bluuebunny/crossref_metadata_2025 huggingface dataset:
Implication of backward contact tracing in the presence of overdispersed transmission in COVID-19 outbreak
Authors: Endo Akira ,   Centre for the Mathematical Modelling of Infectious Diseases (CMMID) COVID-19 Working Group, Leclerc Quentin J , Knight Gwenan M , Medley Graham F , Atkins Katherine E , Funk Sebastian , Kucharski Adam J
Published: August 2020

Unlike forward contact tracing, backward contact tracing identifies the source of newly detected cases. This approach is particularly valuable when there is high individual-level variation in the number of secondary transmissions. By using a simple branching process model, we explored the potential of combining backward contact tracing with more conventional forward contact tracing for control of COVID-19.
EpiGraphDB: A database and data mining platform for health data science
Authors: Liu Yi , Elsworth Benjamin , Erola Pau , Haberland Valeriia , Hemani Gibran , Lyon Matt , Zheng Jie , Gaunt Tom R
Published: August 2020

Motivation

The wealth of data resources on human phenotypes, risk factors, molecular traits and therapeutic interventions presents new opportunities for population health sciences. These opportunities are paralleled by a growing need for data integration, curation and mining to increase research efficiency, reduce mis-inference and ensure reproducible research.

Results

We developed EpiGraphDB (https://epigraphdb.org/), a graph database containing an array of different biomedical and epidemiological relationships and an analytical platform to support their use in human population health data science. In addition, we present three case studies that illustrate the value of this platform. The first uses EpiGraphDB to evaluate potential pleiotropic relationships, addressing mis-inference in systematic causal analysis. In the second case study we illustrate how protein-protein interaction data offer opportunities to identify new drug targets. The final case study integrates causal inference using Mendelian randomization with relationships mined from the biomedical literature to “triangulate” evidence from different sources.

Availability

The EpiGraphDB platform is openly available athttps://epigraphdb.org. Code for replicating case study results is available athttps://github.com/MRCIEU/epigraphdbas Jupyter notebooks using the API, andhttps://mrcieu.github.io/epigraphdb-rusing the R package.

Contact

yi6240.liu@bristol.ac.uk,ben.elsworth@bristol.ac.uk,Tom.Gaunt@bristol.ac.uk
Morphometrical brain markers of sex difference
Authors: Brennan Daniel , Wu Tingting , Fan Jin
Published: August 2020

Many major neuropsychiatric pathologies, some of which appear in adolescence, show differentiated prevalence, onset, and symptomatology across the biological sexes. Therefore, mapping differences in brain structure between males and females during this critical developmental period may provide information about the neural mechanisms underlying the dimorphism of these pathologies. Utilizing a large dataset collected through the Adolescent Brain Cognitive Development study, we investigated the differences of adolescent (9-10 years old) male and female brains (n= 8325) by using a linear Support-Vector Machine Classifier to predict sex based on morphometry and image intensity values of structural brain imaging data. The classifier correctly classified the sex of 86% individuals with the insula, the precentral and postcentral gyri, and the pericallosal sulcus as the most discernable features. The role of these significant dimorphic features in psychopathology was explored by testing them as mediators between sex and clinical symptomology. The results demonstrate the existence of morphometrical brain markers of sex difference.

Significance Statement

Many psychiatric pathologies express differently across the sexes. Therefore, an understanding of the differences in brain structure between males and females during the critical developmental period of adolescence may provide the insights about the dimorphism of clinical symptomology and the general functions of the dimorphic brain structures. Using machine learning, we successfully classified males and females with a high accuracy based on morphometry and image intensity data extracted from structural MRI scans. The features which significantly contributed to classification were examined to determine brain regions which are dimorphic during adolescence. The relevance of these brain regions to the expression of psychopathology symptoms was also explored.
Dynamic encoding of saccade sequences in primate frontal eye field
Authors: Jia Jing , Puyang Zhen , Wang Qingjun , Jin Xin , Chen Aihua
Published: August 2020

Abstract

Frontal eye field (FEF) is a key part of oculomotor system, with dominant responses to the direction of single saccades. However, whether and how FEF contributes to sequential saccades remain largely unknown. Here by training rhesus monkeys to perform sequential saccades and recording the neuronal activities in FEF, we found that the sequence-related activities are clearly represented in FEF, and many neurons’ selectivity to saccade direction undergoes dynamic changes during sequential task. In addition, the sequence-related activities are context-dependent, with different firing activities during memory- versus visually-guided sequence. Supra-threshold microstimulation in FEF evokes saccade without altering the overall sequence structure. Pharmacological inactivation of FEF severely impaired the monkey’s performance of sequential saccades, with different effects on the same actions at different positions within the sequence. These results reveal the context-dependent dynamic encoding of saccade direction in FEF, and underscore a critical role of FEF in planning and execution of sequential saccades.

InBrief

Jia, Puyang et al. employed in vivo recording to reveal the dynamic encoding of sequential saccades in primate frontal eye field (FEF), then used electric microstimulation and reversible inactivation to demonstrate the causal role of FEF in controlling saccade sequences.

Highlights

FEF neurons respond differently during sequential vs. single saccades

Sequence-related FEF activity is context-dependent

FEF microstimulation induced saccade without altering sequence structure

FEF inactivation severely impaired the performance of sequential saccades
Timely Epidemic Monitoring in the Presence of Reporting Delays: Anticipating the COVID-19 Surge in New York City, September 2020
Authors: Harris Jeffrey E.
Published: August 2020

During a fast-moving epidemic, timely monitoring of case counts and other key indicators of disease spread is critical to an effective public policy response. We describe a nonparametric statistical method, originally applied to the reporting of AIDS cases in the 1980s, to estimate the distribution of reporting delays of confirmed COVID-19 cases in New York City during the late summer and early fall of 2020. During August 15 - September 26, the estimated mean delay in reporting was 3.3 days, with 87 percent of cases reported by 5 days from diagnosis. Relying upon the estimated reporting-delay distribution, we projected COVID-19 incidence during the most recent three weeks as if each case had instead been reported on the same day that the underlying diagnostic test had been performed. Applying our delay-corrected estimates to case counts reported as of September 26, we projected a surge in new diagnoses that had already occurred but had yet to be reported. Our projections were consistent with counts of confirmed cases subsequently reported by November 7. The resulting estimate of recently diagnosed cases could have had an impact on timely policy decisions to tighten social distancing measures. While the recent advent of widespread rapid antigen testing has changed the diagnostic testing landscape considerably, delays in public reporting of SARS-CoV-2 case counts remain an important barrier to effective public health policy.
Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder
Authors: Bonelli R , Jackson VE , Prasad A , Munro JE , Heeren TFC , Pontikos N , Scheppke L , Friedlander M ,   MacTel Consortium, Egan CA , Allikmets R , Ansell BRE , Bahlo M
Published: August 2020

Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p<5E-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR=3.9E-47) and glycine depletion (FDR=0.006) as well as alanine abundance (FDR=0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p=0.009). This represents the largest genetic study on MacTel to date, and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.
Using Real-World Data to Rationalize Clinical Trials Eligibility Criteria Design: A Case Study of Alzheimer’s Disease Trials
Authors: Li Qian , Guo Yi , He Zhe , Zhang Hansi , George Thomas J , Bian Jiang
Published: August 2020

Low trial generalizability is a concern. The Food and Drug Administration had guidance on broadening trial eligibility criteria to enroll underrepresented populations. However, investigators are hesitant to do so because of concerns over patient safety. There is a lack of methods to rationalize criteria design. In this study, we used data from a large research network to assess how adjustments of eligibility criteria can jointly affect generalizability and patient safety (i.e the number of serious adverse events [SAEs]). We first built a model to predict the number of SAEs. Then, leveraging an a priori generalizability assessment algorithm, we assessed the changes in the number of predicted SAEs and the generalizability score, simulating the process of dropping exclusion criteria and increasing the upper limit of continuous eligibility criteria. We argued that broadening of eligibility criteria should balance between potential increases of SAEs and generalizability using donepezil trials as a case study.
The Risk of Bias in Iranian Randomized Controlled Trials Included in Cochrane Reviews
Authors: Kabir Ali , Sofi-Mahmudi Ahmad , Behnagh Arman Karimi , Eidkhani Vahid , Baradaran Hamid Reza , Kabiri Payam , Haghdoost Ali Akbar , Mesgarpour Bita
Published: August 2020

Background

Randomised controlled trials (RCT) provide the highest level of evidence among interventional studies. However, RCTs may be susceptible to the risk of bias (RoB). Therefore, systematic reviews appraise the RoB in all included studies in a review by using evaluation tools. This study aimed to describe the main characteristics of RCTs conducted in Iran and included in Cochrane Reviews (CRs) by focusing on their RoB.

Methods

We searched “Iran” by selecting the “Search All Text” field and “Review” in the Cochrane Database of systematic Review within Ovid. We retrieved CRs that included Iranian controlled trials. We selected trials only if they had involved human subjects, described as a controlled clinical trial, included in CRs and therefore the review authors assessed their RoBs. The characteristics of trials have been extracted by looking at the table “Characteristics of included studies” in each CRs as well as the relevant papers. To addressing RoB, we collected the judgment of the review authors according to the table of RoB assessments in CRs.

Results

There were 1166 Iranian RCTs included in 571 CRs. From all these studies, 44.9% were at low RoB for random sequence generation, 20.8% for allocation concealment, 32.3% for blinding of participants/personnel, 36.5% for blinding of outcome assessors, 56.3% for incomplete outcome data, 41.3% selective reporting, and 53.8% for other bias.

Conclusion

RoB was mainly high or unclear in Iranian RCTs. Special attention must be paid to methodological quality of RCTs in Iran accordingly.
Comparing the impact on COVID-19 mortality of self-imposed behavior change and of government regulations across 13 countries
Authors: Jamison Julian C. , Bundy Donald , Jamison Dean T. , Spitz Jacob , Verguet Stéphane
Published: August 2020

Background

Countries have adopted different approaches, at different times, to reduce the transmission of coronavirus disease 2019 (COVID-19). Cross-country comparison could indicate the relative efficacy of these approaches. We assess various non-pharmaceutical interventions (NPIs) over time, comparing the effects of self-imposed (i.e. voluntary) behavior change and of changes enforced via official regulations, by statistically examining their impacts on subsequent death rates in 13 European countries.

Methods and findings

We examine two types of NPI: the introduction of government-enforced closure policies over time; and self-imposed alteration of individual behaviors in response to awareness of the epidemic, in the period prior to regulations. Our proxy for the latter is Google mobility data, which captures voluntary behavior change when disease salience is sufficiently high. The primary outcome variable is the rate of change in COVID-19 fatalities per day, 16-20 days after interventions take place. Linear multivariate regression analysis is used to evaluate impacts. Voluntarily reduced mobility, occurring prior to government policies, decreases the percent change in deaths per day by 9.2 percentage points (95% CI 4.5-14.0 pp). Government closure policies decrease the percent change in deaths per day by 14.0 percentage points (95% CI 10.8-17.2 pp). Disaggregating government policies, the most beneficial are intercity travel restrictions, cancelling public events, and closing non-essential workplaces. Other sub-components, such as closing schools and imposing stay-at-home rules, show smaller and statistically insignificant impacts.

Conclusions

This study shows that NPIs have substantially reduced fatalities arising from COVID-19. Importantly, the effect of voluntary behavior change is of the same order of magnitude as government-mandated regulations. These findings, including the substantial variation across dimensions of closure, have implications for the phased withdrawal of government policies as the epidemic recedes, and for the possible reimposition of regulations if a second wave occurs, especially given the substantial economic and human welfare consequences of maintaining lockdowns.
Relationship between Malnutrition and Functional Disability in Selected Community-Dwelling Geriatric Population in Bangladesh
Authors: Alam Mohammad Rahanur , Hossain Md. Shahadat , Chowdhury Akibul Islam , Akhter Marufa , Mamun Abdullah Al , Reza Sompa
Published: August 2020

Background

The average life expectancy of the Bangladeshi population has been rising over the last decade due to the economic growth along with improved medicare. Although the increased number of geriatric people and their health is a matter of great concern, this issue remains unnoticed here.

Objectives

To assess the nutritional status of the functionality and to analyze the association between nutritional status and functional ability of the selected Bangladeshi geriatric population.

Methods

A community-based cross-sectional study was conducted among 400 participants, covering Chittagong, Noakhali, Comilla, and Jessore district of Bangladesh from December 2019 to February 2020. A standard and pretested questionnaire containing Mini Nutritional Assessment (MNA), Tinetti Performance Oriented Mobility Assessment (POMA), Activities of daily living scale (ADL), Lawton-Brody Instrumental Activities of Daily Living Scale (IADL), was used.

Results

According to our study, The prevalence of malnutrition and people at risk of malnutrition have been 25.4% and 58.8%, respectively. In the case of functionality, 63.3% of subjects have high falling risk, and 61.8% of subjects can independently do their daily activities while 38.3% are dependent. Furthermore, almost 80% of people are dependent in terms of doing living skills. High risk of falling (OR=10.823; 95% CI: 5.846-20.37; p<0.001), poor skill in doing ADL (OR=6.206; 95% CI: 4.021-9.581; p<0.001), along with dependency in performing IADL (OR=4.477; 95% CI: 2.833-7.075; p<0.001) are significantly associated with malnutrition.

Conclusions

Geriatric malnutrition can accelerate disability conditions, which can lead to early functional aging and subsequent loss in the quality of life.
Technological Properties Of Milk For Cheese Making With The Use Of Antioxidants In Diets For Cows With Subtoxic Dose Of Nitrates
Authors: Kokaeva Marina G. , Temiraev Rustem B. , Chabaev Magomed G. , Nekrasov Roman V. , Tsis E.Yu. , Kairov Valery R. , Nikkolova Bella S. , Edigova Saida N. , Konokova Bela A.
Published: August 2020

The most effective means for denitrifying products and fat oxidation processes is to prevent contamination of grain at all stages of cultivation, processing and storage. If it was not possible to prevent these processes, it is necessary to use preparations that reduce the harmful effects of nitrates, mycotoxins and peroxides. These include antioxidants, adsorbents. The aim of the research was to study the efficiency of use in diets containing a subtoxic dose of nitrates, adsorbent preparations ofSantochinum and Mold-Zap to increase the productivity, physicochemical and technological characteristics of milk of lactating cows. To achieve this goal, scientific and economic experiment was conducted on cows of the Swiss breed.Of the 40 cows, according to the method of analoguepairs, 4 groups of 10 animals each were formed. The combined use of preparations of Santochinum at a dose of 0.5 kg/t and Mold-Zap at a dose of 1.5 kg/t of compound feed contributed to an increase in the milk of cows of the 3rdexperimental group, as compared to the control analogues, of the fat content by 0.21%, protein - by 0.17%, density - by 0.61°A, dry matter by 0.48%, vitamin C by 48.2%, vitamin A by 51.9% with a simultaneous decrease in the nitrate content by 45.1% and nitrite - by 55, 3%. Regarding the control, the milk of the cows of the 3rdexperimental group had more fat globules by 11.9%, but with a smaller diameter - by 17.4%.The addition of these preparations to the diets of cows of the 3rdexperimental grou, contributed to an increase in protein milk by 0.21%, the proportion of casein - by 0.31%, and α-casein - by 4.56%.Inthe sample of cheese from milk of cows of the 3rdexperimental group, there was an increase in the concentration of dry matter by 1.68%, protein in the dry matter - by 1.31%. After homogenization, in the milk of cows of the 3rdexperimental group, the nitrate reductase activity of xanthine oxidase exceeded 2.36 times the sample of production of cows in the control group. This technological technique contributed to the stabilization of pH=5.17 in milk, which activates the process of reducing nitrates and nitrites to ammonia. The lowest concentration of nitrates and nitrites was in the sample of cheese from the milk of animals of the 3rdexperimental group, exceeding in these parameters the control sample by 68.5 and 70.0%.
The Effects Of Heavy Metals On The Morphological And Biochemical Composition Of The Blood Of Young Cattle Taking Into Account Of Breed Features
Authors: Temiraev Rustem B. , Yuldashbaev Yusup A. , Cherchesova Susanna K. , Lamarton Sofia F. , Gappoeva Valentina S. , Kairov Valery R. , Doeva Alja N. , Kalabekov Arthur L. , Kornoukhova Inna I.
Published: August 2020

Heavy metals can selectively accumulate in certain organs and remain in them for a long time. As a result, the accumulation of metal in one or another organ may cause strongest intoxication of the animal. The purpose of the research is to study the morphological and biochemical composition of the blood of young cattle of different breeds of the dairy and dairy-and-beef direction of productivity fed in the technogenic zone in the RNO-Alania diets with a high content of heavy metals. According to the principle of analogues, taking into account the breed, origin, age, sex and body weight, 4 groups of 10 animals each of different breed were formed: Group I - black and white, Group II - Danish Red, Group III - Swiss, and Group IV - Simmental. The experimental material was statistically processed using the Microsoft Excel software for mathematical analysis. With a tendency of unreliable differences in morphological indices of blood, in diminishing numbers of erythrocytes and hemoglobin, the test breeds should be arranged in the following order: Simmental → Swiss → Red Danish → Black and White. At the same time, as compared to the animals of the black-and-white breed, the young cattle of the Simmental breed showed the best level of intermediate metabolism, which resulted in an increase in total protein and sugar in the blood, which indicates an improvement in their protein and energy metabolism; an increase in the content of albumin in the liquid internal medium and γ-globulins;an increase inconcentration oftotal lipids in serum, respectively, while reducing the level of cholesterol, which indicates an improvement fat metabolism in animals; a significant (P <0.05) decrease in blood saturation with cadmium, lead and zinc, respectively, by 26.8, 48.8 and 30.6%. The highest content of these elements was noted in the wool, then in decreasing order: in bone tissue → liver → muscle tissue → lungs → kidneys. Moreover, between the level of heavy metals in muscles, liver and lungs, on the one hand, and in the wool, bone tissue and kidneys, on the other hand, there was an inversely proportional relationship.
Nanopore direct RNA sequencing detects differential expression between human cell populations
Authors: Gleeson Josie , Lane Tracy A. , Harrison Paul J , Haerty Wilfried , Clark Michael B
Published: August 2020

Accurately quantifying gene and isoform expression changes is essential to understanding cell functions, differentiation and disease. Therefore, a crucial requirement of RNA sequencing is identifying differential expression. The recent development of long-read direct RNA (dRNA) sequencing has the potential to overcome many limitations of short and long-read sequencing methods that require RNA fragmentation, cDNA synthesis or PCR. dRNA sequences native RNA and can encompass an entire RNA in a single read. However, its ability to identify differential gene and isoform expression in complex organisms is poorly characterised. Using a mixture of synthetic controls and human SH-SY5Y cell differentiation into neuron-like cells, we show that dRNA sequencing accurately quantifies RNA expression and identifies differential expression of genes and isoforms. We generated ∼4 million dRNA reads with a median length of 991 nt. On average, reads covered 74% of SH-SY5Y transcripts and 29% were full-length. Measurement of expression and fold changes between synthetic control RNAs confirmed accurate quantification of genes and isoforms. Differential expression of 231 genes, 291 isoforms, plus 27 isoform switches were detected between undifferentiated and differentiated SH-SY5Y cells and samples clustered by differentiation state at the gene and isoform level. Genes upregulated in neuron-like cells were associated with neurogenesis. We further identified >30,000 expressed transcripts including thousands of novel splice isoforms and transcriptional units. Our results establish the ability of dRNA sequencing to identify biologically relevant differences in gene and isoform expression and perform the key capabilities of expression profiling methodologies.
Molecular Determinants of Prognosis and Evolution in Diffuse-Lower Grade Astrocytomas
Authors: Kumar Mehul , Cairncross J Gregory , Blough Michael D , Bose Pinaki
Published: August 2020

Low grade astrocytomas (LGAs) are classified based on the mutational status of the isocitrate dehydrogenase (IDH) gene. While IDH wild-type (WT) LGAs evolve rapidly to glioblastoma, mutant tumors generally have a more indolent course. To identify potential drivers of the differential progression of LGAs, we analyzed transcriptomes from The Cancer Genome Atlas. Compared to mutant LGAs, platelet-derived growth factor (PDGF) signaling is enriched in WT cases, andPDGFAis the top overexpressed gene in the pathway. Putative mechanisms for differentialPDGFAexpression included copy number gains of chromosome 7 in WT cases and methylation of thePDGFApromoter in mutant LGAs. Additionally, we found that highPDGFAexpression is associated with aneuploidy, immunosuppressive features, and worse prognosis, and that WT LGAs use multiple means to inactivate the p53 pathway to progress to GBM. Our work highlights the contribution of PDGF gene family towards the unique behaviour of LGAs.

STATEMENT OF SIGNIFICANCE

This study of gene expression in LGAs suggests that differential regulation of the PDGF pathway may underlie the different natural histories ofIDHWT andIDHmutant LGAs including divergent evolutionary trajectories to GBM. This insight may inspire new therapeutic strategies to suppress the transformation of LGAs to higher-grade cancers.
Brain Anatomical Covariation Patterns Linked to Binge Drinking and Age at First Full Drink Prior to 21 Years
Authors: Zhao Yihong , Constable R. Todd , Hien Denise , Chung Tammy , Potenza Marc N.
Published: August 2020

Binge drinking and age at first full drink of alcohol prior to 21 years (AFD<21) have been linked to neuroanatomical differences in cortical and subcortical grey matter (GM) volume, cortical thickness, and surface area. Despite the potential to reveal novel network-level relationships, structural covariation patterns among these morphological measures have yet to be examined relative to binge drinking and AFD<21. Here, we used the Joint and Individual Variance Explained (JIVE) method to characterize structural covariation patterns common across and specific to morphological measures in 293 participants (149 individuals with binge drinking and 144 healthy controls) from the Human Connectome Project (HCP). An independent dataset (Nathan Kline Institute Rockland Sample; NKI-RS) was used to examine reproducibility/ generalizability. We identified a highly reproducible joint component dominated by structural covariation between GM volume in the brainstem and thalamus proper, and GM volume and surface area in prefrontal cortical regions. Using linear mixed regression models, we found that this joint component was related to AFD<21 in both the HCP and NKI-RS datasets, whereas the individual thickness component associated with binge drinking and AFD<21 in the HCP dataset was not statistically significant in the NKI-RS sample. Taken together, our results show that a highly reproducible structural pattern involving covariation in brain regions relevant to thalamic-PFC-brainstem neural circuitry is linked to age at first full drink.
Exosome-mediated hematopoietic rejuvenation in a humanized mouse model indicate potential for cancer immunotherapy
Authors: Greco Steven J. , Ayer Seda , Guiro Khadidiatou , Sinha Garima , Donnelly Robert J. , El-Far Markos , Pamarthi Sri Harika , Sandiford Oleta A. , Gergues Marina , Sherman Lauren S. , Schonning Michael J. , Etchegaray Jean-Pierre , Ponzio Nicholas M. , Ramaswamy Narayanan , Rameshwar Pranela
Published: August 2020

Aging is associated with increased morbidity and high economic costs due to a burdened healthcare system and decreased workforce. Parabiotic animal models indicated that secretome from young cells can restore aged tissue functions. We used a heterochronic co-culture system with young and aged mobilized peripheral blood (MPB) or umbilical cord blood (UCB) and showed hematopoietic restoration, independent of allogeneic difference. Bidirectional communication between the aged and young cells influenced the miRNA cargo of exosomes, resulting in partial reprograming of the aged cells. The restored cells enhanced hematopoiesis (e.g., increased lymphoid:myeloid ratio) in immunodeficient mice bearing autologous aged hematopoietic system. Four exosomal miRNAs targeting PAX and PPMIF were partly responsible for the hematopoietic rejuvenation. Notably, increased natural killer (NK) cells within the restored cells eliminated dormant breast cancer cellsin vivo. The findings could be developed as preventive measure and treatment for sustained immune/hematopoietic competence with potential for immunotherapy.
Real time monitoring of peptidoglycan synthesis by membrane-reconstituted penicillin binding proteins
Authors: Hernández-Rocamora Víctor M. , Baranova Natalia , Peters Katharina , Breukink Eefjan , Loose Martin , Vollmer Waldemar
Published: August 2020

Peptidoglycan is an essential component of the bacterial cell envelope that surrounds the cytoplasmic membrane to protect the cell from osmotic lysis. Important antibiotics such as β-lactams and glycopeptides target peptidoglycan biosynthesis. Class A penicillin binding proteins are bifunctional membrane-bound peptidoglycan synthases that polymerize glycan chains and connect adjacent stem peptides by transpeptidation. How these enzymes work in their physiological membrane environment is poorly understood. Here we developed a novel FRET-based assay to follow in real time both reactions of class A PBPs reconstituted in liposomes or supported lipid bilayers and we demonstrate this assay with PBP1B homologues fromEscherichia coli, Pseudomonas aeruginosaandAcinetobacter baumanniiin the presence or absence of their cognate lipoprotein activator. Our assay allows unravelling the mechanisms of peptidoglycan synthesis in a lipid-bilayer environment and can be further developed to be used for high throughput screening for new antimicrobials.
Evaluation Of Biochemical, Hematological And Antioxidant Properties In Mice Exposed To A Triherbal (Nigella sativa, Carica papaya and Boswellia sacra) Formular
Authors: Kehinde S. , Adebayo S. M. , Adesiyan A. L. , Kade E. A. , Gurpreet K.
Published: August 2020

Nigella sativa, Carica papaya and Boswellia sacraare medicinal plants in the commonly used in folkloric medicine due to the presence of its immense therapeutic properties. Fifty (50) female albino mice weighing between 15-22g were divided into five groups of 10 mice each. Animal in group 1 served as control group and were administered distilled water while animal in group 2 were given 2ml of cisplatin (orally). Animal in group 3-5 were given orally; 100 mg/kg (low dose), 200 mg/kg (medium dose) and 400 mg/kg (high dose) of triherbal preparation. The feeding regimens lasted for 28 days. After 28 days, mammary gland and blood samples were collected for haematological and antioxidant analysis. The triherbal formula decreased the GSH and MDA levels of mice treated with 100 mg/kg and 400 mg/kg doses compare to control. The measurement of total protein content, SOD and CAT increased in treated animals compared to control. However, RBC (Red Blood Cell) counts significantly decreased in the low, medium and high dose groups (0.95±0.08, 6.57±0.08 and 3.55±0.55 x 106cells/mm3respectively) compared to control (7.34±0.40) at P<0.05. Also, significant decreases (P<0.05) in the level of the total WBC (White Blood Cell) count, platelet count, PCV (Packed Cell Volume) and Hb (haemoglobin) concentration were observed. The decreases were dose dependent. The MCH (Mean Corpuscular Haemoglobin) and MCHC (Mean Corpuscular Haemoglobin Concentration) except MCV (Mean Corpuscular Volume) significantly decreased in treated group only. The triherbal formulation exhibited significant antioxidant activities showing increased levels of SOD, CAT and Protein content due to activation of the enzyme involve in detoxification of free radicals and decreased in the level of GSH and MDA due to accumulation of peroxides and H2O2. Also, decreased in haematological parameters due to the presence of phytochemicals such as phenol, resins, saponins, sterols, tannis and terpenes in the triherbal formula. Therefore, it has potential to induce haematotoxicity hence consumption of high concentrations should be discouraged.
Stepwise school opening online and off-line and an impact on the epidemiology of COVID-19 in the pediatric population
Authors: Yoon Yoonsun , Kim Kyung-Ran , Park Hwanhee , Kim So young , Kim Yae-Jean
Published: August 2020

Background

Data on SARS-CoV-2 transmission from a pediatric index patient to others at the school setting are limited. Epidemiologic data on pediatric COVID-19 cases after school opening is warranted.

Methods

We analyzed data of the pediatric patients with COVID-19 collected from the press release of the Korea Centers for Disease Control and Prevention. Information on the school opening delay and re-opening policies were achieved from the press release from Korean Ministry of Education.

Findings

The school openings were delayed three times in March 2020. Online classes started from April 9, and off-line classes started from May 20 to June 8 at four steps in different grades of students. There was no sudden increase in pediatric cases after the school opening, and the proportion of pediatric cases remained around 7.0% to 7.1%. As of July 11, 45 children from 40 schools and kindergartens were diagnosed with COVID-19 after off-line classes started. More than 11,000 students and staff were tested; only one additional student was found to be infected in the same classroom. Among those 45, 32 (71.1%) patients had available information for the source of infection. Twenty-five (25/45, 55.6%) were infected by the family members. The proportions of pediatric patients without information on infection sources were higher in older age group (middle and high school students) than in younger age group (kindergarten and elementary school students) (47.6%vs12.5%,p=0.010). In the younger age group, 79.1% of children were infected by family members, while only 28.6% of adolescents in the older age group were infected by family members (p<0.001).

Interpretation

Korea had a successful transition from school closure to re-opening with online and off-line classes. Although partial, off-line school opening did not cause significant school-related outbreak among pediatric population although young children and adolescents may have different epidemiologic features.

Funding

None.
Utilisation of Remote Capillary Blood Testing in an Outpatient Clinic Setting to improve shared decision making and patient and clinician experience: a validation and pilot study
Authors: Nwankwo Lisa , McLaren Kate , Donovan Jackie , Ni Melody Zhifang , Vidal-Diaz Alberto , Loebinger Michael , Shah Anand
Published: August 2020

Background

In a tertiary respiratory centre, large cohorts of patients are managed in an outpatient setting and require blood tests to monitor disease activity and organ toxicity. This requires either visits to tertiary centres for phlebotomy and physician review or utilisation of primary care services.

Objectives

This study aims to validate remote capillary blood testing in an outpatient setting and analyse impact on clinical pathways.

Methods

A single-centre prospective cross-sectional validation and parallel observational study was performed. Remote finger prick capillary blood testing was validated compared to local standard venesection using comparative statistical analysis: paired t-test, correlation and Bland-Altman. Capillary was considered interchangeable with venous samples if all 3 criteria were met: non-significant paired t-test (i.e. p>0.05), Pearson’s correlation coefficient (r) >0.8 and 95% of tests within 10% difference through Bland-Altman (Limits of agreement). In parallel, current clinical pathways including phlebotomy practice was analysed over 4 weeks to review test predictability. A subsequent pilot cohort study analysed potential impact of remote capillary blood sampling on shared decision making and outpatient clinical pathways.

Results

117 paired capillary and venous blood samples were prospectively analysed. Interchangeability with venous blood was seen with HbA1c (%), total protein and CRP. Further tests, although not interchangeable, are likely useful to enable longitudinal remote monitoring (e.g. liver function, total IgE, and vitamin D). 65% of outpatient clinic blood tests were predictable with 16% of patients requiring further contact due to actions required. Pilot implementation of remote capillary sampling showed patient and clinician-reported improvement in shared decision-making given contemporaneous blood test results.

Conclusions

Remote capillary blood sampling can be used accurately for specific tests to monitor chronic disease, and when incorporated into an outpatient clinical pathway can improve shared decision making and patient experience. Further research is required to determine health-economic impact and applicability within telemedicine-based outpatient care.
Ethnic minority groups in England and Wales - factors affecting the size and timing of elevated COVID-19 mortality: a retrospective cohort study linking Census and death records
Authors: Ayoubkhani Daniel , Nafilyan Vahé , White Chris , Goldblatt Peter , Gaughan Charlotte , Blackwell Louisa , Rogers Nicky , Banerjee Ami , Khunti Kamlesh , Glickman Myer , Humberstone Ben , Diamond Ian
Published: August 2020

Objectives

To estimate population-level associations between ethnicity and coronavirus disease 2019 (COVID-19) mortality, and to investigate how ethnicity-specific mortality risk evolved over the course of the pandemic.

Design

Retrospective cohort study using linked administrative data.

Setting

England and Wales, deaths occurring 2 March to 15 May 2020.

Participants

Respondents to the 2011 Census of England and Wales aged ≤100 years and enumerated in private households, linked to death registrations and adjusted to account for emigration before the outcome period, who were alive on 1 March 2020 (n=47,872,412).

Main outcome measure

Death related to COVID-19, registered by 29 May 2020.

Statistical methods

We estimated hazard ratios (HRs) for ethnic minority groups compared with the White population using Cox regression models, controlling for geographical, demographic, socio-economic, occupational, and self-reported health factors. HRs were estimated on the full outcome period and separately for pre- and post-lockdown periods in the UK.

Results

In the age-adjusted models, people from all ethnic minority groups were at elevated risk of COVID-19 mortality; the HRs for Black males and females were 3.13 [95% confidence interval: 2.93 to 3.34] and 2.40 [2.20 to 2.61] respectively. However, in the fully adjusted model for females, the HRs were close to unity for all ethnic groups except Black (1.29 [1.18 to 1.42]). For males, COVID-19 mortality risk remained elevated for the Black (1.76 [1.63 to 1.90]), Bangladeshi/Pakistani (1.35 [1.21 to 1.49]) and Indian (1.30 [1.19 to 1.43]) groups. The HRs decreased after lockdown for all ethnic groups, particularly Black and Bangladeshi/Pakistani females.

Conclusions

Differences in COVID-19 mortality between ethnic groups were largely attenuated by geographical and socio-economic factors, although some residual differences remained. Lockdown was associated with reductions in excess mortality risk in ethnic minority populations, which has major implications for a second wave of infection or local spikes. Further research is needed to understand the causal mechanisms underpinning observed differences in COVID-19 mortality between ethnic groups.
Development of a Flow Cytometry-Based Whole-Blood Prognostic Immune Signature in Metastatic Cancer Patients treated with immune checkpoint inhibitors
Authors: Zhou Jian-Guo , Donaubauer Anna-Jasmina , Frey Benjamin , Becker Ina , Rutzner Sandra , Eckstein Markus , Sun Roger , Ma Hu , Schubert Philipp , Schweizer Claudia , Fietkau Rainer , Deutsch Eric , Gaipl Udo S. , Hecht Markus
Published: August 2020

Recent biomarker research focuses on early immunological changes to predict treatment response to immune checkpoint inhibitors (ICI). Within this prospective ST-ICI trial, pre-planned biomarker analysis was performed and we developed a flow cytometry-based whole-blood prognostic immune signature (FCBPS) to predict overall survival (OS) benefit of cancer patients treated with ICI. For this, fifty-four immune cell subsets were analyzed in the patients’ peripheral blood before the second administration of the ICI. Patients were randomly allocated to a training and validation cohort. Univariate Cox proportional hazards regression analysis and LASSO Cox model were used to develop a predictive and prognostic signature. 104 patients were prospectively enrolled. 89 patients provided blood samples. The identified FCBPS signature bases on five immune cell subtypes: neutrophils, plasmacytoid dendritic cells (pDCs), natural killer (NK)T cells (CD56+/CD16+), monocytes (CD14high) and CD8+ T cells (PD-1+). This signature achieved a high accuracy (C-index 0.74 vs 0.71) for predicting OS benefit in the training and validation cohort. Both in the training and validation cohort, the low-risk group had significantly longer OS than the high-risk group (HR 0.26, 95% CI: 0.12-0.56, p=0.00025; HR 0.30, 95% CI: 0.10 −0.91, p=0.024,respectively). In the whole cohort, FCBPS is a predictor of OS (HROS=0.28, 95% CI: 0.15-0.52) and progression-free survival (HRPFS=0.22, 95% CI: 0.12-0.39) that remained independent in multivariate analyses and subgroup analyses after adjusting for clinical and pathological factors. The identified flow cytometry-based whole-blood prognostic signature (FCBPS) is a powerful predictor for metastatic cancer patients who benefit from ICI treatment.

Trial registration

Prospectively registered in ClinicalTrials.gov (NCT03453892) on January 24, 2018.
Cost burden of type 2 diabetes mellitus (DM) in an urban area of Bangladesh: A hospital-based mix method study
Authors: Saha Monidipa , Kader Shirmin Bintay , Chowdhury Shafquat Haider , Hasan Md. Khaledul , Ashraf Mir Nabila , Rahman Md. Marufur , Koly Kamrun Nahar
Published: August 2020

Background

Longtime treatment of diabetic patients is an added burden for countries that had low GDP and no health insurance facilities like Bangladesh. Urgent cost assessment and proper strategy needs to be developed to overcome the economic burden of a diabetic patient.

Methodology

We have conducted a mixed-methods study in a Bangladesh Institute of Health Sciences (BIHS), a sister concern of BIRDEM hospital between August 2019 to January 2020. Quantitative data was collected by a survey questionnaire from the patients and qualitative data was collected by interviewing five key informants of the facility center.

Results

329 known diabetic patients were enrolled, out of the 70.48% were female and the rest of them were male. The mean age of the respondents was 53.73 years. Nearly 35% of them had a positive family history, and more than 30% of them had both hypertension and dyslipidemia along with DM. The total average cost per year was ∼600USD, which includes drug, investigation, consultancy & transportation costs. Among which drug costs were the most (∼350 USD).We had found that drug cost & investigation cost had a significant associated with increased age, level of education, and the duration of DM. Investigation cost was also associated with positive family history.

Conclusions

As there is no insurance coverage in Bangladesh and subsidy are not available, many of the patients from the lower socio-economic group might discontinue the treatment. Further prospective research is needed to develop a proper guideline for policymakers.

Strength & Limitation

It’s the first mixed method study which discuss about the cost burden of type 2 DM

KII was performed and perspective about the cost burden of type 2 DM from doctors view was reported.

Described that treatment of DM is often hampered due to lack of family & workplace support.

Our only methodological limitation is our sample size, which was smaller than other quantitave studies.
Effect of Aerobic Exercise on Amyloid Accumulation in Preclinical Alzheimer’s: A 1-Year Randomized Controlled Trial
Authors: Vidoni Eric D. , Morris Jill K. , Watts Amber , Perry Mark , Clutton Jon , Van Sciver Angela , Kamat Ashwini S , Mahnken Jonathan , Hunt Suzanne L. , Townley Ryan , Honea Robyn , Shaw Ashley R. , Johnson David K. , Vacek James , Burns Jeffrey M.
Published: August 2020

Background

Our goal was to investigate the role of physical exercise to protect brain health as we age, including the potential to mitigate Alzheimer’s-related pathology. We assessed the effect of 52 weeks of a supervised aerobic exercise program on amyloid accumulation, cognitive performance, and brain volume in cognitively normal older adults with elevated and sub-threshold levels of cerebral amyloid as measured by amyloid PET imaging.

Methods and Findings

This 52-week randomized controlled trial compared the effects of 150 minutes per week of aerobic exercise vs. education control intervention. A total of 117 older adults (mean age 72.9 [7.7]) without evidence of cognitive impairment, with elevated (n=79) or subthreshold (n=38) levels of cerebral amyloid were randomized, and 110 participants completed the study. Exercise was conducted with supervision and monitoring by trained exercise specialists. We conducted 18F-AV45 PET imaging of cerebral amyloid and anatomical MRI for whole brain and hippocampal volume at baseline and Week 52 follow-up to index brain health. Neuropsychological tests were conducted at baseline, Week 26, and Week 52 to assess executive function, verbal memory, and visuospatial cognitive domains. Cardiorespiratory fitness testing was performed at baseline and Week 52 to assess response to exercise. The aerobic exercise group significantly improved cardiorespiratory fitness (11% vs. 1% in the control group) but there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control.

Conclusions

Aerobic exercise was not associated with reduced amyloid accumulation in cognitively normal older adults with cerebral amyloid. In spite of strong systemic cardiorespiratory effects of the intervention, the observed lack of cognitive or brain structure benefits suggests brain benefits of exercise reported in other studies are likely to be related to non-amyloid effects.

Trial Registration

ClinicalTrials.govNCT02000583.