bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of gait cycle time variability in patients with knee osteoarthritis using a triaxial accelerometer
Authors: Akimoto Takeshi , Kawamura Kenji , Wada Takaaki , Ishihara Naomichi , Yokota Akane , Suginoshita Takehiko , Yokoyama Shigeki
Published: July 2021

Knee osteoarthritis can alter gait variability. However, few studies have compared the temporal factors of the gait cycle between patients with knee osteoarthritis and healthy subjects. Furthermore, no studies have investigated the relationship between gait variability and potential contributing factors (knee joint functions such as muscle strength) in knee osteoarthritis. The first objective of this study was to compare gait cycle variability between female patients with knee osteoarthritis and healthy elderly women to determine gait characteristics in patients with knee osteoarthritis. The second objective was to examine whether gait cycle variability in knee osteoarthritis is associated with potential contributing factors. Twenty-four female patients diagnosed with knee osteoarthritis and 12 healthy elderly women participated. Gait cycle variability (coefficient of variation of gait cycle time), knee extension range of motion, knee extension strength, 5-meter walk test, Timed Up & Go Test, and Western Ontario and McMaster Universities Osteoarthritis Index were measured. All assessment results were compared between the knee osteoarthritis and healthy groups. Gait cycle variability was significantly higher in the knee osteoarthritis group (3.2%±1.5%) compared to the healthy group (2.1%±0.7%). A significant positive correlation was found between the gait cycle variability and 5-meter walk test (r=0.46) and Western Ontario and McMaster Universities Osteoarthritis Index (r=0.43). The gait of patients with knee osteoarthritis may be more unstable than that of healthy individuals. In addition, unstable gait may be associated with gait speed and quality of life. Therefore, we believe that rehabilitation to improve unstable gait can enhance the quality of life of patients with knee osteoarthritis.
Nonresponse adjustment using clinical and perioperative patient characteristics is critical for understanding post-discharge opioid consumption
Authors: Kennedy Chris J. , Marwaha Jayson S. , Scalise P. Nina , Robinson Kortney A. , Booth Brandon , Fleishman Aaron , Nathanson Larry A. , Brat Gabriel A.
Published: July 2021

Background

Post-discharge opioid consumption is an important source of data in guiding appropriate opioid prescribing guidelines, but its collection is tedious and requires significant resources. Furthermore, the reliability of post-discharge opioid consumption surveys is unclear. Our group developed an automated short messaging service (SMS)-to-web survey for collecting this data from patients. In this study, we assessed its effectiveness in estimating opioid consumption by performing causal adjustment and comparison to a phone-based survey as reference.

Methods

Patients who underwent surgical procedures at our institution from 2019-2020 were sent an SMS message with a link to a secure web survey to quantify opioids consumed after discharge. Several patient factors extracted from the EHR were tested for association with survey response. Following targeted learning (TL) nonresponse adjustment using these EHR-based factors, opioid consumption survey results were compared to a prior telephone-based survey at our institution as a reference.

Results

6,553 patients were included. Opioid consumption was measured in 2,883 (44%), including 1,342 (20.5%) through survey response. Characteristics associated with inability to measure opioid consumption included age, length of stay, race, tobacco use, and missing preoperative assessment. Among the top 10 procedures by volume, EHR-based TL nonresponse bias adjustment corrected the median opioid consumption reported by an average of 57%, and corrected the 75th percentile of reported consumption by an average of 11%. This brought median estimates for 6/10 procedures closer to telephone survey-based consumption estimates, and 75th percentile estimates for 3/10 procedures closer to telephone survey-based consumption estimates.

Conclusion

We found that applying electronic health record (EHR)-based machine learning nonresponse bias adjustment is essential for debiased opioid consumption estimates from patient surveys. After adjustment, post-discharge surveys can generate reliable opioid consumption estimates. Clinical factors from the EHR combined with TL adjustment appropriately capture differences between responders and nonresponders and should be used prior to generalizing or applying opioid consumption estimates to patient care.
Time Windows Voting Classifier for COVID-19 Mortality Prediction
Authors: Goh Tiong-Thye , Liu MengJun
Published: July 2021

Background

The ability to predict COVID-19 patients’ level of severity (death or survival) enables clinicians to prioritise treatment. Recently, using three blood biomarkers, an interpretable machine learning model was developed to predict the mortality of COVID-19 patients. The method was reported to be suffering from performance stability because the identified biomarkers are not consistent predictors over an extended duration.

Methods

To sustain performance, the proposed method partitioned data into three different time windows. For each window, an end-classifier, a mid-classifier and a front-classifier were designed respectively using the XGboost single tree approach. These time window classifiers were integrated into a majority vote classifier and tested with an isolated test data set.

Results

The voting classifier strengthens the overall performance of 90% cumulative accuracy from a 14 days window to a 21 days prediction window.

Conclusions

An additional 7 days of prediction window can have a considerable impact on a patient’s chance of survival. This study validated the feasibility of the time window voting classifier and further support the selection of biomarkers features set for the early prognosis of patients with a higher risk of mortality.
Evaluating Adoption, Impact, and Factors Driving Adoption for TREWS, a Machine Learning-Based Sepsis Alerting System
Authors: Henry Katharine E. , Adams Roy , Parent Cassandra , Sridharan Anirudh , Johnson Lauren , Hager David N. , Cosgrove Sara E. , Markowski Andrew , Klein Eili Y. , Chen Edward S. , Henley Maureen , Miranda Sheila , Houston Katrina , Linton Robert C. , Ahluwalia Anushree R. , Wu Albert W. , Saria Suchi
Published: July 2021

Machine learning-based clinical decision support tools for sepsis create opportunities to identify at-risk patients and initiate treatments earlier, critical to improving sepsis outcomes. Increasing use of such systems necessitates quantifying and understanding provider adoption. Using real-time provider interactions with a sepsis early detection tool (Targeted Real-time Early Warning System) deployed at five hospitals over a two-year period (469,419 screened encounters, 9,805 (2.1%) retrospectively-identified sepsis cases), we found high sensitivity (82% of sepsis cases identified), high adoption rates (89% of alerts evaluated by a physician or advanced practice provider and 38% of evaluated alerts confirmed) and an association between use of the tool and earlier treatment of sepsis patients (1.85 (95% CI:1.66-2.00) hour reduction in median time to first antibiotics order). Further, we found that provider-related factors were strongly associated with adoption. Beyond improving system performance, efforts to improve adoption should focus on provider knowledge, experience, and perceptions of the system.
Evaluating the Clinical Feasibility of an Artificial Intelligence-Powered Clinical Decision Support System: A Longitudinal Feasibility Study
Authors: Popescu Christina , Golden Grace , Benrimoh David , Tanguay-Sela Myriam , Slowey Dominique , Lundrigan Eryn , Williams Jérôme , Desormeau Bennet , Kardani Divyesh , Perez Tamara , Rollins Colleen , Israel Sonia , Perlman Kelly , Armstrong Caitrin , Baxter Jacob , Whitmore Kate , Fradette Marie-Jeanne , Felcarek-Hope Kaelan , Soufi Ghassen , Fratila Robert , Mehltretter Joseph , Looper Karl , Steiner Warren , Rej Soham , Karp Jordan F. , Heller Katherine , Parikh Sagar V. , McGuire-Snieckus Rebecca , Ferrari Manuela , Margolese Howard , Turecki Gustavo
Published: July 2021

Objective

We examine the feasibility of an Artificial Intelligence (AI)-powered clinical decision support system (CDSS), which combines the operationalized 2016 Canadian Network for Mood and Anxiety Treatments guidelines with a neural-network based individualized treatment remission prediction.

Methods

Due to COVID-19, the study was adapted to be completed entirely at a distance. Seven physicians recruited outpatients diagnosed with major depressive disorder (MDD) as per DSM-V criteria. Patients completed a minimum of one visit without the CDSS (baseline) and two subsequent visits where the CDSS was used by the physician (visit 1 and 2). The primary outcome of interest was change in session length after CDSS introduction, as a proxy for feasibility. Feasibility and acceptability data were collected through self-report questionnaires and semi-structured interviews.

Results

Seventeen patients enrolled in the study; 14 completed. There was no significant difference between appointment length between visits (introduction of the tool did not increase session length). 92.31% of patients and 71.43% of physicians felt that the tool was easy to use. 61.54% of the patients and 71.43% of the physicians rated that they trusted the CDSS. 46.15% of patients felt that the patient-clinician relationship significantly or somewhat improved, while the other 53.85% felt that it did not change.

Conclusions

Our results confirm the primary hypothesis that the integration of the tool does not increase appointment length. Findings suggest the CDSS is easy to use and may have some positive effects on the patient-physician relationship. The CDSS is feasible and ready for effectiveness studies.
Masks in a Post COVID-19 World: A Better Alternative to Curtailing Influenza?
Authors: Froese Henri , Prempeh Angel G. A.
Published: July 2021

Over the course of the coronavirus pandemic, it has become apparent that non-pharmaceutical interventions such as masks and social distancing are of great help in mitigating the transmission of airborne infectious diseases. Additionally, data from respiratory specimen analysis from the past year show that current mask mandates established for COVID-19 have inadvertently reduced the rates of other respiratory diseases, including influenza. Thus, the question arises as to whether comparatively mild measures should be kept in place after the pandemic to reduce the impact of influenza. In this study, we employed a series of differential equations to simulate past influenza seasons, assuming people wore face masks. This was achieved by introducing a variable to account for the efficacy and prevalence of masks and then analyzing its impact on influenza transmission rate in an SEIR model fit to the actual past seasons. We then compared influenza rates in this hypothetical scenario with the actual rates over the seasons. Our results show that several combinations of mask efficacy and prevalence can significantly reduce the burden of seasonal influenza. Particularly, our simulations suggest that a minority of individuals wearing masks greatly reduce the number of influenza infections. Considering the efficacy rates of masks and the relatively insignificant monetary cost, we highlight that it may be a viable alternative or complement to influenza vaccinations. We conclude with a brief discussion of our results and other practical aspects
IFIH1 rs1990760 variants, systemic inflammation and outcome in critically-ill COVID-19 patients
Authors: Amado-Rodríguez Laura , del Riego Estefanía Salgado , de Oña Juan Gómez , López-Alonso Inés , Gil-Peña Helena , López-Martínez Cecilia , Martín-Vicente Paula , López-Vázquez Antonio , González-López Adrián , Cuesta-Llavona Elías , Rodríguez-García Raquel , Boga José Antonio , Álvarez-Arguelles Marta Elena , Mayordomo-Colunga Juan , Vidal-Castiñeira José Ramón , Crespo Irene , Fernández Margarita , Criado Loreto , Salvadores Victoria , Jimeno-Demuth Francisco José , Blanch Lluís , Prieto Belén , Fernández-Fernández Alejandra , López-Larrea Carlos , Coto Eliecer , Albaiceta Guillermo M
Published: July 2021

Rationale

Outcomes in patients with severe SARS-CoV-2 infection (COVID-19) are conditioned by virus clearance and regulation of inflammation. Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections.

Objective

To characterize the impact of IFIH1 rs199076 variants on host response and outcomes after severe COVID-19.

Methods

Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modelled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials.

Measurements and Main Results

227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to a MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids (N=14) survived their ICU stay (HR 2.49, 95% confidence interval 1.29–4.79). Patients with a TT variant treated with dexamethasone (N=50) showed an increased hospital mortality (HR 2.19, 95% confidence interval 1.01–4.87) and serum IL-6. In-silico clinical trials supported these findings.

Conclusions

COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype.
Preserved C-reactive protein responses to blood stream infections following tocilizumab treatment for COVID-19
Authors: Wey Emmanuel Q , Bristow Clare , Nandani Aarti , O’Farrell Bryan , Pang Jay , Lanzman Marisa , Yang Shuang , Ho Soo , Mack Damien , Spiro Michael , Balakrishnan Indran , Bhagani Sanjay , Pollara Gabriele
Published: July 2021

C-reactive protein (CRP) levels are elevated following bacterial infections but may be attenuated by the IL-6-receptor antagonist tocilizumab. In hospitalised COVID-19 patients, tocilizumab induced a transient (<21 day) fall in CRP but retained CRP responses to nosocomial blood stream infections, and therefore its utility in guiding antibiotic prescribing.
Vaccination willingness for COVID-19 among health care workers in Switzerland
Authors: Zürcher Kathrin , Mugglin Catrina , Egger Matthias , Müller Sandro , Fluri Michael , Bolick Laurence , Piso Rein Jan , Hoffmann Matthias , Fenner Lukas
Published: July 2021

Aims of the study

Vaccination is regarded as the most promising response to the COVID-19 pandemic. We assessed opinions towards COVID-19 vaccination, willingness to be vaccinated, and reasons for vaccination hesitancy among health care workers (HCWs).

Methods

We conducted a cross-sectional, web-based survey among 3,793 HCWs in December 2020 in the Canton of Solothurn, Switzerland, before the start of the national COVID-19 vaccination campaign.

Results

Median age was 43 years (interquartile range [IQR] 31-53), 2,841 were female (74.9%). 1,511 HCWs (39.8%) reported willingness to accept vaccination, while 1,114 (29.4%) were unsure, and 1,168 (30.8%) would decline vaccination. Among medical doctors, 76.1% were willing, while only 27.8% of nurses expressed willingness. Among 1,168 HCWs who would decline vaccination, 1,073 (91.9%) expressed concerns about vaccine safety and side effects. The willingness of HCWs to be vaccinated was associated with older age (adjusted odds ratio [aOR] 1.97, 95%Cl 1.71-2.27) and having been vaccinated for influenza this year (aOR 2.70, 95%Cl 2.20-3.31). HCWs who reported a lack of confidence in government were less likely to be willing to be vaccinated (aOR 0.58, 95%Cl 0.40-0.84), and women were less willing to be vaccinated than men (OR 0.33 (0.28-0.38).

Conclusion

Less than half of HCWs reported willingness to be vaccinated before the campaign start, but proportions varied greatly depending on the profession and workplace. Strategies with clear and objective messages that particularly address the concerns of HCWs are needed if their willingness to be vaccinated is to be increased.
Analysis of the association between rs111200466 variants and cervical Cancer susceptibility in Sudanese women
Authors: Andarawi Safaa Othman , Bakheit Sahar
Published: July 2021

Worldwide there are more than 273,000 deaths from cervical cancer each year and it accounts for 9% of female cancer deaths. The high-risk variants of human papillomavirus such as HPV 16 and 18 are major etiological agents of cervical cancer. The persistency of infection with HPV may due to inappropriate immune response due to SNPs interfering with the function of particular part of the immune system. Toll-like receptors (TLRs) play an important role in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. The –196 to –174del polymorphism affects the TLR2 gene and alters its promoter activity.

Aim

In this study we investigated the presence and the influence of TLR2 –196 to – 174del polymorphism on the risk of cervical cancer development in Sudanese. The study was performed on 42 patients with cervical cancer and 27 healthy controls. Genotyping of –196 to –174del polymorphism of TLR2 was investigated using allele-specific polymerase chain reaction method in all subjects. We documented the presence of–196 to –174del polymorphism of TLR2 in Sudanese women with allele frequency 37% of control and 34% of patient sample although there was no observed association between this SNP and the risk of cervical cancer (p value. 394).Further studies are needed in a large and ethnically diverse population to determine the impact of the TLR2 polymorphism in the susceptibility of cervical cancer.
Excess years of life lost to COVID-19 and other causes of death by sex, neighbourhood deprivation and region in England & Wales during 2020
Authors: Kontopantelis Evangelos , Mamas Mamas A. , Webb Roger T. , Castro-Avila Ana , Rutter Martin K. , Gale Chris P. , Ashcroft Darren M. , Pierce Matthias , Abel Kathryn M. , Price Gareth , Faivre-Finn Corinne , Van Spall Harriette G.C. , Graham Michelle M. , Morciano Marcello , Martin Glen P. , Sutton Matt , Doran Tim
Published: July 2021

Background

Deaths in the first year of the COVID-19 pandemic in England & Wales have been shown to be unevenly distributed socioeconomically and geographically. However, the full scale of inequalities may have been underestimated as most measures of excess mortality do not adequately account for varying age profiles of deaths between social groups. We measured years of life lost (YLL) attributable to the pandemic, directly or indirectly, comparing mortality across geographic and socioeconomic groups.

Methods

YLL for registered deaths in England & Wales, from 27th December 2014 until 25th December 2020, were calculated using 2019 single year sex-specific life tables for England & Wales. Panel time-series models were used to estimate expected YLL by sex, geographical region, and deprivation quintile between 7th March 2020 and 25th December 2020 by cause: direct deaths (COVID-19 and other respiratory diseases), cardiovascular disease & diabetes, cancer, and other indirect deaths - all other causes). Excess YLL during the pandemic period were calculated by subtracting observed from expected values. Additional analyses focused on excess deaths for region and deprivation strata, by age-group.

Findings

Between 7th March 2020 and 25th December 2020 there were an estimated 763,550 (95% CI: 696,826 to 830,273) excess YLL in England & Wales, equivalent to a 15% (95% CI: 14 to 16) increase in YLL compared to the equivalent time period in 2019. There was a strong deprivation gradient in all-cause excess YLL, with rates per 100,000 population ranging from (916; 95% CI: 820 to 1,012) for the least deprived quintile to (1,645; 95% CI: 1,472 to 1,819) for the most deprived. The differences in excess YLL between deprivation quintiles were greatest in younger age groups; for all-cause deaths, an average of 9.1 years per death (95% CI: 8.2 to 10.0) were lost in the least deprived quintile, compared to 10.8 (95% CI: 10.0 to 11.6) in the most deprived; for COVID-19 and other respiratory deaths, an average of 8.9 years per death (95% CI: 8.7 to 9.1) were lost in the least deprived quintile, compared to 11.2 (95% CI: 11.0 to 11.5) in the most deprived. There was marked variability in both all-cause and direct excess YLL by region, with the highest rates in both in the North West.

Interpretation

During 2020, the first calendar year of the COVID-19 pandemic, longstanding socioeconomic and geographical health inequalities in England & Wales were exacerbated, with the most deprived areas suffering the greatest losses in potential years of life lost.

Funding

None
What We Learned from COVID-19: From endotheliitis to treatment
Authors: Dirican Adem , Ildir Selin , Uzar Tugce , Karaman Irem , Ozkaya Sevket
Published: July 2021

Objective

COVID-19 may yield a variety of clinical pictures, differing from pneumonitis to Acute Respiratory Distress Syndrome (ARDS) along with vascular damage in the lung tissue, named asendotheliitis. To date, no specific treatment strategy was approved by any authority for the prevention or treatment of COVID-19 in terms of endotheliitis-related comorbidities. Here, we present our experience of COVID-19 by evaluating 11,190 COVID-19 patients with the manifestations of endotheliitis in skin, lung, and brain tissues according to the different phases of COVID-19.

Methods

After a retrospective examination, patients were divided into three groups according to their repercussions of vascular distress, which were represented by radiological, histopathological, and clinical findings. (Group A: no or mild pulmonary involvement, Group B: moderate pulmonary involvement with clinical risk of deterioration, Group C: severe pulmonary involvement and respiratory failure). We presented the characteristics and disease course of seven representative and complicated cases which represents the different phases of the disease, and discussed the treatment strategies in each group. The current pathophysiological mechanisms responsible from SARS-CoV-2 infection, COVID-19 related respiratory failure and current treatment strategies were reviewed and discussed in detail.

Results

Among 11.190 patients, 9294 patients met the criteria for Group A, and 1376 patients were presented to our clinics with Group B characteristics. Among these patients, 1896 individuals(Group B and Group C) were hospitalized. While 1220 inpatients were hospitalized within the first 10 days after the diagnosis, 676 of them were worsened and hospitalized 10 days after their diagnosis. Among hospitalized patients, 520 of them did not respond to group A and B treatments and developed hypoxemic respiratory failure (Group C) and 146 individuals needed ventilator support and were followed in the intensive care unit, and 43 (2.2%) patients died.

Conclusion

Distinctive manifestations in each COVID-19 patient, including non-respiratory conditions in the acute phase and the emerging risk of long-lasting complications, suggest that COVID-19 has anendotheliitis-centred thrombo-inflammatory pathophysiology. Endotheliitis can also explain the mechanism behind the respiratory failure in COVID-19, and the difference of COVID-19 related ARDS from ARDS seen in other critical conditions. In addition, use of early corticosteroid in patients with early symptoms and early tocilizumab in ICU helps to reduce mortality and progression of the disease. Endotheliitis-based pathophysiological mechanisms are known to be momentarily changing and difficut to manage due to their risk of sudden aggrevation. Hence, daily evaluation of clinical, laboratory and radiological findings of patients and deciding appropriate pathophysiological treatment would help to reduce the mortality rate of COVID-19.
High mortality of COVID-19 associated mucormycosis in France: a nationwide retrospective study
Authors: Danion François , Letscher-Bru Valérie , Guitard Juliette , Sitbon Karine , Dellière Sarah , Angoulvant Adela , Desoubeaux Guillaume , Botterel Francoise , Bellanger Anne-Pauline , Gargala Gilles , Uhel Fabrice , Bougnoux Marie-Elisabeth , Gerber Victor , Michel Justin , Cornu Marjorie , Bretagne Stéphane , Lanternier Fanny ,   the COVID-Mucor study group
Published: July 2021

We studied COVID-19 associated mucormycosis based on 17 cases reported nationwide and assessed the differences with India. They differed by frequencies of diabetes mellitus (47% in France versus 95% in India), hematological malignancies (35% versus 1%), anatomical sites (53% lung versus >80% rhino-orbito-cerebral) and prognosis (>80% mortality versus <50%).
Application of nasal spray containing dimethyl sulfoxide (DMSO) and ethanol during the COVID-19 pandemic may protect healthcare workers: A randomized controlled trials
Authors: Hosseinzadeh Ali , Tavakolian Abbas , Kia Vahid , Ebrahimi Hossein , Sheibani Hossein , Binesh Ehsan , Jafari Reza , Mirrezaie Seyed Mohammad , Jafarisani Moslem , Emamian Mohammad Hassan
Published: July 2021

Background

Coronavirus pandemic has affected a large population worldwide. Currently, the standard care for individuals who are exposed is supportive care, symptomatic management, and isolation. The aim of our study was to evaluate effects of combined use of ethanol and DMSO as a nasal spray in preventing COVID-19.

Methods

We conducted a randomized controlled trial on volunteer healthcare workers of medical centers that were at the forefront of the fight against COVID-19 in Shahroud, Iran. Two hundred and thirty-two participants were randomly assigned to intervention and control groups to receive DMSO/ethanol or routine care, respectively. The subjects were followed for 4 weeks to determine the incidence of COVID-19 infection in each group based on the RT-qPCR test. Finally, absolute risk difference and relative risk were calculated to evaluate the effect of DMSO in prevent COVID-19.

Results

The results showed that the incidence of COVID-19 in the control group and intervention group were 0.07 and 0.008, respectively. The relative risk (RR) was 0.12 (0.9-0.02) according to the incidence rate in the two groups.

Conclusion

combined application of DMSO and ethanol in healthcare providers can considerably prevent COVID-19.
Mutation induced infection waves in diseases like COVID-19
Authors: Schwarzendahl Fabian Jan , Grauer Jens , Liebchen Benno , Löwen Hartmut
Published: July 2021

After almost 4 million deaths worldwide, the ongoing vaccination to conquer the COVID-19 disease is now competing with the emergence of increasingly contagious mutations, repeatedly supplanting earlier strains. Following the near-absence of historical examples of the long-time evolution of infectious diseases under similar circumstances, models are crucial to exemplify possible scenarios. Accordingly, in the present work we systematically generalize the popular susceptible-infectedrecovered model to account for mutations leading to repeatedly occurring new strains, which we coarse grain based on tools from statistical mechanics to derive a model predicting the most likely outcomes. The model predicts that mutations can induce a super-exponential growth of infection numbers at early times, which can self-amplify to giant infection waves which are caused by a positive feedback loop between infection numbers and mutations and lead to a simultaneous infection of the majority of the population. At later stages – if vaccination progresses too slowly – mutations can interrupt an ongoing decrease of infection numbers and can cause infection revivals which can occur as single waves or even as whole wave trains featuring alternative periods of decreasing and increasing infection numbers. Our results might be useful for discussions regarding the importance of a release of vaccine-patents to reduce the risk of mutation-induced infection revivals but also to coordinate the release of measures following a downwards trend of infection numbers.
Genetic markers and tree properties predicting wood biorefining potential in aspen (Populus tremula) bioenergy feedstock
Authors: Escamez Sacha , Robinson Kathryn M. , Luomaranta Mikko , Gandla Madhavi Latha , Mähler Niklas , Yassin Zakiya , Grahn Thomas , Scheepers Gerhard , Stener Lars-Göran , Jansson Stefan , Jönsson Leif J. , Street Nathaniel R. , Tuominen Hannele
Published: July 2021

Background

Wood represents the majority of the biomass on land and constitutes a renewable source of biofuels and other bioproducts. However, wood is recalcitrant to bioconversion, raising a need for feedstock improvement in production of, for instance, biofuels. We investigated the properties of wood that affect bioconversion, as well as the underlying genetics, to help identify superior tree feedstocks for biorefining.

Results

We recorded 65 wood-related and growth traits in a population of 113 natural aspen genotypes from Sweden. These traits included three growth and field performance traits, 20 traits for wood chemical composition, 17 traits for wood anatomy and structure, and 25 wood saccharification traits as indicators of bioconversion potential. Glucose release after saccharification with acidic pretreatment correlated positively with tree stem height and diameter and the carbohydrate content of the wood, and negatively with the content of lignin and the hemicellulose sugar units. Most of these traits displayed extensive natural variation within the aspen population and high broad-sense heritability, supporting their potential in genetic improvement of feedstocks towards improved bioconversion. Finally, a genome wide association study (GWAS) revealed 13 genetic loci for saccharification yield (on a whole tree biomass basis), with six of them intersecting with associations for either height or stem diameter of the trees.

Conclusions

The simple growth traits of stem height and diameter were identified as good predictors of wood saccharification yield in aspen trees. GWAS elucidated the underlying genetics, revealing putative genetic markers for bioconversion of bioenergy tree feedstocks.
MSNovelist: De novo structure generation from mass spectra
Authors: Stravs Michael A. , Dührkop Kai , Böcker Sebastian , Zamboni Nicola
Published: July 2021

Structural elucidation of small molecules de novo from mass spectra is a longstanding, yet unsolved problem. Current methods rely on finding some similarity with spectra of known compounds deposited in spectral libraries, but do not solve the problem of predicting structures for novel or poorly represented compound classes. We present MSNovelist that combines fingerprint prediction with an encoder-decoder neural network to generate structures de novo from fragment spectra. In evaluation, MSNovelist correctly reproduced 61% of database annotations for a GNPS reference dataset. In a bryophyte MS2 dataset, our de novo structure prediction substantially outscored the best database candidate for seven features, and a potential novel natural product with a flavonoid core was identified. MSNovelist allows predicting structures solely from MS2 data, and is therefore ideally suited to complement library-based annotation in the case of poorly represented analyte classes and novel compounds.
Isoform resolved measurements of absolute translational efficiency define interplay of HIF and mTOR dysregulation in kidney cancer
Authors: Sugimoto Yoichiro , Ratcliffe Peter J.
Published: July 2021

Hypoxia inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathways orchestrate responses to oxygen and nutrient availability. These pathways are frequently dysregulated in cancer, but their interplay is poorly understood, in part because of difficulties in simultaneous measurement of global and mRNA-specific translation. Here we describe a workflow for measurement of absolute translational efficiency of mRNAs resolved by their transcription start sites (TSSs). Its application to kidney cancer cells revealed a remarkable extent of translational reprogramming by mTOR, strongly affecting many metabolic enzymes and pathways. By contrast, global effects of HIF on translation were limited, and we did not observe reported translational activation by HIF2A. In contrast, HIF-dependent alterations in TSS usage were associated with robust changes in translational efficiency in a subset of genes. Analyses of the interplay of HIF and mTOR revealed that specific classes of HIF1A and HIF2A transcriptional target gene manifest markedly different sensitivity to mTOR, in a manner that supports combined use of HIF2A and mTOR inhibitors in treatment of kidney cancer.
Outer membrane vesicles derived from Klebsiella pneumoniae are a driving force for horizontal gene transfer
Authors: Dell’Annunziata Federica , Dell’Aversana Carmela , Doti Nunzianna , Donadio Giuliana , Dal Piaz Fabrizio , Izzo Viviana , De Filippis Anna , Galdiero Marilena , Altucci Lucia , Boccia Giovanni , Galdiero Massimiliano , Folliero Veronica , Franci Gianluigi
Published: July 2021

Gram-negative bacteria release outer membrane vesicles (OMVs) into the extracellular environment. Recent studies recognized these vesicles as vectors to horizontal gene transfer, however the parameters that mediate OMVs transfer within bacterial communities remain unclear. The present study highlights for the first time the transfer of plasmids containing resistance genes via OMVs derived from Klebsiella pneumoniae (K. pneumoniae). This mechanism confers DNA protection and it is plasmid copy number dependent with a ratio of 3.6 time among high copy-number plasmid (pGR) versus low copy number plasmid (PRM) and the transformation efficiency was 3.6 times greater. Therefore, the DNA amount in the vesicular lumen and the efficacy of horizontal gene transfer was strictly dependent on the identity of the plasmid. Moreover, the role of K. pneumoniae-OMVs in interspecies transfer was described. The transfer ability was not related to the phylogenetic characteristics between the donor and the recipient species. K. pneumoniae-OMVs transferred plasmid to Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa and Burkholderia cepacia. These findings address the pivotal role of K. pneumoniae-OMVs as vectors for antimicrobial resistance genes spread, contributing to the development of antibiotic resistance in the microbial communities.

Author summary

K. pneumoniae is an important opportunistic pathogen that affects several host districts, in particular respiratory and urinary tracts. Hospital-acquired K. pneumoniae infections lead to a 50% mortality rate correlated with rapid acquisition of antibiotic resistance. Currently, the increasing rate of antibiotic resistance among K. pneumoniae isolates is a major concern worldwide. The spread of multidrug-resistant K. pneumoniae strains renders current therapeutic options ineffective. Like all Gram-negative bacteria, K. pneumoniae secretes OMVs. OMVs are spherical structures, with a diameter between 50-250 nm, originating from the outer membrane. OMVs biogenesis allows bacteria to interact with the external environment, increasing bacterial survival under stressful conditions and regulating microbial interactions within bacterial communities. Few evidence recognized OMVs as vectors for horizontal gene transfer, contributing to the spread of resistance. In this scenario, the present study examines the potential role of K. pneumoniae-OMVs in inter- and intra-species diffusion of ß-lactam resistance.
Inhibition of Ras1-MAPK pathways for hypha formation by novel drug candidates in Candida albicans
Authors: Park Young Kwang , Shin Jisoo , Lee Hee-Yoon , Kim Hag Dong , Kim Joon
Published: July 2021

The opportunistic human fungal pathogen Candida albicans has morphogenesis as a virulence factor. The morphogenesis of C. albicans is closely related to pathogenicity (1). Ras1 in C. albicans is an important switch in the MAPK pathway for morphogenesis (2, 3). The MAPK pathway is important for the virulence, such as cell growth, morphogenesis, and biofilm formation (4, 5). Ume6 is a well-known transcriptional factor for hyphal-specific genes (6). Despite numerous studies, as a recent issue, it is necessary to develop a new drug that uses a different pathway mechanism to inhibit resistant C. albicans strains caused by chronic prescription of azole or echinocandin drugs, which are mainly used. Here, we show that the small carbazole derivatives attenuated the pathogenicity of C. albicans through inhibition of the Ras1/MAPK pathway. We found that the small molecules inhibit morphogenesis through repressing protein and RNA levels in Ras/MAPK related genes including UME6 and NRG1. Furthermore, we found the antifungal effect of the small molecules in vivo using a candidiasis murine model. We anticipate our findings are that the small molecules are the promising compounds for the development of new antifungal agents for the treatment of systemic candidiasis and possibly for other fungal diseases.

Author summary

The infection by the opportunistic human fungal pathogen Candida albicans occurs mainly in immunocompetent and immunocompromised humans, such as AIDS patients, immunosuppressant-treated organ transplant patients, and recent COVID-19 patients. Morphogenesis which the ability to switch between yeast and hyphal growth forms is one of the representative virulence factors of C. albicans. Here, we describe novel small molecules that show antifungal effects such as the inhibition of the morphogenesis and the biofilm formation, and maintenance of biofilm. Moreover, we found that these small molecules had antifungal activity in mouse experiments, and confirmed that they were also effective in drug-resistant C. albicans strains. Studies of some small molecules with structures similar to ours have already been reported to exhibit growth inhibitory activity against bacteria and Candida species. However, the mechanism of action of these molecules has not been elucidated. In this study, we demonstrated, for the first time, the mechanism by which these two small molecules inhibit C. albicans pathogenicity through inhibition of specific pathways. Our study, through the research of the mechanism of action of novel small molecules, provides new insights into the development of drug candidates not only for wild-type C. albicans, but also for strains resistant to existing drugs.
Individual history of winning and hierarchy landscape influence stress susceptibility in mice
Authors: LeClair Katherine B , Chan Kenny L , Kaster Manuella P , Parise Lyonna F , Burnett C. Joseph , Russo Scott J
Published: July 2021

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, though gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.
Parafoveal words can modulate sentence meaning: Electrophysiological evidence from an RSVP-with-flanker task
Authors: Li Nan , Dimigen Olaf , Sommer Werner , Wang Suiping
Published: July 2021

During natural reading, readers also take up some visual information from not-yet-fixated words to the right of the current fixation and it is well-established that this parafoveal preview facilitates the subsequent foveal processing of the word. However, the extraction and integration of word meaning from the parafoveal word and its possible influence on the semantic sentence context are controversial. In the current study, we recorded event-related potentials (ERPs) in the RSVP-with-flankers paradigm to test whether and how updates of sentential meaning that are based only on parafoveal information influence the subsequent foveal processing. Using Chinese sentences, the sentence congruency of parafoveal and foveal target words were orthogonally manipulated. In contrast to previous research, we also controlled for potentially confounding effects of parafoveal-to-foveal repetition priming (identity preview effects) on the N400. Crucially, we found that the classic effect of foveal congruency on the N400 component only appeared when the word in preview had been congruent with sentence meaning; in contrast, there was no N400 when the preview word had been incongruent. These results indicate that sentence meaning rapidly adapts to parafoveal preview, which already changes the context for the then fixated word. We also show that a correct parafoveal preview generally attenuates the N400 once a word is fixated, regardless of congruency. Taken together, our findings underline the highly generative and adaptive framework of language comprehension.
A native mass spectrometry-based assay for rapid assessment of the empty/full capsid ratio in AAV gene therapy products
Authors: Strasser Lisa , Morgan Tomos E. , Guapo Felipe , Füssl Florian , Forsey Daniel , Anderson Ian , Bones Jonathan
Published: July 2021

Adeno-associated virus (AAV)-based cell and gene therapy is a rapidly developing field, requiring analytical methods for detailed product characterization. One important quality attribute of AAV products that requires monitoring is the amounts of residual empty capsids following downstream processing. Traditionally, empty and full particles are quantified via analytical ultracentrifugation as well as anion exchange chromatography using ultraviolet or fluorescence detection. Here, we present a native mass spectrometry-based approach to assess the ratio of empty to full AAV-capsids without the need for excessive sample preparation. We report rapid determination of the amount of empty particles in AAV5 and AAV8 samples, with results correlating well with more conventional analysis strategies, demonstrating the potential of state-of-the-art mass spectrometry for the characterization of viral particles.
DynaTMT: A user-friendly tool to process combined SILAC/TMT data
Authors: Klann Kevin , Krause David , Münch Christian
Published: July 2021

The measurement of protein dynamics by proteomics to study cell remodeling has seen increased attention over the last years. This development is largely driven by a number of technological advances in proteomics methods. Pulsed stable isotope labeling in cell culture (SILAC) combined with tandem mass tag (TMT) labeling has evolved as a gold standard for profiling protein synthesis and degradation. While the experimental setup is similar to typical proteomics experiments, the data analysis proves more difficult: After peptide identification through search engines, data extraction requires either custom scripted pipelines or tedious manual table manipulations to extract the TMT-labeled heavy and light peaks of interest. To overcome this limitation, which deters researchers from using protein dynamic proteomics, we developed a user-friendly, browser-based application that allows easy and reproducible data analysis without the need for scripting experience. In addition, we provide a python package that can be implemented in established data analysis pipelines. We anticipate that this tool will ease data analysis and spark further research aimed at monitoring protein translation and degradation by proteomics.
Investigating the Impact of Offer Frame Manipulations On Responders Playing The Ultimatum Game
Authors: Fabre Eve Florianne , Rumiati Rino , Cacciari Cristina , Borau Sylvie , Causse Mickael , Lotto Lorella
Published: July 2021

The present study was designed to test the impact of frame manipulations on the decision-making of responders playing the ultimatum game. Experiment 1 investigated responders’ event-related potentials (ERPs) measured in response to the offers as a function of the frame (i.e., negative: “the proposerkeeps”versuspositive “the proposer offers”). While no difference in acceptation rate was found as a function of the offer’s frame, electrophysiological results suggest that the stronger negative affective response to the offers in the negative frame (N400) was successfully reappraised by the responders (P600), possibly explaining why the offer frame manipulation did not modulate acceptation rates. No framing effect was found when the ultimatum game was played in its one-shot version (Experiment 2), suggesting that repeated measurements did not affect responders’ behavior. However, an offer framing effect was found in female (but not in male) responders, when the players’ cognitive charge was increased using more complex game rules (Experiment 3), presumably reflecting women’s greater affective responses to negative outcomes. Taken together, these results suggest that framing manipulations are associated with complex affective and cognitive processes, supporting the cognitive–affective tradeoff model.
Gut-derived metabolites influence neurodevelopmental gene expression and Wnt signalling events in a germ-free zebrafish model
Authors: Rea Victoria , Bell Ian , Van Raay Terence
Published: July 2021

Small molecule metabolites produced by the microbiome are known to be neuroactive and are capable of directly impacting the brain and central nervous system, yet there is little data on the contribution of these metabolites to the earliest stages of neural development and neural gene expression. Here, we explore the impact of rearing zebrafish embryos in the absence of microbes on early neural development as well as investigate whether any potential changes can be rescued with treatment of metabolites derived from the zebrafish gut microbiota. Overall, we did not observe any gross morphological changes between treatments but did observe a significant decrease in neural gene expression in embryos raised germ-free, which was rescued with the addition of zebrafish metabolites. Specifically, we identified 361 genes significantly down regulated in GF embryos compared to conventionally raised embryos via RNA-Seq analysis. Of these, 42 were rescued with the treatment of zebrafish gut-derived metabolites to GF embryos. Gene ontology analysis revealed that these genes are involved in prominent neurodevelopmental pathways including transcriptional regulation and Wnt signalling. Consistent with the ontology analysis, we found alterations in the development of Wnt dependent events which is rescued in the GF embryos treated with metabolites.