bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence and Predictors of Antiretroviral Treatment Failure among Children in Public Health Facilities of Kolfe Keranyo Sub-City, Addis Ababa, Ethiopia: Institution-based retrospective cohort study
Authors: Misasew Meseret , Angassa Daniel 
Published: March 2022

AbstractBackgroundHuman immunodeficiency virus (HIV) infection is a public health concern globally. The numbers of people living with HIV worldwide in 2018 was estimated at 37.9 million; from those, 1.7 million are children. Globally, 62% of the 37.9 million people were receiving Antiretroviral treatment (ART); 53% had achieved viral suppression. This study aimed to assess the incidence and predictors of Antiretroviral treatment failure among children in Kolfe Keranyo sub-city, Addis Ababa, Ethiopia.MethodsAn institution-based retrospective cohort study was conducted among 250 children who were enrolled to first-line Antiretroviral treatment from January 2013 to May 2020 in Kolfe Keranyo sub-city. Data was collected by using data extraction checklist and data were extracted by reviewing children’s medical chart and electronic database. Kaplan–Meier method was used to estimate the probability of treatment failure. During bivariable analysis variables with p-value < 0.25 were taken for multivariable Cox regression analysis to assess predictors of treatment failure. Statistically significant association was declared at p-value < 0.05 with 95% confidence interval.ResultThe overall treatment failure rate within the follow-up period was 17.2%. This study also found that the overall incidence density rate was 3.45% (95% CI: 2.57-4.67) per 1000 person-month observation. Infant prophylaxis for PMTCT (AHR: 3.59, 95% CI: 1.65-7,82), drug substitution (AHR: 0.18, 95% CI: 0.09-0.37), AZT/3TC/NVP based regimen (AHR: 2.27, 95% CI: 1.14-4.25), and more than 3 episodes of poor ART adherence (AHR: 2.27, 95% CI: 1.17-4.38) were found to be predictors of treatment failure among children.ConclusionHigh proportion of treatment failure was found among children on first-line ART in Kolfe Keranyo sub-city, Addis Ababa. Infant prophylaxis for PMTCT, drug substitution, initial regimen, and poor ART adherence were found to be predictors of first-line ART treatment failure. Close follow-up of children on medication adherence and effective trainings to health care professionals need to be considered.
Modestly protective cytomegalovirus vaccination of young children effectively prevents congenital infection at the population level
Authors: Byrne Catherine , Coombs Daniel , Gantt Soren 
Published: March 2022

AbstractA vaccine to prevent congenital cytomegalovirus infection (cCMV) is a public health priority. cCMV results from maternal primary or non-primary CMV infection (reinfection or reactivation of chronic infection) during pregnancy. Young children are a major source of transmission to pregnant women because they shed CMV at high viral loads for prolonged periods. CMV vaccines evaluated in clinical trials so far have demonstrated only approximately 50% efficacy against maternal primary infection. None of these have been approved, as higher levels of vaccine-induced immunity are assumed to be required to substantially reduce cCMV prevalence. Here, we designed a mathematical model to capture the relationship between viral shedding by young children and maternal CMV infections during pregnancy. Using this model, we were able to quantify the efficacy of CMV immunity following infection to protect against reinfection and viral shedding. There was a 35% reduction in the risk of infection to a seropositive person (reinfection) versus a seronegative person (primary infection), given the same exposure. Viral shedding following reinfection was only 25% the quantity of that following primary infection. We also found that a vaccine that confers the equivalent of infection-induced immunity, when given to young children, markedly reduces both CMV transmission to pregnant women and rates of cCMV. Thus, we predict that vaccine candidates that have already been shown to be only modestly protective may in fact be highly effective at preventing cCMV by interrupting child-to-mother transmission.
T1/T2 Ratio Imaging Improves Cortical Lesion Contrast in Multiple Sclerosis on 3T MRI
Authors: Manning Abigail R , Beck Erin S. , Schindler Matthew K. , Nair Govind , Parvathaneni Prasanna , Reich Daniel S. , Shinohara Russell T. , Solomon Andrew J. 
Published: March 2022

ABSTRACTBackgroundCortical demyelinated lesions are prevalent in multiple sclerosis (MS) and associated with disability; their presence on MRI has recently been incorporated into MS diagnostic criteria. Presently, advanced and ultra-high-field MRI — not routinely available in clinical practice — are the most sensitive methods for detection of cortical lesions, and approaches utilizing MRI sequences obtainable in routine clinical practice remain an unmet need.ObjectiveTo assess the sensitivity of the ratio of T1-weighted and T2-weighted (T1/T2) signal intensity for focal cortical lesions in comparison to other established, sensitive, advanced and high-field imaging methods.Methods3-tesla (3T) and 7-tesla (7T) MRI collected from 10 adults with MS participating in a natural history study at the National Institutes of Health were included in the study. T1/T2 images were calculated by dividing 3T T1w images by 3T T2w fluid-attenuated inversion recovery (FLAIR) images for each participant. Cortical lesions were identified using 7T T2*w and T1w images and corresponding voxels were assessed on registered 3T images. For each participant, ratios derived from the median signal intensity of nonlesional tissue in the cortical region of the lesion and the median lesional voxel intensity were computed. These values were compared across 3T imaging sequences, including the calculated T1/T2 image, as well as T1w, T2w, and Inversion Recovery Susceptibility Weighted Imaging with Enhanced T2 weighting (IR-SWIET) images.Results614 cortical lesions were identified on 7T images. 3T T1/T2 images demonstrated a larger contrast between median nonlesional cortical signal intensity and median cortical lesion signal intensity (median ratio = 1.29, range 1.19 – 1.38) when compared to T1w (1.01, 0.97 – 1.10, p<0.002), T2w (1.17, 1.07 – 1.26, p<0.002), and IR-SWIET (1.21, 1.01 – 1.29, p<0.03).ConclusionT1/T2 images are sensitive to cortical lesions. Approaches incorporating T1/T2 could improve the accessibility of cortical lesion detection in research settings and clinical practice.
Altered Cerebral Blood Flow in Older Adults with Alzheimer’s Disease: A Systematic Review
Authors: Swinford Cecily G. , Risacher Shannon L. , Wu Yu-Chien , Apostolova Liana G. , Gao Sujuan , Saykin Andrew J. 
Published: March 2022

ABSTRACTThe prevalence of Alzheimer’s disease is projected to reach 13 million in the U.S. by 2050. Although major efforts have been made to avoid this outcome, so far there are no treatments that can stop or reverse the progressive cognitive decline that defines Alzheimer’s disease. The utilization of preventative treatment before significant cognitive decline has occurred may ultimately be the solution, necessitating a reliable biomarker of preclinical/prodromal disease stages to determine which older adults are most at risk. Quantitative cerebral blood flow is a promising potential early biomarker for Alzheimer’s disease, but the spatiotemporal patterns of altered cerebral blood flow in Alzheimer’s disease are not fully understood. The current systematic review compiles the findings of 29 original studies that compared quantitative cerebral blood flow in older adults with mild cognitive impairment or Alzheimer’s disease to that of cognitively normal older adults and/or assessed the relationship between cerebral blood flow and objective cognitive function. Individuals with Alzheimer’s disease had relatively decreased cerebral blood flow in all brain regions investigated, especially the temporoparietal and posterior cingulate, while individuals with mild cognitive impairment had less consistent results, with relatively increased cerebral blood flow reported in the temporal lobe and thalamus. Most papers reported a positive correlation between cerebral blood flow and cognitive function. This review highlights the need for more studies comparing cerebral blood flow between cognitively normal individuals and those with mild cognitive impairment, as well as the importance of including potential confounding factors in these analyses.
SPAG6 promotes cell migration and induces epithelial-to-mesenchymal transition in luminal breast cancer cells
Authors: Mijnes Jolein , Bringezu Sarah , Berger Jonas , Schalla Carmen , Rose Michael , von Serenyi Sonja , Knüchel-Clarke Ruth , Sechi Antonio , Dahl Edgar 
Published: March 2022

AbstractUnderstanding the involvement of promoter DNA methylation changes in the development of breast cancer may be highly informative for designing more effective therapeutic treatments. We recently characterized the Sperm Associated Antigen 6 (SPAG6) gene, encoding a flagellar motility protein, as a potential DNA methylation biomarker for blood-based early breast cancer detection. Here we present the first study to evaluate the functional role of SPAG6 in human breast cancer. In silico analysis of the HumanMethylation450 BeadChip and Illumina HiSeq data of The Cancer Genome Atlas (TCGA) was performed in both normal (n=114) and breast cancer patient tissues (n=1104) to determine SPAG6 DNA methylation and expression. Stable SPAG6 overexpressing cancer models for in vitro analysis were obtained by lentivirus-mediated gene delivery in T-47D, MCF-7, MDA-MB-231 and BT-549 breast cancer cells. Subsequently stable mock and SPAG6 cell lines were compared in cellular assays. In addition, involvement of SPAG6 in EMT was analysed by qPCR and immunolabeling experiments. All major molecular subtypes of breast cancer (luminal A, luminal B, basal-type, HER2-enriched) revealed a tumor-specific increased SPAG6 promoter hypermethylation that correlated with strong reduction in SPAG6 mRNA expression. Interestingly, a small group of luminal breast tumors exhibited SPAG6 mRNA overexpression compared to normal breast tissue. SPAG6 overexpression caused a significant reduction (p<0.05) in colony formation in basal MDA-MB-231 and BT-549 cells. In turn, luminal T-47D cells overexpressing SPAG6 showed a significant increase in colony formation (p=0.0004) and both T-47D-and MCF-7 cells overexpressing SPAG6 exhibited a robust increase in migration speed (p<0.0001). In SPAG6-positive T-47D cells SNAIL, TWIST1 and Vimentin expression was found to be significantly upregulated, while E-Cadherin expression was supressed. SPAG6 overexpressing T47D cells showed a typical epithelial-mesenchymal transition (EMT). This was accompanied by a nearly complete displacement of both actin and E-cadherin from cell-cell junctions. Our in vitro analyses give functional evidence that SPAG6 has a profound effect on colony formation, migration and intercellular junction composition in breast cancer cells. Our study is the first to show opposing SPAG6 effects in a single tumour entity depending on the molecular subtype. We propose that SPAG6 might be a key player for inducing the EMT program in luminal-type breast cancers, driving tumour progression and metastasis.
Species-specific bacterial detector for fast pathogen diagnosis of severe pneumonia patients in the intensive care unit
Authors: Wang Yan , Liang Xiaohui , Jiang Yuqian , Dong Danjiang , Zhang Cong , Song Tianqiang , Chen Ming , You Yong , Liu Han , Ge Min , Dai Haibin , Xi Fengchan , Zhou Wanqing , Chen Jian-Qun , Wang Qiang , Chen Qihan , Yu Wenkui 
Published: March 2022

AbstractRapid diagnosis of pathogens is the cornerstone of appropriate therapy and is also a great challenge to be overcome. Although NGS and some other PCR-based pathogen detection methods were applied to improve the speed and accuracy of clinical diagnosis, it was still a long way from the clinical needs of rapid and accurate diagnostic therapy in the intensive care unit (ICU). In this study, we aimed at developing a new rapid diagnostic tool, Species-Specific Bacterial Detector (SSBD), to evaluate the existence and quantification of 10 most usual pathogenic bacteria in ICU in 4 hours. Briefly, the species-specific genome fragments of each bacterium were identified by our algorithm using 1791 microbe genomes from 232 species and then used to combine with CRISPR/Cas12 to establish diagnosis tools. Based on the tests of 77 samples, SSBD demonstrated 100% sensitivity and 87% specificity compared with conventional culture test (CCT). Later on, an interventional random-grouped study was applied to evaluate the clinical benefits of SSBD. Briefly, SSBD demonstrated more accurate and faster diagnosis results and led to earlier antibiotics adjustment than CCT. Based on the results acquired by SSBD, cultivation results could deviate from the real pathogenic situation with polymicrobial infections. In addition, nosocomial infections were found widely in ICU, which should deserve more attention.
Impact of supplementary air filtration on airborne particulate matter in a UK hospital ward
Authors: Sloof D , Butler MB , Peters C , Conway Morris A , Gouliouris T , Thaxter R , Keevil VL , Beggs CB 
Published: March 2022

AbstractBackgroundDuring the COVID-19 pandemic, aerosol spread of SARS-CoV-2 has been a major problem in healthcare facilities, resulting in increased use of supplementary HEPA filtration to mitigate transmission. We report here a natural experiment that occurred when an air filtration unit (AFU) on an inpatient ward for older people was accidentally switched off.AimTo assess aerosol transport within the ward and determine whether the AFU reduced particulate matter (PM) levels in the air.MethodsTime-series PM, CO2, temperature and humidity data (at 1 minute intervals) was collected from multiple sensors around the ward over two days in August 2021. During this period, the AFU was accidentally switched off for approximately 7 hours, allowing the impact of the intervention on particulates (PM1-PM10) to be assessed using a Mann-Whitney test. Pearson correlation analysis of the PM and CO2 signals was also undertaken to evaluate the movement of airborne particulates around the ward.FindingsThe AFU greatly reduced PM counts of all sizes throughout the ward space (p<0.001 for all sensors), with PM signals positively correlated with indoor CO2 levels (r = 0.343 – 0.817; all p<0.001). Aerosol particle counts tended to rise and fall simultaneously throughout the ward space when the AFU was off, with PM signals from multiple locations highly correlated (e.g. r = 0.343 – 0.868 (all p<0.001) for PM1).ConclusionAerosols freely migrated between the various sub-compartments of the ward, suggesting that social distancing measures alone cannot prevent nosocomial transmission of SARS-CoV-2. The AFU greatly reduced PM levels throughout the ward space.Practical implicationsAerosols can freely migrate throughout whole wards, suggesting that social distancing measures alone are not enough to prevent SARS-CoV-2 transmission.Appropriately sized supplementary room air filtration, if utilised correctly, can greatly reduce aerosol levels throughout ward spaces.Air filtration devices are often placed in rooms without any consideration given to their performance. It is therefore important to commission air filtration devices using PM and CO2 sensors before they are utilised in order to demonstrate that they are effective throughout entire ward spaces.
Sex and genetic specific effects on behavioral, but not metabolic, responses to a high fat diet in heterogeneous stock rats
Authors: Deal Aaron W , Thurman Andrew , Seshie Osborne , Szalanczy Alexandria , Beeson Angela , Cockerham Mackenzie , Risemberg Ellen L , Lenzo Anne , Ozimek Noelle , Langefeld Carl , Valdar William , Solberg Woods Leah C 
Published: March 2022

AbstractObesity is a growing epidemic associated with a range of comorbidities, including anxiety and depression. Genetics and environmental factors such as diet contribute to both adiposity and anxiety/depression. Heterogeneous stock (HS) rats are an outbred colony and useful for genetic mapping of complex traits. We have previously shown that HS male rats exhibit worsened metabolic and behavioral health in response to high fat diet (HFD). This study aims to determine if females have similar response to diet and if response to diet interacts with genetic background. We measured multiple metabolic (body weight, fat pad weight, glucose tolerance, fasting glucose and insulin) and behavioral (elevated plus maze, open field test, and forced swim test) outcomes in a large cohort of male and female rats on either HFD or low fat diet (LFD). We estimated overall heritability as well as heritability of response to diet for each outcome. Both sexes showed worsened metabolic measures when fed HFD compared to LFD. In contrast, only males exhibited altered behavioral responses to HFD relative to LFD, with no effect in females. Most metabolic and behavioral measures showed overall heritability in both sexes. In contrast, although there was some evidence for gene by diet (GxD) interactions for behavioral measures in males, GxD interactions were generally not found for the metabolic measures. These data demonstrate an important role of diet, sex and genetics in metabolic and behavioral phenotypes in HS rats, with a potential role of gene by diet interactions for behavioral outcomes only in males.
Population dynamics of free-roaming dogs in Europe and implications for population control
Authors: Smith L. M. , Goold C. , Quinnell R. J. , Munteanu A.M. , Hartmann S. , Villa P. Dalla , Collins L.M. 
Published: March 2022

AbstractChanges in free-roaming dog population size are important indicators of the effectiveness of dog population management. Assessing the effectiveness of different management methods also requires estimating the processes that change population size, such as the rates of recruitment into and removal from a population. This is one of the first studies to quantify the size, rates of recruitment and removal, and health and welfare status of free-roaming dog populations in Europe. We determined the size, dynamics, and health status of free-roaming dog populations in Pescara, Italy, and Lviv, Ukraine, over a 15-month study period. Both study populations had ongoing dog population management through catch-neuter-release and sheltering programmes. Average monthly apparent survival probability was 0.93 (95% CI 0.81-1.00) in Pescara and 0.93 (95% CI 0.84-0.99) in Lviv. An average of 7 dogs km-2 were observed in Pescara and 40 dogs km-2 in Lviv. Per capita entry probabilities varied between 0.09 and 0.20 in Pescara, and 0.12 and 0.42 in Lviv. In Lviv, detection probability was lower on weekdays (odds ratio: 0.74, 95% CI 0.53-0.96) and higher on market days (odds ratio: 2.58, 95% CI 1.28-4.14), and apparent survival probability was lower in males (odds ratio: 0.25, 95% CI 0.03-0.59). Few juveniles were observed in the study populations, indicating that recruitment may be occurring by movement between dog subpopulations (e.g. from local owned or neighbouring free-roaming dog populations), with important consequences for population control. This study provides important data for planning effective dog population management and for informing population and infectious disease modelling. The results emphasise the importance of dog population management efforts that encourage responsible ownership through reduced abandonment and cover the entire city to reduce the risk of dog movement between sections of the city hindering management efforts.
Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database
Authors: Rajcsanyi Luisa Sophie , Zheng Yiran , Fischer-Posovszky Pamela , Wabitsch Martin , Hebebrand Johannes , Hinney Anke 
Published: March 2022

AbstractHomozygosity for pathogenic variants in the leptin gene leads to congenital leptin deficiency causing early-onset extreme obesity. This monogenic form of obesity has mainly been detected in patients from consanguineous families. Prevalence estimates for the general population using the Exome Aggregation Consortium (ExAC) database reported a low frequency of leptin mutations. One in approximately 15 million individuals will be homozygous for a deleterious leptin variant. With the present study, we aimed to extend these findings utilizing the augmented Genome Aggregation Database (gnomAD) v2.1.1 including more than 140,000 samples. In total, 68 non-synonymous and 7 loss-of-function (LoF) leptin variants were deposited in gnomAD. By predicting functional implications with the help of in silico tools, like SIFT, PolyPhen2 and MutationTaster2021, the prevalence of hetero- and homozygosity for putatively pathological variants (n = 32; pathogenic prediction by at least two tools) in the leptin gene were calculated. Across all populations, the estimated prevalence for heterozygosity for functionally relevant variants was approximately 1:2,100 and 1:17,860,000 for homozygosity. This prevalence deviated between the individual populations. Accordingly, people from South Asia were at greater risk to carry a possibly damaging leptin variant than individuals of other ancestries. Generally, this study emphasises the scarcity of deleterious leptin variants in the general population with varying prevalence for distinct study groups.
Rad51 is a druggable target that sustains replication fork progression upon DNA replication stress
Authors: Feu Sònia , Unzueta Fernando , Ercilla Amaia , Jaumot Montserrat , Agell Neus 
Published: March 2022

AbstractSolving the problems that replication forks encounter when synthesizing DNA is essential to prevent genomic instability. Besides their role in DNA repair in the G2 phase, several homologous recombination proteins, specifically Rad51, have prominent roles in the S phase. Using different cellular models, Rad51 has been shown not only to be present at ongoing and arrested replication forks but also to be involved in nascent DNA protection and replication fork restart. Through pharmacological inhibition, here we study the specific role of Rad51 in the S phase. Rad51 inhibition in non-transformed cell lines did not have a major effect on replication fork progression under non-perturbed conditions, but when the same cells were subjected to replication stress, Rad51 became necessary to maintain replication fork progression. Notably, the inhibition or depletion of Rad51 did not compromise fork integrity when subjected to hydroxyurea treatment. Rad51 inhibition also did not decrease the ability to restart, but rather compromised, fork progression during reinitiation. In agreement with the presence of basal replication stress in human colorectal cancer cells, Rad51 inhibition reduced replication fork speed in these cells and increased γH2Ax foci under control conditions. These alterations could have resulted from the reduced association of DNA polymerase α to chromatin, as observed when inhibiting Rad51. It may be possible to exploit the differential dependence of non-transformed cells versus colorectal cancer cells on Rad51 activity under basal conditions to design new therapies that specifically target cancer cells.
Identification of consensus hairpin loop structure among the negative sense sub-genomic RNAs of SARS-CoV-2
Authors: Bokolia Naveen Prakash , Gadepalli Ravisekhar 
Published: March 2022

AbstractSARS-CoV-2 is the causative agent of worldwide pandemic disease COVID-19. SARS-CoV-2 bears positive sense RNA genome, that have organized and complex pattern of replication/transcription process including the generation of subgenomic RNAs. Transcription regulatory sequences (TRS) have important role in the pausing of replication/transcription and generation of subgenomic RNAs. In the present bioinformatics analysis a consensus secondary structure was identified among negative sense subgenomic RNAs at the adjacent of initiation codon. This study proposed that consensus structured domain could involve in mediating the long pausing of replication/transcription complex and responsible for subgenomic RNA production.