end the COVID-19 pandemic. Despite a low mutation rate, isolates with the D614G substitution in the S protein appeared early during the pandemic, and are now the dominant form worldwide. Here, we analyze the D614G mutation in the context of a soluble S ectodomain construct. Cryo-EM structures, antigenicity and proteolysis experiments suggest altered conformational dynamics resulting in enhanced furin cleavage efficiency of the G614 variant. Furthermore, furin cleavage altered the conformational dynamics of the Receptor Binding Domains (RBD) in the G614 S ectodomain, demonstrating an allosteric effect on the RBD dynamics triggered by changes in the SD2 region, that harbors residue 614 and the furin cleavage site. Our results elucidate SARS-CoV-2 spike conformational dynamics and allostery, and have implications for vaccine design.

Highlights

SARS-CoV-2 S ectodomains with or without the K986P, V987P mutations have similar structures, antigenicity and stability.

The D614G mutation alters S protein conformational dynamics.

D614G enhances protease cleavage susceptibility at the S protein furin cleavage site.

Cryo-EM structures reveal allosteric effect of changes at the S1/S2 junction on RBD dynamics.
Gut Dysbiosis with a Pathobiont Shifts the Intestinal Microbiota Profile and Accelerates Lupus Nephritis
Authors: Valiente Giancarlo R. , Munir Armin , Hart Marcia L. , Blough Perry , Wada Takuma T. , Dalan Emma E. , Willis William L. , Wu Lai-Chu , Freud Aharon G. , Jarjour Wael N.
Published: October 2020

The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB. With SFB colonization mice experienced an increase in small intestinal lamina propria Th17 cells and group 3 innate lymphoid cells (ILC3s). However, although serum IL-17A expression was elevated in these mice, Th17 cells and ILC3s were not detected in the inflammatory infiltrate in the kidney. In contrast, serum and kidney tissue expression of the macrophage chemoattractants MCP-1 and CXCL1 were significantly elevated in SFB colonized mice. Furthermore, kidney infiltrating F4/80+CD206+ M2-like macrophages were significantly increased in these mice. Evidence of increased gut permeability or “leakiness” was detected in SFB colonized mice. Finally, the intestinal microbiome of SFB colonized mice at 15 and 30 weeks of age exhibited dysbiosis when compared to uncolonized mice at the same time points. Both microbial relative abundance as well as biodiversity of colonized mice was found to be altered. Collectively, SFB gut colonization in the NZM2410 mouse exacerbates kidney disease, promotes kidney M2-like macrophage infiltration and overall intestinal microbiota dysbiosis.
Finding Pathogenic nsSNP’s and their structural effect on COPS2 using Molecular Dynamic Approach
Authors: Malik Ashish , Pande Kajal , Kumar Abhishek , Vemula Alekhya , Madhuri R , Chandramohan Vivek
Published: October 2020

COP9 Signalosome Subunit 2 is a highly conserved multiprotein complex which is involved in the cellular process and developmental process. It is one of the essential components in the COP9 Signalosome Complex (CSN). It is also involved in neuronal differentiation interacting with NIF3L1. The gene involved in neuronal differentiation is negatively regulated due to the transcription co-repressor interaction of NIF3L1 with COPS2. In the present study, we have evaluated the outcome for 90 non-synonymous single nucleotide polymorphisms (nsSNP’s) in COPS2 gene through computational tools. After the analysis, 4 SNP’s (S120C, N144S, Y159H, R173C) were found to be deleterious. The native and mutated structures were prepared using discovery studio and docked to check the interactions with NIF3L1.On the basis of ZDOCK score the top 3 mutations (N144S, Y159H, R173C) were screened out. Further to analyze the effect of amino acid substitution on the molecular structure of protein Molecular Dynamics simulation was carried out. Analysis based on RMSD, RMSF, RG, H-bond showed a significant deviation in the graph, which demonstrated conformation change and instability compared to the wild structure. As it is known mutations in COPS2 gene can disrupt the normal activity of the CSN2 protein which may cause neuronal differentiation. Our results showed N144S, Y159H and R173C mutations are to be more pathogenic and may cause disease
Eucalyptus plantations in temperate grasslands: responses of taxonomic and functional diversity of plant communities to environmental changes
Authors: Pairo Pamela E. , Rodriguez Estela E. , Bellocq M. Isabel , Aceñolaza Pablo G.
Published: October 2020

Understanding how human land-uses impact on local communities is required to implement management and conservational policies and practices. Tree plantations have become one of the fastest-growing land uses in recent decades and their impact on biodiversity was evaluated mainly at the taxonomic level. Our aim was to analyze the effects of changes in environmental drivers along the 12 years eucalypt plantations chronosequence on alfa, beta, taxonomic and functional diversity of understory plant communities. We selected nine plantation ages with three replicates per age and three protected grasslands as reference habitat. At each replicate, we established three plots to measure plant species cover and environmental variables, which are expected to change with plantation age. Results showed that species richness and all diversity indices significantly declined with increasing plantation age. Canopy cover, soil pH, and leaf litter were the most important drivers that explained the decline in taxonomic and functional diversity of plants through the forest plantation. Based on the Path analyses results, canopy cover had an indirect relationship with plant functional diversity mediated by leaf litter, soil pH and plant species richness. The results of the association between functional traits and environmental variables have revealed that high dispersal potential, annual, barochorous, and zoochorous plant species were the functional traits more affected by the eucalypt plantations. Given that leaf litter was negatively associated with all diversity facets, we recommend reducing their accumulation within eucalypt plantation to enhance biodiversity conservation and the provision of pampean grassland ecosystem functions.
The mammalian cholesterol synthesis enzyme squalene monooxygenase is proteasomally truncated to a constitutively active form
Authors: Coates Hudson W. , Brown Andrew J.
Published: October 2020

Squalene monooxygenase (SM) is a rate-limiting enzyme of cholesterol synthesis that is oncogenic in a range of cancer types. SM is subject to feedback regulation via cholesterol-induced degradation, which depends on its lipid-sensing N terminal regulatory domain. Here, we characterize an endogenous truncated form of SM and show that it is cholesterol-resistant, and therefore constitutively active. Truncation of SM occurs during its endoplasmic reticulum-associated degradation and requires the proteasome, which partially degrades the SM N-terminus and eliminates cholesterol-sensing elements within this region. Using mutagenesis studies, we demonstrate that partial degradation of SM depends on both an intrinsically disordered region near the truncation site and the stability of the adjacent catalytic domain. Finally, truncation converts SM from an integral to a peripheral ER membrane protein. These findings uncover an additional layer of complexity in the cellular control of cholesterol synthesis and establish SM as the first eukaryotic enzyme known to undergo proteasomal truncation.
Alternate primers for whole-genome SARS-CoV-2 sequencing
Authors: Cotten Matthew , Bugembe Dan Lule , Kaleebu Pontiano , Phan My V.T.
Published: October 2020

As the world is struggling to control the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there is an urgency to develop effective control measures. Essential information is encoded in the virus genome sequence with accurate and complete SARS-CoV-2 sequences essential for tracking the movement and evolution of the virus and for guiding efforts to develop vaccines and antiviral drugs. While there is unprecedented SARS-CoV-2 sequencing efforts globally, approximately 19 to 43% of the genomes generated monthly are gapped, reducing their information content. The current study documents the genome gap frequencies and their positions in the currently available data and provides an alternative primer set and a sequencing scheme to help improve the quality and coverage of the genomes.
Visual dysfunction predicts cognitive impairment and white matter degeneration in Parkinson’s disease
Authors: Zarkali Angeliki , McColgan Peter , Leyland Louise-Ann , Lees Andrew J. , Weil Rimona S.
Published: October 2020

Visual dysfunction predicts dementia in Parkinsons disease (PD), but whether this translates to structural change is not known. We aimed to identify longitudinal white matter changes in patients with Parkinsons disease and low visual function and also in those who developed mild cognitive impairment (MCI). We used fixel-based analysis to examine longitudinal white matter change in PD. Diffusion MRI and clinical assessments were performed in 77 patients at baseline (22 low visual function /55 intact vision; and 13 MCI, 13 MCI converters /51 normal cognition) and 25 controls and again after 18 months. We compared micro-structural changes in fibre density, macro-structural changes in fibre bundle cross-section (FC) and combined fibre density and cross-section across white matter, adjusting for age, gender and intracranial volume. Patients with Parkinsons and visual dysfunction showed worse cognitive performance at follow up and were more likely to develop MCI compared with those with normal vision (p=0.008). Parkinsons with poor visual function showed diffuse micro-structural and macro-structural changes at baseline, whereas those with MCI showed fewer baseline changes. At follow-up, Parkinsons with low visual function showed widespread macrostructural changes, involving the fronto-occipital fasciculi, external capsules, and middle cerebellar peduncles bilaterally. No longitudinal change was seen in baseline MCI or in MCI converters, even when the two groups were combined. Parkinsons patients with poor visual function show increased white matter damage over time, providing further evidence for visual function as a marker of imminent cognitive decline.
Long-lasting tagging of neurons activated by seizures or cocaine administration in Egr1-CreERT2transgenic mice
Authors: Longueville Sophie , Nakamura Yuki , Brami-Cherrier Karen , Coura Renata , Hervé Denis , Girault Jean-Antoine
Published: October 2020

Permanent tagging of neuronal ensembles activated in specific experimental situations is an important objective to study their properties and adaptations. In the context of learning and memory these neurons are referred to as engram neurons. Here we describe and characterize a novel mouse line, Egr1-CreERT2, which carries a transgene in which the promoter of the immediate early geneEgr1drives the expression of the CreERT2recombinase that is only active in the presence of tamoxifen metabolite, 4-hydroxy-tamoxifen (4-OHT). Egr1-CreERT2mice were crossed with various reporter mice, Cre-dependently expressing a fluorescent protein. Without tamoxifen or 4-OHT, no or few tagged neurons were observed. Epileptic seizures induced by pilocarpine or pentylenetetrazol in the presence of tamoxifen or 4-OHT, induced the persistent tagging of many neurons and some astrocytes in the dentate gyrus of hippocampus, whereEgr1is transiently induced by seizures. One week after cocaine and 4-OHT administration, these mice displayed a higher number of tagged neurons in the dorsal striatum than saline/4-OHT controls, with differences between reporter lines. Cocaine-induced tagging required ERK activation and tagged neurons were more likely than others to exhibit ERK phosphorylation or Fos induction after a second injection. Interestingly neurons tagged in saline-treated mice also had an increased propensity to express Fos, suggesting the existence of highly responsive striatal neurons susceptible to be re-activated by cocaine repeated administration, which may contribute to the behavioral adaptations. Our report validates a novel transgenic mouse model for permanently tagging activated neurons and studying long term alterations ofEgr1-expressing cells.
Scalable and accurate automated method for neuronal ensemble detection in spiking neural networks
Authors: Herzog Rubén , Morales Arturo , Mora Soraya , Araya Joaquin , Escobar María-José , Palacios Adrian G. , Cofré Rodrigo
Published: October 2020

We propose a novel, scalable, and accurate automated method for detecting neuronal ensembles from a population of spiking neurons. Our approach offers a simple yet powerful tool to study ensemble activity. It allows the participation of neurons in different ensembles, has few parameters to tune and is computationally efficient. We used spike trains of retinal ganglion cells obtained from multi-electrode array recordings under a simple ON-OFF light stimulus to test our method. We found a consistent stimuli-evoked ensemble activity intermingled with spontaneously active ensembles and irregular activity. Our results suggest that the early visual system activity is already organized in clearly distinguishable functional ensembles. To validate the performance and generality of our method, we generated synthetic data, where we found that our method accurately detects neuronal ensembles for a wide range of simulation parameters. Additionally, we found that our method outperforms current alternative methodologies. Finally, we provide a Graphic User Interface, which aims to facilitate our method’s use by the scientific community.

Author summary

Neuronal ensembles are strongly interconnected groups of neurons that tend to fire together (Hebb 1949). However, even when this concept was proposed more than 70 years ago, only recent advances in multi-electrode arrays and calcium imaging, statistical methods, and computing power have made it possible to record and analyze multiple neurons’ activities spiking simultaneously, providing a unique opportunity to study how groups of neurons form ensembles spontaneously and under different stimuli scenarios. Using our method, we found that retinal ganglion cells show a consistent stimuli-evoked ensemble activity, and, when validated with synthetic data, the method shows good performance by detecting the number of ensembles, the activation times, and the core-cells for a wide range of firing rates and number of ensembles accurately.