bluuebunny/crossref_metadata_2025 huggingface dataset:
THE RELATIONSHIP BETWEEN SOCIOECONOMIC STATUS AND THE OUTCOME OF LUMBAR EPIDURAL STEROID INJECTIONS FOR LUMBAR RADICULOPATHY
Authors: Jayabalan Prakash , Bergman Rachel , Huang Kevin , Maas Matthew , Welty Leah
Published: April 2022

OBJECTIVE

Investigate the relationship between socioeconomic status (SES) and pain reduction from epidural steroid injections (ESIs) for lumbar radiculopathy.

METHODS

The retrospective cohort consisted of patients undergoing ESI for lumbar radiculopathy (n = 544). Numeric pain rating scale (NPRS) was measured at baseline and two weeks post-ESI. SES was estimated using median family income in patients’ ZIP code. Linear and mixed models examined demographic and clinical differences in pain pre- and post-injection and whether family income moderated the effect.

RESULTS

Majority of patients were white (72.4%), female (56.4%), engaged in physical activity (68.2%), and underwent unilateral, transforaminal ESI (86.0%, and 92.1%, respectively). Non-white patients and those who did not engage in physical activity had higher baseline pain (p < 0.05)). Lower SES was associated with higher baseline pain (β = 0.06 per $10,000p = 0.01). Patients with lower SES experienced larger improvement in pain following ESI:-1.56 units for patients in the 10th percentile of family income versus -0.81for 90th percentile. Being a current smoker was associated with higher pain (β = 0.76 p = 0.03) and engaging in structured physical activity less pain (β = -0.07 p < 0.01).

CONCLUSIONS

Lower SES was independently associated with higher pain alleviation after controlling for other potentially influential demographics. Modifiable lifestyle factors maybe a target of potential intervention.
THE RELATIONSHIP BETWEEN CACHEXIA AND THE FUNCTIONAL PROGRESS OF PATIENTS WITH CANCER IN INPATIENT REHABILITATION
Authors: Roy Ishan , Huang Kevin , Bhakta Akash , Marquez Emily , Spangenberg Jacqueline , Jayabalan Prakash
Published: April 2022

Purpose

While inpatient rehabilitation can improve functional independence in patients with cancer, the role of cachexia in this population is unknown. Our objectives were to: 1) Establish prevalence of cachexia in a cohort of cancer patients receiving inpatient rehabilitation and its association with demographic and oncological history. 2) Determine the relationship between the presence of cachexia and functional recovery and whether these patients in inpatient rehabilitation have a distinct prognosis

Methods

Retrospective cohort study of 250 patients over 330 admissions to an Inpatient Rehabilitation Facility. Body weight loss (BWL) threshold and Weight Loss Grading Scale (WLGS) indentified patients with and without cachexia. Main Outcomes were Functional independence Measure (FIM) scores, discharge destination, and 6-month survival.

Results

Prevalence of cachexia in inpatient rehabilitation was 59% using consensus BWL criteria and 77% of cancer patients had WLGS>0. Patients with and without cachexia had similar motor and cognitive gains though patients with severe cachexia had more limited functional gains(p < 0.05) and increased odds of acute care return(p < 0.01). Patients with WLGS = 4 had decreased survival at six months(p < 0.05) compared to non-cachectic patients.

Conclusions

These data suggest that there is a relationship between cachexia and recovery for cancer patients that should be further studied in rehabilitation settings.
Can Target-to-Background Ratio Measurement Lead to Detection and Accurate Quantification of Atherosclerosis With FDG PET? Likely Not
Authors: Alavi Abass , Werner Thomas J. , Høilund-Carlsen Poul Flemming. , Revheim Mona-Elisabeth
Published: April 2022

The introduction of FDG in 1976 started a new discipline and enhanced the role of molecular imaging in medicine. While the initial intent with this tracer was to determine brain function in a variety of neuropsychiatric disorders, over time, this powerful approach has made a major impact on managing many other diseases and disorders. During the past 2 decades, FDG PET has been used to detect inflammatory lesions in the atherosclerotic plaques and in other settings. However, the suboptimal spatial resolution of PET limits its ability to visualize plaques that are very small in size. Furthermore, this tracer remains in the blood for an extended period and therefore provides suboptimal results. Target-to-background ratio (TBR) has been suggested to correct for this source of error. Unfortunately, TBR values vary substantially, depending on the timing of image acquisition. Delayed imaging at later time points (3–4 hours) may obviate the need for TBR measurement, but it is impractical with conventional PET instruments. Recently, 18F-sodium fluoride (NaF) has been used for detection and quantification of molecular calcification in the plaques. This tracer is highly specific for calcification and is rapidly cleared from the circulation. In addition, global atherosclerotic burden as measured by NaF PET can be determined accurately either in the heart or major arteries throughout the body. Therefore, the role of FDG PET–based TBR measurement for detection and quantification of atherosclerotic plaques is questionable at this time.
Focal Xanthogranulomatous Pyelonephritis on FDG PET/CT
Authors: Liu Yong , Tong Guansheng , Wen Zhe
Published: April 2022

Xanthogranulomatous pyelonephritis is a rare disease that was often accompanied with urinary obstruction. The focal form of xanthogranulomatous pyelonephritis is frequently misdiagnosed as malignancy. Here we present FDG PET/CT findings of a case focal xanthogranulomatous pyelonephritis in a 66-year-old woman with polycystic liver and kidney disease. The image showed a polycystic mass in the inferior pole of right kidney with high FDG uptake in the cystic wall, which was suggestive of a cystic renal carcinoma. Right radical nephrectomy was subsequently performed. The postsurgical pathology revealed xanthogranulomatous pyelonephritis.
K-mer based prediction of Clostridioides difficile relatedness and ribotypes
Authors: Moore Matthew Phillip , Wilcox Mark H. , Walker A. Sarah , Eyre David W.
Published: April 2022

Comparative analysis of

Clostridioides difficile

whole-genome sequencing (WGS) data enables fine scaled investigation of transmission and is increasingly becoming part of routine surveillance. However, these analyses are constrained by the computational requirements of the large volumes of data involved. By decomposing WGS reads or assemblies into k-mers and using the dimensionality reduction technique MinHash, it is possible to rapidly approximate genomic distances without alignment. Here we assessed the performance of MinHash, as implemented by sourmash, in predicting single nucleotide differences between genomes (SNPs) and

C. difficile

ribotypes (RTs). For a set of 1905 diverse

C. difficile

genomes (differing by 0–168 519 SNPs), using sourmash to screen for closely related genomes, at a sensitivity of 100 % for pairs ≤10 SNPs, sourmash reduced the number of pairs from 1 813 560 overall to 161 934, i.e. by 91 %, with a positive predictive value of 32 % to correctly identify pairs ≤10 SNPs (maximum SNP distance 4144). At a sensitivity of 95 %, pairs were reduced by 94 % to 108 266 and PPV increased to 45 % (maximum SNP distance 1009). Increasing the MinHash sketch size above 2000 produced minimal performance improvement. We also explored a MinHash similarity-based ribotype prediction method. Genomes with known ribotypes (n=3937) were split into a training set (2937) and test set (1000) randomly. The training set was used to construct a sourmash index against which genomes from the test set were compared. If the closest five genomes in the index had the same ribotype this was taken to predict the searched genome’s ribotype. Using our MinHash ribotype index, predicted ribotypes were correct in 780/1000 (78 %) genomes, incorrect in 20 (2 %), and indeterminant in 200 (20 %). Relaxing the classifier to 4/5 closest matches with the same RT improved the correct predictions to 87 %. Using MinHash it is possible to subsample

C. difficile

genome k-mer hashes and use them to approximate small genomic differences within minutes, significantly reducing the search space for further analysis.
A comparative analysis of serial measurements of Soluble Urokinase-type Plasminogen Activator Receptor (suPAR) and C-reactive protein in patients with moderate COVID-19: a single center study from India
Authors: Kakar Atul , Rani Pooja , Batra Tanvi , Hasan Rizwana , Choudhury Sangeeta
Published: April 2022

Soluble urokinase plasminogen-activator receptor (suPAR) is a secreted protein associated with inflammation and proven its usefulness in triage/risk stratifications. This prospective study aimed to evaluate the utility of suPAR in comparison to C-reactive protein (CRP) in hospitalized moderate COVID-19 patients.

This is a prospective comparative study during second pandemic wave. Serum suPAR level and CRP were measured serially in 31 confirmed COVID-19 hospitalized patients (20 males, 11 females) on day-1 (24-hours of admission), day-3 and day-5 using suPARnostic AUTO flex ELISA and Nephelometry (ThermoFischer) respectively. Schapiro Wilk test verified the data distribution; Wilcoxon signed rank test compared CRP and suPAR between deceased/alive subject and identified link between co-morbidity and COVID-19 severity.

In our study, the mean age was 61.8 ranging from 28-82 with 9.7% (n=3/31) mortality rate. Deceased patients showed significant higher suPAR levels correlating with increasing severity from day 1 to 5 (p<0.016-0.006) than CRP (p=0.717). Patients with pre-existing co-morbidities showed significantly elevated suPAR levels on days 1-5, especially those with hypertension (HTN;p<0.03) and chronic kidney disease (CKD;p<0.001).

In conclusion, levels of suPAR were higher in deceased patients with severe symptoms of COVID-19 during hospitalization and in patients with pre-existing co-morbid conditions, HTN and CKD. This preliminary study provides evidence suggesting that circulating suPAR can be a potential biomarker to assess the severity of COVID 19 compared to CRP.
Clinical Impact of IDH1 Mutations and MGMT Methylation in Adult Glioblastoma Multiforme
Authors: Mahmoud Magda Sayed , Khalifa Mohamed K. , Nageeb Amira M , El-Arab Lobna Ezz , El-Mahdy Manal , Ramadan Amal , Hashim Maha , Bakr Noha , Swellam Menha
Published: April 2022

Background

Genetic aberrations and epigenetic alterations have been reported in different types of cancer. Impact of Isocitrate dehydrogenase1 (IDH1) and O6-methylguanine-DNAmethyltransferase (MGMT) in glioblastoma multiforme (GBM) have been of great interest due to their implications in prediction of prognosis of several types of cancer. Authors aimed to investigate the clinical role of IDH1 mutation and MGMT methylation pattern among GBM patients versus non-neurooncological diseases (NND) patients and their impact on survival criteria.

Methods

Formalin-Fixed Paraffin-Embedded (FFPE) tissue sections of 58 GBM and 20 non-onconeurological diseases patients were recruited and IDH1 mutation were detected using Cast-PCR technology and MGMT methylation was detected using Methyl II quantitative PCR approach. Their results were assessed with other clinicopathological criteria and assess its correlation with survival patterns.

Results

IDH1 mutation was detected among 15 GBM cases (15/58) and it was not reported among NND (P=0.011). Receiver operating characteristic (ROC) curve were plotted to discriminate between MGMT methylation among studied groups. Patients with MGMT methylation ≥ 66% was reported as high methylation, which was recorded significantly in 51.7% and 100% of GBM cases and NND, respectively. Both showed significant difference with performance status, while MGMT methylation was significantly related with tumor size and tumor location. IDH1 mutation and MGMT methylation reported significant increase with GBM patients revealed complete response to treatment. Survival pattern was better for IDH1 mutation and MGMT high methylation as compared to IDH1 wild type or MGMT low-moderate methylation, respectively and favorable survival was detected when both were combined than using either of them alone.

Conclusion

Detection of IDH1 mutation and MGMT methylation among GBM patients could aid in prediction of their response to treatment and their survival patterns, and their combination is better than using any of them alone.
Accurate genome-wide germline profiling from decade-old archival tissue DNA reveals the contribution of common variants to precancer disease outcome
Authors: Nachmanson Daniela , Pagadala Meghana , Steward Joseph , Cheung Callie , Bruce Lauryn Keeler , Lee Nicole Q. , O’Keefe Thomas J. , Lin Grace Y. , Hasteh Farnaz , Morris Gerald P. , Carter Hannah , Harismendy Olivier
Published: April 2022

Background

Inherited variants have been shown to contribute to cancer risk, disease progression, and response to treatment. Such studies are, however, arduous to conduct, requiring large sample sizes, cohorts or families, and more importantly, a long follow-up to measure a relevant outcome such as disease onset or progression. Unless collected for a dedicated study, germline DNA from blood or saliva are typically not available retrospectively, in contrast to surgical tissue specimens which are systematically archived.

Results

We evaluated the feasibility of using DNA extracted from low amounts of fixed-formalin paraffin-embedded (FFPE) tumor tissue to obtain accurate germline genetic profiles. Using matching blood and archival tissue DNA from 10 individuals, we benchmarked low-coverage whole-genome sequencing (lc-WGS) combined with genotype imputation and measured genome-wide concordance of genotypes, polygenic risk scores (PRS), and HLA haplotypes. Concordance between blood and tissue was high (r2>0.94) for common genome-wide single nucleotide polymorphisms (SNPs) and across 22 disease-related PRS (mean r=0.93). HLA haplotypes imputed from tissue DNA were 96.7% (Class I genes) and 82.5% (Class II genes) concordant with deep targeted sequencing of HLA from blood DNA. Using the validated methodology, we estimated breast cancer PRS in 36 patients diagnosed with breast ductal carcinoma in situ (11.7 years median follow-up time) including 22 who were diagnosed with breast cancer subsequent event (BSCE). PRS was significantly associated with BCSE (HR=2.5, 95%CI: 1.4–4.5) and the top decile patients were modeled to have a 24% chance of BCSE at 10 years, hence suggesting the addition of PRS could improve prognostic models which are currently inadequate.

Conclusions

The abundance and broad availability of archival tissue specimens in oncology clinics, paired with the effectiveness of germline profiling using lc-WGS and imputation, represents an alternative cost and resource-effective alternative in the design of long-term disease progression studies.
Clinicians’ perspective on use of immune checkpoint inhibitors and related biomarkers for solid tumors
Authors: Moser Kaitlynn , Soto Michelle , Geba Daniela , Allen Paul , Lindpaintner Klaus
Published: April 2022

Background

Immune checkpoint inhibitors (ICIs) are a valuable treatment option for patients with malignant tumors, but only selected patients respond to ICIs. Available biomarkers are of limited use in guiding ICI therapy.

Objective

To examine clinicians’ perspective on the use of ICIs and biomarkers for treatment of malignant tumors and to identify unmet needs related to their use.

Methods

We conducted in-depth telephone interviews of eight oncologists, and 100 oncologists completed online surveys.

Results

Oncologists have a positive attitude toward use of ICIs, and 98% of them prescribe them in all approved indications. Clinicians report that only about half of the patients with solid tumors responded to treatment, overestimated the response rate to ICIs across most types of tumors they treat compared with data in the literature. They ranked the lack of reliability of biomarkers to guide treatment (rating of 4.4 out of 7) as the top challenge with use of ICIs, followed by lack of overall efficacy and toxicity or occurrence of immune-related adverse events. The biomarkers most often used by survey participants were: a comprehensive panel including driver mutations and tumor mutational burden(69% of respondents), programmed cell death ligand-1 (PD-L1) expression (62%), and microsatellite instability (MSI) (56%). Oncologists indicated that they ordered biomarkers for each type of cancer according to their perceived usefulness of each biomarker in predicting the outcomes for ICI therapy, being more likely to use those perceived as useful or very useful.

Conclusion

Clinicians indicate that more reliable therapy-response prediction biomarkers would have a great impact on treatment decisions for patients with solid tumors, reducing unnecessary treatments, side effects, and health care expenditures.
Digital Health Interventions and Quality of Home-based Primary Care for Older Adults: A Scoping Review Protocol
Authors: Silva Isis de Siqueira , Silva Cicera Renata Diniz Vieira , Lopes Rayssa Horacio , Araujo Aguinaldo Jose , Figueiredo Renan Cabral de , Bay Junior Osvaldo de Goes , Lapao Luis Velez , Uchoa Severina Alice da Costa
Published: April 2022

Introduction

The use of digital health interventions has expanded, particularly in home-based primary care (HBPC) following the increase in the older adult population and the need to respond to the higher demand of chronic conditions and health frailties of this population. There was an even greater demand with COVID-19 and subsequent isolation/social distancing measures for this risk group. The objective of this study is to map and identify the uses and types of digital health interventions and their reported impacts on the quality of HBPC for older adults worldwide.

Methods and analysis

This is a scoping review protocol which will enable a rigorous, transparent and reliable synthesis of knowledge. The review will be developed in the theoretical perspective of Arksey and O’malley, with updates by Levac et al. and Peters et al. based on the Joanna Briggs Institute manual, and guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). Data from whiteliterature will be extracted from multidisciplinary health databases such as: the Virtual Health Library, LILACS, PubMed, Scopus, Web of Science, CINAHL and Embase; while Google Scholar will be used for gray literature. No date limit or language restrictions will be determined. The quantitative data will be analyzed through descriptive statistics and qualitative data through thematic analysis. The results will be submitted to stakeholder consultation for preliminary sharing of the study and will later be disseminated through publication in open access scientific journals, scientific events and academic and community journals. The full scoping review report will present the main impacts, challenges, opportunities and gaps found in publications related to the use of digital technologies in primary home care.

Discussion

The organization of this protocol will increase the methodological rigor, quality, transparency and accuracy of scoping reviews, reducing the risk of bias.
Why is leptospirosis hard to avoid for the impoverished? Deconstructing leptospirosis transmission risk and the drivers of knowledge, attitudes, and practices in a disadvantaged community in Salvador, Brazil
Authors: Palma Fabiana Almerinda G. , Costa Federico , Lustosa Ricardo , Mogaji Hammed O. , de Oliveira Daiana Santos , Souza Fábio Neves , Reis Mitermayer G. , Ko Albert I. , Begon Michael , Khalil Hussein
Published: April 2022

Several studies have identified socioeconomic and environmental risk factors for infectious disease, but the relationship between these and knowledge, attitudes, and practices (KAP), and more importantly their web of effects on individual infection risk, have not previously been evaluated. We conducted a cross-sectional KAP survey in an urban disadvantaged community in Salvador, Brazil, leveraging on simultaneously collected fine-scale environmental and epidemiological data on leptospirosis transmission. Residents’ knowledge influenced their attitudes which influenced their practices. However, different KAP variables were driven by different socioeconomic and environmental factors; and while improved KAP variables reduced risk, there were additional effects of socioeconomic and environmental factors on risk. For example, males and those of lower socioeconomic status were at greater risk, but once we controlled for KAP, male gender and lower socioeconomic status themselves were not direct drivers of seropositivity. Employment was linked to better knowledge and a less contaminated environment, and hence lower risk, but being employed was independently associated with a higher, not lower risk of leptospirosis transmission, suggesting travel to work as a high risk activity. Our results show how such complex webs of influence can be disentangled. They indicate that public health messaging and interventions should take into account this complexity and prioritize factors that limit exposure and support appropriate prevention practices.
Doctoring Direct-to-Consumer Genetic Tests with DNA Spike-Ins
Authors: Ney Peter , Bhattacharya Arkaprabha , Ward David , Ceze Luis , Kohno Tadayoshi , Nivala Jeff
Published: April 2022

Direct-to-consumer (DTC) genetic testing companies have provided personal genotyping services to millions of customers. Customers mail saliva samples to DTC service providers to have their genotypes analyzed and receive back their raw genetic data. Both consumers and the DTC companies use the results to perform ancestry analyses, relative matching, trait prediction, and estimate predisposition to disease, often relying on genetic databases composed of the data from millions of other DTC-genotyped individuals. While the digital integrity risks to this type of data have been explored, we considered whether data integrity issues could manifest upstream of data generation through physical manipulation of DNA samples themselves, for example by adding synthetic DNA to a saliva sample (“spiked samples”) prior to sample processing by a DTC company. Here, we investigated the feasibility of this scenario within the standard DTC genetic testing pipeline. Starting with the purchase of off-the-shelf DTC genetic testing kits, we found that synthetic DNA can be used to precisely manipulate the results of saliva samples genotyped by a popular DTC genetic testing service and that this method can be used to modify arbitrary single nucleotide polymorphisms (SNPs) in multiplex to create customized doctored genetic profiles. This capability has implications for the use of DTC-generated results and the outcomes of their downstream analyses.
Age acquired skewed X Chromosome Inactivation is associated with adverse health outcomes in humans
Authors: Roberts Amy L. , Morea Alessandro , Amar Ariella , Zito Antonino , El-Sayed Moustafa Julia S. , Tomlinson Max , Bowyer Ruth C. E. , Zhang Xinyuan , Christiansen Colette , Costeira Ricardo , Steves Claire J. , Mangino Massimo , Bell Jordana T. , Wong Chloe C.Y. , Vyse Timothy J. , Small Kerrin S.
Published: April 2022

Background

Ageing is a heterogenous process characterised by cellular and molecular hallmarks, including changes to haematopoietic stem cells, and is a primary risk factor for chronic diseases. X chromosome inactivation (XCI) randomly transcriptionally silences either the maternal or paternal X in each cell of XX,46 females to balance the gene expression with XY,46 males. Age acquired XCI-skew describes the preferential inactivation of one X chromosome across a tissue, which is particularly prevalent in blood tissues of ageing females and yet its clinical consequences are unknown.

Methods

We assayed XCI in 1,575 females from the TwinsUK population cohort and employed prospective, cross-sectional, and intra-twin designs to characterise the relationship of XCI-skew with molecular, cellular, and organismal measures of ageing, and cardiovascular disease risk and cancer diagnosis.

Results

We demonstrate that XCI-skew is independent of traditional markers of biological ageing and is associated with a haematopoietic bias towards the myeloid lineage. Using an atherosclerotic cardiovascular disease risk score, which captures traditional risk factors, XCI-skew is associated with an increased cardiovascular disease risk both cross-sectionally and within XCI-skew discordant twin pairs. In a prospective 10-year follow-up study, XCI-skew is predictive of future cancer incidence.

Conclusions

Our study demonstrates that age acquired XCI-skew captures changes to the haematopoietic stem cell population and has clinical potential as a unique biomarker of chronic disease risk.

Funding

KSS acknowledges funding from the Medical Research Council (MR/M004422/1 and MR/R023131/1). JTB acknowledges funding from the ESRC (ES/N000404/1). MM acknowledges funding from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, Chronic Disease Research Foundation (CDRF), Zoe Global Ltd and the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London.
Invasion of malaria mosquitoes natural population by parasitic nematodes Dirofilaria along Ob River basin in Western Siberia
Authors: Burlak Vladimir A. , Fedorova Valentina S. , Artemov Gleb N.
Published: April 2022

Dirofilariasis – is a dangerous disease that affects carnivores, felines, and humans. It is caused by parasitic nematodes Dirofilaria repens and D. immitis. These parasites are carried by blood–sucking mosquitoes. In recent decades the habitat of Dirofilaria in Europe has been expanding dramatically. In the present study, we investigated how malaria mosquitoes had been infected by Dirofilaria in Western Siberia (Russia) in the range between 50° 48’ N (Labytnangi) and 66° 39’ N (Kurota) along the Ob River. The extensiveness of parasite infection varied between 0.4 % and 5.7 %, in three species of malaria mosquitoes: Anopheles beklemishevi, An. daciae, An. messeae, which all are showed effective vectors of D. repens. The results demonstrate the significant role of malaria mosquitoes for dirofilariasis transmission in severe climate conditions of Western Siberia.
Genetic Risk for Attention-Deficit/Hyperactivity Disorder Predicts Cognitive Decline and Development of Alzheimer’s Disease Pathophysiology in Cognitively Unimpaired Older Adults
Authors: Leffa Douglas T. , Ferrari-Souza João Pedro , Bellaver Bruna , Tissot Cécile , Ferreira Pamela C. L. , Brum Wagner S. , Caye Arthur , Lord Jodie , Proitsi Petroula , Martins-Silva Thais , Tovo-Rodrigues Luciana , Tudorascu Dana L. , Villemagne Victor L. , Cohen Annie , Lopez Oscar L. , Klunk William E. , Karikari Thomas K. , Rosa-Neto Pedro , Zimmer Eduardo , Molina Brooke S.G. , Rohde Luis Augusto , Pascoal Tharick A. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2022

Background

Attention-Deficit/Hyperactivity Disorder (ADHD) persists in older age and is postulated to be a risk factor for cognitive impairment and Alzheimer’s Disease (AD). However, this notion relies exclusively on epidemiological associations, and no previous study has linked ADHD with a decline in cognitive performance in older adults or with AD progression. Therefore, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with longitudinal cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults.

Methods

We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years) using whole-genome information. These individuals had baseline amyloid-β (Aβ) positron emission tomography, as well as longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181, structural magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers.

Outcomes

Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aβ deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aβ-positive individuals.

Interpretation

Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology in the CU elderly. These findings indicate that ADHD-PRS might inform the risk of developing cognitive decline in this population.

Funding

National Institute of Health and Brain & Behavioral Research Foundation.
Genomic characteristics, virulence and antimicrobial resistance in avian pathogenic Escherichia coli MTR_BAU02 strain isolated from layer farms in Bangladesh
Authors: Ievy Samina , Hoque M. Nazmul , Islam Md. Saiful , Sobur Md. Abdus , Rahman M. Shaminur , Ballah Fatimah Muhammad , Rahman Md. Bahanur , Hassan Jayedul , Rahman Khan Mohammad Ferdousur , Rahman Md. Tanvir
Published: April 2022

Background

Colibacillosis, caused by avian pathogenic Escherichia coli (APEC), is one of the most significant infectious diseases affecting poultry worldwide. APEC is one of the leading causes of mortality and morbidity associated with significant economic losses in the poultry industry.

Objective

This study was aimed to determine the genomic diversity, virulence factor genes (VFGs) and antimicrobial resistance (AMR) genes in the APEC isolated from layer chickens using whole-genome sequencing (WGS).

Method

APEC MTR_BAU02 strain was isolated from the sick and dead birds. Genomic DNA from APEC MTR_BAU02 strain was extracted using commercial DNA extraction kit, WGS libraries were prepared using the Nextera™ DNA Flex Library Prep Kit, and finally, paired-end (2 × 250) WGS performed using Illumina MiSeq sequencer.

Results

The genome size of strain APEC MTR_BAU02 is 4,924,680 bp with a GC content of 51.1% and 4,681 protein-coding sequences. Among the annotated WGS reads, 99.71% reads mapped to Enterobacteriaceae genomes. Based on the phylogenetic analysis of the APEC MTR_BAU02 genome and 99 reference genomes of E. coli, the APEC MTR_BAU02 genome showed sequence similarities with enterotoxigenic E. coli strains isolated from infections of different clinical severity. Metabolic functional annotations detected 380 SEED subsystems including genes coding for carbohydrate metabolism (17.34%), amino acid and derivatives (14.20%), protein metabolism (10.64%), cofactors, vitamins, prosthetic groups and pigments (7.49%), respiration (4.72%), membrane transport (4.49%), stress response (4.47%), motility and chemotaxis (4.46%), and virulence, disease and defense (2.22%). We also detected 92 VFGs and 122 AMR genes in the APEC MTR_BAU02 strain.

Conclusion

Assessment of these genomic features with functional genomic validation in commonly occurring serogroups of APEC will increase our understanding of the molecular pathogenesis, pave the way to early diagnosis and more effective control of colibacillosis, and improved animal welfare.
A Genome-Wide Association Analysis of Happiness: Consistent Genetic Effects Across the Lifespan and Across Genetic Ancestries in Multiple Cohorts
Authors: Ward Joey , Lyall Laura , Cullen Breda , Strawbridge Rona J. , Zhu Xingxing , Stanciu Ioana , Aman Alisha , Niedzwiedz Claire L. , Anderson Jana , Bailey Mark E. S. , Lyall Donald M. , Pell Jill
Published: April 2022

We present a genome-wide association study of a general happiness measure in 118,851 participants from the UK Biobank. Using BOLT-LMM, we identify 3 significant loci with a heritability estimate of 0.8%. Linkage disequilibrium score regression was performed on the ‘big five’ personality traits finding significant associations with lower neuroticism and higher extraversion and conscientiousness. Using a novel approach, we construct LDpred-inf polygenic risk scores in the Adolescent Brain Cognitive Development (ABCD) cohort and the Add Health cohort. We detected nominally significant associations with several well-being measures in ABCD and significant correlations with a happiness measure in Add Health. Additionally, we tested for associations with several brain regions in a white British subsample of UK Biobank finding significant associations with several brain structure and integrity phenotypes.

We demonstrated a genetic basis for general happiness level and brain structure that appears to remain consistent throughout the lifespan and across multiple ancestral backgrounds.

Author summary

At the genetic level, there has been little investigation into whether people may have a baseline happiness level which varies from person to person. Here we perform a genetic analysis in the UK Biobank to identify three genetic loci that associate with general happiness level and preform genetic correlations of our results with the ‘Big Five’ personality traits, identifying significant correlations with neuroticism, conscientiousness and extraversion.

We use the resulting summary statistics to create LDpred-inf polygenic risk scores in UK biobank identifying several brain metrics and regions associate with genetic loading for general happiness level. We also use a novel method to create LDpred-inf polygenic risk scores in two other cohorts, ABCD and Add Health. We found significant correlations with an independent happiness measure in Add Health and nominally significant correlations with several well-being measures in ABCD in both those of European Ancestry and all other ancestries found in these cohorts. We also attempted to replicate our UK Biobank MRi finding in ABCD.

We conclude there is evidence that individuals have a general happiness level that is in part genetic which spans across age and ancestry.
Distinct regions of H. pylori’s bactofilin CcmA regulate protein-protein interactions to control helical cell shape
Authors: Sichel Sophie R , Bratton Benjamin P , Salama Nina R
Published: April 2022

The helical shape of H. pylori cells promotes robust stomach colonization, however, how the helical shape of H. pylori cells is determined is unresolved. Previous work identified helical-cell-shape-promoting protein complexes containing a peptidoglycan-hydrolase (Csd1), a peptidoglycan precursor synthesis enzyme (MurF), a non-enzymatic homologue of Csd1 (Csd2), non-enzymatic transmembrane proteins (Csd5 and Csd7), and a bactofilin (CcmA). Bactofilins are highly conserved, spontaneously polymerizing cytoskeletal bacterial proteins. We sought to understand CcmA’s function in generating the helical shape of H. pylori cells. Using CcmA deletion analysis, in vitro polymerization, and in vivo co-immunoprecipitation experiments we identified that the bactofilin domain and N-terminal region of CcmA are required for helical cell shape and the bactofilin domain of CcmA is sufficient for polymerization and interactions with Csd5 and Csd7. We also found that CcmA’s N-terminal region inhibits interaction with Csd7. Deleting the N-terminal region of CcmA increases CcmA-Csd7 interactions and destabilizes the peptidoglycan-hydrolase Csd1. Using super-resolution microscopy, we found that Csd5 recruits CcmA to the cell envelope and promotes CcmA enrichment at the major helical axis. Thus, CcmA helps organize cell-shape-determining proteins and peptidoglycan synthesis machinery to coordinate cell wall modification and synthesis, promoting the curvature required to build a helical cell.
SimSearch: A Human-in-the-Loop Learning Framework for Fast Detection of Regions of Interest in Microscopy Images
Authors: Gupta Ankit , Sabirsh Alan , Wählby Carolina , Sintorn Ida-Maria
Published: April 2022

Objective

Large-scale microscopy-based experiments often result in images with rich but sparse information content. An experienced microscopist can visually identify regions of interest (ROIs), but this becomes a cumbersome task with large datasets. Here we present SimSearch, a framework for quick and easy user-guided training of a deep neural model aimed at fast detection of ROIs in large-scale microscopy experiments.

Methods

The user manually selects a small number of patches representing different classes of ROIs. This is followed by feature extraction using a pre-trained deep-learning model, and interactive patch selection pruning, resulting in a smaller set of clean (user approved) and larger set of noisy (unapproved) training patches of ROIs and background. The pre-trained deep-learning model is thereafter first trained on the large set of noisy patches, followed by refined training using the clean patches.

Results

The framework is evaluated on fluorescence microscopy images from a large-scale drug screening experiment, brightfield images of immunohistochemistry-stained patient tissue samples, and malaria-infected human blood smears, as well as transmission electron microscopy images of cell sections. Compared to state-of-the-art and manual/visual assessment, the results show similar performance with maximal flexibility and minimal a priori information and user interaction.

Conclusions

SimSearch quickly adapts to different data sets, which demonstrates the potential to speed up many microscopy-based experiments based on a small amount of user interaction.

Significance

SimSearch can help biologists quickly extract informative regions and perform analyses on large datasets helping increase the throughput in a microscopy experiment.
The impact of PrsA over-expression on the Bacillus subtilis transcriptome during fed-batch fermentation of alpha-amylase production
Authors: Geissler Adrian S , Poulsen Line D , Doncheva Nadezhda T , Anthon Christian , Seemann Stefan E , González-Tortuero Enrique , Breüner Anne , Jensen Lars J , Hjort Carsten , Vinther Jeppe , Gorodkin Jan
Published: April 2022

The production of the alpha-amylase (AMY) enzyme in Bacillus subtilis at a high rate leads to the accumulation of unfolded AMY, which causes secretion stress. The over-expression of the PrsA chaperone aids the enzyme folding and reduces stress. To identify affected pathways and potential mechanisms involved in the reduced growth, we analyzed the transcriptomic differences during fed-batch fermentation between a PrsA over-expressing strain and a control in a time-series RNA-seq experiment. We observe transcription in 542 previously un-annotated regions, of which 234 had significant changes in expression levels between the samples. Moreover, 1,791 protein-coding sequences, 80 non-coding genes, and 20 riboswitches overlapping UTR regions of coding genes had significant changes in expression. Via gene-set over-representation analysis of the differentially expressed genes, we identified putatively regulated biological processes; overall the analysis suggests that the PrsA over-expression affects ATP biosynthesis activity, amino acid metabolism, and cell wall stability. The investigation of the protein interaction network points to a potential impact on cell motility signaling. We discuss the impact of these highlighted mechanisms for reducing secretion stress or detrimental aspects of PrsA over-expression during AMY production.
Nucleation complex behaviour is critical for cortical microtubule array homogeneity and patterning
Authors: Jacobs Bas , Schneider René , Molenaar Jaap , Filion Laura , Deinum Eva E.
Published: April 2022

Plant cell walls are versatile materials that can adopt a wide range of mechanical properties through controlled deposition of cellulose fibrils. Wall integrity requires a sufficiently homogeneous fibril distribution to cope effectively with wall stresses. Additionally, specific conditions, such as the negative pressure in water transporting xylem vessels, may require more complex wall patterns, e.g., bands in protoxylem. The orientation and patterning of cellulose fibrils is guided by dynamic cortical microtubules. New microtubules are predominantly nucleated from parent microtubules causing positive feedback on local microtubule density with the potential to yield highly inhomogeneous patterns. Inhomogeneity indeed appears in all current cortical array simulations that include microtubule-based nucleation, suggesting that plant cells must possess an as-yet unknown balancing mechanism to prevent it. Here, in a combined simulation and experimental approach, we show that the naturally limited local recruitment of nucleation complexes to microtubules can counter the positive feedback, whereas local tubulin depletion cannot. We observe that nucleation complexes are preferentially inserted at microtubules. By incorporating our experimental findings in stochastic simulations, we find that the spatial behaviour of nucleation complexes delicately balances the positive feedback, such that differences in local microtubule dynamics – as in developing protoxylem – can quickly turn a homogeneous array into a patterned one. Our results provide insight into how the plant cytoskeleton is wired to meet diverse mechanical requirements and greatly increase the predictive power of computational cell biology studies.

Significance statement

The plant cortical microtubule array is an established model system for self-organisation, with a rich history of complementary experiments, computer simulations, and analytical theory. Understanding how array homogeneity is maintained given that new microtubules nucleate from existing microtubules has been a major hurdle for using mechanistic (simulation) models to predict future wall structures. We overcome this hurdle with detailed observations of the nucleation process from which we derive a more “natural” nucleation algorithm. With this algorithm, we enable various new lines of quantitative, mechanistic research into how cells dynamically control their cell wall properties. At a mechanistic level, moreover, this work relates to the theory on cluster coexistence in Turing-like continuum models and demonstrates its relevance for discrete stochastic entities.
Prime-pull immunization of mice with a BcfA-adjuvanted vaccine elicits mucosal immunity and prevents SARS CoV-2 infection and pathology
Authors: Shamseldin Mohamed M. , Zani Ashley , Kenney Adam , Evans Jack , Zeng Cong , Read Kaitlin A. , Caution Kyle , Hall Jesse M. , Brown Jessica M. , Gunsch Gilian , Corps Kara N. , Chaiwatpongsakorn Supranee , Mahesh KC , Lu Mijia , Deora Rajendar , Peeples Mark E. , Li Jianrong , Oestreich Kenneth J. , Liu Shan-Lu , Yount Jacob S. , Dubey Purnima
Published: April 2022

Vaccines against SARS-CoV-2 that induce mucosal immunity capable of preventing infection and disease remain urgently needed. We show that intramuscular priming of mice with an alum and BcfA-adjuvanted Spike subunit vaccine, followed by a BcfA-adjuvanted mucosal booster, generated Th17 polarized tissue resident CD4+ T cells, and mucosal and serum antibodies. The serum antibodies efficiently neutralized SARS-CoV-2 and its Delta variant, suggesting cross-protection against a recent variant of concern (VOC). Immunization with this heterologous vaccine prevented weight loss following challenge with mouse-adapted SARS-CoV-2 and reduced viral replication in the nose and lungs. Histopathology showed a strong leukocyte and polymorphonuclear (PMN) cell infiltrate without epithelial damage in mice immunized with BcfA-containing vaccines. In contrast, viral load was not reduced in the upper respiratory tract of IL-17 knockout mice immunized with the same formulation, suggesting that the Th17 polarized T cell responses are critical for protection. We show that vaccines adjuvanted with alum and BcfA, delivered through a heterologous prime-pull regimen, protect against SARS-CoV-2 infection without causing enhanced respiratory disease.

SIGNIFICANCE

There remains a need for SARS CoV-2 booster vaccines that generate mucosal immunity and prevent transmission. We show that systemic priming followed by a mucosal booster with a BcfA-adjuvanted subunit vaccine generates neutralizing antibodies and Th17 polarized systemic and tissue-resident immune responses that provide sterilizing immunity against wildtype SARS CoV-2, and a variant of concern. Importantly, in contrast to alum alone, the addition of BcfA prevents respiratory pathology. These results suggest that a BcfA-adjuvanted mucosal booster may elicit mucosal immunity in individuals previously immunized systemically with approved vaccines. This foundational study in mice sets the stage for testing our vaccine regimen in larger animal models as a booster vaccine.
Crystal structure of 4-bromo-N-(propylcarbamoyl)benzenesulfonamide
Authors: Bookwala Mustafa , Patel Saloni , Flaherty Patrick T. , Wildfong Peter L. D.
Published: April 2022

The title compound, C10H13BrN2O3S, 1, contains a sulfonyl urea moiety, which possesses potential therapeutic functions (e.g., anti-diabetic and herbicidal). The geometry of 1 is similar to its closely related analogues, chlorpropamide and tolbutamide. This compound crystallizes in the monoclinic space group C2/c, having one molecule in its asymmetric unit. The crystal structure of 1, recorded at 296 K, shows intermolecular N—H...O and C—H...O-type infinite hydrogen-bonded chains involving the sulfonyl urea moiety. Hirshfeld surface analysis and the two-dimensional fingerprint plots confirmed hydrogen bonding as the dominant feature in the crystal packing.
Ferrite effects on the hydrogen embrittlement of 17-4PH stainless steel
Authors: Zheng Yaojie , Sun Huili , Yan Luchun , Yang Huisheng , Gao Kewei , Pang Xiaolu , Volinsky Alex A.
Published: April 2022

Purpose

The purpose of this study is to investigate the effect of ferrite on hydrogen embrittlement (HE) of the 17-4PH stainless steels.

Design/methodology/approach

The effects of ferrite on HE of the 17-4PH stainless steels were investigated by observing microstructure and conducting slow-strain-rate tensile tests and hydrogen permeability tests.

Findings

The microstructure of the ferrite-bearing sample is lath martensite and banded ferrite, and the ferrite-free sample is lath martensite. After hydrogen charging, the plasticity of the two steels is significantly reduced, along with the tensile strength of the ferrite-free sample. The HE susceptibility of the ferrite-bearing sample is significantly lower than the ferrite-free steel, and the primary fracture modes gradually evolved from typical dimple to quasi-cleavage and intergranular cracking. After aging at 480°C for 4 h and hydrogen charging for 12 h, the 40.9% HE susceptibility of ferrite-bearing samples was the lowest. In addition, the hydrogen permeation tests show that ferrite is a fast diffusion channel for hydrogen, and the ferrite-bearing samples have higher effective hydrogen diffusivity and lower hydrogen concentration.

Originality/value

There are a few studies of the ferrite effect on the HE properties of martensitic precipitation hardening stainless steel.
Fractal analysis of thermal fatigue crack growth behavior in bionic units of vermicular cast iron
Authors: Liu Yan , Wang Yan
Published: April 2022

Purpose

The purpose of this paper is to clarify the growth behavior of fatigue cracks on bionic coupling surface of vermicular cast iron.

Design/methodology/approach

The thermal fatigue cyclic experiments were carried out on the bionic specimens processed by laser bionic treatment, in which the thermal fatigue was generated by heating at 600°C ± 5°C and cooling at 25°C ± 5°C. The thermal fatigue cracks of bionic units were analyzed using fractal theory. The relation between fractal dimensions of thermal fatigue cracks and thermal fatigue cycles was discussed.

Findings

The results show that the fractal dimensions can better characterize the fatigue crack growth behavior on bionic coupling surface of vermicular cast iron.

Originality/value

The fractal theory is first used to discuss the growth behavior of fatigue cracks on bionic coupling surface of vermicular cast iron, which is processed by laser bionic treatment.