bluuebunny/crossref_metadata_2025 huggingface dataset:
Circular mRNA encoded PROTAC (RiboPROTAC) as a new platform for the degradation of intracellular therapeutic targets
Authors: Yang Jiali , Sun Jiaojiao , Zhu Jiafeng , Du Yaran , Tan Yiling , Wei Lixiang , Zhao Yang , Hou Qiangbo , Zhang Yan , Sun Zhenhua , Zuo Chijian
Published: May 2022

Although proteolysis targeting chimera (PROTAC) technology that hijacking the ubiquitin-proteasome system (UPS) to artificially degrade protein is an emerging promising technology for many undruggable targets, it still faces several challenges, such as the difficulty to select high specificity molecule to protein of interest (POI), and only few of the E3-ligase are suitable for PROTAC mediated protein degradation. Protein-based PROTAC, termed BioPROTAC, owns the advantage of specificity but lacks membrane permeability. Here, we develop a new targeted protein degrading platform, which we termed RiboPROTAC, by encoding BioPROTAC protein degraders with circular mRNA (cmRNA) and delivering intracellularly. In this way, intracellular protein GFP and nuclear protein PCNA were successfully degraded. For PCNA targeting, not only the level of target protein is strongly decreased, but also the cell function related is strongly interfered, such as cell proliferation, apoptosis, as well as the cell cycle. What is more, for the first time, we observed that degrading PCNA with RiboPROTAC causes immunogenic cell death (ICD), although not strong, but was verified in vivo. Importantly, our in vivo results demonstrated that cmRNA encoded PCNA degrader exhibited significant tumor suppression effect, thus we provide the first proof of concept for the application of RiboPROTAC as potential mRNA therapeutic. We consider that RiboPROTAC is a new and superior PROTAC technology for targeting the undruggable targets.
A method to enrich polypeptidyl-tRNAs to capture snapshots of translation in the cell
Authors: Yamakawa Ayako , Niwa Tatsuya , Chadani Yuhei , Kobo Akinao , Taguchi Hideki
Published: May 2022

Life depends on proteins, which all exist in nascent states when the growing polypeptide chain is covalently attached to a tRNA within the ribosome. Although the nascent chains; i.e., polypeptidyl-tRNAs (pep-tRNAs), are considered as merely transient intermediates during protein synthesis, recent advances have revealed that they are directly involved in a variety of cell functions, such as gene expression control. An increasing appreciation for fine-tuning at translational levels demands a general method to handle the pep-tRNAs on a large scale. Here, we developed a method termed peptidyl-tRNA enrichment using organic extraction and silica adsorption (PETEOS), and then identify their polypeptide moieties by mass spectrometry. As a proof-of-concept experiment using Escherichia coli, we identified ∼800 proteins derived from the pep-tRNAs, which were markedly biased towards the N-termini in the proteins, reflecting that PETEOS captured the intermediate pep-tRNA population during translation. Furthermore, we observed the changes in the pep-tRNA set in response to heat shock or antibiotic treatments. In summary, PETEOS will complement conventional methods for profiling nascent chains such as ribosome profiling.

Significance Statement

In the central dogma of biology, RNA and protein are usually regarded as two completely independent molecular species. However, they are combined into a single species called peptidyl-tRNA (pep-tRNA) during the translation process in the ribosome. Despite the importance of pep-tRNAs as precursors of all proteins in the cell, a general method to analyze pep-tRNAs on a large scale was lacking. Taking advantage of the properties of pep-tRNAs as RNA and protein, we developed a method to enrich the pep-tRNAs by organic solvent extraction and silica column separation. The method, termed PETEOS, not only provides a unique approach to examine the nascent state of proteins but also may be effective in capturing snapshots of translation status in the cell.
Saturation mutagenesis of a predicted ancestral Syk-family kinase
Authors: Hobbs Helen T. , Shah Neel H. , Shoemaker Sophie R. , Amacher Jeanine F. , Marqusee Susan , Kuriyan John
Published: May 2022

Many tyrosine kinases cannot be expressed readily in E. coli, limiting facile production of these proteins for biochemical experiments. We used ancestral sequence reconstruction to generate a spleen tyrosine kinase (Syk) variant that can be expressed in bacteria and purified in soluble form, unlike the human members of this family (Syk and ZAP-70). The catalytic activity, substrate specificity, and regulation by phosphorylation of this Syk variant are similar to the corresponding properties of human Syk and ZAP-70. Taking advantage of the ability to express this novel Syk-family kinase in bacteria, we developed a two-hybrid assay that couples the growth of E.coli in the presence of an antibiotic to successful phosphorylation of a bait peptide by the kinase. Using this assay, we screened a site-saturation mutagenesis library of the kinase domain of this reconstructed Syk-family kinase. Sites of loss-of-function mutations identified in the screen correlate well with residues established previously as critical to function and/or structure in protein kinases. We also identified activating mutations in the regulatory hydrophobic spine and activation loop, which are within key motifs involved in kinase regulation. Strikingly, one mutation in an ancestral Syk-family variant increases the soluble expression of the protein by 75-fold. Thus, through ancestral sequence reconstruction followed by deep mutational scanning, we have generated Syk-family kinase variants that can be expressed in bacteria with very high yield.
Ancestral Body Plan and Adaptive Radiation of Sauropterygian Marine Reptiles
Authors: Wang Wei , Shang Qinghua , Cheng Long , Wu Xiao-Chun , Li Chun
Published: May 2022

Mesozoic was the age of reptiles that not only occupied the land and sky but also adapted to the sea. Sauropterygia, from turtle-like placodonts, lizard-like pachypleurosaurs, and predatory nothosaurs to long-necked pistosaurs including plesiosaurs, is one of the most predominant lineages among secondarily aquatic reptiles. However, we know little about the early evolution of sauropterygians involving the morphological gaps among aforementioned sub-groups and their ancestral body-plan, because the Early Triassic fossil remains are scarce shortly after their origin. Here we report a skeleton from the Early Triassic in South China, representing the oldest known complete specimen related to Sauropterygia. It can be referred to Hanosaurus hupehensis and shows a mosaic morphology combining the characters of multiple sauropterygian sub-lineages. We constructed an updated character matrix obtaining the hitherto most comprehensive phylogeny of Triassic sauropterygians, and Hanosaurus hupehensis is stably resolved as the basal-most member of the Sauropterygiformes (clade nov.). Sauropterygians were previously considered using limb propulsion for the movement that is distinguishable from ichthyosaurs and other marine reptiles, but this skeleton reflects an ancestral body plan of sauropterygians unexpectedly developing an elongate trunk and four short limbs, being different from most sauropterygians but more convergently similar to the basal members of other marine reptilian lineages in body shape. After this convergence, we confirm the rapid adaptive radiation of sauropterygiform reptiles following the end-Permian mass extinction. Our results provide an evolutionary framework of sauropterygian marine reptiles and highlight the integrations of both convergences and divergences when an emerging animal lineage arises.
A highly contiguous, scaffold-level nuclear genome assembly for the Fever tree (Cinchona pubescens Vahl) as a novel resource for research in the Rubiaceae
Authors: Canales Nataly Allasi , Pérez-Escobar Oscar A. , Powell Robyn F. , Töpel Mats , Kidner Catherine , Nesbitt Mark , Maldonado Carla , Barnes Christopher J. , Rønsted Nina , Przelomska Natalia A. S. , Leitch Ilia J. , Antonelli Alexandre
Published: May 2022

Background

The Andean Fever tree (Cinchona L.; Rubiaceae) is the iconic source of bioactive quinine alkaloids, which have been vital to treating malaria for centuries. C. pubescens Vahl, in particular, has been an essential source of income for several countries within its native range in north-western South America. However, an absence of available genomic resources is essential for placing the Cinchona species within the tree of life and setting the foundation for exploring the evolution and biosynthesis of quinine alkaloids.

Findings

We address this gap by providing the first highly contiguous and annotated nuclear and organelle genome assemblies for C. pubescens. Using a combination of ∼120 Gb of long sequencing reads derived from the Oxford Nanopore PromethION platform and 142 Gb of short-read Illumina data. Our nuclear genome assembly comprises 603 scaffolds comprising a total length of 904 Mb, and the completeness represents ∼85% of the genome size (1.1 Gb/1C). This draft genome sequence was complemented by annotating 72,305 CDSs using a combination of de novo and reference-based transcriptome assemblies. Completeness analysis revealed that our assembly is moderately complete, displaying 83% of the BUSCO gene set and a small fraction of genes (4.6%) classified as fragmented. Additionally, we report C. pubescens plastome with a length of ∼157 Kb and a GC content of 37.74%. We demonstrate the utility of these novel genomic resources by placing C. pubescens in the Gentianales order using additional plastid and nuclear datasets.

Conclusions

Our study provides the first genomic resource for C. pubescens, thus opening new research avenues, including the provision of crucial genetic resources for analysis of alkaloid biosynthesis in the Fever tree.
Top-down modulation of the retinal code via histaminergic neurons of the hypothalamus
Authors: Warwick Rebekah A. , Riccitelli Serena , Heukamp Alina S. , Yaakov Hadar , Ankri Lea , Mayzel Jonathan , Gilead Noa , Parness-Yossifon Reut , Rivlin-Etzion Michal
Published: May 2022

The mammalian retina is considered an autonomous circuit, yet work dating back to Ramon y Cajal indicates that it receives inputs from the brain. How such inputs affect retinal processing has remained unknown. We identified brain-to-retina projections of histaminergic neurons from the mouse hypothalamus, which densely innervated the dorsal retina. Histamine application, or chemogenetic activation of histaminergic axons, altered spontaneous and light-evoked activity of various retinal ganglion cells (RGCs), including direction-selective RGCs. These cells exhibited broader directional tuning and gained responses to high motion velocities. Such changes could improve vision when objects move fast across the visual field (e.g. while running), which fits with the known increased activity of histaminergic neurons during arousal. In humans, an antihistamine drug non-uniformly modulated visual sensitivity across the visual field, indicating an evolutionary conserved function of the histaminergic system. Our findings expose a previously unappreciated role for brain-to-retina projections in modulating retinal function.
Generation of Gausemycin A-resistant Staphylococcus aureus
Authors: Poshvina Darya V. , Dilbaryan Diana S. , Kasyanov Sergey P. , Sadykova Vera S. , Lapchinskaya Olda A. , Rogozhin Eugene A. , Vasilchenko Alexey S.
Published: May 2022

Gausemycins A and B are the first members of the novel lipoglycopeptides family produced by Streptomyces roseoflavus INA-Ac-5812, which showed the ability to fight clinically important Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. However, new antibiotics need to be studied in depth to determine their full potential. In this study, we concentrated our efforts to investigate resistance emerging within S. aureus upon gausemycin A application.

Using serial passaging of S. aureus FDA209P in increasing concentrations of gausemycin A, we obtained the resistant variant S. aureus 5812R which are 80-times more resistant comparing to the origin strain. Moreover, obtained resistance is stable, since 15 passages in a drug-free medium did not restore bacterial susceptibility to gausemycin A.

Elucidating of the differences between resistant and parent strains was concerned antibiotic cross-resistance, structure of bacterial membrane, and response at genetic level.

Susceptibility testing of S. aureus 5812R revealed the acquisition of cross-resistance to daptomycin, cefazolin, and tetracycline, while resistance to vancomycin, nisin and ramoplanin absence. The composition of fatty acids constituting the cytoplasmic membrane of S. aureus 5812R, was represented by increased content of anteiso- branched chain fatty acids, while iso-branched chain fatty acids was decreased comparing the origin S. aureus FDA209P strain. The relative expression of the cls gene catalyzing the synthesis of cardiolipin in the resistant cells was higher compared to the S. aureus FDA209P.
Efficacy and Specificity of Melanopsin Reporters for Retinal Ganglion Cells
Authors: Maloney Ryan , Quattrochi Lauren , Yoon James , Souza Rachel , Berson David
Published: May 2022

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are specialized retinal output neurons that mediate behavioral, neuroendocrine, and developmental responses to environmental light. There are diverse molecular strategies for marking ipRGCs, especially in mice, making them among the best characterized retinal ganglion cells. With the development of more sensitive reporters, new subtypes of ipRGCs have emerged. We therefore tested high-sensitivity reporter systems to see whether we could reveal yet more. Substantial confusion remains about which of the available methods, if any, label all and only ipRGCs. Here, we compared many different methods for labeling of ipRGCs, including anti-melanopsin immunofluorescence, Opn4-GFP BAC transgenic mice, and Opn4cre mice crossed with three different Cre-specific reporters (Z/EG; Ai9; and Ai14) or injected with Cre-dependent (DIO) AAV2. We show that Opn4cre mice, when crossed with sensitive Cre-reporter mice, label numerous ganglion cell types that lack intrinsic photosensitivity. Though other methods label ipRGCs specifically, they do not label the entire population of ipRGCs. We conclude that no existing method labels all and only ipRGCs. We assess the appropriateness of each reporter for particular applications and integrate findings across reporters to estimate that the overall abundance of ipRGCs among mouse retinal ganglion cells may approach 11%.
Computational analysis of 4-1BB-induced NFκB signaling suggests improvements to CAR cell design
Authors: Tserunyan Vardges , Finley Stacey D.
Published: May 2022

Background

Chimeric antigen receptor (CAR)-expressing cells are a powerful modality of adoptive cell therapy against cancer. The strength and dynamics of signaling events initiated upon antigen binding depend on the costimulatory domain within the structure of the CAR. One such costimulatory domain is 4-1BB, which affects cellular response via the NFκB pathway. However, the quantitative aspects of 4-1BB-induced NFκB signaling are not fully understood.

Methods

We developed an ordinary differential equation-based mathematical model representing canonical NFκB signaling activated by CAR-4-1BB. We first performed a global sensitivity analysis on our model to quantify the impact of kinetic parameters and initial protein concentrations. We ran Monte Carlo simulations of cell population-wide variability in NFκB signaling and used Kraskov’s algorithm to quantify the mutual information between the extracellular signal and different levels of the NFκB signal transduction pathway.

Results

We determined that in response to a wide range of antigen concentrations, the magnitude of the transient peak in the nuclear concentration of NFκB varies significantly, while the timing of this peak is relatively consistent. Our global sensitivity analysis showed that the model is robust to variations in parameter values, and thus, its quantitative predictions would remain applicable to a broad range of parameter values. Next, we found that overexpressing NEMO and disabling IKKβ deactivation are predicted to increase the mutual information between antigen levels and NFκB activation.

Conclusions

Our modeling predictions provide actionable insights to guide CAR development. Particularly, we propose specific manipulations to the NFκB signal transduction pathway that can fine-tune the response of CAR-4-1BB cells to the antigen concentrations they are likely to encounter.
T32 training is associated with increased likelihood of obtaining an academic research faculty position: a cross-sectional study
Authors: Mueller Adrienne L. , Schnirel Addie , Kleppner Sofie , Tsao Philip , Leeper Nicholas J.
Published: May 2022

Background

The main mission of NIH-sponsored institutional training programs such as the T32 is to provide strong research and career training for early career scientists, while preparing those individuals to become leaders working to meet the health-related research needs of the nation. One of the main avenues to pursue health-related research is becoming research faculty at an academic institution. It is therefore important to know whether these programs are succeeding in this mission, or, if barriers exist that prevent trainees from pursuing these careers.

Methods

Our institution currently trains ~ 2400 post-doctoral scholars per year, approximately 5% of whom are enrolled in one of our 33 T32 programs. In this study, we 1) compare the professional outcomes of T32 trainees with non-T32 trainees at our institution, and 2) survey past and current T32 trainees in a subset of high-performing cardiovascular programs about the barriers and enablers they experienced to pursuing research-oriented careers.

Results

Former T32 trainees are significantly more likely to attain appointments as primarily research faculty members, compared to other trainees. Trainees report a perceived lack of stability, the paucity of open positions, and the ‘publish or perish’ competitive mentality of academia as their top reasons for abandoning careers in academia. However, they were still more likely to choose research over clinical careers after participating in a dedicated T32 program.

Conclusions

Our results support the conclusion that structured training programs strengthen the pipeline of young scientists pursuing careers in academic research, including those from underrepresented backgrounds. However, T32 postdoctoral researchers are held back from pursuing academic careers by a perceived lack of stability and high competition for faculty positions.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Cocoa extract exerts sex-specific anti-diabetic effects in an aggressive type-2 diabetes model: a pilot study
Authors: Racine Kathryn C. , Iglesias-Carres Lisard , Herring Jacob A. , Ferruzzi Mario G. , Kay Colin D. , Tessem Jeffery S. , Neilson Andrew P.
Published: May 2022

Type 2 diabetes (T2D) is characterized by hyperglycemia and insulin resistance. Cocoa may slow T2D development and progression. This study employed male and female BTBR.Cg-Lepob/ob/WiscJ (ob/ob) and wild type (WT) controls to assess the potential for cocoa to ameliorate progressive T2D and compare responses between sexes. Mice received diet without (WT,ob/ob) or with cocoa extract (ob/ob+ c) for 10 weeks. Acute cocoa reduced fasting hyperglycemia in females, but not males, after 2 weeks. Chronic cocoa supplementation (6-10 weeks) ameliorated hyperinsulinemia in males and worsened hyperlipidemia and hyperinsulinemia in females, yet also preserved and enhanced beta cell survival in females. The underlying mechanisms of these differences warrant further study. If sex differences are apparent in subsequent preclinical studies, clinical studies will be warranted to establish whether these differences are relevant in humans. Sex differences may need to be considered when designing human dietary interventions for T2D.
Estimates of excess mortality for the five Nordic countries during the Covid-19 pandemic 2020-2021
Authors: Kepp Kasper P. , Björk Jonas , Bæk Kristoffer T. , Lallukka Tea
Published: May 2022

Excess deaths during the covid-19 pandemic are of major scientific and political interest. Here we review excess all-cause death estimates from different methods for the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden), which have been much studied during the covid-19 pandemic. In the comparison of the methods, we use simple sensitivity estimates and linear interpolations of the death data to discuss uncertainties and implications for reporting ratios and infection fatality rates. We show using back-calculation of expected deaths from Nordic all-cause deaths that a recent study in Lancet, which is a clear outlier in the overviewed estimates, most likely substantially overestimates excess deaths of Finland and Denmark, and probably Sweden. The other estimates are more consistent and suggest a range of total Nordic excess deaths of approximately half of that in the Lancet study, a more uniform ability to identify covid-19-related deaths, and more similar infection fatality rates for the Nordic countries.
Reaching the Remote: Dried blood spot analysis for disease diagnosis on a protein microarray platform
Authors: Mowoe Metoboroghene O. , Rensburg Tristan , Ali Hisham , Gqada Joshua , Kotze Urda , Bernon Marc , Africa Bradley , Jonas Eduard , Blackburn Jonathan M.
Published: May 2022

Cancer remains one of the leading causes of death globally with an estimated 19.3 million cases and 10 million mortalities in 2020. In Africa and Asia, where remoteness is prevalent, access to healthcare facilities is limited, providing a significant barrier to effective screening and early detection of cancers in at-risk groups and thus, incomplete registries. Here, we utilised low resource, low-cost dried blood spots (DBS)-based sample collection coupled with robust, protein microarray technology to enable quantitative, multiplexed measurements of diagnostic autoantibody biomarkers of disease, in minimal sample volumes. Specifically, we describe the development of a DBS extraction and elution method from low cost, home-made blood cards. We then show that DBS stored at room temperature (25 □, RT) for up to 15 d yield comparable autoantibody signatures to autologous serum samples stored at -80 □ and those from samples prepared on a commercially available blood card. We further conducted a pilot study, comparing total IgG and three previously identified autoantibodies upregulated in pancreatic cancer (PC), in DBS from 11 PC patients stored at RT for up to 15 d. We found comparable protein profiles across commercially developed blood cards and our low cost, in-house kit with no significant difference in autoantibody profiles over 15 d (p > 0.05). Such low cost, DBSbased sample collection methods, combined with regular, RT courier shipments and ultrasensitive protein microarraybased detection in a remote laboratory, thus have the potential to facilitate future, unbiased, large scale serosurveys and serological diagnostic testing within remote, rural communities.
Exposure to Prenatal Social Disadvantage and Maternal Psychosocial Stress: Relationships to Neonatal White Matter Connectivity
Authors: Lean Rachel E. , Smyser Christopher D. , Brady Rebecca G. , Triplett Regina L. , Kaplan Sydney , Kenley Jeanette K. , Shimony Joshua S. , Smyser Tara A. , Miller J. Phillip , Barch Deanna M. , Luby Joan L. , Warner Barbara B. , Rogers Cynthia E.
Published: May 2022

Childhood exposure to poverty and related psychosocial stressors are associated with altered microstructure in fronto-limbic pathways evident at age 8-10 years. How early in neurodevelopment these associations can be detected remains unclear. In this longitudinal study, 399 mothers were oversampled for low income and completed social experience and background measures during pregnancy. Measures were analyzed with structural equation analysis resulting in two latent constructs: Social Disadvantage (education, insurance status, income-to-needs ratio [INR], neighborhood deprivation, nutrition) and Psychosocial Stress (depression, stress, life events, racial discrimination). At birth, 289 healthy term-born neonates underwent a diffusion MRI (dMRI) scan. Mean diffusivity (MD) and fractional anisotropy (FA) were measured for the dorsal and inferior cingulum bundle (CB), uncinate, and fornix using probabilistic tractography in FSL. Social Disadvantage and Psychosocial Stress were fitted to dMRI parameters using regression models adjusted for infant postmenstrual age at scan and sex. Social Disadvantage, but not Psychosocial Stress, was independently associated with lower MD in the bilateral inferior CB and left uncinate, right fornix, and lower MD and higher FA in the right dorsal CB. Results persisted after accounting for maternal medical risk in pregnancy and prenatal drug exposure. In moderation analysis, Psychosocial Stress was associated with lower MD in the left inferior CB among the lower-to-higher SES (INR ≥200%) group, but not the extremely low SES (INR <200%) group. Increasing access to social welfare programs that reduce the burden of poverty and related psychosocial stressors may be an important target to protect fetal brain development in fronto-limbic pathways.
Accurate Prostate Cancer Detection based on Circulating Tumor Cell Profiling
Authors: Limaye Sewanti , Chowdhury Simon , Rohatgi Nitesh , Ranade Anantbhushan , Syed Nelofer , Riedemann Johann , Page Raymond , Patil Darshana , Akolkar Dadasaheb , Datta Vineet , Patil Revati , Bendale Kiran , Fulmali Pooja , Fulmali Pradeep , Apurwa Sachin , Schuster Stefan , Murthy Sudha S , Bose Chirantan , John Jinumary , Srinivasan Ajay , Datar Rajan
Published: May 2022

Background

Evaluation of serum prostate specific antigen (PSA) is a part of standard prostate cancer diagnostic work-up in symptomatic males as well as for elective prostate cancer screening in asymptomatic males. The low specificity of serum PSA leading to an inability to effectively differentiate prostate cancer from benign prostate conditions is a persistent clinical challenge. Further, the low sensitivity of serum PSA leading to false negatives can miss high-grade / aggressive prostate cancers.

Objective

We describe a non-invasive prostate cancer detection test based on functional enrichment of prostate adenocarcinoma associated circulating tumor cells (PrAD-CTCs) from blood samples and their identification via immunostaining for pan-cytokeratins (PanCK), prostate specific membrane antigen (PSMA), alpha methyl-acyl coenzyme-A racemase (AMACR), epithelial cell adhesion molecule (EpCAM) and common leucocyte antigen (CD45).

Design, Setting, and Participants

The analytical validation studies used VCaP reference prostate cancer cell line to evaluate the performance characteristics of the test. The clinical performance characteristics of the test were first evaluated in a case-control study with 160 known prostate cancer cases and 800 healthy males. A prospective clinical study was performed with samples from 210 suspected cases of prostate cancer.

Outcome Measurements and Statistical Analysis

Analytical validation established analyte stability as well as acceptable performance characteristics. The test showed 100% specificity and 100% sensitivity to differentiate prostate cancer cases from healthy individuals in the case control study and 91.2% sensitivity and 100% specificity to differentiate prostate cancers from benign prostate conditions in the prospective clinical study.

Results and Limitations

The test accurately detects PrAD-CTCs with high sensitivity and specificity irrespective of stage or grade (Gleason score), which translates into low risks of false negatives or overdiagnosis. The test does not detect minor non-adenocarcinoma subtypes of prostate cancer.

Conclusions

The high accuracy of the test offers advantages over PSA based prostate cancer detection.
The maternal anthropometry and hemoglobin status in relations to newborn birth weight among primiparous mothers at Adama Hospital Medical College, Eastern Ethiopia: a cross-sectional study
Authors: Sento Midekso , Negera Atoma
Published: May 2022

Background

Anthropometric measurements are quantitative measurements of the human body size, shape, and nutritional status. It is a simple, inexpensive, and non-invasive approach used to identify mothers at risk of labor outcomes. On the other hand, hematological disorders are common during pregnancy with deleterious health effects on the mother and the fetus, which consequently cause fetal growth retardation and low weight.

Objectives

To assess the relationship between maternal anthropometry and hemoglobin status with the newborn birth weight among primiparous mothers at Adama Hospital Medical College, Eastern Ethiopia 2021.

Methods

An institutional-based cross-sectional study design involving 269 primiparous pregnant mothers was conducted at Adama Hospital Medical College from September 15 to October 30, 2021. The consecutive sampling technique was used till the required sample size was attained. Interviewer-administered questionnaires, instruments for anthropometric measurement, hemoglobinometer, and electronic weighing scales were used to collect the data. The data was entered into EpiData version 3.1 and exported to SPSS software version 21 for analysis. Multivariate logistic regression was used to analyze the relationship between the independent variables and the outcome variables.

Results

About 269 mothers and their neonates participated in this study. Multivariate logistic regression shows that maternal ANC visit less than two [AOR=4.149, 95% CI: (1.27, 13.52)], maternal height [AOR= 0.878, 95% CI: (0.806, 0.95)], and maternal Hgb <11g/dl [AOR=4.127, 95% CI: (1.63, 10.43)] were significantly associated with the occurrences of low birth weight (p<0.05).

Conclusion

This study has shown that maternal anthropometric characteristics and hemoglobin status were important factors associated birth weight. Health facilities should emphasize routine measurements of maternal anthropometry and hemoglobin during ANC visits in order to reduce complications related to labor outcomes.
Comparison of mechanical homogenization versus enzymatic digestion sample preparation methodologies for SARS-CoV-2 detection in saliva for surveillance of variants of concern on the University of Tennessee campus in early 2021
Authors: Poindexter Magen R. , Xu Tingting , Swift Cynthia M. , Proctor Caleb M , Kara-Murdoch Fadime , Morehouse Zachary P , Ryan Gabriella L , Löffler Frank E. , Nash Rodney J
Published: May 2022

The SARS-CoV-2 pandemic has profoundly impacted communities across the globe, requiring accurate and accessible diagnostic technologies in support of public health mitigation efforts. As testing has evolved throughout the course of the pandemic, varying sample preparation methodologies have been employed. Herein we perform a comparison of three commercial sample preparation methods: two mechanical homogenization workflows and one enzymatic digestion approach for the detection of SARS-CoV-2 from biomarker genes in 20 human saliva pools. SARS-CoV-2 variants of concern were also identified on the University of Tennessee, Knoxville campus during the spring semester of 2021 utilizing the commercial PerkinElmer PKamp VariantDetect SARS-CoV-2 RT-PCR Assay kit. Two hundred and ten (210) human saliva pools were selected and analyzed for the presence of SARS-CoV-2 variants of concern providing insight into the utility of these various commercial workflows for integration into current public health SARS-CoV-2 surveillance measures.
Sleep Duration and the Prevalence of Metabolic Syndrome in adolescents and children: a Systematic Review and Meta-analysis
Authors: Xu Yiyang , Hua Jianian , Shen Yueping
Published: May 2022

Objective

Previous studies discussing the association between sleep duration and the prevalence of metabolic syndrome have reported different results, most of which targeted at adults. We are devoted to investigating the effects of sleep time for metabolic syndrome in children conducting a meta-analysis.

Methods

Several cross-sectional studies were retrieved from Pubmed, Ovid, Cochrane, and Embase from inception to October 2021. Fixed-effect models and random-effect models were used to analyze the effects of sleep time on metabolic syndrome in adolescents based on the research above.

Results

We collected data from 10 cross-sectional studies including 15877 children. Using random-effect models, compared with normal sleep time, we found out that both relatively short (OR = 0.81, 95%CI = 0.55-1.07, I-squared = 45.6%, p = 0.075) and long (OR = 0.86, 95%CI = 0.54-1.19, I-squared = 67.8%, p = 0.003) sleep durations were not associated with high prevalence of metabolic syndrome in adolescents and children. Using fixed-effect model on short sleep duration and it turned out to be statistically significant (OR = 0.76, 95%CI = 0.59-0.93).

Conclusions

Long sleep duration made no significant difference in the risk of metabolic syndrome in adolescents and children, while short sleep duration seems to be a protective factor. Further studies are required to establish whether the association is causal and modifiable.
Empowering Research on Epilepsy Surgery Outcomes
Authors: Dickey Adam S. , Krafty Robert T. , Pedersen Nigel P.
Published: May 2022

Low statistical power is a recognized problem in many fields. We performed a systematic review to determine the median statistical power of studies of epilepsy surgery outcomes. We performed a PubMed search for studies reporting epilepsy surgery outcomes for the years 1980-2020, focusing on studies using stereoelectroencephalography (SEEG). We extracted patient count data for comparisons of surgical outcome between two groups, based on a reported prognostic factor. We defined a clinically meaningful difference as the difference in seizure freedom for MRI positive (66.9%) versus negative (45.5%) from the largest study found. Based on 69 studies of surgery outcomes in patients undergoing SEEG, the median sample size was 38 patients, and the median statistical power was 24%. This implies at least a 17% chance a study with a significant result is false, assuming 1:1 pre-test odds. Results from simulation studies suggest that, if a typical SEEG study finds a significant effect, then the median observed effect size will be more than double the true effect size. We conclude that studies of epilepsy surgery outcomes using SEEG are often statistically underpowered, which limits the reproducibility and reliability of the literature. We discuss how statistical power could be improved.

SHORT SUMMARY

We performed a systematic review to determine the median statistical power of studies of epilepsy surgery outcomes, focused on stereoelectroencephalography. We extracted patient count data for comparisons of outcomes between two groups. We defined a clinically meaningful difference as the prognostic value of a normal versus abnormal MRI. Based on 69 studies, the median sample size was 38 patients, and the median statistical power was 24%. Underpowered studies will overestimate the size of true effects and are more likely to report false positive results. We discuss how statistical power, and thus reproducibility and reliability of results, can be improved.
Infection prevention and control preparedness among public hospitals and COVID-19 temporary treatment and monitoring facilities in the Philippines
Authors: de Claro Vergil , Bautista Noemi , Torralba Ma. Rosario , Castro Vina Vanessa , Lucero Miguel Angelo , Molleno Lady Jedfeliz , Stan Laurentiu
Published: May 2022

Objectives

An effective response to COVID-19 necessitates rigid compliance of health facilities to infection prevention and control (IPC) protocols to protect HCWs, prevent onward transmission, and mitigate the impact of the outbreak on the health care system. The study aims to assess the compliance of public hospitals and temporary treatment and monitoring facilities (TTMFs) to IPC standards for COVID-19.

Methods

A baseline assessment survey was conducted between July 20 to August 18, 2020, from selected facilities in 38 local government units (LGU) across the country utilising a 35-point questionnaire corresponding to a set of standards issued by the Philippine Department of Health.

Results

The study shows that public hospitals reported sufficient IPC preparedness and compliance compared to TTMFs in the domains of engineering and administrative controls. Both types of facilities reported weak compliance in the use of color-coded bags and in having a central storage for infectious waste. In addition, among TTMFs adherence to proper labelling of waste bins, presence of instructional materials for waste disposal, directional signages for movements of HCWs and patients, availability of an IPC policy, and advocacy materials on proper handwashing, respiratory etiquette, and physical distancing, and PPE use were also low.

Conclusion

The COVID-19 pandemic has shown the importance of IPC preparedness among health care facilities to effectively prevent disease transmission and mitigate its impact on the health care system. The findings suggests that periodic monitoring and augmentation of resources are needed to immediately address the compliance gaps. However, systemic improvements and long-term investments are required to sustain IPC practices over time.

What is already known?

Infection prevention and control measures are effective at protecting patients and health care workers from facility-acquired infections and averting onward transmission of the disease.

What are the new findings?

Findings from this study highlight the critical gaps in infection prevention and control preparedness among established healthcare settings like hospitals and in repurposed spaces such as temporary facilities for COVID-19 isolation that were primarily set up to manage the surge in cases.

What do the new findings imply?

It focuses attention on the periodic monitoring of health facilities’ compliance to standard infection prevention and control practices especially during outbreak situations as a basis for identifying immediate resource and technical requirements, and for planning the needed investments in the long term.
Photoacoustic imaging to monitor outcomes during hyperbaric oxygen therapy: Validation in a small cohort and case study in a bilateral chronic ischemic wound
Authors: Mantri Yash , Mishra Aditya , Anderson Caesar A. , Jokerst Jesse V.
Published: May 2022

Diseases of the microcirculatory system are well-known risk factors for chronic wound healing. Hyperbaric oxygen therapy (HBO2) is a common therapeutic modality that drives oxygen into hypoxic tissue to promote healing. Ischemia/hypoxia are common confounding variables associated with failure of wound progress and/or relapse, and hence it is important to develop tools that map and measure perfusion and oxygen saturation in the wound bed. Photoacoustic (PA) imaging is an ideal tool to address these concerns. Ten patients undergoing HBO2underwent PA oximetry of the left radial artery and forearm pre- and post-HBO2; this cohort validated the use of PA imaging in HBO2. There was a significant increase in radial artery oxygenation after HBO2(p=0.002) in the validation cohort. PA significantly underestimated arterial oxygenation compared to a pulse oximeter. We also include a case study: a non-diabetic male in his 50s (HB 010) presenting with bilateral ischemic and gangrenous wounds. HB 010 underwent additional scanning of the wound sites both pre- and post-HBO2. HB 010 showed higher perfusion and oxygen saturation on the right foot than the left after HBO2which correlated with independent surgical observations. Imaging assisted with limb salvage treatment options by limiting the initial amputation site to only the toes. Hence, this work shows that PA imaging can measure changes in arterial oxygen saturation due to HBO2; it can also produce 3D maps of tissue oxygenation and evaluate response to therapy during HBO2.

Key Points

Photoacoustic oximetry can measure and map changes in arterial oxygenation due to hyperbaric oxygen therapy. Photoacoustic imaging shows changes in perfusion in a patient presenting with bilateral ischemic and gangrenous wounds and thus informing limb salvage treatment.
ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10
Authors: Morato Torres C. Alejandra , Zafar Faria , Tsai Yu-Chih , Vazquez Jocelyn Palafox , Gallagher Michael D. , McLaughlin Ian , Hong Karl , Lai Jill , Lee Joyce , Chirino-Perez Amanda , Romero-Molina Angel Omar , Torres Francisco , Fernandez-Ruiz Juan , Ashizawa Tetsuo , Ziegle Janet , Jiménez Gil Francisco Javier , Schüle Birgitt
Published: May 2022

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850 to 4500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures.

Here, we describe a Hispanic kindred in which we identified both pure (ATTCT)n expansions and mixed (ATTCT)n-(ATTCC)n in the same family. We used No-Amp targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism in the repeat expansion. This mosaicism was confirmed in skin fibroblasts from ATXN10 carriers with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson’s disease or are unaffected even more than 20 years older than the average age at onset for SCA10.

Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions, including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions is critical for clinical practice, and genetic counseling as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.
Green space and loneliness: a systematic review with theoretical and methodological guidance for future research
Authors: Astell-Burt Thomas , Hartig Terry , Putra I Gusti Ngurah Edi , Walsan Ramya , Dendup Tashi , Feng Xiaoqi
Published: May 2022

Urban greening may help to reduce the population health impacts of loneliness and its concomitants, such as hopelessness and despair. However, the literature lacks both a critical appraisal of extant evidence and a conceptual model to explain how green space would work as a structural intervention. Both are needed to guide decision making and further research. We conducted a systematic review of quantitative studies testing associations between green space and loneliness, searching seven databases. Twenty two studies were identified by 25/01/2022. Most of the studies were conducted in high-income countries and fifteen (68%) had cross-sectional designs. Green space was measured inconsistently using either objective or subjective indicators. Few studies examined specific green space types or qualities. The majority of studies measured general loneliness (e.g. using the UCLA loneliness scale). Different types of loneliness (social, emotional, existential) were not analysed. Of 132 associations, 88 (66.6%) indicated potential protection from green space against loneliness, with 44 (33.3%) reaching statistical significance (p<0.05). We integrated these findings with evidence from qualitative studies to elaborate and extend the existing pathway domain model linking green space and health. These elaborations and extensions acknowledge the following: (a) different types of green space have implications for different types of loneliness; (b) multilevel circumstances influence the likelihood a person will benefit or suffer harm from green space; (c) personal, relational, and collective processes operate within different domains of pathways linking green space with loneliness and its concomitants; (d) loneliness and its concomitants are explicitly positioned as mediators within the broader causal system that links green space with health and wellbeing. This review and model provide guidance for decision making and further epidemiological research on green space and loneliness.
Using set visualization techniques to investigate and explain patterns of missing values in electronic health records
Authors: Ruddle Roy A. , Adnan Muhammad , Hall Marlous
Published: May 2022

Objectives

Missing data is the most common data quality issue in electronic health records (EHRs). Checks are typically limited to counting the number of missing values in individual fields, but researchers and organisations need to understand multi-field missing data patterns, and counts or numerical summaries are poorly suited to that. This study shows how set-based visualization enables multi-field missing data patterns to be discovered and investigated.

Design

Development and evaluation of interactive set visualization techniques to find patterns of missing data and generate actionable insights.

Setting and participants

Anonymised Admitted Patient Care health records for NHS hospitals and independent sector providers in England. The visualization and data mining software was run over 16 million records and 86 fields in the dataset.

Results

The dataset contained 960 million missing values. Set visualization bar charts showed how those values were distributed across the fields, including several fields that, unexpectedly, were not complete. Set intersection heatmaps revealed unexpected gaps in diagnosis, operation and date fields. Information gain ratio and entropy calculations allowed us to identify the origin of each unexpected pattern, in terms of the values of other fields.

Conclusions

Our findings show how set visualization reveals important insights about multi-field missing data patterns in large EHR datasets. The study revealed both rare and widespread data quality issues that were previously unknown to an epidemiologist, and allowed a particular part of a specific hospital to be pinpointed as the origin of rare issues that NHS Digital did not know exist.

ARTICLE SUMMARY

Strengths and limitations of this study

This study demonstrates the utility of interactive set visualization techniques for finding and explaining patterns of missing values in electronic health records, irrespective of whether those patterns are common or rare.

The techniques were evaluated in a case study with a large (16-million record; 86 field) Admitted Patient Care dataset from NHS hospitals.

There was only one data table in the dataset. However, ways to adapt the techniques for longitudinal data and relational databases are described.

The evaluation only involved one dataset, but that was from a national organisation that provides many similar datasets each year to researchers and organisations.