bluuebunny/crossref_metadata_2025 huggingface dataset:
Randomised clinical trial: comparison of efficacy and adverse effects of a standard triple clarithromycin-containing regimen with high-dose amoxicillin and bismuth therapy in Helicobacter pylori eradication
Authors: Sjomina Olga , Lielause Alise , Rūdule Aiga , Vangravs Reinis , Paršutins Sergejs , Poļaka Inese , Daugule Ilva , Stonāns Ilmārs , Park Jin Young , Leja Mārcis
Published: December 2021

Background

The clarithromycin-based triple therapy is the most prescribed Helicobacter pylori eradication regimen in Europe; it causes adverse effects in a significant proportion of subjects, leading to discontinuation. Alternative therapies are required because of increasing clarithromycin resistance or to decrease the adverse effects.

Aims

We compared the efficacy and spectrum of adverse effects of clarithromycin-based triple therapy with the high-dose amoxicillin/bismuth regimen.

Methods

A randomised clinical trial enrolled healthy individuals aged 40–64 years. H. pylori was assessed with a 13C-urea breath test. In total 579 H. pylori-positive subjects were randomly allocated in two groups: group 1: clarithromycin 500 mg, amoxicillin 1000 mg, esomeprazole 40 mg, all twice daily; group 2: bismuth subcitrate 240 mg twice daily, amoxicillin 1000 mg three times daily, esomeprazole 40 mg twice daily. Regimens were administered for 14 days.

Information on treatment completion and adverse effects were collected via a telephone interview at 21–28 days after medication delivery. The efficacy was assessed by UBT 6 months after the treatment.

Results

We analysed 483 subjects for adverse effects (248 vs. 235 respectively). Furthermore, 316 subjects were analysed for efficacy. In per-protocol analysis, a higher efficacy was seen in group 1 (88.4 vs. 77.0%; P < 0.001); no difference was observed in compliance (90.3 and 91.2%). Therapy-related adverse effects were more common in group 1 (56.9 vs. 40.0%; P < 0.01). In intention-to-treat analysis no statistical difference in efficacy was revealed.

Conclusions

Bismuth-based high-dose amoxicillin therapy showed a lower efficacy but was less frequently associated with adverse effects. Further research is required to examine the high-dose amoxicillin and bismuth-containing regimens in various populations to maximise eradication efficacy.
Uterus Transplantation: A 50-Year Journey
Authors: Vali Saaliha , Jones Benjamin P. , Saso Srdjan , Yazbek Joseph , Quiroga Isabel , Smith JAMES RICHARD
Published: December 2021

This paper provides an analysis of the last 50 years of uterus transplantation (UTx). Animal research on UTx began in the 1960s, aiming to solve tubal factor infertility. The success of in vitro fertilization shifted the focus onto uterine factor infertility. Early research in small and large animals improved following the advent of immunosuppression and established the uterus’ ability to tolerate cold ischemia and to function following vessel reanastamosis. Upon the achievement of the first live birth following UTx in 2014, human research has started to focus on reducing donor morbidity, optimal immunosuppression regimes, and the development of deceased donor UTx programmes.
High Prevalence of Constitutional Mismatch Repair Deficiency in a Pediatric T-cell Lymphoblastic Lymphoma Cohort
Authors: Kroeze Emma , Weijers Dilys D. , Hagleitner Melanie M. , de Groot-Kruseman Hester A. , Jongmans Marjolijn C. J. , Kuiper Roland P. , Pieters Rob , Meijerink Jules P. P. , Loeffen Jan L. C.
Published: December 2021

This study describes the clinical characteristics of a complete Dutch T-cell lymphoblastic lymphoma (T-LBL) cohort, including second primary malignancies and comorbidities. We show that over 10% of patients in this complete T-LBL cohort have been diagnosed with a cancer predisposition syndrome (CPS), consisting almost exclusively of constitutional mismatch repair deficiency (CMMRD). The clinical characteristics of sporadic T-LBL patients were compared with T-LBL patients that have been diagnosed with CMMRD. This shows that disease presentation is comparable but that disease localization in CMMRD patients might be more localized. The percentage of CPS seems reliable considering the completeness of the cohort of Dutch T-LBL patients and might even be an underestimation (possibility of undiagnosed CPS patients in cohort). As the frequency of an underlying predisposition syndrome among T-LBL patients may be underestimated at present, we advocate for screening all pediatric T-LBL patients for the presence of germline mutations in mismatch repair genes.
The Effect of Splenectomy on the Risk of Infection in Patients With Liver Cirrhosis
Authors: Feng Tiantong , Hou Xiaoxue , Zhang Wen , Tian Anran , Chen Nian , Li Jun , Zhu Chuanlong
Published: December 2021

Background:

Splenectomy has been reported to improve liver function as well as hypersplenism, but it is still controversial whether splenectomy will further damage the immune function of patients with liver cirrhosis. This study aims to evaluate the impact of splenectomy on the risk of infection in patients with liver cirrhosis.

Methods:

A total of 4355 patients with liver cirrhosis admitted to the First Affiliated Hospital of Nanjing Medical University from October 1, 2016 to September 30, 2020 were enrolled. The patients were first divided into the splenectomy group (SG) and the non-splenectomy group (NSG). After standardization, patients were further divided according to the stage of cirrhosis. Infection rates in different stages were calculated, respectively. Laboratory results and infection sites of patients with cirrhosis were analyzed in combination with clinical data. Continuous variables conforming to normal distribution were presented as mean ± standard deviation, compared by sample t test or paired sample t test. Non-normal variables were presented as the median (interquartile range) and compared by Mann-Whitney U test or Wilcoxon signed rank test.

Results:

Five hundred and two patients received splenectomy and 3853 patients did not. Bacterial infection was diagnosed in 497 of the 4355 (11.41%) hospitalizations of patients with cirrhosis. The infection rate of the compensated cirrhosis SG was higher than that of the NSG (8.06% vs. 5.18%, P < 0.05). However, the infection rate in the SG with decompensated cirrhosis was lower than that in the NSG (11.35% vs. 22.22%, P < 0.001). The peak level of leukocytes did not differ significantly between the SG with compensated liver cirrhosis and the NSG [11.97 (7.65) × 109/L vs. 12.19 (14.04) × 109/L, P > 0. 05]. The peak value of leukocytes in SG suffering from decompensated liver cirrhosis was significantly higher than that in NSG [12.29 (11.52) × 109/L vs. 6.37 (8.90) × 109/L, P = 0.004]. Patients with decompensated liver cirrhosis had a significantly higher rate of abdominal infection than patients with compensated liver cirrhosis, and splenectomy itself did not affect the sites of infection.

Conclusions:

Splenectomy increases the risk of infection for patients with compensated liver cirrhosis, but significantly decreases the risk in patients with decompensated liver cirrhosis.
Context-Rich Medical Device Reports
Authors: Morabito Julie , Marszalek John
Published: December 2021

Healthcare technology management (HTM) professionals and other clinicians can provide critical information to help the Food and Drug Administration (FDA) understand serious device issues from the hospital's perspective. By reporting context-rich adverse events to the FDA, HTM professionals help ensure that medical devices remain as safe and effective as possible throughout their use across the continuum of patient care. The medical device reports discussed in this case example were submitted to the FDA by HTM professionals and incorporated additional clinicians' observations. Key context in the medical device reports indicated the scope and relative degree of health hazard of a recurrent device malfunction and informed a class I recall classification for the device.
Scoping review to evaluate existing measurement parameters and clinical outcomes of transtibial prosthetic alignment and socket fit
Authors: Won Nae Yeon , Paul Alexandra , Garibaldi Matthew , Baumgartner Rita E. , Kaufman Kenton R. , Reider Lisa , Wrigley Jordan , Morshed Saam
Published: December 2021

Introduction:

Fit and alignment are observable objectives of the prosthesis rendering process for individuals with lower limb amputation. Nevertheless, there is a dearth of validated measures to directly assess the quality of this clinical procedure.

Objectives:

The objectives of this scoping review are to evaluate existing measurement parameters and clinical outcomes used in investigations of transtibial socket fit or prosthetic alignment and to identify gaps in the literature regarding tools for evaluation of prosthetic fitting.

Study design:

Scoping literature review.

Methods:

A comprehensive search was conducted in the following databases: MEDLINE (through PubMed), Embase (through Elsevier), Scopus (through Elsevier), and Engineering Village (through Elsevier), resulting in 6107 studies to be screened.

Results:

Sixty-three studies were included in the review. When measuring fit, studies most frequently reported on patient-reported comfort (n = 22) and socket size compared with the residual limb volume (n = 9). Alignment was most frequently measured by the prosthetists' judgment and/or use of an alignment jig (n = 34). The measurement parameters used to determine alignment or fit varied greatly among the included studies.

Conclusion:

This review demonstrated that most measures of socket fit rely on a patient's self-report and may vary with biopsychosocial factors unrelated to the socket fitting process. Meanwhile, alignment is determined mostly by the prosthetist's judgment, paired with objective measurements, such as alignment jigs and gait analysis. Efforts to standardize and validate measures of these parameters of prosthetic fitting are vital to improving clinical practice and reporting outcomes.
Genetic advantage and equality of opportunity in education: Two definitions and an empirical application
Authors: Pereira Rita Dias
Published: December 2021

The literature of Equality of Opportunity (EOp) has long acknowledged the existence of ‘talents’, ‘innate ability’ or ‘genetic ability’. Nonetheless, attempts to explicitly incorporate a measure of innate ability in the quantification of EOp have been rare. On the other hand, the literature of social-science genetics has found credible genetic-based components of EOp, without an explicit quantification of overall EOp. In addition, there exists prevalent disagreement within both kinds of literature on whether innate ability should be perceived as a fair or unfair source of advantage. This paper proposes to quantify EOp while explicitly including a genetic-based measure of innate ability. It proposes two formal definitions of EOp that draw on both stances regarding the compensation of innate ability. Novel testable implications are derived. The educational attainment polygenic index is used as a measure of innate ability while correcting for genetic nurture and accounting for the correlation between genes and other circumstances. An empirical application in the US Health and Retirement Study finds that the share of inequality of opportunity is 26% under the view that genetic differences are unfair sources of advantage and 21% otherwise. A comparative analysis over cohorts reveals that the trend in EOp depends on the definition adopted; if genetic advantage is a fair source of inequality then EOp has improved; the opposite holds if one considers genetic advantage an unfair source of inequality. These results highlight the importance of accounting for genetic differences in the EOp framework.
Unraveling the antiviral activity of plitidepsin by subcellular and morphological analysis
Authors: Sachse Martin , Tenorio Raquel , de Castro Isabel Fernández , Muñoz-Basagoiti Jordana , Perez-Zsolt Daniel , Raïch-Regué Dàlia , Rodon Jordi , Losada Alejandro , Avilés Pablo , Cuevas Carmen , Paredes Roger , Segalés Joaquim , Clotet Bonaventura , Vergara-Alert Júlia , Izquierdo-Useros Nuria , Risco Cristina
Published: December 2021

The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation factor 1 alpha 1) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin completely blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work.
The rise and fall of SARS-CoV-2 variants and the mutational profile of Omicron
Authors: Wiegand Tanner , McVey Aidan , Nemudraia Anna , Nemudryi Artem , Wiedenheft Blake
Published: December 2021

In late December of 2019, high throughput sequencing technologies enabled rapid identification of SARS-CoV-2 as the etiological agent of COVID-19, and global sequencing efforts are now a critical tool for monitoring the ongoing spread and evolution of this virus. Here, we analyze a subset (n=87,032) of all publicly available SARS-CoV-2 genomes (n=∼5.6 million) that were randomly selected, but equally distributed over the course of the pandemic. We plot the appearance of new variants of concern (VOCs) over time and show that the mutation rates in Omicron viruses are significantly greater than those in previously identified SARS-CoV-2 variants. Mutations in Omicron are primarily restricted to the spike protein, while 25 other viral proteins— including those involved in SARS-CoV-2 replication—are highly conserved. Collectively, this suggests that the genetic distinction of Omicron primarily arose from selective pressures on the spike, and that the fidelity of replication of this variant has not been altered.

Importance

Omicron is the fifth SARS-CoV-2 variant to be designated a Variant of Concern (VOC) by the World Health Organization (WHO). Here we provide a retrospective analysis of SARS-CoV-2 variants and explain how the Omicron variant is distinct. Our work shows that the spike protein is a ‘hotspot’ for viral evolution in all variants, suggesting that existing vaccines and diagnostics that target this protein may become less effective against Omicron and that our therapeutic and public health strategies will have to evolve along with the virus.
Genome-wide tandem repeat expansions contribute to schizophrenia risk
Authors: Mojarad Bahareh A , Engchuan Worrawat , Trost Brett , Backstrom Ian , Yin Yue , Thiruvahindrapuram Bhooma , Pallotto Linda , Khan Mahreen , Pellecchia Giovanna , Haque Bushra , Guo Keyi , Heung Tracy , Costain Gregory , Scherer Stephen W , Marshall Christian R , Pearson Christopher E , Bassett Anne S , Yuen Ryan KC
Published: December 2021

Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in the general population, compared with non-psychiatric controls. These TREs are disproportionately found at loci known to be associated with schizophrenia from genome-wide association studies, in individuals with clinically-relevant genetic variants at other schizophrenia loci, and in families where multiple individuals have schizophrenia. Our findings support the involvement of genome-wide rare TREs in the polygenic nature of schizophrenia.
Sputnik Light booster after Sputnik V vaccination induces robust neutralizing antibody response to B.1.1.529 (Omicron) SARS-CoV-2 variant
Authors: Dolzhikova IV , Iliukhina AA , Kovyrshina AV , Kuzina AV , Gushchin VA , Siniavin AE , Pochtovyi AA , Shidlovskaya EV , Kuznetsova NA , Megeryan MM , Dzharullaeva AS , Erokhova AS , Izhaeva FM , Grousova DM , Botikov AG , Shcheblyakov DV , Tukhvatulin AI , Zubkova OV , Logunov DY , Gintsburg AL
Published: December 2021

COVID-19 vaccination campaign has been launched around the world. More than 8 billion vaccines doses have been administered, according to the WHO. Published studies shows that vaccination reduces the number of COVID-19 cases and dramatically reduces COVID-19-associated hospitalizations and deaths worldwide. In turn, the emergence of SARS-CoV-2 variants of concern (VOC) with mutations in the receptor-binding domain (RBD) of S glycoprotein poses risks of diminishing the effectiveness of the vaccination campaign. In November 2021, the first information appeared about a new variant of the SARS-CoV-2 virus, which was named Omicron. The Omicron variant is of concern because it contains a large number of mutations, especially in the S glycoprotein (16 mutation in RBD), which could be associated with resistance to neutralizing antibodies (NtAB) and significantly reduce the effectiveness of COVID-19 vaccines. Neutralizing antibodies are one of the important parameters characterizing the protective properties of a vaccine. We conducted a study of neutralizing antibodies in the blood serum of people vaccinated with Sputnik V, as well as those revaccinated with Sputnik Light after Sputnik V. Results showed that a decrease in the level of neutralizing antibodies was observed against SARS-CoV-2 Omicron (B.1.1.529) variant in comparison to B.1.1.1 variant. Analysis of the sera of individuals vaccinated with Sputnik V 6-12 months ago showed that there was a decrease in the level of neutralizing antibodies by 11.76 folds. While no direct comparison with other vaccines declines has been done in this study, we note their reported decline in antibody neutralization at a much more significant level of 40-84 times. At the same time, the analysis of sera of individuals who were vaccinated with Sputnik V, and then revaccinated Sputnik Light, showed that 2-3 months after revaccination the decrease in the level of neutralizing antibodies against the Omicron variant was 7.13 folds. Despite the decrease in NtAb, we showed that all revaccinated individuals had NtAb to Omicron variant. Moreover, the NtAb level to Omicron variant in revaccinated sera are slightly higher than NtAb to B.1.1.1 in vaccinated sera.
Conformational rearrangements upon start codon recognition in human 48S translation initiation complex
Authors: Yi Sung-Hui , Petrychenko Valentyn , Schliep Jan Erik , Goyal Akanksha , Linden Andreas , Chari Ashwin , Urlaub Henning , Stark Holger , Rodnina Marina , Adio Sarah , Fischer Niels
Published: December 2021

Selection of the translation start codon is a key step during protein synthesis in human cells. We obtained cryo-EM structures of human 48S initiation complexes and characterized the intermediates of codon recognition by kinetic methods using eIF1A as a reporter. Both approaches capture two distinct ribosome populations formed on an mRNA with a cognate AUG codon in the presence of eIF1, eIF1A, eIF2–GTP–Met-tRNAiMet, and eIF3. The ‘open’ 40S subunit conformation differs from the human 48S scanning complex and represents an intermediate preceding the codon recognition step. The ‘closed’ form is similar to reported structures of complexes from yeast and mammals formed upon codon recognition, except for the orientation of eIF1A, which is unique in our structure. Kinetic experiments show how various initiation factors mediate the population distribution of open and closed conformations until 60S subunit docking. Our results provide insights into the timing and structure of human translation initiation intermediates and suggest the differences in the mechanisms of start codon selection between mammals and yeast.
ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection
Authors: Ching Krystal L. , de Vries Maren , Gago Juan , Dancel-Manning Kristen , Sall Joseph , Rice William J. , Barnett Clea , Liang Feng-Xia , Thorpe Lorna E. , Shopsin Bo , Segal Leopoldo N. , Dittmann Meike , Torres Victor J. , Cadwell Ken
Published: December 2021

Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases. We recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, we investigated the role of defensosomes during infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchioalveolar lavage fluid from critically ill COVID-19 patients was associated with reduced ICU and hospitalization times. We found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. We further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.
Comparative effectiveness of the BNT162b2 vs ChAdOx1 vaccine against Covid-19
Authors: xie Junqing , Feng Shuo , Li Xintong , Gea-Mallorquí Ester , Prats-Uribe Albert , Prieto-Alhambra Dani
Published: December 2021

Although pivotal trials with varying populations and study methods suggest higher efficacy for mRNA than adenoviral Covid-19 vaccines, no direct evidence is available. Here, we conducted a head-to-head comparison of BNT162b2 versus ChAdOx1 against Covid-19. We analysed 235,181 UK Biobank participants aged 50 years or older and vaccinated with one or two doses of BNT162b2 or ChAdOx1. People were followed from the vaccination date until 18/10/2021. Inverse probability weighting was used to minimise confounding and the Cox models to derive hazard ratio. We found that, compared with two doses of ChAdOx1, vaccination with BNT162b2 was associated with 30% lower risks of both SARS-CoV-2 infection and related hospitalisation during the period dominated by the delta variant. Also, this comparative effectiveness was consistent across several subgroups and persisted for at least six months, suggesting no differential waning between the two vaccines. Our findings can inform evidence-based Covid-19 vaccination campaigns and booster strategies.
Temporal associations of B and T cell immunity with robust vaccine responsiveness in a 16-week interval BNT162b2 regimen
Authors: Nayrac Manon , Dubé Mathieu , Sannier Gérémy , Nicolas Alexandre , Marchitto Lorie , Tastet Olivier , Tauzin Alexandra , Brassard Nathalie , Beaudoin-Bussières Guillaume , Vézina Dani , Gong Shang Yu , Benlarbi Mehdi , Gasser Romain , Laumaea Annemarie , Bourassa Catherine , Gendron-Lepage Gabrielle , Medjahed Halima , Goyette Guillaume , Ortega-Delgado Gloria-Gabrielle , Laporte Mélanie , Niessl Julia , Gokool Laurie , Morrisseau Chantal , Arlotto Pascale , Richard Jonathan , Tremblay Cécile , Martel-Laferrière Valérie , Finzi Andrés , Kaufmann Daniel E.
Published: December 2021

Spacing of the BNT162b2 mRNA doses beyond 3 weeks raised concerns about vaccine efficacy. We longitudinally analyzed B cell, T cell and humoral responses to two BNT162b2 mRNA doses administered 16 weeks apart in 53 SARS-CoV-2 naïve and previously-infected donors. This regimen elicited robust RBD-specific B cell responses whose kinetics differed between cohorts, the second dose leading to increased magnitude in naïve participants only. While boosting did not increase magnitude of CD4+ T cell responses further compared to the first dose, unsupervised clustering analyses of single-cell features revealed phenotypic and functional shifts over time and between cohorts. Integrated analysis showed longitudinal immune component-specific associations, with early Thelper responses post-first dose correlating with B cell responses after the second dose, and memory Thelper generated between doses correlating with CD8 T cell responses after boosting. Therefore, boosting elicits a robust cellular recall response after the 16-week interval, indicating functional immune memory.
Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa
Authors: Viana Raquel , Moyo Sikhulile , Amoako Daniel G , Tegally Houriiyah , Scheepers Cathrine , Althaus Christian L , Anyaneji Ugochukwu J , Bester Phillip A , Boni Maciej F , Chand Mohammed , Choga Wonderful T , Colquhoun Rachel , Davids Michaela , Deforche Koen , Doolabh Deelan , Engelbrecht Susan , Everatt Josie , Giandhari Jennifer , Giovanetti Marta , Hardie Diana , Hill Verity , Hsiao Nei-Yuan , Iranzadeh Arash , Ismail Arshad , Joseph Charity , Joseph Rageema , Koopile Legodile , Pond Sergei L Kosakovsky , Kraemer Moritz UG , Kuate-Lere Lesego , Laguda-Akingba Oluwakemi , Lesetedi-Mafoko Onalethatha , Lessells Richard J , Lockman Shahin , Lucaci Alexander G , Maharaj Arisha , Mahlangu Boitshoko , Maponga Tongai , Mahlakwane Kamela , Makatini Zinhle , Marais Gert , Maruapula Dorcas , Masupu Kereng , Matshaba Mogomotsi , Mayaphi Simnikiwe , Mbhele Nokuzola , Mbulawa Mpaphi B , Mendes Adriano , Mlisana Koleka , Mnguni Anele , Mohale Thabo , Moir Monika , Moruisi Kgomotso , Mosepele Mosepele , Motsatsi Gerald , Motswaledi Modisa S , Mphoyakgosi Thongbotho , Msomi Nokukhanya , Mwangi Peter N , Naidoo Yeshnee , Ntuli Noxolo , Nyaga Martin , Olubayo Lucier , Pillay Sureshnee , Radibe Botshelo , Ramphal Yajna , Ramphal Upasana , San James E , Scott Lesley , Shapiro Roger , Singh Lavanya , Smith-Lawrence Pamela , Stevens Wendy , Strydom Amy , Subramoney Kathleen , Tebeila Naume , Tshiabuila Derek , Tsui Joseph , van Wyk Stephanie , Weaver Steven , Wibmer Constantinos K , Wilkinson Eduan , Wolter Nicole , Zarebski Alexander E , Zuze Boitumelo , Goedhals Dominique , Preiser Wolfgang , Treurnicht Florette , Venter Marietje , Williamson Carolyn , Pybus Oliver G , Bhiman Jinal , Glass Allison , Martin Darren P , Rambaut Andrew , Gaseitsiwe Simani , von Gottberg Anne , de Oliveira Tulio
Published: December 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in southern Africa has been characterised by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, whilst the second and third waves were driven by the Beta and Delta variants respectively1–3. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng Province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, predicted to influence antibody neutralization and spike function4. Here, we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.
Bounding the levels of transmissibility & immune evasion of the Omicron variant in South Africa
Authors: Pearson Carl A. B. , Silal Sheetal P. , Li Michael W.Z. , Dushoff Jonathan , Bolker Benjamin M. , Abbott Sam , van Schalkwyk Cari , Davies Nicholas G. , Barnard Rosanna C. , Edmunds W. John , Bingham Jeremy , Meyer-Rath Gesine , Jamieson Lise , Glass Allison , Wolter Nicole , Govender Nevashan , Stevens Wendy S. , Scott Lesley , Mlisana Koleka , Moultrie Harry , Pulliam Juliet R. C.
Published: December 2021

A new SARS-CoV-2 variant of concern, Omicron (B.1.1.529), has been identified based on genomic sequencing and epidemiological data in South Africa. Presumptive Omicron cases in South Africa have grown extremely rapidly, despite high prior exposure and moderate vaccination coverage. The available evidence suggests that Omicron spread is at least in part due to evasion of this immune protection, though Omicron may also exhibit higher intrinsic transmissibility. Using detailed laboratory and epidemiological data from South Africa, we estimate the constraints on these two characteristics of the new variant and their relationship. Our estimates and associated uncertainties provide essential information to inform projection and scenario modeling analyses, which are crucial planning tools for governments around the world.

One Sentence Summary

We report a region of plausibility for the relative transmissibility and immune escape characteristics of the SARS-CoV-2 Omicron variant estimated by integrating laboratory and epidemiological data from South Africa.
Government messaging about COVID-19 vaccination in Canada and Australia: a Narrative Policy Framework study
Authors: Saich Freya , Martiniuk Alexandra
Published: December 2021

Background

Storytelling and narratives are critical components to public policy and have been central to public policy communicators throughout the COVID-19 pandemic.

Aim

This study applied the Narrative Policy Framework to compare and contrast the policy narratives of the Canadian and Australian Prime Ministers regarding COVID-19 vaccination.

Methods

Official media releases, transcripts and speeches published on the websites of Prime Minister Morrison and Prime Minister Trudeau between 31 August 2020 and 10 September 2021 relating to COVID-19 vaccines were thematically analysed according to the Narrative Policy Framework.

Results

The policy narratives of Scott Morrison and Justin Trudeau tended towards describing both governments as heroes for securing and rolling out vaccines. Trudeau tended to focus on the villain of COVID-19 while Morrison regularly described other countries as victims of COVID-19 to position Australia as superior in its decision-making. These findings also demonstrate how narratives shifted over time due to changing COVID-19 case numbers, emergence of rare complications associated with the AstraZeneca vaccine and as new information arose.

Conclusion

These findings offer lessons for COVID-19 times as well as future pandemics and disease outbreaks by providing insight into how policy narratives influenced policy processes in both Australia and Canada.
Deep Learning Auto-Segmentation of Cervical Neck Skeletal Muscle for Sarcopenia Analysis Using Pre-Therapy CT in Patients with Head and Neck Cancer
Authors: Naser Mohamed A. , Wahid Kareem A. , Grossberg Aaron J. , Olson Brennan , Jain Rishab , El-Habashy Dina , Dede Cem , Salama Vivian , Abobakr Moamen , Mohamed Abdallah S.R. , He Renjie , Jaskari Joel , Sahlsten Jaakko , Kaski Kimmo , Fuller Clifton D.
Published: December 2021

Background/Purpose

Sarcopenia is a prognostic factor in patients with head and neck cancer (HNC). Sarcopenia can be determined using the skeletal muscle index (SMI) calculated from cervical neck SM segmentations. However, SM segmentation requires manual input, which is time-consuming and variable. Therefore, we developed a fully-automated approach to segment cervical vertebra SM.

Materials/Methods

390 HNC patients with corresponding contrast-enhanced computed tomography (CT) scans were utilized (300-training, 90-testing). Ground-truth single-slice SM segmentations at the C3 vertebra were manually generated. A multi-stage deep learning pipeline was developed, where a 3D ResUNet auto-segmented the C3 section (33 mm window), the middle slice of the section was auto-selected, and a 2D ResUNet auto-segmented the auto-selected slice. Both the 3D and 2D approaches trained five sub-models (5-fold cross-validation) and combined sub-model predictions on the test set using majority vote ensembling. Model performance was primarily determined using the Dice similarity coefficient (DSC). Predicted SMI was calculated using the auto-segmentation cross-sectional area. Finally, using established SMI cutoffs, we performed a Kaplan-Meier analysis to determine associations with overall survival.

Results

Mean test set DSC of the 3D and 2D models were 0.96 and 0.95, respectively. Predicted SMI had high correlation to the ground-truth SMI in males and females (r>0.96). Predicted SMI stratified patients for overall survival in males (log-rank p = 0.01) but not females (log-rank p = 0.07), consistent with ground-truth SMI.

Conclusion

We developed a high-performance, multi-stage, fully-automated approach to segment cervical vertebra SM. Our study is an essential step towards fully-automated sarcopenia-related decision-making.
A two-sex model of human papillomavirus infection: Vaccination strategies and a case study
Authors: Gao Shasha , Martcheva Maia , Miao Hongyu , Rong Libin
Published: December 2021

Vaccination is effective in preventing human papillomavirus (HPV) infection. It still remains debatable whether males should be included in a vaccination program and unclear how to allocate the vaccine in genders to achieve the maximum benefits. In this paper, we use a two-sex model to assess HPV vaccination strategies and use the data from Guangxi Province in China as a case study. Both mathematical analysis and numerical simulations show that the basic reproduction number, an important indicator of the transmission potential of the infection, achieves its minimum when the priority of vaccination is given to the gender with a smaller recruit rate. Given a fixed amount of vaccine, splitting the vaccine evenly usually leads to a larger basic reproduction number and a higher prevalence of infection. Vaccination becomes less effective in reducing the infection once the vaccine amount exceeds the smaller recruit rate of the two genders. In the case study, we estimate the basic reproduction number is 1.0333 for HPV 16/18 in people aged 15-55. The minimal bivalent HPV vaccine needed for the disease prevalence to be below 0.05% is 24050 per year, which should be given to females. However, with this vaccination strategy it would require a very long time and a large amount of vaccine to achieve the goal. In contrast with allocating the same vaccine amount every year, we find that a variable vaccination strategy with more vaccine given in the beginning followed by less vaccine in later years can save time and total vaccine amount. The variable vaccination strategy illustrated in this study can help to better distribute the vaccine to reduce the HPV prevalence. Although this work is for HPV infection and the case study is for a province in China, the model, analysis and conclusions may be applicable to other sexually transmitted diseases in other regions or countries.
Genome-Wide Analysis of Horizontal Transfer in Non-Model Wild Species from a Natural Ecosystem Reveals New Insights into Genetic Exchange in Plants
Authors: Aubin Emilie , Llauro Christel , Garrigue Joseph , Mirouze Marie , Panaud Olivier , El Baidouri Moaine
Published: December 2021

Background

Horizontal transfer (HT) refers to the exchange of genetic material between divergent species by mechanisms other than reproduction. In recent years, several studies have demonstrated HTs in eukaryotes, particularly in the context of parasitic relationships and in model species. However, very little is known about HT in natural ecosystems, especially those involving non-parasitic wild species, and the nature of the ecological relationships that promote these HTs.

Results

In this work, we conducted a pilot study investigating HTs by sequencing the genomes of 17 wild non-model species from a natural ecosystem, the Massane forest, located in southern France. To this end, we developed a new computational pipeline called INTERCHANGE that is able to characterize HTs at the whole genome level without prior annotation and directly in the raw sequencing reads. Using this pipeline, we identified 12 HT events, half of which occurred between lianas and trees. We found that mainly low copy number LTRs retrotransposons from the Copia superfamily were transferred between these wild plant species, especially those of the Ivan and Ale lineages.

Conclusion

This study revealed a possible new route for HTs between non-parasitic plants and provides new insights into the genomic characteristics of horizontally transferred DNA in plant genomes.
Human embryos arrest in a quiescent-like state characterized by metabolic and zygotic genome activation problems
Authors: Yang Yang , Shi Liyang , Fu Xiuling , Ma Gang , Yang Zhongzhou , Li Yuhao , Zhou Yibin , Yuan Lihua , Xia Ye , Zhong Xiufang , Yin Ping , Sun Li , Wuwen Zhang , Babarinde Isaac A. , Wang Yongjun , Zhao Xiaoyang , Hutchins Andrew P. , Tong Guoqing
Published: December 2021

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3-8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a quiescent-like state, marked by cell cycle arrest, the downregulation of ribosomes and histones and downregulation of MYC and p53 activity. Mechanistically, the arrested embryos can be divided into three types. Type I embryos fail to complete the maternal-zygotic transition, and type II/III embryos have erroneously low levels of glycolysis and variable levels of oxidative phosphorylation. Treatment with resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype. The mechanism of reactivation involves the upregulation of SIRT1, and activation of glycolysis and fatty acid oxidation which forces the embryos out of a quiescent state. Overall, our data reveal how human embryo arrest can be overcome by modulating metabolic pathways.
Expression of γ-globin genes in β-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin)
Authors: Zuccato Cristina , Cosenza Lucia Carmela , Zurlo Matteo , Gasparello Jessica , Papi Chiara , D’Aversa Elisabetta , Breveglieri Giulia , Lampronti Ilaria , Finotti Alessia , Borgatti Monica , Scapoli Chiara , Stievano Alice , Fortini Monica , Ramazzotti Eric , Marchetti Nicola , Prosdocimi Marco , Gamberini Maria Rita , Gambari Roberto
Published: December 2021

Introduction

The β-thalassemias are due to autosomal mutations of the β-globin gene, inducing absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that high production of fetal hemoglobin (HbF) is beneficial for β-thalassemia patients. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus found to be a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular and clinical results of the sirolimus-basedNCT03877809clinical trial (A Personalized Medicine Approach for β-thalassemia Transfusion Dependent Patients: Testing sirolimus in a First Pilot Clinical Trial: Sirthalaclin).

Methods

Accumulation of γ-globin mRNA was analyzed by reverse-transcription-quantitative PCR and the hemoglobin pattern by HPLC. The immunophenotype was analyzed by FACS using antibodies against CD3, CD4, CD8, CD14, CD19, CD25.

Results

The results were obtained in 8 patients with β+/β+ and β+/β0 genotypes, treated with a starting dosage of 1 mg/day sirolimus for 24-48 weeks. The first finding of the study was that expression of γ-globin mRNA was increased in blood and erythroid precursor cells isolated from β-thalassemia patients treated with low-dose sirolimus. A second important conclusion of our trial was that sirolimus influences erythropoiesis and reduces biochemical markers associated to ineffective erythropoiesis (I.E.) (excess of free α-globin chains, bilirubin, soluble transferrin receptor and ferritin). In most (7/8) of the patients a decrease of the transfusion demand index was observed. The drug was well tolerated with minor effects on immunophenotype, the only side effect being frequently occurring stomatitis.

Conclusions

The data obtained indicate that sirolimus given at low doses modifies hematopoiesis and induces increased expression of γ-globin genes in a sub-set of β-thalassemia patients. Further clinical trials are warranted, considering the possibility to test the drug in patients with less severe forms of the disease and exploring combination therapies.
Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: A Danish cohort study
Authors: Hansen Christian Holm , Schelde Astrid Blicher , Moustsen-Helm Ida Rask , Emborg Hanne-Dorthe , Krause Tyra Grove , Mølbak Kåre , Valentiner-Branth Palle
Published: December 2021

In this brief communication we are showing original research results with early estimates from Danish nationwide databases of vaccine effectiveness (VE) against the novel SARS-CoV-2 Omicron variant (B.1.1.529) up to five months after a primary vaccination series with the BNT162b2 or mRNA-1273 vaccines.

Our study provides evidence of protection against infection with the Omicron variant after completion of a primary vaccination series with the BNT162b2 or mRNA-1273 vaccines; in particular, we found a VE against the Omicron variant of 55.2% (95% confidence interval (CI): 23.5 to 73.7%) and 36.7% (95% CI: -69.9 to 76.4%) for the BNT162b2 and mRNA-1273 vaccines, respectively, in the first month after primary vaccination. However, the VE is significantly lower than that against Delta infection and declines rapidly over just a few months. The VE is re-established upon revaccination with the BNT162b2 vaccine (54.6%, 95% CI: 30.4 to 70.4%).
Bacterial Outer Membrane Vesicles Induce a Transcriptional Shift in Arabidopsis Towards Immune System Activation Leading to Suppression of Pathogen Growth in Planta
Authors: Chalupowicz Laura , Mordukhovich Gideon , Assoline Nofar , Katsir Leron , Sela Noa , Bahar Ofir
Published: December 2021

Gram negative bacteria form spherical blebs on their cell periphery, which later dissociate and released into the surrounding environment. Previous studies have shown that these nano scale structures, derived primarily from the bacterial outer membrane and are termed outer membrane vesicles (OMVs), induce typical immune outputs in both mammals and plants. On the other hand, these same structures have been shown to promote infection and disease. To better understand the broad transcriptional change plants undergo following exposure to OMVs, we treated Arabidopsis thaliana (Arabidopsis) seedlings with OMVs purified from the Gram-negative plant pathogenic bacterium Xanthomonas campestris pv. campestris and performed RNA-seq analysis on OMV- and mock-treated samples at 2, 6 and 24 h post challenge. We found that the most pronounced transcriptional shift occurred in the first two time points, as was reflected by both the number of differentially expressed genes (DEGs) and the average fold change. Gene ontology enrichment analysis revealed that OMVs induce a major transcriptional shift in Arabidopsis towards immune system activation, upregulating a multitude of immune-related pathways including a variety of immune receptors and transcriptional factors. Comparing Arabidopsis response to OMVs and to single purified elicitors, revealed that while OMVs induce a similar suite of genes and pathways as single elicitors, some differential pathways activated by OMVs were detected including response to drug and apoptosis, which may indicate exposure to toxic compounds via OMV. To examine whether the observed transcriptional shift in Arabidopsis leads to an effective immune response, plants were pretreated with OMVs and then inoculated with a bacterial pathogen. OMV-mediated priming led to a significant reduction in bacterial titer in inoculated leaves two days following inoculation. Mutations in the elongation factor receptor (EFR), flagellin receptor (FLS2), or the brassinosteroid-insensitive 1–associated kinase (BAK1) receptor, did not significantly affect OMV-priming. All together these results show that OMV induce a broad transcriptional shift in Arabidopsis leading to upregulation of multiple immune pathways, and that this transcriptional change is reflected in the ability to better resist bacterial infection.
Nucleolar targeting in an early-branching eukaryote suggests a general physicochemical mechanism for ribosome protein sorting
Authors: Jeilani Milad , Billington Karen , Sunter Jack Daniel , Dean Samuel , Wheeler Richard John
Published: December 2021

The eukaryotic cell targets proteins to the organelles in which they function, both membrane-bound (like the nucleus) and non-membrane-bound (like the nucleolus). Nucleolar targeting relies on positively charged localisation signals, and has received rejuvenated interest since the widespread recognition of liquid-liquid phase separation (LLPS) as a mechanism contributing to nucleolus formation. Here, we exploit a new genome-wide analysis of protein localisation in an early-branching eukaryote,Trypanosoma brucei, to analyse general nucleolar protein properties.T. bruceinucleolar proteins have similar properties to those in common model eukaryotes, specifically basic amino acids. Using protein truncations and addition of candidate targeting sequences to proteins, we show both homopolymer runs and distributed basic amino acids give nucleolar partition, further aided by a nuclear localisation signal (NLS). These findings are consistent with phase separation models of nucleolar formation and protein physical properties being a major contributing mechanism for eukaryotic nucleolar targeting, conserved from the last eukaryotic common ancestor. Importantly, cytoplasmic ribosome proteins in comparison to mitochondrial ribosome proteins followed the same pattern – pointing to adaptation of physicochemical properties to assist segregation.

Summary Statement

We show protein targeting to the nucleolus is mediated by positive charge, likely across eukaryotes, and contributes to sorting of mitochondrial from cytoplasmic ribosome proteins.