bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pre-exposure Prophylaxis (PrEP) Care Continuum Among English-Speaking Latino Sexual Minority Men in the United States (2014–2020)
Authors: Lee Jane J. , Barry Michael P. , Kerani Roxanne P. , Sanchez Travis H. , Katz David A.
Published: March 2023

Background:

There is limited understanding of the pre-exposure prophylaxis (PrEP) care continuum specific to Latino/x gay, bisexual, and other sexual minority men (SMM) that encompasses the population residing outside of large metropolitan or urban areas.

Setting:

We examined trends and characteristics associated with the PrEP care continuum with data from the 2014–2020 cycles of the American Men's Internet Survey, an annual online cross-sectional behavioral survey of cisgender SMM in the United States.

Methods:

We calculated PrEP continuum outcomes overall and by year among Hispanic/Latino SMM (n = 9010). We used generalized estimating equations with Poisson links to examine (1) temporal trends (2014–2020) in each step of the PrEP continuum and PrEP use in the past year stratified by PrEP eligibility and (2) correlates of each step of the PrEP continuum in 2020 using multivariable models.

Results:

Among 2283 Latino SMM in 2020, 84% reported PrEP awareness, 30% discussed PrEP with a provider, 15% used PrEP in the past year, and 12% were currently using PrEP. PrEP awareness increased from 52% in 2014 to 84% in 2020; and PrEP use in the past year increased from 4% in 2014 to 15% in 2020. In the multivariable models, age and PrEP eligibility were associated with PrEP use in the past year, and urban–rural classification was associated with current PrEP use.

Conclusions:

While most of the Latino SMM are aware of PrEP, significant gaps remain in this population in discussing PrEP with a provider and using PrEP that require tailored strategies to enhance access to HIV prevention services.
Causes of Reoperation Consultation and Clinical Review of Actual Reoperation After Previous Orthognathic Surgery
Authors: Kim Ci Young , Ha Sung-Ho , Lee Pa Ran , Baek Seung-Hak , Choi Jin-Young
Published: March 2023

Objective:

To investigate the causes of reoperation consultation, and the actual percentage and procedures of reoperation after previous orthognathic surgery.

Methods:

The samples consisted of 30 patients who visited our clinic for reoperation consultation from October 2015 to September 2021 (6 males and 24 females; mean age at reoperation consultation, 28.4 y). Patient’s causes of reoperation consultation were divided into “esthetic dissatisfaction,” “airway changes,” “temporomandibular disorders,” “uncomfortable occlusion,” and “other complications”. In terms of esthetic dissatisfaction, the more detailed esthetic problem was evaluated by the clinical chart, facial photographs, and radiographs. In patients who actually underwent reoperation, the actual percentage and procedures of reoperation were investigated.

Results:

The most prevalent causes for reoperation consultation were “esthetic dissatisfaction” (n = 21, 70.0%), followed by “airway changes” (n = 11, 36.7%), “uncomfortable occlusion” (n = 8, 26.7%), “other complications” (n = 5, 16.7%), and “temporomandibular disorder” (n = 4, 13.3%). Less than half of patients actually underwent reoperation (n = 13, 43.3%). Actual reoperation procedures included minor revision surgery, reconstruction surgery, or complete reoperation according to the patient’s need. In case of complete reoperation, more accurate and predictable results were obtained by using virtual surgical planning, customized surgical guides, titanium surgical plates made with computer-aided design and computer-aided manufacturing technique, and a 3-dimensional printing method.

Conclusion:

It is important to communicate with patients about expectations for facial esthetic improvement by orthognathic surgery for obtaining the patient’s postoperative satisfaction.
A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model
Authors: Tsikis Savas T. , Fligor Scott C. , Hirsch Thomas I. , Mitchell Paul D. , Pan Amy , Moskowitzova Kamila , Whitlock Ashlyn E. , Loring Greta , First Eric , Nedder Arthur , Gura Kathleen M. , Puder Mark
Published: March 2023

Objective:

To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF).

Background:

SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy.

Methods:

Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n=6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline.

Results:

ILC animals demonstrated a 19% greater reduction in PN calories (P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P=0.03) and 1.9-fold higher crypt cell proliferation (P=0.02) compared with controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 (P = 0.02), eicosapentaenoic acid (P < 0.0001), docosahexaenoic acid (P = 0.004), vitamin A (P = 0.02), low-density lipoprotein (P = 0.02), and high-density lipoprotein (P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups.

Conclusions:

ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF.
Comparison Between Terminal or Preterminal Conditioning of Donor Livers by Ex Situ Machine Perfusion
Authors: von Horn Charlotte , Lüer Bastian , Malkus Laura , Minor Thomas
Published: March 2023

Background.

The successful implementation of end-ischemic normothermic machine perfusion (NMP) into clinical practice comes along with unusual demands for trained personnel and technical facilities in the implantation clinic. This creates an interest to bundle expertise and professional equipment for execution of MP at regional pump centers at the disadvantage of adding a second short period of cold preservation while sending the reconditioned grafts to the actual implant clinic. Differences of liver recovery upon reperfusion either immediately after NMP or after 3 h of cold storage subsequent to NMP should therefore be evaluated.

Methods.

Rat livers were cold stored for 18 h, subjected to 2 h of NMP, and then either directly evaluated by ex vivo reperfusion or exposed to a second cold storage period of 3 h to simulate transport from the hub center to the implant clinic. Livers stored for 18 h by cold storage only served as controls.

Results.

Both MP regimens significantly reduced hepatic enzyme release and improved bile production, clearance of lactate, and energetic recovery compared with the controls. However, no differences were seen between the 2 MP groups.

Conclusions.

The study provides first evidence that machine perfusion at regional perfusion centers may be a safe and economical alternative to the widespread individual efforts in the respective implantation clinics.
Evaluating the genetic interaction effects of gut microbiome and diet on the risk of neuroticism in the UK Biobank cohort
Authors: He Dan , Wang Xi , Ye Jing , Yao Yao , Wen Yan , Jia Yumeng , Meng Peilin , Yang Xuena , Wu Cuiyan , Ning Yujie , Wang Sen , Zhang Feng
Published: March 2023

Objectives

In this study designed to investigate the effect of diet and gut microbiome on neuropsychiatric disorders, we explored the mechanisms of the interaction between diet and gut microbiome on the risk of neuroticism.

Methods

First, using the individual genotype data from the UK Biobank cohort (N = 306 165), we calculated the polygenic risk score (PRS) based on 814 dietary habits single nucleotide polymorphisms (SNPs), 21 diet compositions SNPs and 1001 gut microbiome SNPs, respectively. Gut microbiome and diet-associated SNPs were collected from three genome-wide association studies (GWAS), including the gut microbiome (N = 3890), diet compositions (over 235 000 subjects) and dietary habits (N = 449 210). The neuroticism score was calculated by 12 questions from the Eysenck Personality Inventory Neuroticism scale. Then, regression analysis was performed to evaluate the interaction effects between diet and the gut microbiome on the risk of neuroticism.

Results

Our studies demonstrated multiple candidate interactions between diet and gut microbiome, such as protein vs. Bifidobacterium (β = 4.59 × 10−3; P = 9.45 × 10−3) and fat vs. Clostridia (β = 3.67 × 10−3; P = 3.90 × 10−2). In addition, pieces of fresh fruit per day vs. Ruminococcus (β = −5.79 × 10−3, P = 1.10 × 10−3) and pieces of dried fruit per day vs. Clostridiales (β = −5.63 × 10−3, P = 1.49 × 10−3) were found to be negatively associated with neuroticism in fruit types. We also identified several positive interactions, such as tablespoons of raw vegetables per day vs. Veillonella (β = 5.92 × 10−3, P = 9.21 × 10−4) and cooked vegetables per day vs. Acidaminococcaceae (β = 5.69 × 10−3, P = 1.24 × 10−3).

Conclusions

Our results provide novel clues for understanding the roles of diet and gut microbiome in the development of neuroticism.
Emergence of ADC-5 Cephalosporinase in environmental Acinetobacter baumannii from a German tank milk with a novel Sequence Type
Authors: Sykes Ellen ME , Mateo-Estrada Valeria , Zhanel George , Dettman Jeremy , Chapados Julie , Gerdis Suzanne , Akineden Ömer , Khan Izhar , Castillo-Ramirez Santiago , Kumar Ayush
Published: March 2023

Bacteria resistant to antibiotics arguably pose the greatest threat to human health in the 21 st century. One such bacterium that typifies antibiotic resistance is Acinetobacter baumannii. Frequently, hospital strains of A. baumannii display multidrug resistant (MDR) or extreme drug resistant (XDR) phenotypes, often requiring the use of last resort antibiotics for treatment. In addition to hospital settings, A. baumannii has been isolated from many highly divergent sources including wastewater treatment plant effluent, soil, and agricultural run-off with global distribution. However, such isolates remain poorly characterized. In this study, we characterized a strain of A. baumannii, AB341-IK15, isolated from bulk tank milk in Germany that demonstrated resistance to ceftazidime and intermediate resistance to ceftriaxone and piperacillin/tazobactam. Further genetic characterization identified an ADC-5 cephalosporinase, first incidence in an environmental isolate; and an OXA-408 oxacillinase that may contribute to this phenotype. Interestingly, AB341-IK15 is of a novel sequence type. This research underscores the importance of studying isolates of A. baumannii of non-clinical origin to understand the antibiotic resistance and virulence potential of environmental isolates of A. baumannii as well to understand the diversity of this species.
Helicobacter kumamotonensis sp. nov., isolated from human clinical specimens
Authors: Kawamura Yoshiaki , Fujimoto Yuko , Kutsuna Ryo , Tomida Junko , Yamamoto Kei-ichi , Miyoshi-Akiyama Tohru , Okuno Miki , Ogura Yoshitoshi , Matsuoka Masao , Kawaguchi Tatusya , Tsutsuki Hiroyasu , Sawa Tomohiro
Published: March 2023

A Gram-stain-negative, spiral bacterium (PAGU 1991T) was isolated from the blood of a patient with diffuse large B-cell lymphoma. Phylogenetic analysis based on 16S rRNA gene sequences showed that the isolate was very closely related to

Helicobacter equorum

LMG 23362T (99.1 % similarity), originally isolated from a faecal sample from a healthy horse. PAGU 1991T was also very closely related to PAGU 1750 in our strain library (=CCUG 41437) with 99.7 % similarity. Additional phylogenetic analyses based on the 23S rRNA gene sequence and GyrA amino acid sequence further supported the close relationship between the two human isolates (PAGU 1991T and PAGU 1750) and the horse strain. However, a phylogenetic analysis based on 16S rRNA showed that the two human isolates formed a lineage that was distinct from the horse strain (less than 99.2 % similarity). In silico whole-genome comparisons based on digital DNA–DNA hybridization, average nucleotide identity based on blast and orthologous average nucleotide identity using usearch between the two human isolates and the type strain of

H. equorum

showed values of less than 52.40, 93.47, and 93.50 %, respectively, whereas those between the two human isolates were 75.8, 97.2, and 97.2 %, respectively. These data clearly demonstrated that the two human isolates formed a single species, distinct from

H. equorum

. Morphologically, the human isolates could be distinguished by the type of flagella; the human isolates showed a bipolar sheathed flagellum, whereas that of

H. equorum

was monopolar. Biochemically, the human isolate was characterized by growth at 42 °C under microaerobic conditions and nitrate reduction unability. We conclude that the two human isolates, obtained from geographically and temporally distinct sources, were a novel species, for which we propose the name Helicobacter kumamotonensis sp. nov., with the type strain PAGU 1991T (=GTC 16810T=CCUG 75774T).
Scleromatobacter humisilvae gen. nov., sp. nov., a novel bacterium isolated from oak forest soil
Authors: Mieszkin Sophie , Trouche Blandine , Ancousture Julien , Raouf Youssef , Uroz Stéphane , Alain Karine
Published: March 2023

A novel bacterial strain, designated BS-T2-15T, isolated from forest soil in close proximity to decaying oak wood, was characterized using a polyphasic taxonomic approach. Phylogenetic analyses based on 16S rRNA gene sequences as well as phylogenomic analyses based on coding sequences of 340 concatenated core proteins indicated that strain BS-T2-15T forms a distinct and robust lineage in the Rubrivivax–Roseateles
–Leptothrix–Azohydromonas
–Aquincola–Ideonella branch of the order

Burkholderiales

. The amino acid identity and the percentage of conserved proteins between the genome of strain BS-T2-15T and genomes of closely related type strains ranged from 64.27 to 66.57% and from 40.89 to 49.27 %, respectively, providing genomic evidence that strain BS-T2-15T represents a new genus. Its cells are Gram-stain-negative, aerobic, motile by a polar flagellum, rod-shaped and form incrusted white to ivory colonies. Optimal growth is observed at 20–22 °C, pH 6 and 0% NaCl. The predominant fatty acids of strain BS-T2-15T are C16 : 1 ω7c, C16 : 0 and C14 : 0 2-OH. Its polar lipid profile consists of a mixture of phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol and its main respiratory quinone is ubiquinone 8. The estimated size of its genome is 6.28 Mb with a DNA G+C content of 69.56 mol%. Therefore, on the basis of phenotypic and genotypic properties, the new strain BS-T2-15T represents a novel genus and species for which the name Scleromatobacter humisilvae gen. nov., sp. nov., is proposed. The type strain is BS-T2-15T (DSM 113115T=UBOCC-M-3373T).
Neobacillus terrae sp. nov., isolated from mountain soil
Authors: Han Dong Min , Choi Dae Gyu , Baek Ju Hye , Hao Lujiang , Jeon Che Ok
Published: March 2023

A Gram-stain-positive, spore-forming and facultative aerobic bacterium, designated C11T, was isolated from mountain soil collected in the Republic of Korea. The cells were motile rods with peritrichous flagella, and positive for catalase and oxidase activities. Strain C11T grew at 15–45 °C (optimum, 30–37 °C) and pH 6.0–8.0 (optimum, pH 6.0) and in the presence of 0–1 % (w/v) NaCl (optimum, 0.5 %). Strain C11T contained menaquinone-7 as the sole isoprenoid quinone and iso-C15 : 0, iso-C16 : 0 and anteiso-C15 : 0 as the major fatty acids. Diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine were the major polar lipids. The G+C content of the genomic DNA was 38.8 mol%. Strain C11T was most closely related to

Neobacillus drentensis

IDA1967T and

Mesobacillus foraminis

CV53T, with 98.0 and 97.7 %, 71.7 and 69.9 %, and 20.1 and 20.3 % 16S rRNA gene sequence similarity, average nucleotide identity, and digital DNA–DNA hybridization values, respectively. Phylogenetic analyses based on 16S rRNA gene and genome sequences showed that strain C11T was included in a phyletic lineage with members of the genus

Neobacillus

but was distinct from members of the genus

Mesobacillus

. Phenotypic, chemotaxonomic and molecular properties suggested that strain C11T represents a novel species of the genus

Neobacillus

, for which the name Neobacillus terrae sp. nov. is proposed. The type strain is C11T (=KACC 21661T=JCM 33943T).
The foundations of aetiology: a common language for infection science
Authors: Inglis Timothy J. J.
Published: March 2023

With the adoption of infection science as an umbrella term for the disciplines that inform our ideas of infection, there is a need for a common language that links infection’s constituent parts. This paper develops a conceptual framework for infection science from the major themes used to understand causal relationships in infectious diseases. The paper proposes using the four main themes from the Principia Aetiologica to classify infection knowledge into four corresponding domains: Clinical microbiology, Public health microbiology, Mechanisms of microbial disease and Antimicrobial countermeasures. This epistemology of infection gives form and process to a revised infection ontology and an infectious disease heuristic. Application of the proposed epistemology has immediate practical implications for organization of journal content, promotion of inter-disciplinary collaboration, identification of emerging priority themes, and integration of cross-disciplinary areas such as One Health topics and antimicrobial resistance. Starting with these foundations, we can build a coherent narrative around the idea of infection that shapes the practice of infection science.
Longitudinal SARS-CoV-2 neutralization of Omicron BA.1, BA.5 and BQ.1.1 after four vaccinations and the impact of break-through infections in hemodialysis patients
Authors: Platen Louise , Liao Bo-Hung , Tellenbach Myriam , Cheng Cho-Chin , Holzmann-Littig Christopher , Christa Catharina , Dächert Christopher , Kappler Verena , Bester Romina , Werz Maia Lucia , Schönhals Emely , Platen Eva , Eggerer Peter , Tréguer Laëtitia , Küchle Claudius , Schmaderer Christoph , Heemann Uwe , Keppler Oliver T. , Renders Lutz , Braunisch Matthias Christoph , Protzer Ulrike
Published: March 2023

Background

Individuals on hemodialysis are more vulnerable to SARS-CoV-2 infection than the general population due to end-stage kidney disease-induced immunosuppression.

Methods

26 hemodialysis patients experiencing SARS-CoV-2 infection after 3rdvaccination were matched 1:1 to 26 out of 92 SARS-CoV-2 naïves by age, sex, dialysis vintage and immunosuppressive drugs receiving a 4thvaccination with an mRNA-based vaccine. A competitive surrogate neutralization assay was used to monitor vaccination success. To determine infection neutralization titers, Vero-E6 cells were infected with SARS-CoV-2 variants of concern (VoC), Omicron sub-lineage BA.1, BA.5, and BQ.1.1. 50% inhibitory concentration (IC50, serum dilution factor 1:x) was determined before, four weeks after and 6 months after the 4thvaccination.

Results

52 hemodialysis patients received four COVID-19 vaccinations and were followed up for a median of 6.3 months. Patient characteristics did not differ between the matched cohorts. Patients without a SARS-CoV-2 infection had a significant reduction of real virus neutralization capacity for all Omicron sub-lineages after six months (p<0.001 each). Those patients with a virus infection did not experience a reduction of real virus neutralization capacity after six months. Compared to the other Omicron VoC the BQ.1.1 sub-lineage had the lowest virus neutralization capacity.

Conclusions

SARS-CoV-2-naïve hemodialysis patients had significantly decreased virus neutralization capacity six months after the 4thvaccination whereas patients with a SARS-CoV-2 infection had no change in neutralization capacity. This was independent of age, sex, dialysis vintage and immunosuppression. Therefore, in infection-naïve hemodialysis patients a fifth COVID-19 vaccination might be reasonable 6 months after the 4thvaccination.
Predicting Functional Dependency in Patients with Disorders of Consciousness: A TBI-Model Systems and TRACK-TBI Study
Authors: Snider Samuel B. , Temkin Nancy R. , Barber Jason , Edlow Brian L. , Giacino Joseph T. , Hammond Flora M. , Izzy Saef , Kowalski Robert G. , Markowitz Amy J. , Rovito Craig A. , Shih Shirley L. , Zafonte Ross D. , Manley Geoffrey T. , Bodien Yelena G. ,   The TRACK-TBI Investigators
Published: March 2023

Importance

There are currently no models that predict long-term functional dependency in patients with disorders of consciousness (DoC) after traumatic brain injury (TBI).

Objective

Fit, test, and externally validate a prediction model for 1-year dependency in patients with DoC 2 or more weeks after TBI.

Design

Secondary analysis of patients enrolled in TBI Model Systems (TBI-MS, 1988-2020, Discovery Sample) or Transforming Research and Clinical Knowledge in TBI (TRACK-TBI, 2013-2018, Validation Sample) and followed 1-year post-injury.

Setting

Multi-center study at USA rehabilitation hospitals (TBI-MS) and acute care hospitals (TRACK-TBI).

Participants

Adults with TBI who were not following commands at rehabilitation admission (TBI-MS; days post-injury vary) or 2-weeks post-injury (TRACK-TBI).

Exposures

In the TBI-MS database (model fitting and testing), we screened demographic, radiological, clinical variables, and Disability Rating Scale (DRS) item scores for association with the primary outcome.

Main Outcome

The primary outcome was death or complete functional dependency at 1-year post-injury, defined using a DRS-based binary measure (DRSDepend), indicating need for assistance with all activities and concomitant cognitive impairment.

Results

In the TBI-MS Discovery Sample, 1,960 subjects (mean age 40 [18] years, 76% male, 68% white) met inclusion criteria and 406 (27%) were dependent at 1-year post-injury. A dependency prediction model had an area under the receiver operating characteristic curve (AUROC) of 0.79 [0.74, 0.85], positive predictive value of 53%, and negative predictive value of 86% for dependency in a held-out TBI-MS Testing cohort. Within the TRACK-TBI external validation sample (N=124, age 40 [16], 77% male, 81% white), a model modified to remove variables not collected in TRACK-TBI, had an AUROC of 0.66 [0.53, 0.79], equivalent to the gold-standard IMPACTcore+CTscore (0.68; 95% AUROC difference CI: -0.2 to 0.2, p=0.8).

Conclusions and Relevance

We used the largest existing cohort of patients with DoC after TBI to develop, test and externally validate a prediction model of 1-year dependency. The model’s sensitivity and negative predictive value were greater than specificity and positive predictive value. Accuracy was diminished in an external sample, but equivalent to the best-available models. Further research is needed to improve dependency prediction in patients with DoC after TBI.
Evaluation of The Everyday Memory Questionnaire-Revised in Menopausal Population: Understanding the Brain Fog During Menopause
Authors: Zhu Chen , Thomas Elizabeth HX , Li Qi , Arunogiri Shalini , Thomas Natalie , Gurvich Caroline
Published: March 2023

Introduction

Brain fog (i.e., memory complaints and concentration difficulties) is frequently reported during the menopausal transition. There is lack of standardized scales available to measure brain fog across the menopause transition. This study aimed to evaluate the factor structure of the Everyday Memory Questionnaire-Revised (EMQ-R) and to determine the most commonly reported everyday cognitive symptoms in a menopausal population.

Methods

417 females, including 107 pre-menopausal, 149 peri-menopausal, and 161 early post-menopausal, met criteria and were included in the analyses. Memory and attention related symptoms were measured using the EMQ-R. Confirmatory factor analysis (CFA) was conducted to test the model fit of the bifactor structure (attentional and retrieval) of the EMQ-R in menopausal populations and evaluated by Cronbach’s alpha test. One way ANOVA and MANCOVA were used to investigate the group differences of individual items and two subscales.

Results

CFA indicated that the bifactor model (retrievalandattentional) of the EMQ-R has a good fit in all three groups. A significant difference (with the highest mean score observed in peri-menopausal group) was identified in the retrieval subscale score (F=3.17,p=0.043) but not in the attentional subscale or total scores amongst the three groups. Items (1, 3, 5) related to daily information retrieval problems were significantly reported in the peri-menopausal group.

Discussion

The EMQ-R serves as an instrument to measure memory and attention symptoms, referred to as ‘brain fog’ in menopause. Increased memory retrieval complaints reported by peri-menopausal group suggests a transition-related memory retrieval dysfunction during menopausal transition.
Association of serum platelet-to-lymphocyte ratio levels with the risk of stent thrombosis and long-term prognosis in patients undergoing percutaneous coronary intervention with and without type 2 diabetes mellitus: a large-scale prospective cohort study
Authors: Song Yanjun , Lin Zhangyu , He Jining , Cui Kongyong , Song Chenxi , Zhang Rui , Shi Boqun , Dong Qiuting , Dou Kefei
Published: March 2023

Background

The platelet-to-lymphocyte ratio (PLR) is a promising inflammatory biomarker contributing to the development of atherosclerosis and type 2 diabetes mellitus (T2DM). Therefore, this study aims to document the value of PLR in predicting adverse events in patients undergoing percutaneous coronary intervention (PCI) with and without T2DM.

Methods

This study consecutively enrolled 8831 patients who received PCI, and we divided them into 4 groups according to the PLR level and glycemic metabolic statuses (PLR-low/high with non-T2DM, PLR-low/high with T2DM). The endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) and stent thrombosis. Multivariate COX regression analysis was used to determine the association.

Results

During the 2.4-year follow-up, a total of 663 (7.5%) MACCE and 75 (0.85%) stent thrombosis were recorded. Results showed that patients with high PLR levels presented a significantly higher risk of MACCE (HR: 1.26, 95%CI: 1.07 to 1.47,P= 0.005) and stent thrombosis (HR: 2.29, 95%CI, 1.39 to 3.79,P= 0.001) when compared with the PLR-low group. When focused on patients with T2DM, the PLR-high group showed a significantly higher risk of MACCE (HR: 1.53, 95%CI: 1.17 to 2.00,P= 0.002) and stent thrombosis (HR: 3.79, 95%CI, 1.62 to 8.86,P= 0.002). However, these associations were not significant in patients without T2DM.

Conclusions

For the first time, PLR is documented as a great predictor for the poor prognosis and high incidence of stent thrombosis in patients with CAD, especially in those with T2DM.

CLINICAL PERSPECTIVE

What Is New?

In patients undergoing percutaneous coronary intervention (PCI), high serum platelet-to-lymphocyte ratio (PLR) is associated with poor prognosis and a high risk of stent thrombosis.

When focusing on patients with different glycemia statuses, we found that the predictive value of PLR for poor prognosis and high risk of stent thrombosis was significant in patients with type 2 diabetes mellitus (T2DM), but not in patients without T2DM.

Among patients with different PLR levels and glycemia statuses, those combined with both high PLR levels and T2DM showed the highest risk of poor prognosis and stent thrombosis.

In stent thrombosis events, very late stent thrombosis is the most common type in patients with high PLR.

What Are the Clinical Implications?

Patients undergoing PCI with high PLR levels should be monitored closely.

Residual inflammation should be focused among patients with coronary heart disease after revascularization to improve the long-term prognosis.
Insufficient evidence for natural selection associated with the Black Death
Authors: Barton Alison R. , Santander Cindy G. , Skoglund Pontus , Moltke Ida , Reich David , Mathieson Iain
Published: March 2023

Klunk et al. analyzed ancient DNA data from individuals in London and Denmark before, during and after the Black Death [1], and argued that allele frequency changes at immune genes were too large to be produced by random genetic drift and thus must reflect natural selection. They also identified four specific variants that they claimed show evidence of selection including atERAP2, for which they estimate a selection coefficient of 0.39–several times larger than any selection coefficient on a common human variant reported to date. Here we show that these claims are unsupported for four reasons. First, the signal of enrichment of large allele frequency changes in immune genes comparing people in London before and after the Black Death disappears after an appropriate randomization test is carried out: thePvalue increases by ten orders of magnitude and is no longer significant. Second, a technical error in the estimation of allele frequencies means that none of the four originally reported loci actually pass the filtering thresholds. Third, the filtering thresholds do not adequately correct for multiple testing. Finally, in the case of theERAP2variant rs2549794, which Klunk et al. show experimentally may be associated with a host interaction withY. pestis, we find no evidence of significant frequency change either in the data that Klunk et al. report, or in published data spanning 2,000 years. While it remains plausible that immune genes were subject to natural selection during the Black Death, the magnitude of this selection and which specific genes may have been affected remains unknown.
Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection
Authors: Moyo-Gwete Thandeka , Richardson Simone I. , Keeton Roanne , Hermanus Tandile , Spencer Holly , Manamela Nelia P. , Ayres Frances , Makhado Zanele , Motlou Thopisang , Tincho Marius B. , Benede Ntombi , Ngomti Amkele , Baguma Richard , Chauke Masego V. , Mennen Mathilda , Adriaanse Marguerite , Skelem Sango , Goga Ameena , Garrett Nigel , Bekker Linda-Gail , Gray Glenda , Ntusi Ntobeko A.B. , Riou Catherine , Burgers Wendy A. , Moore Penny L.
Published: March 2023

The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 33-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection.

The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.
Reproducible chemostat cultures to eliminate eukaryotic viruses from fecal transplant material
Authors: Adamberg Signe , Rasmussen Torben Sølbeck , Larsen Sabina Brigitte , Mao Xiaotian , Nielsen Dennis Sandris , Adamberg Kaarel
Published: March 2023

The effect of fecal microbiota transplantation (FMT) on various gut-related diseases is intensively investigated in clinical trials. In addition to bacteria, the gut microbiome also contains eukaryotic, archaeal, and bacterial viruses (bacteriophages, in short phages), which collectively is referred to as the gut virome. Application of FMT in clinical settings is associated with a potential risk for the recipient of transferring infectious eukaryotic viruses or bacteria, despite strict screening procedures for the donor material. A safer and more targeted method to modulate the gut microbiota is therefore needed to extend the application width of FMT. Emerging evidence suggests that gut phages play a key role in maintaining a balanced gut microbiome as well as in FMT efficacy. Thus, a phageome from a cultured fecal donor microbiome may be a more efficient alternative to modulate the gut bacteriome than FMT. Here, we analyzed the dynamic changes of the viromes of mice cecal and human fecal matter inoculated chemostat cultures. Sequencing results showed that the relative abundance of eukaryotic viruses remarkably decreased during continuous cultivation, likely due to the lack of eukaryotic hosts. The corresponding phageome profiles showed dilution rate dependency, a reproducibility between biological replicates, and maintained high diversity of phages although being different from the inoculum phageome. This proof-of-concept study may constitute the first step of developing therapeutic tools to target a broad spectrum of gut-related diseases and thereby replacing FMT with a safer phage-mediated therapy.
Differentiation trajectories of theHydranervous system reveal transcriptional regulators of neuronal fate
Authors: Primack Abby S , Cazet Jack F , Little Hannah Morris , Mühlbauer Susanne , Cox Ben D , David Charles N , Farrell Jeffrey A , Juliano Celina E
Published: March 2023

The small freshwater cnidarian polypHydra vulgarisuses adult stem cells (interstitial stem cells) to continually replace neurons throughout its life. This feature, combined with the ability to image the entire nervous system (Badhiwala et al., 2021; Dupre & Yuste, 2017) and availability of gene knockdown techniques (Juliano, Reich, et al., 2014; Lohmann et al., 1999; Vogg et al., 2022), makesHydraa tractable model for studying nervous system development and regeneration at the whole-organism level. In this study, we use single-cell RNA sequencing and trajectory inference to provide a comprehensive molecular description of the adult nervous system. This includes the most detailed transcriptional characterization of the adultHydranervous system to date. We identified eleven unique neuron subtypes together with the transcriptional changes that occur as the interstitial stem cells differentiate into each subtype. Towards the goal of building gene regulatory networks to describeHydraneuron differentiation, we identified 48 transcription factors expressed specifically in theHydranervous system, including many that are conserved regulators of neurogenesis in bilaterians. We also performed ATAC-seq on sorted neurons to uncover previously unidentified putative regulatory regions near neuron-specific genes. Finally, we provide evidence to support the existence of transdifferentiation between mature neuron subtypes and we identify previously unknown transition states in these pathways. All together, we provide a comprehensive transcriptional description of an entire adult nervous system, including differentiation and transdifferentiation pathways, which provides a significant advance towards understanding mechanisms that underlie nervous system regeneration.
Novel VCP activator reverses multisystem proteinopathy nuclear proteostasis defects and enhances TDP-43 aggregate clearance
Authors: Phan Jessica M. , Creekmore Benjamin C. , Nguyen Aivi T. , Bershadskaya Darya D. , Darwich Nabil F. , Lee Edward B.
Published: March 2023

Pathogenic variants inVCPcause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget’s disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature, ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified four novel compounds that activate VCP primarily by increasing D2 ATPase activity whereby pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that MSP may be the result of impaired nuclear proteostasis, and that VCP activation may be potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.
The structure and function of neural connectomes are shaped by a small number of design principles
Authors: Haber Adam , Wanner Adrian A. , Friedrich Rainer W. , Schneidman Elad
Published: March 2023

The map of synaptic connectivity among neurons in the brain shapes the computations that neural circuits may perform. Inferring the design principles of neural connectomes is, therefore, fundamental for understanding brain development and architecture, neural computations, learning, and behavior. Here, we learn probabilistic generative models for the connectomes of the olfactory bulb of zebrafish, part of the mouse visual cortex, and ofC. elegans. We show that, in all cases, models that rely on a surprisingly small number of simple biological and physical features are highly accurate in replicating a wide range of properties of the measured circuits. Specifically, they accurately predict the existence of individual synapses and their strength, distributions of synaptic indegree and outdegree of the neurons, frequency of sub-network motifs, and more. Furthermore, we simulate synthetic circuits generated by our model for the olfactory bulb of zebrafish and show that they replicate the computation that the real circuit performs in response to olfactory cues. Finally, we show that specific failures of our models reflect missing design features that we uncover by adding latent features to the model. Thus, our results reflect surprisingly simple design principles of real connectomes in three different systems and species, and offer a novel general computational framework for analyzing connectomes and linking structure and function in neural circuits.
Phosphorylation alters FMRP granules and determines their transport or protein synthesis abilities
Authors: Kharod Shivani C. , Hwang Dong-woo , Choi Heejun , Yoon Kyle J. , Castillo Pablo E. , Singer Robert H. , Yoon Young J.
Published: March 2023

Fragile X messenger ribonucleoprotein (FMRP) is an RNA-binding protein implicated in autism that suppresses translation and forms granules. While FMRP function has been well-studied, how phosphorylation regulates granule binding and function remains limited. Here, we found that Fragile X patient-derived I304N mutant FMRP could not stably bind granules, underscoring the essential nature of FMRP granule association for function. Next, phosphorylation on serine 499 (S499) led to differences in puncta size, intensity, contrast, and transport as shown by phospho-deficient (S499A) and phospho-mimic (S499D) mutant FMRP granules. Additionally, S499D exchanged slowly on granules relative to S499A, suggesting that phosphorylated FMRP can attenuate translation. Furthermore, the S499A mutant enhanced translation in presynaptic boutons of the mouse hippocampus. Thus, the phospho-state of FMRP altered the structure of individual granules with changes in transport and translation to achieve spatiotemporal regulation of local protein synthesis.

Teaser

The phosphorylation-state of S499 on FMRP can change FMRP granule structure and function to facilitate processive transport or local protein synthesis.
Point mutations in IMPDH2 which cause early-onset neurodevelopmental disorders disrupt enzyme regulation and filament structure
Authors: O’Neill Audrey G , Burrell Anika L , Zech Michael , Elpeleg Orly , Harel Tamar , Edvardson Simon , Shaked Hagar Mor , Rippert Alyssa L , Nomakuchi Tomoki , Izumi Kosuke , Kollman Justin M
Published: March 2023

Inosine 5’ monophosphate dehydrogenase (IMPDH) is a critical regulatory enzyme in purine nucleotide biosynthesis that is inhibited by the downstream product GTP. Multiple point mutations in the human isoform IMPDH2 have recently been associated with dystonia and other neurodevelopmental disorders, but the effect of the mutations on enzyme function has not been described. Here, we report identification of two additional affected individuals with missense variants inIMPDH2and show that all of the disease-associated mutations disrupt GTP regulation. Cryo-EM structures of one IMPDH2 mutant suggest this regulatory defect arises from a shift in the conformational equilibrium toward a more active state. This structural and functional analysis provides insight into IMPDH2-associated disease mechanisms that point to potential therapeutic approaches and raises new questions about fundamental aspects of IMPDH regulation.

Significance Statement

Point mutations in the human enzyme IMPDH2, a critical regulator of nucleotide biosynthesis, are linked to neurodevelopmental disorders, such as dystonia. Here, we report two additional IMPDH2 point mutants associated with similar disorders. We investigate the effects of each mutation on IMPDH2 structure and functionin vitroand find that all mutations are gain of function, preventing allosteric regulation of IMPDH2 activity. We report high resolution structures of one variant and present a structure-based hypothesis for its dysregulation. This work provides a biochemical basis for understanding diseases caused byIMPDH2mutation and lays a foundation for future therapeutic development.
A low-dimensional approximation of optimal confidence
Authors: Le Denmat Pierre , Verguts Tom , Desender Kobe
Published: March 2023

Human decision making is accompanied by a sense of confidence. According to Bayesian decision theory, confidence reflects the learned probability of making a correct response, given available data (e.g., accumulated stimulus evidence and response time). Although optimal, independently learning these probabilities for all possible combinations of data is computationally intractable. Here, we describe a novel model of confidence implementing a low-dimensional approximation of this optimal yet intractable solution. Using a low number of free parameters, this model allows efficient estimation of confidence, while at the same time accounting for idiosyncrasies, different kinds of biases and deviation from the optimal probability correct. Our model dissociates confidence biases resulting from individuals’ estimate of the reliability of evidence (captured by parameter α), from confidence biases resulting from general stimulus-independent under- and overconfidence (captured by parameter β). We provide empirical evidence that this model accurately fits both choice data (accuracy, response time) and trial-by-trial confidence ratings simultaneously. Finally, we test and empirically validate two novel predictions of the model, namely that 1) changes in confidence can be independent of performance and 2) selectively manipulating each parameter of our model leads to distinct patterns of confidence judgments. As the first tractable and flexible account of the computation of confidence, our model provides concrete tools to construct computationally more plausible models, and offers a clear framework to interpret and further resolve different forms of confidence biases.

Significance statement

Mathematical and computational work has shown that in order to optimize decision making, humans and other adaptive agents must compute confidence in their perception and actions. Currently, it remains unknown how this confidence is computed. We demonstrate how humans can approximate confidence in a tractable manner. Our computational model makes novel predictions about when confidence will be biased (e.g., over- or underconfidence due to selective environmental feedback). We empirically tested these predictions in a novel experimental paradigm, by providing continuous model-based feedback. We observed that different feedback manipulations elicited distinct patterns of confidence judgments, in ways predicted by the model. Overall, we offer a framework to both interpret optimal confidence and resolve confidence biases that characterize several psychiatric disorders.
Remembering what is relevant: how is goal-directed memory reactivation supported by attentional selection?
Authors: Sabo Melinda , Wascher Edmund , Schneider Daniel
Published: March 2023

Goal-directed memory reactivation involves retrieving the most relevant information for the current behavioral goal. Previous research has linked this process to activations in the fronto-parietal network, but the underlying selection mechanisms remain poorly understood. The current electroencephalogram (EEG) study investigates attention as a possible mechanism supporting goal-directed retrieval. Participants learned associations between objects and two screen locations in an episodic long-term memory experiment. In a following phase, we changed the relevance of some locations to simulate goal-directed retrieval. This was subsequently contrasted to a control condition, in which the original associations remained unchanged. Behavior performance measured during final retrieval revealed faster and more confident responses in the selective vs. neutral condition. At the EEG level, we found significant differences in decoding accuracy, with above-chance effects in the selective cue condition but not in the neutral cue condition. Additionally, we observed a stronger posterior contralateral negativity and lateralized alpha power in the selective cue condition. Overall, these results suggest that attentional selection enhances task-relevant information accessibility, emphasizing its role in goal-directed memory retrieval.