bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal PrEP use in HIV-uninfected pregnant women in South Africa: Role of Stigma in PrEP initiation, retention and adherence
Authors: Moran Alexander , Mashele Nyiko , Mvududu Rufaro , Gorbach Pamina , Bekker Linda-Gail , Coates Thomas J. , Myer Landon , Davey Dvora Joseph
Published: November 2020

Pregnant women in sub-Saharan Africa are at high risk of HIV acquisition and require effective methods to prevent HIV. In a cohort of pregnant women offered pre-exposure prophylaxis (PrEP), we evaluate the relationship between internalized and anticipated stigma and PrEP initiation at first antenatal visit, 3-month continuation and adherence using multivariable logistic regression. High internalized and anticipated PrEP stigma are associated with lower PrEP initiation at first antenatal visit (aOR internalized stigma=0.06; 95%CI=0.03-0.12 & aOR anticipated stigma=0.53; 95%CI=0.29-0.97) compared to women with low reported stigma, after controlling for covariates. Women whose partners have not been tested for HIV or whose serostatus remains unknown have 1.6-times odds of PrEP retention at 3-months compared to women whose partners have been tested (aOR=1.60; 95%CI=1.02-2.52) after adjusting for covariates. PrEP counseling and maternal PrEP interventions must consider individual- and relational-level interventions to overcome anticipated PrEP stigma and other barriers to PrEP initiation and adherence.
Pediatric Multi-Organ Dysfunction Syndrome: Analysis by an Untargeted “Shotgun” Lipidomic Approach Reveals Low-abundance Plasma Phospholipids and Dynamic Recovery Over 8-Day Period, a Single-Center Observational Study
Authors: Leimanis Laurens Mara L. , Ferguson Karen , Wolfrum Emily , Boville Brian , Sanfilippo Dominic , Lydic Todd A. , Prokop Jeremy W. , Rajasekaran Surender
Published: November 2020

Lipids are stable molecules involved in metabolism and inflammation. We investigated the plasma lipidome for markers of severity and nutritional status in critically ill children. Children with multi-organ dysfunction syndrome (MODS) (n=24) were analyzed at three time points and cross referenced to sedation controls (n = 4) for a total of N=28. Eight of the patients with MODS, needed veno-arterial extracorporeal membrane oxygenation (VA ECMO) support to survive. Blood plasma lipid profiles were quantified by nano-electrospray (nESI), direct infusion high resolution/accurate mass spectrometry (MS), and tandem mass spectrometry (MS/MS) and compared to nutritional profiles and PEdiatric Logistic Organ Dysfunction (PELOD) scores. PELOD scores were not significantly different between MODS and ECMO cases across time-points (p = 0.66). Lipid profiling provided stratification between sedation controls and all MODS patients for lysophosphatidylserine (lysoPS) (p-value = 0.004), total phosphatidylserine (PS) (p-value = 0.015), and total ether-linked phosphatidylethanolamine (PE) (p-value = 0.03). Phospholipids in patients needing ECMO were observably closer to sedation controls than other MODS patients. Nutrition intake revealed changes in lipid profiles that corresponded to calorie and protein intake. Lipid measurement in the intensive care environment shows dynamic changes over an 8-day PICU course, suggesting novel indicators for defining critically ill children.
Practical considerations for Ultraviolet-C radiation mediated decontamination of N95 respirator against SARS-CoV-2 virus
Authors: Golovkine Guillaume R. , Roberts Allison W. , Cooper Chase , Riano Sebastian , DiCiccio Angela M. , Worthington Daniel L. , Clarkson Jeffrey P. , Krames Michael , Zhang Jianping , Gao Ying , Zhou Ling , Biering Scott B. , Stanley Sarah A.
Published: November 2020

Decontaminating N95 respirators for reuse could mitigate shortages during the COVID-19 pandemic. We tested a portable UV-C light-emitting diode disinfection chamber and found that decontamination efficacy depends on mask model, material and location on the mask. This emphasizes the need for caution when interpreting efficacy data of UV-C decontamination methods.
Overlooked bias with thermometer evaluations using quickly retaken temperatures in EHR: applications to axillary, oral, temporal artery, and tympanic thermometry
Authors: Harding Charles , Pompei Marybeth , Burmistrov Dmitriy , Pompei Francesco
Published: November 2020

Studies related to COVID-19 increasingly use electronic health records (EHR) to obtain large-scale evidence. However, EHR-based research must be performed with care because it can involve new study design problems that are unfamiliar to much of the medical community. Haimovich et al. (2020) sought to inform COVID-19 practice by evaluating temporal artery thermometers (TATs). They retrospectively searched EHR for temperatures measured twice within 15 minutes, including once with a TAT. The TAT often disagreed with reference measurements, so Haimovich et al. concluded TATs perform poorly. Here, we extended Haimovich et al.’s study design to all other major thermometer types using the eICU Collaborative Research Database. We retrospectively identified 80,065 pairs of quickly retaken temperatures from 24,765 adult U.S. critical care patients treated in 2014-2015. We found that oral, tympanic, and axillary thermometers disagreed with reference measurements as much as TATs did. Moreover, all thermometer types showed unprecedentedly worse agreement than observed in research using other study designs: every thermometer type broke ±0.9°F (±0.5°C) limits of clinically acceptable agreement by >2-fold and no type satisfied basic standards for repeatability. A natural explanation for these findings is that clinicians often retook temperatures within minutes because of user or patient errors during measurement, such as probe misplacement or patient movement. This means that quickly retaken EHR measurements do not reflect device accuracy or precision in correct use and, contrary to Haimovich et al.’s conclusions, should not be used to evaluate thermometer performance or revise COVID-19 fever thresholds. Our study provides an illustrative example of unexpected study design problems that can undermine EHR-based research.
Multiday cycles of heart rate are associated with seizure likelihood
Authors: Karoly Philippa J. , Stirling Rachel E. , Freestone Dean R. , Nurse Ewan S. , Maturana Matias , Halliday Amy , Neal Andrew , Gregg Nicholas M. , Brinkmann Benjamin , Richardson Mark P. , Dumanis Sonya B. , Gerche Andre La , Grayden David B. , D’Souza Wendyl , Cook Mark J.
Published: November 2020

Circadian and multiday rhythms are found across many biological systems, including cardiology, endocrinology, neurology, and immunology. In people with epilepsy, epileptic brain activity and seizure occurrence have been found to follow circadian, weekly, and monthly rhythms. Understanding the relationship between these cycles of brain excitability and other physiological systems can provide new insight into the causes of multiday cycles. The brain-heart link is relevant for epilepsy, with implications for seizure forecasting, therapy, and mortality (i.e., sudden unexpected death in epilepsy).

We report the results from a non-interventional, observational cohort study, Tracking Seizure Cycles. This study sought to examine multiday cycles of heart rate and seizures in adults with diagnosed uncontrolled epilepsy (N=31) and healthy adult controls (N=15) using wearable smartwatches and mobile seizure diaries over at least four months (M=12.0, SD=5.9; control M=10.6, SD=6.4). Cycles in heart rate were detected using a continuous wavelet transform. Relationships between heart rate cycles and seizure occurrence were measured from the distributions of seizure likelihood with respect to underlying cycle phase.

Heart rate cycles were found in all 46 participants (people with epilepsy and healthy controls), with circadian (N=46), about-weekly (N=25) and about-monthly (N=13) rhythms being the most prevalent. Of the participants with epilepsy, 19 people had at least 20 reported seizures, and 10 of these had seizures significantly phase locked to their multiday heart rate cycles.

Heart rate cycles showed similarities to multiday epileptic rhythms and may be comodulated with seizure likelihood. The relationship between heart rate and seizures is relevant for epilepsy therapy, including seizure forecasting, and may also have implications for cardiovascular disease. More broadly, understanding the link between multiday cycles in the heart and brain can shed new light on endogenous physiological rhythms in humans.
The economic value of quarantine is higher at lower case prevalence, with quarantine justified at lower risk of infection
Authors: Petrie James , Masel Joanna
Published: November 2020

1.

Some infectious diseases, such as COVID-19, are so harmful that they justify broad scale social distancing. Targeted quarantine can reduce the amount of indiscriminate social distancing needed to control transmission. Finding the optimal balance between targeted vs. broad scale policies can be operationalized by minimizing the total amount of social isolation needed to achieve a target reproductive number. Optimality is achieved by quarantining on the basis of a risk threshold that depends strongly on current disease prevalence, suggesting that very different disease control policies should be used at different times or places. Aggressive quarantine is warranted given low disease prevalence, while populations with a higher base rate of infection should rely more on social distancing by all. The total value of a quarantine policy rises as case counts fall, is relatively insensitive to vaccination unless the vaccinated are exempt from distancing policies, and is substantially increased by the availability of modestly more information about individual risk of infectiousness.
Comprehensive Joint Modeling of First-Line Therapeutics in Non-Small Cell Lung Cancer
Authors: Schneider Benjamin K , Benzekry Sebastien , Mochel Jonathan P
Published: November 2020

First-line antiproliferatives for non-small cell lung cancer (NSCLC) have a relatively high failure rate due to high intrinsic resistance rates and acquired resistance rates to therapy. 57% patients are diagnosed in late-stage disease due to the tendency of early-stage NSCLC to be asymptomatic. For patients first diagnosed with metastatic disease the 5-year survival rate is approximately 5%. To help accelerate the development of novel therapeutics and computer-based tools for optimizing individual therapy, we have collated data from 11 different clinical trials in NSCLC and developed a semi-mechanistic, clinical model of NSCLC growth and pharmacodynamics relative to the various therapeutics represented in the study. In this study, we have produced extremely precise estimates of clinical parameters fundamental to cancer modeling such as the rate of acquired resistance to various pharmaceuticals, the relationship between drug concentration and rate of cancer cell death, as well as the fine temporal dynamics of anti-VEGF therapy. In the simulation sets documented in this study, we have used the model to make meaningful descriptions of efficacy gain in making bevacizumab-antiproliferative combination therapy sequential, over a series of days, rather than concurrent.
Effect of a multi-faceted Rapid Response System re-design on repeat calling of the Rapid Response Team
Authors: Chalwin Richard , Salter Amy , Karnon Jonathon , Eaton Victoria , Giles Lynne
Published: November 2020

Background

Repeat Rapid Response Team (RRT) calls are associated with increased mortality risk to patients and pose a resource burden to organisations. Use of Non-Technical Skills (NTS) at calls has the potential to reduce potentially preventable repeat calling. NTS are usually improved through training, however this consumes time and financial resources. Modifications to the Rapid Response System (RRS) that promote use of NTS are worth exploring as a cost-effective alternative.

Methods

A pre-post observational study of a RRS re-design on proportion of admissions each month subject to repeat RRT calling and number of calls per admission, with univariate and multivariable interrupted time series analyses comparing outcomes between study phases.

Results

The proportion of admissions with repeat calls each month increased across both phases of the study period, but the increase was lower in the post re-design phase (change in adjusted regression slope -0.12 (standard error 0.07) post versus pre re-design). The multivariable model showed an estimated 6.0% reduction (P=0.19) in the proportion of admissions having repeat calls at the end of the study versus that predicted had the re-design not occurred.

For the number of calls per the multivariable model predicted a reduction of 0.07 calls per admission at the end of the post re-design phase (95% confidence interval -0.23 – 0.08, P=0.35), equating to one fewer repeat call per 14 patients having RRT calls.

Conclusion

This study showed no observed statistically significant effect on rates of repeat calling or numbers of repeat calls per admission from the implementation of a RRS re-design. However, the results demonstrate, at an organisational level, the feasibility of a low-cost initiative to improve NTS use by the RRS.
Transition to multi-type mixing in d-dimensional spreading dynamics
Authors: Vazquez Alexei
Published: November 2020

The spreading dynamics of infectious diseases is determined by the interplay between geography and population mixing. There is homogeneous mixing at the local level and human mobility between distant populations. Here I model spatial location as a type and the population mixing by intra- and inter-type mixing patterns. Using the theory of multi-type branching process, I calculate the expected number of new infections as a function of time. In 1-dimension the analysis is reduced to the eigenvalue problem of a tridiagonal Teoplitz matrix. Ind-dimensions I take advantage of the graph cartesian product to construct the eigenvalues and eigenvectors from the eigenvalue problem in 1-dimension. Using numerical simulations I uncover a transition from linear to multi-type mixing exponential growth with increasing the population size. Given that most countries are characterized by a network of cities with more than 100,000 habitants, I conclude that the multi-type mixing approximation should be the prevailing scenario.
Symptom-based prediction model of SARS-CoV-2 infection developed from self-reported symptoms of SARS-CoV-2-infected individuals in an online survey
Authors: Schulze Hansjörg , Hoffmann Daniel , Bayer Wibke
Published: November 2020

Background

Infections with the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2) have quickly reached pandemic proportions and are causing a global health crisis. First recognized for the induction of severe disease, the virus also causes asymptomatic infections or infections with mild symptoms that can resemble common colds. Since infections with mild course are probably a major contributor to the spread of SARS-CoV-2, better detection of such cases is important. To provide better understanding of these mild SARS-CoV-2 infections and to improve information for potentially infected individuals, we performed a detailed analysis of self-reported symptoms of SARS-CoV-2 positive and SARS-CoV-2 negative individuals.

Methods

In an online-based survey, 963 individuals provided information on symptoms associated with an acute respiratory infection, 336 of the participants had tested positive for SARS-CoV-2 infection, 107 had tested negative, and 520 had not been tested for SARS-CoV-2 infection.

Results

The symptoms reported most frequently by SARS-CoV-2 infected individuals were tiredness, loss of appetite, impairment of smell or taste and dry cough. The symptoms with the highest odds ratios between SARS-CoV-2 positive and negative individuals were loss of appetite and impairment of smell or taste. Based on the most distinguishing symptoms, we developed a Bayesian prediction model, which had a positive predictive value of 0.80 and a negative predictive value of 0.72 on the SARS-CoV-2 tested individuals. The model predicted 56 of 520 non-tested individuals to be SARS-CoV-2 positive with more than 75% probability, and another 84 to be SARS-CoV-2 positive with probability between 50% and 75%.

Conclusions

A combination of symptoms can provide a good estimate of the probability of SARS-CoV-2 infection.
HPV16 and HPV18 type-specific APOBEC3 and integration profiles in different diagnostic categories of cervical samples
Authors: Lagström Sonja , Løvestad Alexander Hesselberg , Umu Sinan Uğur , Ambur Ole Herman , Nygård Mari , Rounge Trine B. , Christiansen Irene Kraus
Published: November 2020

Human papillomavirus 16 and 18 are the most predominant types in cervical cancer. Only a small fraction of HPV infections progress to cancer, indicating that genomic factors, such as minor nucleotide variation caused by APOBEC3 and chromosomal integration, contribute to the carcinogenesis.

We analysed minor nucleotide variants (MNVs) and integration in HPV16 and HPV18 positive cervical samples with different morphology. Samples were sequenced using an HPV whole genome sequencing protocol TaME-seq. A total of 80 HPV16 and 51 HPV18 positive cervical cell samples passed the sequencing depth criteria of 300× reads, showing the following distribution: non-progressive disease (HPV16 n=21, HPV18 n=12); cervical intraepithelial neoplasia (CIN) grade 2 (HPV16 n=27, HPV18 n=9); CIN3/adenocarcinoma in situ (AIS) (HPV16 n=27, HPV18 n=30); cervical cancer (HPV16 n=5).

Similar rates of MNVs in HPV16 and HPV18 samples were observed for most viral genes but for HPV16, the non-coding region (NCR) showed a trend towards increasing variation with increasing lesion severity. APOBEC3 signatures were observed in HPV16 lesions, while similar mutation patterns were not detected for HPV18. The proportion of samples with integration was 13% for HPV16 and 59% for HPV18 positive samples, with a noticeable portion located within or close to cancer-related genes.
Spatially resolved simulations of the spread of COVID-19 in European countries
Authors: Parisi Andrea , Brand Samuel P. C. , Hilton Joe , Aziza Rabia , Keeling Matt , Nokes D. James
Published: November 2020

We explore the spatial and temporal spread of the novel SARS-CoV-2 virus under containment measures in three European countries based on fits to data of the early outbreak. Using data from Spain and Italy, we estimate an age dependent infection fatality ratio for SARS-CoV-2, as well as risks of hospitalization and intensive care admission. We use them in a model that simulates the dynamics of the virus using an age structured, spatially detailed agent based approach, that explicitly incorporates governamental interventions, changes in mobility and contact patterns occurred during the COVID-19 outbreak in each country. Our simulations reproduce several of the features of its spatio-temporal spread in the three countries studied. They show that containment measures combined with high density are responsible for the containment of cases within densely populated areas, and that spread to less densely populated areas occurred during the late stages of the first wave. The capability to reproduce observed features of the spatio-temporal dynamics of SARS-CoV-2 makes this model a potential candidate for forecasting the dynamics of SARS-CoV-2 in other settings, and we recommend its application in low and lower-middle countries which remain understudied.
Prevalence of Mental Health Disorders among Elderly Diabetics and Associated Risk Factors in Indonesia
Authors: Azam Mahalul , Sulistiana Rina , Fibriana Arulita Ika , Savitri Soesmeyka , Al Junid Syed Mohamed
Published: November 2020

This cross-sectional study aimed to explore the prevalence of mental health disorders (MHD) among elderly diabetics in Indonesia and their associated risk factors. Data were extracted from the 2018 national basic health survey, Indonesia (abbreviated as the acronym of RISKESDAS). The survey involved households randomly selected from 34 provinces, 416 districts, and 98 cities in Indonesia, with 1,017,290 respondents. The number of subjects selected in this study was 2,818 elderly diabetic subjects. MHD was determined by self-reporting assessment. Secondary data acquired from the RISKESDAS 2018 data involved age, sex, urban-rural residence status, marital status, educational level, employment status, obesity, hypertension, heart disease, stroke, family history of MHD, and duration of DM. Binary logistic regression was used to analyze the risk factors related to MHD among elderly diabetics. Prevalence of MHD among elderly diabetics in Indonesia was 19.3%. Factors associated with MHD among elderly diabetics were obesity (prevalence odds ratio [POR]=4.57; 95% CI: 3.312-6.297), family history of MHD (POR=2.43; 95% CI: 1.707-3.471), lower education (POR=1.93; 95% CI: 1.464-2.533), stroke (POR=1.76; 95% CI: 1.292-2.384), hypertension (POR=1.74; 95% CI: 1.416-2.145), heart diseases (POR=1.49; 95% CI: 1.123-1.973), female (POR=1.43; 95% CI: 1.122-1.813), and urban residence (POR=0.75; 95% CI: 0.607-1.183). The prevalence of MHD among elderly diabetics in Indonesia was 19.3%, suggesting that screening for psychological problems and educating elderly diabetic patients is essential. Obesity, family history of MHD, lower education, stroke, hypertension, heart disease, female, and rural residence altogether more likely to experience MHD in elderly diabetics.
Autosomal Dominant Polycystic Kidney Disease does not significantly alter major COVID-19 outcomes among veterans
Authors: Cui Xiangqin , Gallini Julia W. , Jasien Christine L. , Mrug Michal
Published: November 2020

Chronic kidney disease (CKD), as well as its common causes (e.g., diabetes and obesity), are recognized risk factors for severe COVID-19 illness. To explore whether the most common inherited cause of CKD, autosomal dominant polycystic kidney disease (ADPKD), is also an independent risk factor, we studied data from the VA health system and the VA COVID-19-shared resources (e.g., ICD codes, demographics, pre-existing conditions, pre-testing symptoms, and post-testing outcomes). Among 61 COVID-19-positive ADPKD patients, 21 (34.4%) were hospitalized, 10 (16.4%) were admitted to ICU, 4 (6.6%) required ventilator, and 4 (6.6%) died by August 18, 2020. These rates were comparable to patients with other cystic kidney diseases and cystic liver-only diseases. ADPKD was not a significant risk factor for any of the four outcomes in multivariable logistic regression analyses when compared with other cystic kidney diseases and cystic liver-only diseases. In contrast, diabetes was a significant risk factor for hospitalization [OR 2.30 (1.61, 3.30), p<0.001], ICU admission [OR 2.23 (1.47, 3.42), p<0.001], and ventilator requirement [OR 2.20 (1.27, 3.88), p=0.005]. Black race significantly increased the risk for ventilator requirement [OR 2.00 (1.18, 3.44), p=0.011] and mortality [OR 1.60 (1.02, 2.51), p=0.040]. We also examined the outcome of starting dialysis after COVID-19 confirmation. The main risk factor for starting dialysis was CKD [OR 6.37 (2.43, 16.7)] and Black race [OR 3.47 (1.48, 8.1)]. After controlling for CKD, ADPKD did not significantly increase the risk for newly starting dialysis comparing with other cystic kidney diseases and cystic liver-only diseases. In summary, ADPKD did not significantly alter major COVID-19 outcomes among veterans when compared to other cystic kidney and liver patients.
The psychosocial impact on frontline health and social care professionals in the UK during the COVID-19 pandemic: a qualitative interview study
Authors: Aughterson Henry , McKinlay Alison , Fancourt Daisy , Burton Alexandra
Published: November 2020

Objectives

To explore the psychosocial well-being of health and social care professionals working during the COVID-19 pandemic.

Design

This was a qualitative study deploying in-depth, individual interviews, which were audio-recorded and transcribed verbatim. Thematic analysis was used for coding.

Participants

This study involved 25 participants from a range of frontline professions in health and social care.

Setting

Interviews were conducted over the phone or video call, depending on participant preference.

Results

From the analysis, we identified 5 overarching themes: communication challenges, work-related stressors, support structures, personal growth, and individual resilience. The participants expressed difficulties such as communication challenges and changing work conditions, but also positive factors such as increased team unity at work, and a greater reflection on what matters in life.

Conclusions

This study provides evidence on the support needs of health and social care professionals amid continued and future disruptions caused by the pandemic. It also elucidates some of the successful strategies (such as mindfulness, hobbies, restricting news intake, virtual socialising activities) deployed by health and social care professionals that can support their resilience and well-being and be used to guide future interventions.

Strengths and limitations of this study

This is the first study in the UK to interview both health and social care professionals working in a range of settings on their experiences working through COVID-19.

This study used a strong theoretical approach to inform the topic guide, and one-to-one interviews allowed in-depth analysis of the psychosocial experiences of health and social care professionals, complementing the wider availability of quantitative evidence.

We interviewed a wide range of professions, which provided breadth of experience but might limit the specificity of findings.

Given the fluctuating nature of the pandemic, attitudes of health and social care professionals may change over time. This can be challenging to capture during a single interview, however we did ask questions on how their experience had progressed longitudinally.

Our sample may have been biased towards people who had more free time to participate and so were coping better than others. However, our sample still described a number of stressful experiences during the pandemic, and it is also possible that workers who were frustrated or stressed wished to express their views.
Endometrial Receptivity on Assisted Reproductive Technology Cycles – a correlation between Serial Serum Estradiol levels and Serial Endometrial Volume Assessment
Authors: Silva Martins R. , Helio Oliani A. , Vaz Oliani D. , Martinez de Oliveira J.
Published: November 2020

Research Question

Diagnosis of endometrial receptivity is still unclear and conflicting. Despite advances in embryo development during assisted reproductive technologies (ART) cycles, the intricate process of implantation is still matter for debate and research.

Design

Serial serum estradiol levels and 3D transvaginal ultrasound performed in women on ART cycle to evaluate a pattern that better predicts implantation rates. 169 subjects on a prospective case control study were assessed. Serial biochemical and biophysical parameters were assessed during ovarian controlled stimulation and results compared in terms of pregnancy outcome.

Results

No statistical difference was noted between the two groups in terms of demographics and ART procedures and scores. Serum estradiol was significantly higher in the positive group from day 8 after ovarian controlled stimulation. Endometrial volume and adjusted endometrial volume were significantly higher in the positive group as soon as day 6 of ovarian controlled stimulation.

Conclusions

Continuous serum estradiol and 3D endometrial volume and adjusted endometrial volumes may reflect endometrial changes during ART procedures and provide a useful real time tool for clinicians in predicting endometrial receptivity.
Large-Scale Meta-Analysis of Potential Biomarkers for Treatment Response to Anti-PD-1/PD-L1 Immune Checkpoint Inhibitors
Authors: Mariam Arshiya , Kamath Suneel , Schveder Kimberly , McLeod Howard L. , Rotroff Daniel M.
Published: November 2020

Immune checkpoint inhibitors (ICIs) blocking programmed death receptor 1 or its ligand (anti-PD-1/PD-L1) are a burgeoning class of promising cancer treatments. However, not all patients respond to these treatments. Although studies have suggested potential biomarkers to predict patients likely to respond to treatment, no consensus biomarker has been identified. Here, 95 peer-reviewed studies representing 18,978 subjects across 15 cancer types were meta-analyzed to determine biomarkers that best predicted ICI response within and across cancers. Performance was assessed using the sensitivity, specificity, area under the receiver operating characteristic curve, and others. Across all cancers, multimodal biomarkers and tumor mutational burden discriminated ICI response better than PD-L1 immunohistochemistry assays (IHC) (P=.04) with sensitivities of 0.57 and 0.70 and specificities of 0.76 and 0.53, respectively. Marginal improvements were also observed for nascent microbiome biomarkers compared to IHC (P=.06). Current ICI biomarker performances indicate that additional research is needed to develop highly accurate and precise biomarkers for widespread clinical adoption.
Regulating enzymatic reactions in Escherichia coli utilizing light-responsive cellular compartments based on liquid-liquid phase separation
Authors: Huang Zikang , Sun Lize , Lu Genzhe , Liu Hongrui , Zhai Zihan , Feng Site , Gao Ji , Chen Chunyu , Qing Chuheng , Fang Meng , Chen Bowen , Fu Jiale , Wang Xuan , Chen Guo-Qiang
Published: November 2020

Enzymatic reactions in cells are well organized into different compartments, among which protein-based membraneless compartments formed through liquid-liquid phase separation (LLPS) are believed to play important roles1,2. Hijacking them for our own purpose has promising applications in metabolic engineering3. Yet, it is still hard to precisely and dynamically control target enzymatic reactions in those compartments4. To address those problems, we developed Photo-Activated Switch in E. coli (PhASE), based on phase separating scaffold proteins and optogenetic tools. In this system, a protein of interest (POI) can be enriched up to 15-fold by LLPS-based compartments from cytosol within only a few seconds once activated by light, and become fully dispersed again within 15 minutes. Furthermore, we explored the potentiality of the LLPS-based compartment in enriching small organic molecules directly via chemical-scaffold interaction. With enzymes and substrates co-localized under light induction, the overall reaction efficiency could be enhanced. Using luciferin and catechol oxidation as model enzymatic reactions, we found that they could accelerate 2.3-fold and 1.6-fold, respectively, when regulated by PhASE. We anticipate our system to be an extension of the synthetic biology toolkit, facilitating rapid recruitment and release of POIs, and reversible regulation of enzymatic reactions.
Precise oculocentric mapping of TMS-evoked phosphenes
Authors: Silva Andrew E. , Tsang Katelyn , Hasan Syeda Javeria , Thompson Benjamin
Published: November 2020

Transcranial Magnetic Stimulation (TMS) – evoked phosphenes are oculocentric; their perceived location depends upon eye position. We investigated the accuracy and precision of TMS-evoked phosphene oculocentric mapping and demonstrate that perceived phosphene locations map veridically to eye position, although there are considerable individual differences in the reliability of this mapping. Our results emphasize the need to carefully control eye movements when carrying out phosphene localization studies and suggest that individual differences in the reliability of the reported position of individual phosphenes must be considered.
First demonstration of the FLASH effect with ultrahigh dose-rate high-energy X-rays
Authors: Gao Feng , Yang Yiwei , Zhu Hongyu , Wang JianXin , Xiao Dexin , Zhou Zheng , Dai Tangzhi , Zhang Yu , Feng Gang , Li Jie , Lin Binwei , Xie Gang , Ke Qi , Zhou Kui , Li Peng , Shen Xuming , Wang Hanbin , Yan Longgang , Lao Chenglong , Shan Lijun , Li Ming , Lu Yanhua , Chen Menxue , Feng Song , Zhao Jianheng , Wu Dai , Du Xiaobo
Published: November 2020

Ultrahigh dose-rate (FLASH) radiotherapy has attracted immense attention because of its tumor control efficiency and healthy tissue protection during preclinical experiments with electrons, kilo-voltage X-rays, and protons. Using high-energy X-rays (HEXs) in FLASH is advantageous owing to its deep penetration, small divergence, and cost-effectiveness. This is the first report on the implementation of HEXs with FLASH (HEX-FLASH) and its corresponding applicationin vivo. With a high-current and high-energy superconducting linear accelerator, FLASH with a good dose rate and high penetration was achieved. Breast cancers artificially induced in BAL b/c mice were efficiently controlled, and normal tissues surrounding the thorax/abdomen in C57BL/6 mice were protected from radiation with HEX-FLASH. Theoretical analyses of cellular responses following HEX-FLASH irradiation were performed to interpret the experimental results and design further experiments. Thus, this study highlights the generation of HEX-FLASH for the first time and its potential in future clinical applications.
Effect of RBD mutation (Y453F) in spike glycoprotein of SARS-CoV-2 on neutralizing antibody affinity
Authors: Hayashi Takuma , Yaegashi Nobuo , Konishi Ikuo
Published: November 2020

Natural selection “adaptation” in the coronavirus can occur during coronavirus amplification in vivo in farmed minks. Natural selection in such viruses is observed by introduction of mutations in SARS- CoV-2 that are not observed during the growth process in humans. Infection with a mutant (Y453F) of SARS-CoV-2 from farmed minks is known to widely spread among humans. We investigated the virological characteristics of this SARS-CoV-2 mutant (Y453F) using three-dimensional protein structural analysis. Our experimental study suggests that virus variants with the Y453F mutation partially escaped detection by four neutralizing monoclonal antibodies. The spread of SARS-CoV-2 variants mediated by millions of infected farmed minks is uncontrolled; consequently, raising a concern that infection of SARS-CoV-2 mutants that cause serious symptoms in humans may spread globally.
The Coding And Small-Non-Coding Hippocampal Synaptic RNAome
Authors: Epple Robert , Krüger Dennis , Berulava Tea , Brehm Gerrit , Islam Rezaul , Köster Sarah , Fischer Andre
Published: November 2020

Neurons are highly compartmentalized cells that depend on local protein synthesis. Thus, messenger RNAs (mRNAs) have been detected in neuronal dendrites and more recently also at the pre- and postsynaptic compartment. Other RNA species, such as microRNAs, have also been described at synapses where they are believed to control mRNA availability for local translation. Nevertheless, a combined dataset analyzing the synaptic coding and non-coding RNAome via next-generation sequencing approaches is missing. Here we isolate synaptosomes from the hippocampus of young wild type mice and provide the coding and non-coding synaptic RNAome. These data are complemented by a novel approach to analyze the synaptic RNAome from primary hippocampal neurons grown in microfluidic chambers. Our data show that synaptic microRNAs control almost the entire synaptic mRNAome and we identified several hub microRNAs. By combining the in vivo synaptosomal data with our novel microfluidic chamber system, we also provide evidence to support the hypothesis that part of the synaptic microRNAome may be supplied to neurons via astrocytes. Moreover, the microfluidic system is suitable to study the dynamics of the synaptic RNAome in response to stimulation. In conclusion, our data provide a valuable resource and hint to several important targets for future experiments.
Mutations associated with pyrethroid resistance in Varroa mites, a parasite of honey bees, are widespread across the USA
Authors: Millán-Leiva Anabel , Marín Óscar , Christmon Krisztina , vanEngelsdorp Dennis , González-Cabrera Joel
Published: November 2020

BACKGROUND

Managed honey bees are key pollinators of many crops and play an essential role in the United States food production. For more than 10 years, beekeepers in the US have been reporting high rate of colony losses. One of the drivers of this colony loss is the parasitic mite Varroa destructor. Preserving healthy honey bee colonies in the US is dependent on a successful control of this mite. The pyrethroid tau-fluvalinate (Apistan®) was among the first synthetic varroacide registered in the US. With over 20 years of use, population of mites resistant to Apistan® have emerged, and so it is unsurprising that treatment failures have been reported. Resistance in US mite populations to tau-fluvalinate is associated with point mutations at position 925 of the voltage-gated sodium channel, L925I and L925M.

RESULTS

Here, we have generated a distribution map of pyrethroid resistance alleles in Varroa samples collected from US apiaries in 2016 and 2017, using a high throughput allelic discrimination assay based on TaqMan®. Our results evidence that these kdr-type mutations are widely distributed in Varroa populations across the country showing high variability among apiaries.

CONCLUSION

We highlight the relevance of monitoring the resistance in mite populations to achieve an efficient control of this pest, and the benefit of implementing this methodology in pest management programs for varroosis.
Cryo-EM structure and kinetics reveal electron transfer by 2D diffusion of cytochromecin the yeast III-IV respiratory supercomplex
Authors: Moe Agnes , Di Trani Justin , Rubinstein John L. , Brzezinski Peter
Published: November 2020

Energy conversion in aerobic organisms involves an electron current from low-potential donors, such as NADH and succinate, to dioxygen through the membrane-bound respiratory chain. Electron transfer is coupled to transmembrane proton transport that maintains the electrochemical proton gradient used to produce ATP and drive other cellular processes. Electrons are transferred between respiratory complexes III and IV (CIII and CIV) by water-soluble cyt.c. InS. cerevisiaeand some other organisms, these complexes assemble into larger CIII2CIV1/2supercomplexes, the functional significance of which has remained enigmatic. In this work, we measured the kinetics of theS. cerevisiaesupercomplex’s cyt.c-mediated QH2:O2oxidoreductase activity under various conditions. The data indicate that the electronic link between CIII and CIV is confined to the surface of the supercomplex. Cryo-EM structures of the supercomplex with cyt.creveal distinct states where the positively-charged cyt.cis bound either to CIII or CIV, or resides at intermediate positions. Collectively, the structural and kinetic data indicate that cyt.ctravels along a negatively-charged surface patch of the supercomplex. Thus, rather than enhancing electron-transfer rates by decreasing the distance cyt.cmust diffuse in 3D, formation of the CIII2CIV1/2supercomplex facilitates electron transfer by 2D diffusion of cyt.c. This mechanism enables the CIII2CIV1/2supercomplex to increase QH2:O2oxidoreductase activity and suggests a possible regulatory role for supercomplex formation in the respiratory chain.

Significance Statement

In the last steps of food oxidation in living organisms, electrons are transferred to oxygen through the membrane-bound respiratory chain. This electron transfer is mediated by mobile carriers such as membrane-bound quinone and water-soluble cyt.c. The latter transfers electrons from respiratory complex III to IV. In yeast these complexes assemble into III2IV1/2supercomplexes, but their role has remained enigmatic. This study establishes a functional role for this supramolecular assembly in the mitochondrial membrane. We used cryo-EM and kinetic studies to show that cyt.cshuttles electrons by sliding along the surface of III2IV1/2(2D diffusion). The structural arrangement into III2IV1/2supercomplexes suggests a mechanism to regulate cellular respiration.
Predicting Brain Regions Related to Alzheimer’s Disease Based on Global Feature
Authors: Wang Qi , Chen Siwei , Wang He , Chen Luzeng , Sun Yongan , Yan Guiying
Published: November 2020

Alzheimer’s disease (AD) is a common neurodegenerative disease in the elderly, early diagnosis and timely treatment are very important to delay the course of the disease. In the past, most of the brain regions related to AD were identified based on the imaging method, which can only identify some atrophic brain regions. In this work, we used mathematical models to find out the potential brain regions related to AD. First, diffusion tensor imaging (DTI) was used to construct the brain structural network. Next, we set a new local feature index 2hop-connectivity to measure the correlation among different areas. The 2hop-connectivity utilizes the higher-order information of the graph structure relative to the traditional graph theory metrics. And for this, we proposed a novel algorithm named 2hopRWR to measure 2hop-connectivity. At last, we proposed a new index GFS (Global Feature Score) based on a global feature by combing 5 local features: degree centrality, betweenness centrality, closeness centrality, the number of maximal cliques, and 2hop-connectivity, to judge which brain regions are likely related to Alzheimer’s Disease. As a result, all the top ten brain regions in the GFS scoring difference between the AD group and the non-AD group were related to AD by literature verification. Literature validation results comparing GFS with local features showed that GFS outperforms individual local features. Finally, the results of the canonical correlation analysis showed that the GFS was significantly correlated with the scores of the mini-mental state examination (MMSE) scale and the Montreal cognitive assessment (MoCA) scale. So, we believe the GFS can also be used as a new index to assist in diagnosis and objective monitoring of disease progression. Besides, the method proposed in this paper can be used as a differential network analysis method in other areas of network analysis.
FiberAI: A Deep Learning model for automated analysis of nascent DNA Fibers
Authors: Mohsin Azam , Arnovitz Stephen , Khan Aly A , Gounari Fotini
Published: November 2020

All life forms undergo cell division and are dependent on faithful DNA replication to maintain the stability of their genomes. Both intrinsic and extrinsic factors can stress the replication process and multiple checkpoint mechanisms have evolved to ensure genome stability. Understanding these molecular mechanisms is crucial for preventing and treating genomic instability associated diseases including cancer. DNA replicating fiber fluorography is a powerful technique that directly visualizes the replication process and a cell’s response to replication stress. Analysis of DNA-fiber microscopy images provides quantitative information about replication fitness. However, a bottleneck for high throughput DNA-fiber studies is that quantitative measurements are laborious when performed manually. Here we introduce FiberAI, which uses state-of-the art deep learning frameworks to detect and quantify DNA-fibers in high throughput microscopy images. FiberAI efficiently detects DNA fibers, achieving a bounding box average precision score of 0.91 and a segmentation average precision score of 0.90. We then use FiberAI to measure the integrity of replication checkpoints. FiberAI is publicly available and allows users to view model predicted selections, add their own manual selections, and easily analyze multiple image sets. Thus, FiberAI can help elucidate DNA replication processes by streamlining DNA-fiber analyses.
Comparative analysis of Wnt signaling-related proteins in normal, benign, malignant and metastasised human liver tumors
Authors: Kanwal Bushra , Zen Yoh , Deheragoda Maesha , Millar Michael , Thrasivoulou Christopher , Rashid Sheikh Tamir , Ahmed Aamir
Published: November 2020

Background and Aims

Liver cancer comprises of benign or malignant tumors including hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), hepatoblastoma (HB), and other rarer tumor types. There is evidence of aberrant Wnt signaling during initiation and progression of HCC, CC and HB.

Methods

We investigated the expression of Wnt/β-catenin transcription related proteins, Cyclin D1, c-Myc, Fra-1 and Pygo-1, in human liver tumors by using an unbiased, quantitative immunohistochemical (qIHC) approach.

Results

Semi-automated, unbiased quantitation of individual proteins revealed reduced expression of Cyclin D1 and Pygo-1 in CC (P < 0.0001 and P < 0.01, respectively) and HB (P < 0.05 and P < 0.01, respectively) compared to normal liver (NL). Receiver operating characteristic curves showed Cyclin D1 as a putative marker for CC (AUC > 0.8) that discriminates CC from both NL and HCC (P ≤ 0.0001), and Pygo-1 (AUC > 0.7) as a marker for both CC and HCC (P < 0.01) compared to NL. Combining Cyclin D1/Pygo-1 and applying a logistic regression model further improved the diagnostic potential (classifying 84% of NL and CC cases, P < 0.0001). Quantitative co-localisation of tissue samples simultaneously labeled with the four biomarkers, indicated that co-localisation of both Pygo-1/Fra-1 and c-Myc/Fra-1 was also significantly changed in CC and HCC (P < 0.0001) vs NL. Additionally, co-localisation of Pygo-1/Fra-1, in particular, could also distinguish CC from HCC (P < 0.05).

Conclusion

Our results indicate that measurement of Wnt signaling markers could be used to stratify liver cancer.
Architecture and mechanism of metazoan retromer:SNX3 tubular coat assembly
Authors: Leneva Natalya , Kovtun Oleksiy , Morado Dustin R. , Briggs John A. G. , Owen David J.
Published: November 2020

Retromer is a master regulator of cargo retrieval from endosomes, which is critical for many cellular processes including signalling, immunity, neuroprotection and virus infection. To function in different trafficking routes, retromer core (VPS26/VPS29/VPS35) assembles with a range of sorting nexins to generate tubular carriers and incorporate assorted cargoes. We elucidate the structural basis of membrane remodelling and coupled cargo recognition by assembling metazoan and fungal retromer core trimers on cargo-containing membranes with sorting nexin adaptor SNX3 and determining their structures using cryo-electron tomography. Assembly leads to formation of tubular carriers in the absence of canonical membrane curvature drivers. Interfaces in the retromer coat provide a structural explanation for Parkinson’s disease-linked mutations. We demonstrate that retromer core trimer forms an invariant, evolutionarily-conserved scaffold that can incorporate different auxiliary membrane adaptors by changing its mode of membrane recruitment, so modulating membrane bending and cargo incorporation and thereby allowing retromer to traffic assorted cargoes along different cellular transport routes.