bluuebunny/crossref_metadata_2025 huggingface dataset:
Theta burst stimulation versus high-frequency repetitive transcranial magnetic stimulation for poststroke dysphagia
Authors: Yu-Lei Xie , Shan Wang , Ju Yang , Yu-Han Xie , Wu Qing , Yin-Xu Wang
Published: January 2022

Background:

Repetitive transcranial magnetic stimulation (rTMS) of high-frequency (10 Hz) on suprahyoid motor cortex has been an evidence-based treatment for poststroke dysphagia. Intermittent theta burst stimulation (iTBS) can be performed in 3 minutes compared with 20 ± 5 minutes for 10 Hz rTMS. This study aimed to ensure the clinical efficacy, safety, and tolerability of iTBS compared with 10 Hz rTMS for patients with poststroke dysphagia.

Method:

In this randomized, double-blind, single-center, controlled trial, 47 participants were randomly assigned to iTBS (n = 24) and rTMS (n = 23) group. Each participant received iTBS or rTMS daily at suprahyoid motor cortex of affected hemisphere for 10 consecutive days. The outcomes were assessed at baseline, immediately, and 2 weeks after intervention, including water-swallowing test, standardized swallowing assessment, Mann assessment of swallowing ability, Murray Secretion Scale, Yale Pharyngeal Residue Severity Rating Scale, Penetration-Aspiration Scale, and motor evoked potential (MEP) of bilateral suprahyoid muscle.

Results:

There were no significant differences between groups. There was a significant improvement on all rating scales and MEP after rTMS and iTBS. No significant differences on water-swallowing test, Mann assessment of swallowing ability, standardized swallowing assessment, Murray Secretion Scale scores, and MEP were observed between groups. In particular, there was significant differences on Penetration-Aspiration Scale scores (viscous liquid: mean difference = 1.016; 95% CI: 0.32–1.71; effect size: 0.360; P = .005) and the residue rate of pyriform fossa (viscous liquid: mean difference = 0.732; 95% CI: 0.18–1.28; effect size: 0.248; P = .010) in between-group. Comparing the differences over the changes of all rating scales, only the residue rate of epiglottis valley between groups was found to be significantly different (dilute liquid: mean difference = –0.567; 95% CI: –0.98 to –0.15; P = .009). There was no severe adverse effect and high dropout rates in both groups.

Conclusion:

The clinical efficacy, safety, and tolerability of iTBS showed non-inferior to 10 Hz rTMS for patients with poststroke dysphagia. The present study can be used to improve the clinicians’ knowledge and clinical decision skills on iTBS and rTMS for poststroke dysphagia.
Efficacy and safety of Ma's Bamboo-based medicinal moxibustion therapy for chronic fatigue syndrome
Authors: Xue Kaiyang , Wang Xianzhu , Quan Fei , Tang Jiaxuan , Wang Xin , Lan Lan , Fu Jing , Cui Jin
Published: January 2022

Background:

Chronic fatigue syndrome (CFS) is a recurrent functional disease with an unknown pathogenesis. Modern treatment mainly focuses on symptomatic and supportive care, but no specific treatment has emerged. Ma's Bamboo-based Medicinal Moxibustion therapy is a folk traditional Chinese medicine developed in Jinsha County, Guizhou Province. Over a long period of practice in the primary health care setting, it has been confirmed in folk medicine that the therapy can significantly improve the symptoms of patients with CFS, but there is no sufficient and scientific clinical evidence. Therefore, this randomised controlled pilot study was designed to preliminarily evaluate the efficacy and safety of Ma's Bamboo-based Medicinal Moxibustion therapy.

Methods/design:

This is a parallel, randomized, controlled, and exploratory study. Sixty patients with CFS admitted to the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine will be randomly assigned to the experimental or control group. The experimental group will receive Ma's Bamboo-based Medicinal Moxibustion therapy, whereas the control group will undergo conventional acupuncture. Both groups will be treated once daily for 6 consecutive days as a course of treatment, and two courses separated by 1 day will be completed (12 total treatments). All patients will undergo follow-up after the end of treatment. The baseline period is 2 days. The Fatigue Assessment Instrument score as the primary efficacy measure and secondary efficacy measures, including the Clinical Symptom Score and Fatigue Scale-14, will be evaluated at baseline, after one and two courses of treatment, and during follow-up. Serum T lymphocyte subset counts (CD3
+, CD4
+, CD8
+, CD4
+/CD8
+) and safety measures ((blood routine test, liver and kidney function and electrocardiogram) will be evaluated at baseline and after two courses of treatment. All adverse events occurring between baseline and the end of follow-up will be summarised at the end of the follow-up.

Discussion:

The results of this trial will clarify whether Ma's Bamboo-based Medicinal Moxibustion therapy can improve the symptoms of patients with CFS and provide preliminary evidence for the effectiveness and safety of Ma's Bamboo-based Medicinal Moxibustion therapy for this indication.

Ethics approval:

This study has been approved by the Ethics Review Committee of the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine (No.K2020–038).

Trial Registration:

Chinese Clinical Trial Registry, ChiCTR2000038860. Registered on 7 October 2020.
Exploring Parental Decision Making for a Child With a Life-Limiting Condition
Authors: Yazdani Nahal , Chartrand Julie , Stacey Dawn
Published: January 2022

The purpose of this study was to explore parents' and health care professionals' perception of parents' experiences in making decisions between acute and palliative therapies along the trajectory of their child's life-limiting condition. An interpretive description qualitative study was conducted. Semistructured interviews were completed with 6 parents and 6 health care professionals. Qualitative thematic analysis was used to identify, analyze, and report 4 themes: (1) “Going by your heart and gut”: the process of making a unique decision; (2) “Not black and white”: experiencing decisional conflict when making difficult decisions; (3) “Widening the circle of care”: various sources of decision-making support; and (4) “Always a worry”: concerns regarding parents' decision quality and outcomes.

Parents described experiencing decisional conflict when making health care decisions for their child with a life-limiting condition. Decision support provided by health care professionals in an interprofessional manner was preferred and supplemented by a parent-based support network. Reassurance regarding their good parenting from health care professionals was described as supportive throughout the decision-making experience.
A Worldwide Bibliometric Analysis of Published Literature on Medication Errors
Authors: Giannetta Noemi , Dionisi Sara , Tonello Monica , Di Simone Emanuele , Di Muzio Marco
Published: January 2022

Objectives

The aim of the study was to map the recent literature on medication error to monitor the state of research and explore emerging research fronts. Specifically, the co-occurrences analysis aimed to research the conceptual structure of the medication errors, whereas the coauthorship analysis aimed to research the “authorities” that influenced the academic and political discussion on medication errors.

Methods

The search for relevant studies was carried out through the Scopus. To map and monitor the state of research on medication error, a preliminary analysis was conducted through the year of publication, type of article, and language. The count of citation shows the most relevant work among those included. Bibliometric analyses were conducted, such as coauthorship analysis and co-occurrences analysis.

Results

The search strategy yielded 5393 articles. Of these, 1267 articles were included. Four main themes emerged from this bibliometric analysis: (a) the exploration of human factors related to health care professionals that increase the risk of medication error, (b) the investigation of behaviors and strategies that can prevent the error in the preparation and administration stage, (c) the analysis of the benefits related to the presence of the pharmacist in hospital settings, and (d) the exploration of the consequences of a medication error and/or adverse effects of drugs.

Conclusions

For the first time, a bibliometric analysis of medication errors research in the world has been conducted and demonstrated that there is a wealth of contributions already being made that are well aligned to the World Health Organization challenge.
Grading Trigone Meningiomas Using Conventional Magnetic Resonance Imaging With Susceptibility-Weighted Imaging and Perfusion-Weighted Imaging
Authors: Yang Xinyi , Xiao Zebin , Xing Zhen , Lin Xiang , Wang Feng , Cao Dairong
Published: January 2022

Objective

To compare conventional magnetic resonance imaging (MRI), susceptibility-weighted imaging (SWI), and perfusion-weighted imaging (PWI) characteristics in different grades of trigone meningiomas.

Methods

Thirty patients with trigone meningiomas were enrolled in this retrospective study. Conventional MRI was performed in all patients; SWI (17 cases), dynamic contrast-enhanced PWI (10 cases), and dynamic susceptibility contrast PWI (6 cases) were performed. Demographics, conventional MRI features, SWI- and PWI-derived parameters were compared between different grades of trigone meningiomas.

Results

On conventional MRI, the irregularity of tumor shape (ρ = 0.497, P = 0.005) and the extent of peritumoral edema (ρ = 0.187, P = 0.022) might help distinguish low-grade and high-grade trigone meningiomas. On multiparametric functional MRI, rTTPmax (1.17 ± 0.06 vs 1.30 ± 0.05, P = 0.048), Kep, Ve, and iAUC demonstrated their potentiality to predict World Health Organization grades I, II, and III trigone meningiomas.

Conclusions

Conventional MRI combined with dynamic susceptibility contrast and dynamic contrast-enhanced can help predict the World Health Organization grade of trigone meningiomas.
Midurethral Sling Removal or Revision in Women with Chronic Pain
Authors: Rockefeller Nicholas F. , Petersen Timothy R. , Jeppson Peter C. , Dunivan Gena , Ninivaggio Cara , Meriwether Kate , Gallegos Maxx A. , Komesu Yuko M.
Published: January 2022

Objectives

The objectives of this study are (1) to estimate the incidence of midurethral sling revision/removal in women with preexisting pain diagnoses versus those without these diagnoses and (2) to describe associations between numbers and type of pain diagnoses with revision/removal.

Methods

Women who underwent midurethral sling surgery between 2009 through 2014 were identified in the MarketScan database and tracked and December 31, 2014. Patients with preoperative chronic pain diagnoses (fibromyalgia, endometriosis, irritable bowel, dyspareunia, low back pain, temporomandibular joint syndrome, interstitial cystitis, pelvic/perineal pain) were compared with controls (those without these diagnoses) regarding mesh sling revision/removal. Logistic regression identified variables associated with mesh revision/removal, and survival analysis compared timing of mesh removal/revision.

Results

There were 161,459 women who underwent midurethral sling surgery (pain, 83,484; nonpain, 77,975). Pain and nonpain groups differed in age (52.1 vs 53.5 years, P < 0.01) and insurance status (P < 0.01), with the pain group more commonly living in the South or West. Mean follow-up was 42.3 months. Cumulative risk for sling revision/removal was higher in patients with 1 pain diagnosis relative to controls (relative risk, 1.54; 95% confidence interval [CI], 1.41–1.54). Risks increased with increased pain diagnoses (≥4 diagnoses; relative risk, 3.13; 95% CI, 2.81–3.47). Pelvic pain conditions had greatest odds of mesh revision/removal (dyspareunia adjusted odds ratio [aOR], 2.44; 95% CI, 2.23–2.63; interstitial cystitis aOR, 1.46; 95% CI, 1.27–1.66; pelvic/perineal pain aOR, 1.41; 95% CI, 1.33–1.48). Co-occurrence of dyspareunia and interstitial cystitis or pelvic/perineal pain had 12.7% cumulative incidence of sling revision/removal. Cox proportional hazards revealed greatest risk for those with pelvic pain conditions (hazard ratio, 2.40; 95% CI, 2.13–2.70).

Conclusions

Chronic pain diagnoses increased risk of midurethral sling revision/removal; pelvic pain and numbers of diagnoses increased this risk.
A panoptic segmentation approach for tumor-infiltrating lymphocyte assessment: development of the MuTILs model and PanopTILs dataset
Authors: Liu Shangke , Amgad Mohamed , Rathore Muhammad A. , Salgado Roberto , Cooper Lee A.D.
Published: January 2022

Tumor-Infiltrating Lymphocytes (TILs) have strong prognostic and predictive value in breast cancer, but their visual assessment is subjective. To improve reproducibility, the International Immuno-oncology Working Group recently released recommendations for the computational assessment of TILs that build on visual scoring guidelines. However, existing resources do not adequately address these recommendations due to the lack of annotation datasets that enable joint, panoptic segmentation of tissue regions and cells. Moreover, existing deep-learning methods focus entirely on either tissue segmentation or cell nuclei detection, which complicates the process of TILs assessment by necessitating the use of multiple models and reconciling inconsistent predictions. We introducePanopTILs, a region and cell-level annotation dataset containing 814,886 nuclei from 151 patients, openly accessible at: sites.google.com/view/panoptils. Using PanopTILs we developedMuTILs, a neural network optimized for assessing TILs in accordance with clinical recommendations. MuTILs is a concept bottleneck model designed to be interpretable and to encourage sensible predictions at multiple resolutions. Using a rigorous internal-external cross-validation procedure, MuTILs achieves an AUROC of 0.93 for lymphocyte detection and a DICE coefficient of 0.81 for tumor-associated stroma segmentation. Our computational score closely matched visual scores from 2 pathologists (Spearman R=0.58-0.61, p<0.001). Moreover, computational TILs scores had a higher prognostic value than visual scores, independent of TNM stage and patient age. In conclusion, we introduce a comprehensive open data resource and a novel modeling approach for detailed mapping of the breast tumor microenvironment.
Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study
Authors: Howe Laurence J , Rasheed Humaira , Jones Paul R , Boomsma Dorret I , Evans David M , Giannelis Alexandros , Hayward Caroline , Hopper John L , Hughes Amanda , Lahtinen Hannu , Li Shuai , Lind Penelope A , Martin Nicholas G , Martikainen Pekka , Medland Sarah E , Morris Tim T , Nivard Michel G , Pingault Jean-Baptiste , Silventoinen Karri , Smith Jennifer A , Willoughby Emily A , Wilson James F ,   Within Family Consortium, Olav Åsvold Bjørn , Næss Øyvind E , Smith George Davey , Kaprio Jaakko , Brumpton Ben , Davies Neil M
Published: January 2022

Previous Mendelian randomization (MR) studies using population samples (population-MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. Mendelian randomization using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis.

Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72,932 siblings from UK Biobank and the Norwegian HUNT study and summary-level data from a within-sibship Genome-wide Association Study including over 140,000 individuals.

Both population and within-sibship MR estimates provided evidence that educational attainment influences BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect. These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independent of potential demographic and family-level confounders.
XTRA Study protocol: eXploring medical sTudents’ caReer reAdiness - A cross sectional study in the UK
Authors: Godoi Amanda , McDade-Kumar Mia , Virk Farazi , Casteleyn Charlotte , Marei Omar , Yang Ting , Moussa Ahmed , Aman Kashif , Byrne Matthew H V , Babu Priya Rose , Trikha Sanya , Bamdad Kiana , Tombs Michal
Published: January 2022

Background and objectives

Professional and career enhancing opportunities are essential for developing skills required for a successful career in medicine. Research to date has mainly focused on the extent to which medical schools prepare students for clinical work as junior doctors. However, there remains a need to ascertain how students prepare for their career and what facilitates or hinders learning regarding careers in medicine. The purpose of the XTRA study is to examine career readiness of medical students at UK universities and the support they receive during their studies regarding career planning.

Methods

The eXploring medical sTudents’ caReer reAdiness (XTRA) study is a national cross sectional study of all medical students enrolled at a UK medical school. Data collection will occur via a secure online survey designed as a training need analysis based on the principles of Super’s theory (Super, 1953) of career development. A snowball sampling strategy will be used to recruit participants via social media and networks. Results will be analysed using quantitative analysis and thematic analysis to identify themes in qualitative responses. The primary outcome is to understand the perspective of current medical students on how well prepared they are about entering their careers in healthcare.

Conclusions

We anticipate that findings from this study will help identify career readiness of medical students to facilitate the development of career development programmes and resources to ensure medical students are well equipped for their future careers.
In vivo single-cell profiling of lncRNAs during Ebola virus infection
Authors: Santus Luisa , García-Pérez Raquel , Sopena-Rios Maria , Lin Aaron E , Adams Gordon C , Barnes Kayla G , Siddle Katherine J , Wohl Shirlee , Reverter Ferran , Rinn John L , Bennett Richard S , Hensley Lisa E , Sabeti Pardis C , Melé Marta
Published: January 2022

Long non-coding RNAs (lncRNAs) are pivotal mediators of systemic immune response to viral infection, yet most studies concerning their expression and functions upon immune stimulation are limited to in vitro bulk cell populations. This strongly constrains our understanding of how lncRNA expression varies at single-cell resolution, and how their cell-type specific immune regulatory roles may differ compared to protein-coding genes. Here, we perform the first in-depth characterization of lncRNA expression variation at single-cell resolution during Ebola virus (EBOV) infection in vivo. Using bulk RNA-sequencing from 119 samples and 12 tissue types, we significantly expand the current macaque lncRNA annotation. We then profile lncRNA expression variation in immune circulating single-cells during EBOV infection and find that lncRNAs’ expression in fewer cells is a major differentiating factor from their protein-coding gene counterparts. Upon EBOV infection, lncRNAs present dynamic and mostly cell-type specific changes in their expression profiles especially in monocytes, the main cell type targeted by EBOV. Such changes are associated with gene regulatory modules related to important innate immune responses such as interferon response and purine metabolism. Within infected cells, several lncRNAs have positively and negatively correlated expression with viral load, suggesting that expression of some of these lncRNAs might be directly hijacked by EBOV to attack host cells. This study provides novel insights into the roles that lncRNAs play in the host response to acute viral infection and paves the way for future lncRNA studies at single-cell resolution.
The SARS-CoV-2 Omicron (B.1.1.529) variant exhibits altered pathogenicity, transmissibility, and fitness in the golden Syrian hamster model
Authors: Yuan Shuofeng , Ye Zi-Wei , Liang Ronghui , Tang Kaiming , Zhang Anna Jinxia , Lu Gang , Ong Chon Phin , Poon Vincent Kwok-Man , Chan Chris Chung-Sing , Mok Bobo Wing-Yee , Qin Zhenzhi , Xie Yubin , Sun Haoran , Tsang Jessica Oi-Ling , Yuen Terrence Tsz-Tai , Chik Kenn Ka-Heng , Chan Chris Chun-Yiu , Cai Jian-Piao , Luo Cuiting , Lu Lu , Yip Cyril Chik-Yan , Chu Hin , To Kelvin Kai-Wang , Chen Honglin , Jin Dong-Yan , Yuen Kwok-Yung , Chan Jasper Fuk-Woo
Published: January 2022

The newly emerging SARS-CoV-2 Omicron (B.1.1.529) variant first identified in South Africa in November 2021 is characterized by an unusual number of amino acid mutations in its spike that renders existing vaccines and therapeutic monoclonal antibodies dramatically less effective. The in vivo pathogenicity, transmissibility, and fitness of this new Variant of Concerns are unknown. We investigated these virological attributes of the Omicron variant in comparison with those of the currently dominant Delta (B.1.617.2) variant in the golden Syrian hamster COVID-19 model. Omicron-infected hamsters developed significantly less body weight losses, clinical scores, respiratory tract viral burdens, cytokine/chemokine dysregulation, and tissue damages than Delta-infected hamsters. The Omicron and Delta variant were both highly transmissible (100% vs 100%) via contact transmission. Importantly, the Omicron variant consistently demonstrated about 10-20% higher transmissibility than the already-highly transmissible Delta variant in repeated non-contact transmission studies (overall: 30/36 vs 24/36, 83.3% vs 66.7%). The Delta variant displayed higher fitness advantage than the Omicron variant without selection pressure in both in vitro and in vivo competition models. However, this scenario drastically changed once immune selection pressure with neutralizing antibodies active against the Delta variant but poorly active against the Omicron variant were introduced, with the Omicron variant significantly outcompeting the Delta variant. Taken together, our findings demonstrated that while the Omicron variant is less pathogenic than the Delta variant, it is highly transmissible and can outcompete the Delta variant under immune selection pressure. Next-generation vaccines and antivirals effective against this new VOC are urgently needed.

One Sentence Summary

The novel SARS-CoV-2 Omicron variant, though less pathogenic, is highly transmissible and outcompetes the Delta variant under immune selection pressure in the golden Syrian hamster COVID-19 model.
Systematic analysis of human antibody response to ebolavirus glycoprotein reveals high prevalence of neutralizing public clonotypes
Authors: Chen Elaine C. , Gilchuk Pavlo , Zost Seth J. , Ilinykh Philipp A. , Binshtein Elad , Huang Kai , Myers Luke , Bonissone Stefano , Day Samuel , Kona Chandrahaas R. , Trivette Andrew , Reidy Joseph X. , Sutton Rachel E. , Gainza Christopher , Monroig Summer , Davidson Edgar , Saphire Erica Ollmann , Doranz Benjamin J. , Castellana Natalie , Bukreyev Alexander , Carnahan Robert H. , Crowe James E.
Published: January 2022

Understanding the human antibody response to emerging viral pathogens is key to epidemic preparedness. As the size of the B cell response to a pathogenic virus protective antigen is undefined, we performed deep paired heavy and light chain sequencing in EBOV-GP specific memory B cells, allowing analysis of the ebolavirus-specific antibody repertoire both genetically and functionally. This approach facilitated investigation of the molecular and genetic basis for evolution of cross-reactive antibodies by elucidating germline-encoded properties of antibodies to EBOV and identification of the overlap between antibodies in the memory B-cell and serum repertoire. We identified 73 public clonotypes to EBOV, 20% of which encoded antibodies with neutralization activity and capacity to protect in vivo. This comprehensive analysis of the public and private antibody repertoire provides insight into the molecular basis of the humoral immune response to EBOV-GP, which informs vaccine design of new vaccines and improved therapeutics.
Staphylococcus aureus does not synthesize arginine from proline under physiological conditions
Authors: Jeong Bohyun , Shah Majid Ali , Roh Eunjung , Kim Kyeongkyu , Park Indal , Bae Taeok
Published: January 2022

The Gram-positive pathogen Staphylococcus aureus is the only bacterium known to synthesize arginine from proline via the arginine-proline interconversion pathway, despite having genes for the well-conserved glutamate pathway. Since the proline-arginine interconversion pathway is repressed by CcpA-mediated carbon catabolite repression (CCR), CCR has been attributed to the arginine auxotrophy of S. aureus. Using ribose as a secondary carbon source, here, we demonstrate that S. aureus arginine auxotrophy is not due to CCR but due to the inadequate concentration of proline degradation product. Proline is degraded by proline dehydrogenase (PutA) into pyrroline-5-carboxylate (P5C). Although the PutA expression was fully induced by ribose, the P5C concentration remained insufficient to support arginine synthesis because P5C was constantly consumed by the P5C reductase ProC. When the P5C concentration was artificially increased by either PutA overexpression or proC-deletion, S. aureus could synthesize arginine from proline regardless of carbon source. In contrast, when the P5C concentration was reduced by overexpression of proC, it inhibited the growth of the ccpA-deletion mutant without arginine. Intriguingly, the ectopic expression of the glutamate pathway enzymes converted S. aureus into arginine prototroph. In an animal experiment, the arginine-proline interconversion pathway was not required for the survival of S. aureus. Based on these results, we concluded that S. aureus does not synthesize arginine from proline under physiological conditions. We also propose that arginine auxotrophy of S. aureus is not due to the CcpA-mediated CCR but due to the inactivity of the conserved glutamate pathway.

Importance

Staphylococcus aureus is a versatile Gram-positive human pathogen infecting various human organs. The bacterium’s versatility is partly due to efficient metabolic regulation via the carbon catabolite repression system (CCR). S. aureus is known to interconvert proline and arginine, and CCR represses the synthesis of both amino acids. However, when CCR is released by a non-preferred carbon source, S. aureus can synthesize proline but not arginine. In this study, we show that, in S. aureus, the intracellular concentration of pyrroline-5-carboxylate (P5C), the degradation product of proline and the substrate of proline synthesis, is too low to synthesize arginine from proline. These results call into question the notion that S. aureus synthesizes arginine from proline.
In vivo growth of Staphylococcus lugdunensis is facilitated by the concerted function of heme and non-heme iron acquisition mechanisms
Authors: Flannagan Ronald S. , Brozyna Jeremy R. , Kumar Brijesh , Adolf Lea A. , Power Jeffrey John , Heilbronner Simon , Heinrichs David E.
Published: January 2022

Acquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Here we show that S. lugdunensis utilizes diverse genome encoded iron acquisition mechanisms to satisfy its need for this nutrient. Indeed, S. lugdunensis can usurp hydroxamate siderophores, and staphyloferrin A and B from S. aureus, using the fhuC ATPase-encoding gene. Acquisition of catechol siderophores and catecholamine stress hormones necessitates the presence of the sst-1 transporter-encoding locus, but not the sst-2 locus. Iron-dependent growth in acidic culture conditions necessitates the feoAB locus. Heme iron is acquired via expression of the iron-regulated surface determinant (isd) locus. During systemic infection of mice we demonstrate that while S. lugdunensis does not cause overt illness, it does colonize and proliferate to high numbers in the kidneys. By combining mutations in the various iron acquisition loci, we further demonstrate that only a strain mutated for all of isd, fhuC, sst-1, and feo, versus combination mutants carrying wild type copies of any one of those loci, was attenuated in its ability to proliferate to high numbers in kidneys. Taken together our data reveal that S. lugdunensis requires a repertoire of both heme and non-heme iron acquisition mechanisms to proliferate during systemic infection of mammals.

Importance

Acquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Owing to an inability to synthesize siderophores, growth of S. lugdunensis is dramatically impaired in the presence of transferrin or serum, yet S. lugdunensis nonetheless uses several other genome-encoded iron acquisition mechanisms, in concert, to proliferate within the mammalian host. Therefore, the development of interventions that target bacterial iron acquisition systems should consider the overlapping function of distinct metal acquisition strategies deployed by bacterial pathogens.
People with HIV Have Higher Risk of COVID-19 Diagnosis but Similar Outcomes than the General Population
Authors: Tang Michael E , Gaufin Thaidra , Anson Ryan , Zhu Wenhong , Mathews William C , Cachay Edward R
Published: January 2022

Background

We investigated the effect of HIV on COVID-19 outcomes with attention to selection bias due to differential testing and to comorbidity burden.

Methods

Retrospective cohort analysis using four hierarchical outcomes: positive SARS-CoV-2 test, COVID-19 hospitalization, intensive care unit (ICU) admission, and hospital mortality. The effect of HIV status was assessed using traditional covariate-adjusted, inverse probability weighted (IPW) analysis based on covariate distributions for testing bias (testing IPWs), HIV infection status (HIV IPWs), and combined models. Among PWH, we evaluated whether CD4 count and HIV plasma viral load (pVL) discriminated between those who did or did not develop study outcomes using receiver operating characteristic analysis.

Results

Between March and November 2020, 63,319 people were receiving primary care services at UCSD, of whom 4,017 were people living with HIV (PWH). PWH had 2.1 times the odds of a positive SARS-CoV-2 test compared to those without HIV after weighting for potential testing bias, comorbidity burden, and HIV-IPW (95% CI 1.6-2.8). Relative to persons without HIV, PWH did not have an increased rate of COVID-19 hospitalization after controlling for comorbidities and testing bias [adjusted incidence rate ratio (aIRR): 0.5, 95% CI: 0.1 – 1.4]. PWH had neither a different rate of ICU admission (aIRR:1.08, 95% CI; 0.31 – 3.80) nor in-hospital death (aIRR:0.92, 95% CI; 0.08 – 10.94) in any examined model. Neither CD4 count nor pVL predicted any of the hierarchical outcomes among PWH.

Conclusions

PWH have a higher risk of COVID-19 diagnosis but similar outcomes compared to those without HIV.

Summary point

After considering the effects of potential bias due to differential testing, comorbidities, and other patient characteristics, people with HIV had an increased rate of SARS-CoV-2 positivity and similar rates of hospitalization, ICU admission, and death.
Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population
Authors: Zaghlool Shaza B. , Halama Anna , Stephan Nisha , Thangam Manonanthini , Ahlqvist Emma , Albagha Omar M. E. , Abou⍰Samra Abdul Badi , Suhre Karsten
Published: January 2022

Background

Type 2 diabetes (T2D) has a heterogeneous etiology which is increasingly recognized to influence the risk of complications and choice of treatment. A data driven cluster analysis in four separate European populations of patients with type 2 diabetes identified four subtypes of severe insulin dependent (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) (Ahlqvist et al., Lancet Diabetes Endocrinology, 2018). Our aim was to extend this classification to the Arab population of Qatar and characterize the biological processes that differentiate these subtypes in relation to metabolomic and proteomic signatures.

Methods

The Ahlqvist et al. subtype clustering approach was applied to 631 individuals with T2D from the Qatar Biobank (QBB) and validated in an independent set of 420 participants from the same population. The association between blood metabolites (n=1,159) and protein levels (n=1,305) with each cluster were established.

Findings

The four subtypes of T2D were reproduced and validated in the population of Qatar. Cluster-specific metabolomic and proteomic associations revealed subtype-specific molecular processes. Activation of the complement system with many features of autoimmune diabetes and reduced 1,5-anhydroglucitol (1,5-AG) characterized SIDD, with evidence of impaired insulin signaling in SIRD, elevated leptin and fatty acid binding protein in MOD, whilst MARD appeared to be the healthiest subgroup.

Interpretation

We have replicated the four T2D clusters in an Arab population and identified distinct metabolic and proteomic signatures, providing insights into underlying etiology with the potential to deploy subtype-specific treatment options.
Immunity in Omicron SARS-CoV-2 breakthrough COVID-19 in vaccinated adults
Authors: Kared Hassen , Wolf Asia-Sophia , Alirezaylavasani Amin , Ravussin Anthony , Solum Guri , Tran Trung The , Lund-Johansen Fridtjof , Vaage John Torgils , Nissen-Meyer Lise Sofie , Nygaard Unni C. , Hungnes Olav , Robertson Anna H , Næss Lisbeth Meyer , Trogstad Lill , Magnus Per , Munthe Ludvig A , Mjaaland Siri
Published: January 2022

The new SARS-CoV-2 variant of concern (VOC) Omicron has more than 30 mutations in the receptor binding domain (RBD) of the Spike protein enabling viral escape from antibodies in vaccinated individuals and increased transmissibility1-6. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a superspreader event had robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergentde novoT cell response to non-Spike antigens. We compared cases from a Christmas party where 81 of 110 (74%) developed Omicron breakthrough COVID-197, with Delta breakthrough cases and vaccinated non-infected controls. Omicron cases had significantly increased activated SARS-CoV-2 wild type Spike-specific (vaccine) cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, activated anti-Spike plasmablasts and anti-RBD memory B cells compared to controls. Omicron cases had significantly increasedde novomemory T cell responses to non-Spike viral antigens compared to Delta breakthrough cases demonstrating development of broad immunity. The rapid release of Spike and RBD-specific IgG+B cell plasmablasts and memory B cells into circulation suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity.
The impact of major depressive disorder on glycaemic control in type 2 diabetes: a longitudinal cohort study using UK Biobank primary care records
Authors: Gillett Alexandra C , Hagenaars Saskia P , Handley Dale , Casanova Francesco , Young Katherine G , Green Harry , Lewis Cathryn M , Tyrrell Jess
Published: January 2022

Background

This study evaluates longitudinal associations between glycaemic control (mean and within-patient variability of glycated haemaglobin (HbA1c) levels) in individuals with type 2 diabetes (T2D) and major depressive disorder (MDD), focusing on the timings of these diagnoses.

Methods

In UK Biobank, T2D was defined using self-report and linked health outcome data, then validated using polygenic scores. Repeated HbA1c measurements (mmol/mol) over the 10 years following T2D diagnosis were outcomes in mixed effects models, with T2D disease duration included using restricted cubic splines. Four MDD exposures were considered: MDD diagnosis prior to T2D diagnosis (pre-T2D MDD), time between pre-T2D MDD diagnosis and T2D, new MDD diagnosis during follow-up (post-T2D MDD) and time since post-T2D MDD diagnosis. Models with and without covariate adjustment were considered.

Results

T2D diagnostic criteria were robustly associated with T2D polygenic scores. In 11,837 T2D cases (6.9 year median follow-up), pre-T2D MDD was associated with a 0.92 increase in HbA1c (95% CI: [0.00, 1.84]), but earlier pre-T2D MDD diagnosis correlated with lower HbA1c. These pre-T2D MDD effects became non-significant after covariate adjustment. Post-T2D MDD individuals demonstrated increasing HbA1c with years since MDD diagnosis (/3 = 0.51, 95% CI: [0.17, 0.86]). Retrospectively, looking across all follow-up, within-patient variability in HbA1c was 1.16 (95% CI: 1.13-1.19) times higher in post-T2D MDD.

Conclusions

The timing of MDD diagnosis is important for understanding glycaemic control in T2D. Poorer control was observed in MDD diagnosed post-T2D, highlighting the importance of depression screening in T2D, and closer monitoring for individuals who develop MDD after T2D.
Immunogenicity of convalescent and vaccinated sera against clinical isolates of ancestral SARS-CoV-2, beta, delta, and omicron variants
Authors: Banerjee Arinjay , Lew Jocelyne , Kroeker Andrea , Baid Kaushal , Aftanas Patryk , Nirmalarajah Kuganya , Maguire Finlay , Kozak Robert , McDonald Ryan , Lang Amanda , Gerdts Volker , Straus Sharon E. , Gilbert Lois , Li Angel Xinliu , Mozafarihasjin Mohammad , Walmsley Sharon , Gingras Anne-Claude , Wrana Jeffrey L. , Mazzulli Tony , Colwill Karen , McGeer Allison J. , Mubareka Samira , Falzarano Darryl
Published: January 2022

The omicron variant of concern (VOC) of SARS-CoV-2 was first reported in November 2021 in Botswana and South Africa. Omicron has evolved multiple mutations within the spike protein and the receptor binding domain (RBD), raising concerns of increased antibody evasion. Here, we isolated infectious omicron from a clinical specimen obtained in Canada. The neutralizing activity of sera from 65 coronavirus disease (COVID-19) vaccine recipients and convalescent individuals against clinical isolates of ancestral SARS-CoV-2, beta, delta, and omicron VOCs was assessed. Convalescent sera from unvaccinated individuals infected by the ancestral virus during the first wave of COVID-19 in Canada (July, 2020) demonstrated reduced neutralization against beta and omicron VOCs. Convalescent sera from unvaccinated individuals infected by the delta variant (May-June, 2021) neutralized omicron to significantly lower levels compared to the delta variant. Sera from individuals that received three doses of the Pfizer or Moderna vaccines demonstrated reduced neutralization of the omicron variant relative to ancestral SARS-CoV-2. Sera from individuals that were naturally infected with ancestral SARS-CoV-2 and subsequently received two doses of the Pfizer vaccine induced significantly higher neutralizing antibody levels against ancestral virus and all VOCs. Importantly, infection alone, either with ancestral SARS-CoV-2 or the delta variant was not sufficient to induce high neutralizing antibody titers against omicron. This data will inform current booster vaccination strategies, and we highlight the need for additional studies to identify longevity of immunity against SARS-CoV-2 and optimal neutralizing antibody levels that are necessary to prevent infection and/or severe COVID-19.
Rapid and specific degradation of endogenous proteins in mouse models using auxin-inducible degrons
Authors: Macdonald Lewis , Taylor Gillian , Brisbane Jennifer , Christodoulou Ersi , Scott Lucy , Von Kriegsheim Alex , Rossant Janet , Gu Bin , Wood Andrew
Published: January 2022

Auxin-inducible degrons are a chemical genetic tool for targeted protein degradation and are widely used to study protein function in cultured mammalian cells. Here, we develop CRISPR-engineered mouse lines that enable rapid and highly specific degradation of tagged endogenous proteins in vivo. Most but not all cell types are competent for degradation. Using mouse genetics, we show that degradation kinetics depend upon the dose of the tagged protein, ligand, and the E3 ligase subunit Tir1. Rapid degradation of condensin I and condensin II – two essential regulators of mitotic chromosome structure - revealed that both complexes are individually required for cell division in precursor lymphocytes, but not in their differentiated peripheral lymphocyte derivatives. This generalisable approach provides unprecedented temporal control over the dose of endogenous proteins in mouse models, with implications for studying essential biological pathways and modelling drug activity in mammalian tissues.

Highlights

Auxin-inducible degradation of endogenously tagged proteins in living mice and a range of primary cells.

Most but not all cell types are competent for degradation

Dosage of the tagged protein, E3 ligase substrate receptor and ligand can all determine degradation kinetics

Rapid degradation of condensin subunits in lymphocytes reveals stage-specific requirements during cell division
Site-specific adaptation mechanisms of an oral pathobiont in the oral and gut mucosae
Authors: Guo Yijie , Kitamoto Sho , Caballero-Flores Gustavo , Watanabe Daisuke , Sugihara Kohei , Núñez Gabriel , Alteri Christopher J. , Inohara Naohiro , Kamada Nobuhiko
Published: January 2022

Periodontal inflammation leads to oral dysbiosis with the expansion of oral pathobionts. Besides the pathogenic role of oral pathobionts during periodontal inflammation, studies have revealed that oral pathobionts contribute to diseases in distant organs beyond the oral mucosa. For example, the oral pathobiont Klebsiella aerogenes, which accumulates in the oral mucosa during periodontitis in mice, can exacerbate colitis when it ectopically colonizes the gastrointestinal tract. However, the precise mechanisms by which oral pathobionts establish their colonization in extra-oral mucosal sites remains incompletely understood. We performed high-throughput in vivo genetic screening to identify fitness genes required for the adaptation of the oral pathobiont K. aerogenes to different mucosal sites – the oral and gut mucosae – at the steady state and during inflammation. In addition, the global transcriptome of K. aerogenes in different environments was analyzed. We determined that K. aerogenes employs genes related to iron acquisition and chaperone usher pili, which are encoded on a newly identified genomic locus named “locus of colonization in the inflamed gut” (LIG), for adaptation in the gut mucosa, particularly during inflammation. In contrast, the LIG virulence factors are not required for K. aerogenes to adapt to the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their original niche.

Author Summary

The symbiotic bacterial community evolves uniquely at each body site. However, under certain circumstances, symbionts may disseminate far from their original niche and colonize a site ectopically. It has been reported that oral resident bacteria associated with periodontal disease, namely oral pathobionts, contribute to gastrointestinal diseases, such as inflammatory bowel disease and colorectal cancer, through ectopic colonization of the gut. However, the molecular mechanisms by which oral pathobionts adapt to the gut environment remain largely unexplored. In this study, using a model oral pathobiont Klebsiella aerogenes, we screened genes essential for the colonization of the pathobiont at different mucosal sites. We discovered that the oral pathobiont uses distinct virulence mechanisms at two different mucosal sites – the oral and gut mucosae. Understanding the strategies of bacteria localized in ectopic organs may lead to the development of strategies to prevent disease caused by the dissemination of pathogenic oral bacteria.
Seasonality and competition select for variable germination behavior in perennials
Authors: Brink Hanna ten , Haaland Thomas R. , Opedal Øystein H.
Published: January 2022

The common occurrence of within-population variation in germination behavior and associated traits such as seed size has long fascinated evolutionary ecologists. In annuals, unpredictable environments are known to select for bet-hedging strategies causing variation in dormancy duration and germination strategies. Variation in germination timing and associated traits is also commonly observed in perennials, and often tracks gradients of environmental predictability. Although bet-hedging is thought to occur less frequently in long-lived organisms, these observations suggest a role of bet-hedging strategies in perennials occupying unpredictable environments. We use complementary analytical and evolutionary simulation models of within-individual variation in germination behavior in seasonal environments to show how bet-hedging interacts with fluctuating selection, life-history traits, and competitive asymmetries among germination strategies. We reveal substantial scope for bet-hedging to produce variation in germination behavior in long-lived plants, when ‘false starts’ to the growing season results in either competitive advantages or increased mortality risk for alternative germination strategies. Additionally, we find that lowering adult survival may, in contrast to classical bet-hedging theory, result in less spreading of germination by decreasing density-dependent competition. These models extend insights from bet-hedging theory to perennials and explore how competitive communities may be affected by ongoing changes in climate and seasonality patterns.