bluuebunny/crossref_metadata_2025 huggingface dataset:
Chia: Host Status for Meloidogyne incognita and Activity of Plant Extracts
Authors: Meyer Susan L. F. , MacDonald Margaret H. , Reetz Nathan D. , Kantor Mihail R. , Carta Lynn K. , Handoo Zafar A. , Camp Mary J. , Phillips Tim D.
Published: April 2020

Chia (Salvia hispanica L.) seeds are used for food, drinks, oil, and animal feed, and all plant parts are employed in traditional medicine. The growing demand for the seed has created a need for improved disease management. Plant-parasitic nematodes have been found on other Salvia spp., but none have been reported from S. hispanica. Chia has also not been tested for production of compounds active against these nematodes. Therefore, aqueous extracts from shoots and roots of six chia lines, Brad’s Organic, Cono, E2, G3, G5, and W13.1, were tested in laboratory assays. Some concentrations of all extracts were nematotoxic, killing about one-third of Meloidogyne incognita (Kofoid & White) Chitwood second-stage juveniles (J2s) in shoot extracts and up to nearly half of J2s in root extracts. Hatch was generally not affected by the extracts. In greenhouse trials, all six chia lines were hosts of M. incognita. Chia line G3 had approximately two times or more eggs per gram of root than Brad’s Organic or Cono. When cucumber seedlings were transplanted into soil amended with chopped chia shoots (2.3 or 2.5% weight of fresh shoots/weight of dry soil), galling and egg production on cucumber roots were not suppressed. To our knowledge, this is the first report that chia is a host to M. incognita (or any phytoparasitic nematode) and that chia shoots and roots produce compounds active against a nematode.
Detrimental Effects of Multiple Mutations in Position 240 of Fusarium graminearum β2-Tubulin
Authors: Zhu Yuanye , Zhang Yuanshuai , He Zongzhe , Duan Yabing , Li Yanjun , Wang Jianxin , Zhou Mingguo
Published: April 2020

Fusarium graminearum causes Fusarium head blight (FHB), a destructive disease of cereal crops worldwide. Carbendazim (methylbenzimidazol-2-ylcarbamate [MBC]) is widely used for controlling FHB. A previous study showed that the F240L mutation in the β2-tubulin of F. graminearum (Fgβ2-tubulin) confers hypersensitivity to MBC. Whether the substitution of phenylalanine by other amino acids in position 240 of the Fgβ2-tubulin gene also confers hypersensitivity to MBC is unknown. Moreover, the biological fitness of these mutants is poorly understood. In this study, we substituted position 240 of Fgβ2-tubulin with other amino acids. We found that the F240A, F240E, F240I, and F240Y mutations in Fgβ2-tubulin could also confer F. graminearum hypersensitivity to MBC, although the effective concentration resulting in 50% inhibition (EC50) differed among the mutations. The F240G mutation, in contrast, decreased the sensitivity to MBC. In addition, a molecular docking assay indicated that the binding affinity between Fgβ2-tubulin and MBC were increased by the F240A, F240E, F240I, and F240Y mutations but decreased by the F240G mutation. All mutants had normal conidial morphology, but the growth rates and pathogenicity of the F240A, F240E, F240G, F240I, and F240Y mutants were significantly decreased. Moreover, the F240A and F240G mutants produced twisted hyphae. In addition, microtubules were sparse and rarely observed in β2F240A-EGFP, β2F240E-EGFP, and β2F240G-EGFP. These results indicate that position 240 (phenylalanine) is not only vital to the function of Fgβ2-tubulin but also plays an important role in regulating the sensitivity of F. graminearum to MBC. Any mutation in this site would be detrimental to survival.
Risk Factors for Prolonged Opioid Use and Effects of Opioid Tolerance on Clinical Outcomes After Anterior Cervical Discectomy and Fusion Surgery
Authors: Reyes Ariana A. , Canseco Jose A. , Mangan John J. , Divi Srikanth N. , Goyal Dhruv K.C. , Bowles Daniel R. , Patel Parthik D. , Salmons Harold I. , Morgenstern Monica , Anderson David Greg , Rihn Jeffrey A. , Kurd Mark F. , Hilibrand Alan S. , Kepler Christopher K. , Vaccaro Alexander R. , Schroeder Gregory D.
Published: April 2020

Study Design.

Retrospective study.

Objective.

The aim of this study was to determine risk factors for prolonged opioid use and to investigate whether opioid-tolerance affects patient-reported outcomes following anterior cervical discectomy and fusion (ACDF) surgery.

Summary of Background Data.

There is a lack of consensus on risk factors that can affect continued opioid use after cervical spine surgery and the influence of opioid use on patient-reported outcomes.

Methods.

Ninety-two patients who underwent ACDF for degenerative cervical pathologies were retrospectively identified and their opioid usage before surgery was investigated using a state-sponsored prescription drug monitoring registry. Opioid-naïve and opioid tolerant groups were defined using criteria most consistent with the Federal Drug Administration (FDA) definition. Patient-reported outcomes were then collected, including the Short Form-12 (SF-12) Physical Component (PCS-12) and Mental Component (MCS-12), the Neck Disability Index (NDI), the Visual Analogue Scale Neck (VAS neck) and the Visual Analogue Scale Arm (VAS Arm) pain scores. Logistic regression was used to determine predictors for prolonged opioid use following ACDF. Univariate and multivariate analyses were conducted to compare change in outcomes over time between the two groups.

Results.

Logistic regression analysis demonstrated that opioid tolerance was a significant predictor for prolonged opioid use after ACDF (odds ratio [OR]: 18.2 [1.46, 226.4], P = 0.02). Duration of usage was also found to be a significant predictor for continued opioid use after surgery (OR: 1.10 [1.0, 1.03], P = 0.03). No other risk factors were found to be significant predictors. Both groups overall experienced improvements in patient-reported outcomes after surgery. Multiple linear regression analysis, controlling for patient demographics, demonstrated that opioid-tolerant user status positively affected change in outcomes over time for NDI (β = −13.7 [−21.8,−5.55], P = 0.002) and PCS-12 (β = 6.99 [2.59, 11.4], P = 0.003) but no other outcomes measured.

Conclusion.

Opioid tolerance was found to be a significant predictor for prolonged opioid use after ACDF. Additionally, opioid-naïve and opioid-tolerant users experienced overall improvements across PROMs following ACDF. Opioid-tolerance was associated with NDI and PCS-12 improvements over time compared to opioid-naïve users.

Level of Evidence: 4
Reliability and Validity of the English Version of the AOSpine PROST (Patient Reported Outcome Spine Trauma)
Authors: Sadiqi Said , Dvorak Marcel F. , Vaccaro Alexander R. , Schroeder Gregory D. , Post Marcel W. , Benneker Lorin M. , Kandziora Frank , Rajasekaran S. , Schnake Klaus J. , Vialle Emiliano N. , Oner F. Cumhur
Published: April 2020

Study Design.

Multicenter validation study.

Objective.

The aim of this study was to translate and adapt the AOSpine PROST (Patient Reported Outcome Spine Trauma) into English, and test its psychometric properties among North-American spine trauma patients.

Summary of Background Data.

In the absence of an outcome instrument specifically designed and validated for traumatic spinal column injury patients, it is difficult to measure the effect size of various treatment options. The AOSpine Knowledge Forum Trauma initiated a project and developed the AOSpine PROST consisting of 19 items.

Methods.

Patients were recruited from two level-1 North-American trauma centers. For concurrent validity, next to AOSpine PROST also 36-item Short-Form Health Survey (SF-36) was filled out by patients. Patient characteristics were analyzed using descriptive statistics. Floor and ceiling effects as well as the number of inapplicable and missing questions were analyzed for content validity. Cronbach α and item-total correlation coefficients (ITCCs) were calculated for internal consistency. Spearman correlation tests were performed within AOSpine PROST items and in correlation to SF-36. Test-retest reliability was assessed using intraclass correlation coefficients (ICCs). Factor analysis was performed to explore any dimensions within AOSpine PROST.

Results.

The AOSpine PROST was translated adapted into English using established guidelines. Of 196 enrolled patients, 162 (82.7%) met the inclusion criteria and provided sufficient data. Content validity showed good results, and no floor and ceiling effects were seen. The internal consistency was excellent (Cronbach α = 0.97; ITCC 0.50–0.90) as well as test–retest reliability (ICC = 0.97). Spearman correlations were good (0.29–0.85). The strongest correlations of AOSpine PROST with SF-36 were seen with the physical components (0.69–0.82; P < 0.001). Factor analysis revealed two possible dimensions (Eigen values >1), explaining 75.7% of variance.

Conclusion.

The English version of AOSpine PROST showed very good validity and reliability. It is considered as a valuable tool, and has the potential to contribute to the reduction of ongoing controversies in spine trauma care.

Level of Evidence: 2
The Long-term Reoperation Rate Following Surgery for Lumbar Stenosis
Authors: Jung Jong-myung , Chung Chun Kee , Kim Chi Heon , Choi Yunhee , Kim Min-Jung , Yim Dahae , Yang Seung Heon , Lee Chang Hyun , Hwang Sung Hwan , Kim Dong Hwan , Yoon Joon Ho , Park Sung Bae
Published: April 2020

Study Design.

Retrospective cohort study of a nationwide sample database.

Objective.

The objective of the present study was to compare the long-term incidence of reoperation for lumbar spinal stenosis (LSS) after anterior fusion, posterior fusion, and decompression.

Summary of Background Data.

Surgical treatment for LSS can be largely divided into 2 categories: decompression only and decompression with fusion. A previous nationwide study reported that fusion surgery was performed in 10% of patients with LSS, and the 10-year reoperation rate was approximately 17%. However, with the development of surgical techniques and changes in surgical trends, these results should be reassessed.

Methods.

The National Health Insurance Service-National Sample Cohort of the Republic of Korea was utilized to establish a cohort of adult patients (N = 1400) who first underwent surgery for LSS during 2005 to 2007. Patients were followed for 8 to 10 years. Considering death before reoperation as a competing event, reoperation hazards were compared among surgical techniques using a Fine and Gray regression model after adjustment for sex, age, diabetes, osteoporosis, Charlson comorbidity index, severity of disability, type of medical coverage, and type of hospital.

Results.

The overall cumulative incidence of reoperation was 6.2% at 2 years, 10.8% at 5 years, and 18.4% at 10 years. The cumulative incidence of reoperation was 20.6%, 12.6%, and 18.6% after anterior fusion, posterior fusion, and decompression, respectively, at 10 years postoperatively (P = 0.44). The first surgical technique did not affect the reoperation type (P = 0.27). Decompression was selected as the surgical technique for reoperation in 83.5% of patients after decompression, in 72.7% of patients after anterior fusion, and in 64.3% of patients after posterior fusion.

Conclusion.

The initial surgical technique did not affect reoperation during the 10-year follow-up period. Decompression was the most commonly used technique for reoperation.

Level of Evidence: 4
Advance Directives in the Neurocritically Ill: A Systematic Review
Authors: Sutter Raoul , Meyer-Zehnder Barbara , Baumann Sira M. , Marsch Stephan , Pargger Hans
Published: April 2020

Objectives:

To determine the frequency of advance directives or directives disclosed by healthcare agents and their influence on decisions to withdraw/withhold life-sustaining care in neurocritically ill adults.

Data Sources:

PubMed, Embase, and Cochrane databases.

Study Selection:

Screening was performed using predefined search terms to identify studies describing directives of neurocritically ill patients from 2000 to 2019. The review was registered prior to the screening process (International Prospective Register of Systematic Reviews identification number 149185).

Data Extraction:

Data were collected using standardized forms. Primary outcomes were the frequency of directives and associated withholding/withdrawal of life-sustaining care.

Data Synthesis:

Out of 721 articles, 25 studies were included representing 35,717 patients. The number of studies and cohort sizes increased over time. A median of 39% (interquartile range, 14–72%) of patients had directives and/or healthcare agents. The presence of directives was described in patients with stroke, status epilepticus, neurodegenerative disorders, neurotrauma, and neoplasms, with stroke patients representing the largest subgroup. Directives were more frequent among patients with neurodegenerative disorders compared with patients with other illnesses (p= 0.043). In reference to directives, care was adapted in 71% of European, 50% of Asian, and 42% of American studies, and was withheld or withdrawn more frequently over time with a median of 58% (interquartile range, 39–89%). Physicians withheld resuscitation in reference to directives in a median of 24% (interquartile range, 22–70%).

Conclusions:

Studies regarding the use and translation of directives in neurocritically ill patients are increasing. In reference to directives, care was adapted in up to 71%, withheld or withdrawn in 58%, and resuscitation was withheld in every fourth patient, but the quality of evidence regarding their effects on critical care remains weak and the risk of bias high. The limited number of patients having directives is worrisome and studies aiming to increase the use and translation of directives are scarce. Efforts need to be made to increase the perception, use, and translation of directives of the neurocritically ill.
Global Contributions and Trends in Research within the Top-ranked Plastic Surgery Journal
Authors: Esmaeeli Shooka , Xu Thomas Q. , Wiegmann Aaron Lee , Jaraczewski Taylor , Seu Michelle , Akin Jennifer , Dorafshar Amir H.
Published: April 2020

Background:

We aimed to longitudinally study the relative research contributions of US and international plastic surgeons by evaluating publications within the premier plastic surgery journal over the last 2 decades. We hypothesized that even with an increased pressure to publish in this journal, the relative research contributions from American plastic surgeons will continue to be the largest overall and in all subspecialties.

Methods:

Data for the surgical subspecialty, corresponding author’s country of origin, and region were extracted from all original articles in 2 randomly selected monthly issues of Plastic & Reconstructive Surgery (PRS) from the last 2 decades to evaluate longitudinal trends. Data were also extracted from all of the original articles published in PRS for the last 3 years to analyze the recent distribution of research output.

Results:

During the last 2 decades, the relative proportion of total original articles written by US authors has increased. They have published proportionally more articles in the Reconstructive and Breast field while publishing relatively less in the hand/peripheral nerve field. From the first decade of analysis, US authors wrote relatively fewer articles in the hand/peripheral nerve field, whereas in the second decade, the US authors wrote relatively fewer articles in the Experimental field. In the last 3 years, US authors published relatively fewer articles in the Experimental and Cosmetic fields.

Conclusions:

Each country’s scientific productivity in PRS is related to funding, interest, patients’ demand, and healthcare market pressure. In this study, we see that these factors influence trends within research publications over the last 2 decades.
The Journal of Cardiopulmonary Rehabilitation and Prevention at 40 Years and Its Role in Promoting Lifestyle Medicine for Prevention of Cardiovascular Diseases
Authors: Franklin Barry A. , Brubaker Peter H. , Harber Matthew P. , Lavie Carl J. , Myers Jonathan , Kaminsky Leonard A.
Published: April 2020

Risk to individuals for cardiovascular events are invariably tied to their exposure to major coronary risk factors. This risk can be substantially mitigated by lifestyle behaviors. This first part of this Commentary focuses on the important role both adopting healthful dietary patterns and regularly obtaining adequate physical activity have as preventative therapies for cardiovascular diseases.
Interferon Alfa-2b for Pigmented Ocular Surface Squamous Neoplasia: A Report of 8 Lesions
Authors: Kaliki Swathi , Sharma Abhimanyu , Vempuluru Vijitha S.
Published: April 2020

Purpose:

To study the efficacy of interferon alfa-2b (IFN-a2b) on pigmented ocular surface squamous neoplasia (p-OSSN) and assess the resolution of the pigment to the treatment.

Methods:

A retrospective case series of 8 tumors in 7 patients.

Results:

The mean age at diagnosis of p-OSSN was 65 years (median, 61 years; range, 51–84 years), and all patients were men. The mean duration of symptoms was 2 months (median, 1 month; range, 1–4 months). One patient had 2 distinct lesions in the same eye. Tumor epicenter was located at the limbus (n = 5) or bulbar conjunctiva (n = 2). Complexion-associated melanosis was noted in all eyes. The mean basal dimension of the tumor was 8 mm (median, 7 mm; range, 5–12 mm). The mean % of tumor pigmentation was 47% (median, 30%; range, 10%–100%). The treatment details included topical IFN-a2b (n = 1) or a combination of topical and subconjunctival injection of IFN-a2b (n = 7). All patients with p-OSSN showed excellent response to IFN-a2b with complete tumor regression and resolution of tumor-associated pigment with a mean number of 2 subconjunctival IFN-a2b injections (median, 2; range, 0–3) and topical IFN-a2b for an average of 2 months (median, 2 months; range, 1–3 months). There was no change in the complexion-associated melanosis with IFN-a2b.

Conclusions:

IFN-a2b is very effective in the management of p-OSSN. There is a complete resolution of the pigment along with the tumor.
Development of a reliable preoperative risk stratification system for phacoemulsification
Authors: Mylona Ioanna , Dermenoudi Maria , Glynatsis Mikes , Ziakas Nikolaos , Tsinopoulos Ioannis
Published: April 2020

Purpose:

To present a statistically validated risk classification system for intraoperative complications in cataract surgery.

Setting:

2nd Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Design:

Prospective observational study.

Methods:

All patients underwent phacoemulsification surgery by experienced, high-volume surgeons for cases with intraoperative complications. The presence of several risk factors was statistically assessed with the help of multiple correspondence analysis to determine the more reliable rank categorization for severity and to calculate a total risk score.

Results:

This study included 1572 consecutive patients. The proposed system had 3 risk groups and a no-risk group and had high statistical reliability. A comparison of this system against a previously asserted empirical system showed higher internal reliability.

Conclusions:

Previous efforts to construct a risk classification system for intraoperative complications in cataract surgery have been empirically defined and tested against practice-as-usual. The system in this study quantified risk more accurately and provided an experienced clinician with a reliable means of assessing the preoperational likelihood of intraoperative complications.
Plastic Surgery and the COVID-19 Pandemic
Authors: Ozturk Cemile Nurdan , Kuruoglu Doga , Ozturk Can , Rampazzo Antonio , Gurunian (Gurunluoglu) Raffi
Published: April 2020

Background

A novel coronavirus disease (COVID-19) was first reported in December 2019 in China and was soon declared a pandemic by the World Health Organization. Many elective and nonessential surgeries were postponed worldwide in an effort to minimize spread of disease, as well as to conserve resources. Our goal with this article is to review current practice guidelines in setting of the COVID-19 pandemic, based on available data and literature.

Methods

Websites pertaining to surgical and medical societies, and government agencies were reviewed, along with recently published literature to identify recommendations related to COVID-19 and plastic surgery procedures.

Results

Clinical practice modifications are recommended during the pandemic in outpatient and perioperative settings. Use of personal protective equipment is critical for aerosol-generating procedures, such as surgery in the head and neck area. Care for trauma and malignancy should continue during the pandemic; however, definitive reconstruction could be delayed for select cases. Specific recommendations were made for surgical treatment of cancer, trauma, and semiurgent reconstructive procedures based on available data and literature.

Conclusions

The risk and benefit of each reconstructive procedure should be carefully analyzed in relation to necessary patient care, minimized COVID-19 spread, protection of health care personnel, and utilization of resources. Recommendations in this article should be taken in the context of each institute's resources and prevalance of COVID-19 in the region. It should be emphasized that the guidelines provided are a snapshot of current practices and are subject to change as the pandemic continues to evolve.
Autosomal Dominant Polycystic Kidney Disease Is a Risk Factor for Posttransplantation Diabetes Mellitus: An Updated Systematic Review and Meta-analysis
Authors: Culliford Alice , Phagura Nuvreen , Sharif Adnan
Published: April 2020

Background.

Autosomal dominant polycystic kidney disease (ADPKD) is linked with risk for posttransplantation diabetes mellitus (PTDM), but this association has methodologic limitations like diagnostic criteria. The aim of this study was to use contemporary diagnostic criteria for PTDM and explore any risk association for kidney transplant recipients with ADPKD.

Methods.

We undertook a retrospective analysis of 1560 nondiabetic kidney transplant recipients between 2007 and 2018 at a single center, of whom 248 (15.9%) had ADPKD. Local/national data were linked for every patient, with manual data capture of PTDM diagnosis by International Consensus Recommendations. We then pooled our data with eligible studies after an updated systematic review and performed a meta-analysis to estimate the pooled effect.

Results.

Comparing ADPKD versus non-ADPKD kidney transplant recipients, PTDM risk was not significantly different at our center (19.4% versus 14.9%, respectively; P = 0.085). ADPKD patients who developed PTDM were older, borderline heavier, and less likely to be recipients of living kidney donor compared with ADPKD patients who remained free of PTDM. Systematic review of the literature identified 14 eligible studies, of which 8 had a PTDM diagnosis consistent with Consensus recommendations. In the meta-analysis, we observed an increased odds ratio (OR) of kidney transplant recipients with ADPKD developing PTDM regardless of all study inclusion (OR, 1.98; 95% confidence interval, 1.43-2.75) or restricted study inclusion based on robust PTDM diagnostic criteria (OR, 1.81; 95% confidence interval, 1.16-2.83).

Conclusions.

ADPKD kidney transplant candidates should be counseled of their increased risk for PTDM, with further work warranted to investigate any underlying metabolic pathophysiology.
Estimating the early death toll of COVID-19 in the United States
Authors: Weinberger Daniel M. , Cohen Ted , Crawford Forrest W. , Mostashari Farzad , Olson Don , Pitzer Virginia E , Reich Nicholas G , Russi Marcus , Simonsen Lone , Watkins Anne , Viboud Cecile
Published: April 2020

Background

Efforts to track the severity and public health impact of the novel coronavirus, COVID-19, in the US have been hampered by testing issues, reporting lags, and inconsistency between states.

Evaluating unexplained increases in deaths attributed to broad outcomes, such as pneumonia and influenza (P&I) or all causes, can provide a more complete and consistent picture of the burden caused by COVID-19.

Methods

We evaluated increases in the occurrence of deaths due to P&I above a seasonal baseline (adjusted for influenza activity) or due to any cause across the United States in February and March 2020. These estimates are compared with reported deaths due to COVID-19 and with testing data.

Results

There were notable increases in the rate of death due to P&I in February and March 2020. In a number of states, these deaths pre-dated increases in COVID-19 testing rates and were not counted in official records as related to COVID-19. There was substantial variability between states in the discrepancy between reported rates of death due to COVID-19 and the estimated burden of excess deaths due to P&I. The increase in all-cause deaths in New York and New Jersey is 1.5-3 times higher than the official tally of COVID-19 confirmed deaths or the estimated excess death due to P&I.

Conclusions

Excess P&I deaths provide a conservative estimate of COVID-19 burden and indicate that COVID-19-related deaths are missed in locations with inadequate testing or intense pandemic activity.

RESEARCH IN CONTEXT

Evidence before this study

Deaths due to the novel coronavirus, COVID-19, have been increasing sharply in the United States since mid-March. However, efforts to track the severity and public health impact of COIVD-19 in the US have been hampered by testing issues, reporting lags, and inconsistency between states. As a result, the reported number of deaths likely represents an underestimate of the true burden.

Added Value of this study

We evaluate increases in deaths due to pneumonia across the United States and relate these increases to the number of reported deaths due to COVID-19 in different states and evaluate the trajectories of these increases in relation to the volume of testing and to indicators of COVID-19 morbidity. This provides a more complete picture of mortality due to COVID-19 in the US and demonstrates how delays in testing led to many coronavirus deaths not being counted in certain states.

Implications of all the available evidence

The number of deaths reported to be due to COVID-19 represents just a fraction of the deaths linked to the pandemic. Monitoring trends in deaths due to pneumonia and all-causes provides a more complete picture of the tool of the disease.
Inequalities in COVID19 mortality related to ethnicity and socioeconomic deprivation
Authors: Rose Tanith C. , Mason Kate , Pennington Andy , McHale Philip , Buchan Iain , Taylor-Robinson David C. , Barr Ben
Published: April 2020

Background

Initial reports suggest that ethnic minorities may be experiencing more severe coronavirus disease 2019 (COVID19) outcomes. We therefore assessed the association between ethnic composition, income deprivation and COVID19 mortality rates in England.

Methods

We performed a cross-sectional ecological analysis across England’s upper-tier local authorities. We assessed the association between the proportion of the population from Black, Asian and Minority Ethnic (BAME) backgrounds, income deprivation and COVID19 mortality rates using multivariable negative binomial regression, adjusting for population density, proportion of the population aged 50–79 and 80+ years, and the duration of the epidemic in each area.

Findings

Local authorities with a greater proportion of residents from ethnic minority backgrounds had statistically significantly higher COVID19 mortality rates, as did local authorities with a greater proportion of residents experiencing deprivation relating to low income. After adjusting for income deprivation and other covariates, each percentage point increase in the proportion of the population from BAME backgrounds was associated with a 1% increase in the COVID19 mortality rate [IRR=1.01, 95%CI 1.01–1.02]. Each percentage point increase in the proportion of the population experiencing income deprivation was associated with a 2% increase in the COVID19 mortality rate [IRR=1.02, 95%CI 1.01–1.04].

Interpretation

This study provides evidence that both income deprivation and ethnicity are associated with greater COVID19 mortality. To reduce these inequalities, Government needs to target effective control and recovery measures at these disadvantaged communities, proportionate to their greater needs and vulnerabilities, during and following the pandemic.

Funding

National Institute of Health Research; Medical Research Council
Searching the Sigmoid-type trend in Lock Down period covid19 data of India and its different states
Authors: Mondal Supriya , Ghosh Sabyasachi
Published: April 2020

We have worked on imported covid19 cases of India, detected after declaration of lock down. They are marked as hidden travelers, who are detected later during 1-2 weeks period of lock down. We have investigated the impact of those travelers on selective 15 states, having large number cases. Among them 5 states have faced a noticeable effect on their data profile, although its overall effect in country level is quite negligible. Searching the Sigmoid trends of all 15 states, we have identified 3 categories depending upon latest data of new case with respect to the peak value of Sigmoid functions. Based on our optimistic predicted curves, ongoing lock down period might be enough for getting marginal values of new cases for KL, HR, JK, TN and AP but the reamining of 15 states might need a third phase of lock down or alternative preventive measures.
Curricular change in a medical school: a new method for analysis of students’ academic pathways
Authors: Sánchez Damián Canales , Godínez Tomás Bautista , Salinas J. Gerardo Moreno , García-Minjares Manuel , Sánchez-Mendiola Melchor
Published: April 2020

Background

Curricular changes in medical schools occur due to advances in medical sciences, but its evaluation is limited and fragmented, with scant data of students’ success as they progress through the program. Longitudinal follow-up can be “natural experiments” to explore innovative methodologies.

Objective

To propose a method for analyzing students’ academic pathways, and identify changes associated with a medical school curricular reform.

Methods

We analyzed the academic pathways of students throughout the program in two different curricula (1993 and 2010), at the National Autonomous University of Mexico (UNAM) Faculty of Medicine. Advancement of each student in the program was calculated with the “academic trajectory” using the accumulated credits in a defined time period, and the percentage of students that completed the credits for each stage of the curriculum. The theoretical framework is based on the “life course” approach, applying concepts of trajectory, transition and state. Data was analyzed with R software and TraMineR algorithm.

Results

Five student cohorts of the older curriculum were studied (classes of 1994, 1995, 1996, 2004 and 2005), and two cohorts of the new curriculum (2011, 2012), a population of 6829 students. Students in the newer curriculum had a faster, more timely and efficient advancement in academic pathways, than cohorts in the older one. There was a higher percentage of students with “regular” trajectory (without failed courses) in the newer curriculum. Regularity is a straightforward metric that allows identification of complex curricular changes’ associated effects.

Conclusions

Analysis of students’ academic pathways offers valuable information to evaluate curricular changes, which is difficult to obtain with traditional cross-sectional studies. The study does not provide proof of causality regarding the educational impact of different programs, although it can be useful to complement the array of program evaluation strategies in higher education.
A collection of designed peptides to target SARS-Cov-2 – ACE2 interaction: PepI-Covid19 database
Authors: Molina Ruben , Oliva Baldo , Fernandez-Fuentes Narcis
Published: April 2020

The angiotensin-converting enzyme 2 is the cellular receptor used by SARS coronavirus SARS-CoV and SARS-CoV-2 to enter the cell. Both coronavirus use the receptor-binding domain (RBD) of their viral spike protein to interact with ACE2. The structural basis of these interactions are already known, forming a dimer of ACE2 with a trimer of the spike protein, opening the door to target them to prevent the infection. Here we present PepI-Cov19 database, a repository of peptides designed to target the interaction between the RDB of SARS-CoV-2 and ACE2 as well as the dimerization of ACE2 monomers. The peptides were modelled using our method PiPreD that uses native elements of the interaction between the targeted protein and cognate partner that are subsequently included in the designed peptides. These peptides recapitulate stretches of residues present in the native interface plus novel and highly diverse conformations that preserve the key interactions on the interface. PepI-Covid19 database provides an easy and convenient access to this wealth of information to the scientific community with the view of maximizing its potential impact in the development of novel therapeutic agents.
Robust gene expression-based classification of cancers without normalization
Authors: Jiang Aixiang , Hilton Laura K. , Tang Jeffrey , Rushton Christopher K. , Grande Bruno M. , Scott David W. , Morin Ryan D.
Published: April 2020

Binary classification using gene expression data is commonly used to stratify cancers into molecular subgroups that may have distinct prognoses and therapeutic options. A limitation of many such methods is the requirement for comparable training and testing data sets. Here, we describe and demonstrate aself-training implementation ofprobabilityratio-based classificationpredictionscore (PRPS-ST) that facilitates the porting of existing classification models to other gene expression data sets. We demonstrate its robustness through application to two binary classification problems in diffuse large B-cell lymphoma using a diverse variety of gene expression data types and normalization methods.
Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation
Authors: King Hamish W , Orban Nara , Riches John C , Clear Andrew J , Warnes Gary , Teichmann Sarah A , James Louisa K
Published: April 2020

In response to antigen challenge, B cells clonally expand, undergo selection and differentiate to produce mature B cell subsets and high affinity antibodies. However, the interplay between dynamic B cell states and their antibody-based selection is challenging to decipher in primary human tissue. We have applied an integrated analysis of bulk and single-cell antibody repertoires paired with single-cell transcriptomics of human B cells undergoing affinity maturation. We define unique gene expression and antibody repertoires of known and novel B cell states, including a pre-germinal centre state primed to undergo class switch recombination. We dissect antibody class-dependent gene expression of germinal centre and memory B cells to find that class switching prior to germinal centre entry dictates the capacity of B cells to undergo antibody-based selection and differentiate. Together, our analyses provide unprecedented resolution into the gene expression and selection dynamics that shape B cell-mediated immunity.
BCL-XL is essential for the protection from secondary anemia caused by radiation-induced fatal kidney damage
Authors: Brinkmann Kerstin , Waring Paul , Glaser Stefan , Wimmer Verena , Nhu Duong , Whitehead Lachlan , Delbridge Alex RD , Lessene Guillaume , Herold Marco J , Kelly Gemma L , Grabow Stephanie , Strasser Andreas
Published: April 2020

Studies of gene-targeted mice identified the roles of the different pro-survival BCL-2 proteins during embryogenesis, but less is known about the roles of these proteins in adults, including in the response to cytotoxic stresses, such as treatment with anti-cancer agents. We investigated the role of BCL-XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL-XL exclusively in non-hematopoietic tissues to prevent anemia caused by BCL-XL-deficiency in erythroid cells. Unexpectedly, the combination of total-body γ-irradiation (TBI) and genetic loss ofBcl-xcaused secondary anemia resulting from chronic renal failure due to apoptosis of renal tubular epithelium with secondary obstructive nephropathy. These findings identify a critical protective role of BCL-XL in the adult kidney and inform on the use of BCL-XL inhibitors in combinations with DNA damage-inducing drugs for cancer therapy.

The inducible loss of BCL-XL in all cells of adult mice causes primary anemia due to apoptosis of erythroid and megakaryocytic cell populations. In contrast γ-radiation plus loss of BCL-XL in all cells except hematopoietic cells causes secondary anemia resulting from kidney damage.
Characterization of brown adipose tissue thermogenesis in the naked mole-rat (Heterocephalus glaber), a poikilothermic mammal
Authors: Oiwa Yuki , Oka Kaori , Yasui Hironobu , Higashikawa Kei , Bono Hidemasa , Kawamura Yoshimi , Miyawaki Shingo , Watarai Akiyuki , Kikusui Takefumi , Shimizu Atsushi , Okano Hideyuki , Kuge Yuji , Kimura Kazuhiro , Okamatsu-Ogura Yuko , Miura Kyoko
Published: April 2020

The naked mole-rat (NMR) is a poikilothermic mammal that forms eusocial colonies consisting of one breeding queen, several breeding kings, and subordinates. Despite their poikilothermic feature, NMRs possess brown adipose tissue (BAT), which in homeothermic mammals induces thermogenesis in cold environments. However, NMR-BAT thermogenic potential is controversial, and its physiological roles are unknown. Here, we show that NMR-BAT has beta-3 adrenergic receptor (ADRB3)-dependent thermogenic potential, which contributes to thermogenesis in the isolated queen in non-cold environments. NMR-BAT expressed several brown adipocyte marker genes and showed noradrenaline-dependent thermogenic activityin vitroandin vivo. Although our ADRB3 inhibition experiments revealed that NMR-BAT thermogenesis slightly delays the decrease in body temperature in a cold environment, it was insufficient to maintain the body temperatures of the NMRs. In a non-cold environment, NMRs are known to increase their body temperature by a heat-sharing behavior. Interestingly, we found that the body temperatures of NMRs isolated from the colony were also significantly higher than the ambient temperature. We also show that queens, but not subordinates, induce BAT thermogenesis in isolated, non-cold conditions. Our research provides novel insights into the role and mechanism of thermoregulation in this unique poikilothermic mammal.
Viroid-sized rings self-assemble from mononucleotides through wet-dry cycling: implications for the origin of life
Authors: Hassenkam Tue , Damer Bruce , Mednick Gabriel , Deamer David
Published: April 2020

It is possible that early life relied on RNA polymers that served as ribozyme-like catalysts and store genetic information1,2. The source of such polymers is uncertain, but previous investigations reported that wet-dry cycles simulating prebiotic hot springs provide sufficient energy to drive condensation reactions of mononucleotides to form oligomers3. The aim of the study reported here was to visualize the products by atomic force microscopy. In addition to globular oligomers, ring-like structures ranging from 10-200 nm in diameter with an average around 30-40 nm were abundant, particularly when nucleotides capable of base pairing were present. The thickness of the rings was consistent with single stranded products, but some had thicknesses indicating base pair stacking. Others had more complex structures in the form of short polymer attachments and pairing of rings. These observations suggest the possibility that template-directed synthesis may occur during wet-dry cycling followed by solvation of the rings. We conclude that RNA-like rings and structures could have been synthesized non-enzymatically on the prebiotic Earth with sizes sufficient to fold into ribozymes and genetic molecules required for life to begin.
A nonequilibrium strategy for fast target search on the genome
Authors: Cagnetta F. , Michieletto D. , Marenduzzo D.
Published: April 2020

Vital biological processes such as genome repair require fast and efficient binding of selected proteins to specific target sites on DNA. Here we propose an active target search mechanism based on “chromophoresis”, the dynamics of DNA-binding proteins up or down gradients in the density of epigenetic marks, or colours (biochemical tags on the genome). We focus on a set of proteins that deposit marks from which they are repelled - a case which is only encountered away from thermodynamic equilibrium. For suitable ranges of kinetic parameter values, chromophoretic proteins can perform undirectional motion and are optimally redistributed along the genome. Importantly, they can also locally unravel a region of the genome which is collapsed due to self-interactions and “dive” deep into its core, for a striking enhancement of the efficiency of target search on such an inaccessible substrate. We discuss the potential relevance of chromophoresis for DNA repair.
High-resolution cryo-EM structure of urease from the pathogenYersinia enterocolitica
Authors: Righetto Ricardo D. , Anton Leonie , Adaixo Ricardo , Jakob Roman P. , Zivanov Jasenko , Mahi Mohamed-Ali , Ringler Philippe , Schwede Torsten , Maier Timm , Stahlberg Henning
Published: April 2020

Urease converts urea into ammonia and carbon dioxide and makes urea available as a nitrogen source for all forms of life except animals. In human bacterial pathogens, ureases also aid in the invasion of acidic environments such as the stomach by raising the surrounding pH. Here, we report the structure of urease from the pathogenYersinia enterocoliticaat better than 2 Å resolution from cryo-electron microscopy.Y. enterocoliticaurease is a dodecameric assembly of a trimer of three protein chains, ureA, ureB and ureC. The high data quality enables detailed visualization of the urease bimetal active site and of the impact of radiation damage. Our data are of sufficient quality to support drug development efforts.
Single-cell copy number calling and event history reconstruction
Authors: Kuipers Jack , Tuncel Mustafa Anıl , Ferreira Pedro F. , Jahn Katharina , Beerenwinkel Niko
Published: April 2020

Copy number alterations are driving forces of tumour development and the emergence of intra-tumour heterogeneity. A comprehensive picture of these genomic aberrations is therefore essential for the development of personalised and precise cancer diagnostics and therapies. Single-cell sequencing offers the highest resolution for copy number profiling down to the level of individual cells. Recent high-throughput protocols allow for the processing of hundreds of cells through shallow whole-genome DNA sequencing. The resulting low read-depth data poses substantial statistical and computational challenges to the identification of copy number alterations. We developed SCICoNE, a statistical model and MCMC algorithm tailored to single-cell copy number profiling from shallow whole-genome DNA sequencing data. SCICoNE reconstructs the history of copy number events in the tumour and uses these evolutionary relationships to identify the copy number profiles of the individual cells. We show the accuracy of this approach in evaluations on simulated data and demonstrate its practicability in applications to two breast cancer samples from different sequencing protocols.
Direct analysis of ribosome targeting illuminates thousand-fold regulation of translation initiation
Authors: Niederer Rachel O. , Rojas-Duran Maria F. , Zinshteyn Boris , Gilbert Wendy V.
Published: April 2020

Translational control shapes the proteome in normal and pathophysiological conditions. Current high-throughput approaches reveal large differences in mRNA-specific translation activity but cannot identify the causative mRNA features. We developed direct analysis of ribosome targeting (DART) and used it to dissect regulatory elements within 5′ untranslated regions that confer thousand-fold differences in ribosome recruitment in biochemically accessible cell lysates. Using DART, we identified novel translational enhancers and silencers, determined a functional role for most alternative 5′ UTR isoforms expressed in yeast, and revealed a general mode of increased translation via direct binding to a core translation factor. DART enables systematic assessment of the translational regulatory potential of 5′ UTR variants, whether native or disease-associated, and will facilitate engineering of mRNAs for optimized protein production in various systems.

Highlights

DART illuminates thousand-fold differences in 5′ UTR-specific translation activity

SNPs and alternative 5′ UTR isoforms affect ribosome recruitment significantly

Inhibitory effects of RNA structures are highly dependent on 5′ UTR context

5′ UTR motifs bind initiation factors directly, broadly stimulating translation
Cancer LncRNA Census 2 (CLC2): an enhanced resource reveals clinical features of cancer lncRNAs
Authors: Vancura Adrienne , Lanzós Andrés , Bosch Núria , Torres Mònica , Gutierrez Alejandro Hionides , Haefliger Simon , Johnson Rory
Published: April 2020

Long noncoding RNAs play key roles in cancer and are at the vanguard of precision therapeutic development. These efforts depend on large and high-confidence collections of cancer lncRNAs. Here we present the Cancer LncRNA Census 2 (CLC2): at 492 cancer lncRNAs, it is 4-fold greater than its predecessor, without compromising on strict criteria of confident functional / genetic roles and inclusion in the GENCODE annotation scheme. This increase was enabled by leveraging high-throughput transposon insertional mutagenesis (TIM) screening data, yielding 95 novel cancer lncRNAs. CLC2 makes a valuable addition to existing collections: it is amongst the largest, holds the greatest number of unique genes, and carries functional labels (oncogene / tumour suppressor). Analysis of this dataset reveals that cancer lncRNAs are impacted by germline variants, somatic mutations, and changes in expression consistent with inferred disease functions. Furthermore, we show how clinical / genomic features can be used to vet prospective gene sets from high-throughput sources. The combination of size and quality makes CLC2 a foundation for precision medicine, demonstrating cancer lncRNAs’ evolutionary and clinical significance.
Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer
Authors: Theard Patricia L. , Sheffels Erin , Sealover Nancy E. , Linke Amanda J. , Pratico David J. , Kortum Robert L.
Published: April 2020

Drug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR- and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.