bluuebunny/crossref_metadata_2025 huggingface dataset:
1157. Immune Persistence and Booster Response of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) 5 Years After Primary Vaccination of Adults ≥59 Years of Age
Authors: Robertson Corwin A , Galarza Katherine , Jacqmein Jeffry , Selmani Alexandre , Oster Philipp
Published: November 2023

Background

MenACYW-TT (MenQuadfi®, Sanofi) is a quadrivalent (serogroups A, C, W, and Y) meningococcal tetanus toxoid conjugate vaccine. It is approved for use in persons aged ≥2 years in the US and persons aged ≥1 year in Europe and certain other countries; trials in infants as young as 6 weeks are ongoing. The second stage of a 2-stage study of MenACYW-TT, reported herein, evaluated immune persistence among older adults who received primary vaccination with either quadrivalent meningococcal polysaccharide vaccine (MSPV4) or MenACYW-TT five years earlier at age ≥ 56 years. The immunogenicity and safety of a MenACYW-TT booster dose given to this population were also evaluated.

Methods

This was a Phase 3, 2-stage, randomized, open-label, multi-center study (NCT04142242) of adults aged ≥59 years who participated in previous studies of MenACYW-TT vs MPSV4 (NCT01732627 and NCT02842866). The study was conducted in the US and Puerto Rico. Immune persistence and response were assessed with a serum bactericidal assay using human complement (hSBA). Safety data were collected for up to 30 days after booster vaccination. All analyses were descriptive.

Results

Of the initial study population (N=471), 70 adults participated in Stage II of the study. At 5 years post-primary vaccination, seroprotection (hSBA ≥ 1:8) rates (SPRs) and hSBA geometric mean titers (GMTs) declined in both MenACYW-TT- and MPSV4-primed subjects, with SPRs and hSBA GMTs for serogroups A, C, W, and Y trending higher in MenACYW-TT- vs MPSV4-primed subjects (Table 1). Thirty days after booster vaccination, hSBA GMTs and SPRs increased from pre-booster for all serogroups and were, along with seroresponse rates, higher in MenACYW-TT-primed subjects compared to MPSV4-primed subjects (Table 2). Rates of AEs following booster vaccination were similar regardless of priming vaccine. No safety concerns were identified.

Conclusion

Five years after primary vaccination, immune persistence tended to be greater for MenACYW-TT vs MPSV4. A MenACYW-TT booster was well tolerated and immunogenic in adults ≥ 61 years, when administered 5 years after primary vaccination with either MPSV4 or MenACYW-TT.

Disclosures

Corwin A. Robertson, MD, MPH, FACP, Sanofi: Sanofi employee|Sanofi: Sanofi's Employee|Sanofi: Stocks/Bonds Katherine Galarza, MD, Sanofi: Sanofi employee|Sanofi: Stocks/Bonds Alexandre Selmani, PhD, Sanofi: Sanofi employee|Sanofi: Stocks/Bonds Philipp Oster, MD, Sanofi: Sanofi employee
A divergent tumor overexpressed gene domain and oligomerization contribute to SPIRAL2 function in stabilizing microtubule minus ends
Authors: Fan Yuanwei , Bilkey Natasha , Bolhuis Derek L , Slep Kevin C , Dixit Ram
Published: November 2023

The acentrosomal cortical microtubules (MTs) of higher plants dynamically assemble into specific array patterns that determine the axis of cell expansion. Recently, the Arabidopsis (Arabidopsis thaliana) SPIRAL2 (SPR2) protein was shown to regulate cortical MT length and light-induced array reorientation by stabilizing MT minus ends. SPR2 autonomously localizes to both the MT lattice and MT minus ends, where it decreases the minus end depolymerization rate. However, the structural determinants that contribute to the ability of SPR2 to target and stabilize MT minus ends remain unknown. Here, we present the crystal structure of the SPR2 N-terminal domain, which reveals a unique tumor overexpressed gene (TOG) domain architecture with 7 HEAT repeats. We demonstrate that a coiled-coil domain mediates the multimerization of SPR2, which provides avidity for MT binding, and is essential to bind soluble tubulin. In addition, we found that an SPR2 construct spanning the TOG domain, basic region, and coiled-coil domain targets and stabilizes MT minus ends similar to full-length SPR2 in plants. These results reveal how a TOG domain, which is typically found in microtubule plus-end regulators, has been appropriated in plants to regulate MT minus ends.
Partnership approaches in policing: An analysis of different types of partnerships and how they work to reduce crime and disorder
Authors: Mazerolle Lorraine
Published: November 2023

Partnerships in policing are commonplace approaches to reduce crime and disorder problems across most parts of the world. Police forge partnerships with businesses, government agencies, and communities to co-produce public safety, usually cooperatively but sometimes using coercion. The co-production approach to crime control permeates all levels of law enforcement from tackling complex corporate crimes to reducing the flow of drugs to street-level markets. In this paper, I draw from the Global Policing Database (GPD) and the final stage of the search and screening from a systematic review of third-party policing (TPP) interventions to analyse 29 unique TPP interventions in 36 studies described across 45 documents. Each of the 29 unique TPP interventions depicts different types of partnerships and how they work to reduce crime and disorder. Partnerships are grouped along two continuums: the number and complexity of partners involved and the level and type of engagement. Some partnerships in policing are extremely complex involving multiple agencies, whereas others are dyadic. The type of engagement between partners also varies: some partnerships are collaborative, guided by memorandums of understanding, and motivated by mutual need for crime control solutions. Other partnerships are more coercive and dictated through legislated mandates and forceful measures. In this paper, I examine the range of partnerships evident within the review and offer insights into how those partnerships work to tackle different types of problems.
Metrology supporting the European regulation for radiation protection
Authors: Alves João G , Caldeira Margarida C , Röttger Annette , Khanbabaee Behnam , Adam-Guillermin Christelle , Siiskonen Teemu , Živanović Miloš , Šabeta Amra , Glavič-Cindro Denis
Published: November 2023

The European Association of National Metrology Institutes (EURAMET) within its research programme European Metrology Programme for Innovation and Research (EMPIR) funded project EMPIR 19NET03 supportBSS that contributes to the establishment of a European Metrology Network (EMN) for Radiation Protection (RP). The EMN-RP was established in September 2021 with the intent to work as a meeting point for the metrology community and all stakeholders in the field of ionising radiation regulation, thus providing quality assurance for measurements in each of the exposure situations contemplated in the European Legislation. Within project EMPIR 19NET03, work package 3 aims at the preparation of a Strategic Research Agenda (SRA) by identifying the metrology needs to support the European legislation and regulation in Radiation Protection and of two Roadmaps for metrology services, one under the European Council Directive 2013/59/EURATOM and the other under the EURATOM Treaty. Following a Gaps Workshop held in September 2020 and a second internal workshop that took place in April 2022, a questionnaire was prepared for distribution to the stakeholders, e.g. RP platforms and authorities, academia, industry, among other, together with an accompanying paper. In this paper, the authors present the state of the art of European legislation in RP, address the importance of metrology, the practices and activities that need metrology to meet the requirements set in the regulations, emphasise the need for quality assured measurements in all fields, highlight the stakeholders contributions in their specific area and show their vision of the EMN-RP.
The Characteristics of Respiratory Bocavirus Infection in Acutely Sick Children Admitted to a Tertiary Hospital in Jordan
Authors: AL-Iede Montaha , Ezar Daniel , Armouty Layan , Abdoh Momen , Karmi Munia , Sarhan Lena , AL-Zayadneh Eans , Daher Amirah , Alqutawneh Basim , Toubasi Ahmad A.
Published: November 2023

Objective:

The clinical manifestations of human bocavirus infections are diverse, ranging from mild common cold to severe lower respiratory tract infections. Bocaviruses have frequently been codetected with other respiratory viruses. We aimed to estimate the burden of bocavirus and multiple viral infections and to investigate the risk factors associated with these infections.

Methods:

This study was a retrospective chart review of admitted patients. The medical records of the included children were searched, and data on demographics, clinical presentation, imaging, laboratory and nasopharyngeal swab results were collected.

Results:

A total of 157 patients were included. Most of the patients were males (62.1%) and under 6 months of age (52%). The 3 most common symptoms presented in the patients were cough (81.8%), rhinorrhea (58.6%) and fever (55.8%). Bocavirus DNA was detected in 12.66% of the patients, while 22.30% had multiple viruses. Age distribution was significantly different between bocavirus and nonbocavirus groups, with a lower proportion of bocavirus infection in all age groups (P = 0.032). The radiograph patterns significantly differed between the 2 study groups, with a lower number of patients in the bocavirus group having normal radiographs (P = 0.007). Patients infected with multiple viruses had more severe respiratory distress symptoms and diarrhea than those infected with only 1 virus.

Conclusions:

The prevalence of multiple viruses and bocavirus respiratory infections is significant. This study can guide physicians toward the clinical presentation and characteristics of children with respiratory bocavirus and multiple viral infections and propose future studies conducted in this regard.
A Case Series of New-Onset Ulcerative Colitis Following Recent Diagnosis of COVID-19
Authors: Swatski Matthew D. , Kaur Panamdeep , Borlack Rachel E. , McBain Shonnell , Uffer Joshua , Almadhoun Osama
Published: November 2023

There have been only 2 reported cases of new-onset ulcerative colitis in pediatrics following acute coronavirus disease 2019 (COVID-19). We are reporting a case series of 3 adolescent female patients, 2 of whom were vaccinated against COVID-19, who developed new-onset ulcerative colitis following a recent diagnosis of COVID-19 infections at a singular pediatric hospital. This case series should be an impetus to clinicians who have pediatric patients with persistent symptoms of hematochezia, diarrhea, and abdominal pain following acute COVID-19 infection to consider further workup for inflammatory bowel disease.
Concurrent, New-Onset Autoimmune Hepatitis, Celiac Disease, and Hashimoto’s Thyroiditis Following COVID-19: A Case Report
Authors: Mostafavi Mojdeh , Abraham Annie , Mueller James , Sayej Wael
Published: November 2023

Here we describe a 13-year-old adolescent female diagnosed with concurrent autoimmune disorders including Grave disease, Celiac disease, and autoimmune hepatitis within 3 months after infection with severe acute respiratory syndrome coronavirus 2. The patient initially presented to her pediatrician with complaints of epistaxis, cessation of menses, palpitations, and weight loss. Initial evaluation showed evidence of hyperthyroidism, elevated liver enzymes, and abnormal Celiac disease serologies. Additional testing including laboratory tests, liver biopsy, and an upper endoscopy with biopsies confirmed the diagnosis of Grave disease, Celiac disease, and type 1 autoimmune hepatitis. This case highlights the importance of recognizing the risk of autoimmune disorders associated with the novel coronavirus disease 2019.
Emergence of a Technology-Dependent Phenotype of Pediatric Sepsis in a Large Children’s Hospital
Authors: Aldewereld Zachary , Horvat Christopher , Carcillo Joseph A. , Clermont Gilles
Published: November 2023

Objective

To investigate whether pediatric sepsis phenotypes are stable in time.

Methods

Retrospective cohort study examining children with suspected sepsis admitted to a PICU at a large free-standing children’s hospital during two distinct periods: 2010-2014 (Early Cohort) and 2018-2020 (Late Cohort). K-means consensus clustering was used to derive types separately in the cohorts. Variables included ensured representation of all organ systems.

Results

1,091 subjects were in the Early Cohort and 737 subjects in the Late Cohort. Clustering analysis yielded 4 phenotypes in the Early Cohort and 5 in the Late Cohort. Four types were in both: Type A (34% of Early Cohort, 25% of Late Cohort), mild sepsis, with minimal organ dysfunction and low mortality; Type B (25%, 22%), primary respiratory failure; Type C (25%, 18%), liver dysfunction, coagulopathy, and higher measures of systemic inflammation; Type D (16%, 17%), severe multiorgan dysfunction, with high degrees of cardiorespiratory support, renal dysfunction, and highest mortality. Type E was only detected in the Late Cohort (19%) and was notable for respiratory failure less severe than B or D, mild hypothermia, and high proportion of diagnoses and technologic dependence associated with medical complexity. Despite low mortality, this type had the longest PICU length of stay.

Conclusions

This single center study identified 4 pediatric sepsis phenotypes in an earlier epoch but 5 in a later epoch, with the new type having a large proportion of characteristics associated with medical complexity, particularly technology dependence. Personalized sepsis therapies need to account for this expanding patient population.
Early Blood Lactate as a Biomarker for Cardiovascular Collapse in Experimental Sepsis
Authors: Calente Thander Jacson Nunes , Albino Lucas Braga , de Oliveira Junior Garcia , Delfrate Gabrielle , Sordi Regina , Santos Fábio André , Fernandes Daniel
Published: November 2023

Cecal ligation and puncture (CLP) is the gold standard model for studying septic shock which is characterized by hypotension and hyporeactivity to vasoconstrictors. However, approximately 30% of CLP animals do not exhibit cardiovascular changes, requiring more replicates due to the high variability of the model. Therefore, biomarkers enabling the early prediction of cardiovascular collapse in sepsis would greatly benefit sepsis nonclinical studies, refining experimental models and improving clinical translation. Thus, this study aimed to test whether the early increase in lactate levels could predict hypotension and hyporesponsiveness to vasoconstrictors in a rat model of sepsis. Male and female Wistar rats were subjected to CLP or sham procedure. Tail blood lactate was measured 6, 12 and 24 hours after surgery. Then, inflammatory, biochemical, and hemodynamic parameters were evaluated. Rats subjected to CLP developed hypotension, hyporesponsiveness to vasoconstrictors, an intense inflammatory process, and increased plasma markers of organ dysfunction. By employing ROC curve analysis, we have established that a lactate value of 2.45 mmol/L can accurately discriminate between a rat exhibiting a normal vasoconstrictive response and a vasoplegic rat with 84% accuracy (AUC: 0.84, CI: 0.67-1.00). The sensitivity, which is the ability to identify the true positive rats, was 75% (CI: 41 – 95), and the true negative rate was 81% (CI: 57 – 93). Therefore, early measurement of lactate levels in sepsis could serve as a valuable biomarker for distinguishing vasoplegic rats from those exhibiting normal vasoconstrictive responses.
CircESPL1 silencing protects against lipopolysaccharide-induced lung fibroblast dysfunction partly by targeting the miR-146b-3p/TRAF1 axis in pneumonia
Authors: Tian Yubo , Wang Yi , Wang Zhen
Published: November 2023

Background

Neonatal pneumonia is a common disease in the neonatal period with high mortality. The present work concentrated on the role and mechanism of circular RNA (circRNA) extra spindle pole bodies like 1, separase (circESPL1) in lipopolysaccharide (LPS)-induced dysfunction of lung fibroblasts.

Methods

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were conducted to analyze RNA and protein expression, respectively. Cell viability, proliferation, apoptosis, and inflammation were assessed by Cell Counting Kit-8 (CCK8) assay, 5-Ethynyl-2’-deoxyuridine (EdU) assay, flow cytometry, and enzyme-linked immunosorbent assay (ELISA), respectively. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the intermolecular interactions among circESPL1, miR-146b-3p and TRAF1.

Results

CircESPL1 expression was up-regulated in the serum samples of pneumonia patients and LPS-induced lung fibroblasts. CircESPL1 silencing protected lung fibroblasts against LPS-induced dysfunction. CircESPL1 bound to microRNA-146b-3p (miR-146b-3p) in lung fibroblasts. CircESPL1 knockdown-mediated protective effects on LPS-induced lung fibroblasts were largely reversed by the silence of miR-146b-3p. miR-146b-3p directly interacted with the 3’ untranslated region (3’UTR) of TNF receptor associated factor 1 (TRAF1), and TRAF1 expression was regulated by the circESPL1/miR-146b-3p axis in lung fibroblasts. TRAF1 overexpression largely reversed miR-146b-3p accumulation-mediated protective effects on LPS-induced lung fibroblasts.

Conclusion

CircESPL1 knockdown protected lung fibroblasts from LPS-induced injury partly by targeting the miR-146b-3p/TRAF1 axis.
Coagulopathy Parameters Predictive of Outcomes in Sepsis-induced Acute Respiratory Distress Syndrome: A Sub-Analysis of the Two Prospective Multicenter Cohort Studies
Authors: Matsuoka Tadashi , Fujishima Seitaro , Sasaki Junchi , Gando Satoshi , Saitoh Daizoh , Kushimoto Shigeki , Ogura Hiroshi , Abe Toshikazu , Shiraishi Atsushi , Mayumi Toshihiko , Kotani Joji , Takeyama Naoshi , Tsuruta Ryosuke , Takuma Kiyotsugu , Yamashita Norio , Shiraishi Shin-ichiro , Ikeda Hiroto , Shiino Yasukazu , Tarui Takehiko , Nakada Taka-aki , Hifumi Toru , Otomo Yasuhiro , Okamoto Kohji , Sakamoto Yuichiro , Hagiwara Akiyoshi , Masuno Tomohiko , Ueyama Masashi , Fujimi Satoshi , Yamakawa Kazuma , Umemura Yutaka ,   on behalf of the JAAM Focused Outcomes Research on Emergency Care for Acute respiratory distress syndrome, Sepsis and Trauma (FORECAST) Group and Sepsis Prognostication in Intensive Care unit and Emergency room (SPICE) Group
Published: November 2023

Background

Although coagulopathy is often observed in acute respiratory distress syndrome (ARDS), its clinical impact remains poorly understood.

Objectives

This study aimed to clarify the coagulopathy parameters that are clinically applicable for prognostication and to determine anticoagulant indications in sepsis-induced ARDS.

Method

This study enrolled patients with sepsis-derived ARDS from two nationwide multicenter, prospective observational studies. We explored coagulopathy parameters that could predict outcomes in the FORECAST cohort, and the defined coagulopathy criteria were validated in the SPICE-ICU cohort. The correlation between anticoagulant use and outcomes was also evaluated.

Results

A total of 181 patients with sepsis-derived ARDS in the FORECAST study and 61 patients in the SPICE-ICU study were included. In a preliminary study, we found the set of PT-INR ≥1.4 and platelets ≤12 × 104/μL, Thrombocytopenia and Elongated Prothrombin time, TEP, coagulopathy as the best coagulopathy parameters, and used for further analysis, of which odds ratio of TEP coagulopathy for in-hospital mortality adjusted for confounding was 3.84 (95% CI, 1.66–8.87; p = 0.005). In the validation cohort, the adjusted odds ratio for in-hospital mortality was 32.99 (95% CI, 2.60–418.72; p = 0.002). Although patients without TEP coagulopathy showed significant improvements in oxygenation over the first 4 days, patients with TEP coagulopathy showed no significant improvement (ΔPaO2/FiO2ratio, 24 ± 20 vs. 90 ± 9; p = 0.026). Furthermore, anticoagulant use was significantly correlated with mortality and oxygenation recovery in patients with TEP coagulopathy but not in patients without TEP coagulopathy.

Conclusion

TEP coagulopathy is closely associated with better outcomes and responses to anticoagulant therapy in sepsis-induced ARDS, and our coagulopathy criteria may be clinically useful.

Trial registration

FORECAST study: UMIN-CTR ID: UMIN000019742. Registration date: November 11th, 2015.

SPICE-ICU study: UMIN-CTR ID: UMIN000027258. Registration date: May 6th, 2017.
Soluble guanylate cyclase (sGC) stimulators in heart failure with preserved ejection fraction: a systematic review and meta-analysis
Authors: Zhao Yang , Zang Bin , Wang Qian
Published: November 2023

Aims

We conducted a systemic review and meta-analysis to evaluate the therapeutic efficacy and safety of soluble guanylate cyclase(sGC) stimulators in patients with heart failure with preserved ejection fraction(HFpEF).

Methods

We systematically searched PubMed, EMBASE and Cochrane Library databases for original randomized controlled trials comparing sGC stimulators with placebo in HFpEF patients. A random-effects model was applied to evaluate the mortality, quality of life and drug-related adverse events. This meta-analysis is registered in PROSPERO under the number CRD42023457382.

Results

We included five studies involving 1600 HFpEF patients. Comprehensively, the combined risk ratio (RR) for mortality was not significant(RR(95% CI) = 1.44 (0.71-2.91), p = 0.31). Furthermore, there were no statistically significant differences in the Kansas City Cardiomyopathy Questionnaire (KCCQ) results, including the Clinical Summary Score(CSS) (WMD (95% CI) =0.32( -7.38-8.02), p = 0.94) and the Overall Summary Score(OSS) (WMD (95% CI) = -0.87( -8.87-7.14), P = 0.83). Similarly, there was no significant improvement in the 6-minute walk distance(6MWD) (WMD(95% CI) = -6.22(-18.56-6.12), p = 0.32). Additionally, drug-related adverse events were more common in patients treated with sGC stimulators(RR(95%CI) = 1.63,(1.25-2.14), p < 0.05).

Conclusions

Oral sGC stimulators do not significantly improve mortality outcomes, functional capacity and quality of life in HFpEF patients but are associated with increased drug-related adverse events. Therefore, we should consider using sGC stimulators in HFpEF patients carefully.
Adaptability of the Pulsta valve to the diverse main pulmonary artery shape of native right ventricular outflow tract disease
Authors: Park Woo Young , Kim Gi Beom , Lee Sang Yun , Kim Ah Young , Choi Jae Young , Chang So Ick , Kim Seong Ho , Cha Seul Gi , Wang Jou-Kou , Lin Ming-Tai , Chen Chun-An
Published: November 2023

Background

Pulsta valve is increasingly used for percutaneous pulmonary valve implantation (PPVI) in patients with large native right ventricular outflow tract (RVOT). The aim of this study is to reveal Pulsta valve implantation outcomes within the native RVOT and to evaluate the adaptability of Pulsta valve to diverse native main pulmonary artery (PA).

Methods

A multicenter retrospective study encompassing 183 patients with moderate to severe pulmonary regurgitation (PR) in the native RVOT who underwent PPVI with Pulsta valves® between February 2016 and August 2023 at the five Korean and Taiwanese tertiary referral centers.

Results

Successful implantation of the Pulsta valves was achieved in 180 out of 183 patients (98.4 %) with an average age of 26.6 ± 11.0 years. Mean follow-up duration was 29 months. Baseline assessments revealed enlarged right ventricle (RV) volume (mean indexed RV end-diastolic volume: 163.1(Interquartile range, IQR, 152.2-179.9) mL/m2), which significantly decreased to 123.0(IQR: 106.9-137.2) mL/m2after one year. In this study, the main PA types were classified as follows: pyramidal (3.8%), straight (38.3%), reverse pyramidal (13.7%), convex (26.2%), and concave (18.0%) shapes. Pulsta valve placement was adapted, with distal main PA for pyramidal shapes and proximal or mid-PA for reverse pyramidal shapes. The remaining patients underwent Pulsta valve implantation in the proximal or mid part of the main PA, depending on the anatomical features and size of the main PA. Two patients experienced Pulsta valve embolization to RV, necessitating surgical removal, and one patient encountered valve migration to the distal main PA, necessitating surgical fixation.

Conclusions

Customized valve insertion sites are pivotal in self-expandable PPVI considering diverse native RVOT shape. Rather soft and compact structure of Pulsta valve has characteristics to be adaptable to diverse native RVOT geometries.

What is Known?

The Pulsta valve is a self-expandable knitted nitinol-wire stent mounted with a treated tri-leaflet α-Gal-free porcine pericardial valve for percutaneous pulmonary valve implantation in patients with native right ventricular outflow tract lesions.

What the study adds?

To this date, this study is the largest study among the previous reports that examined the outcomes of the Pulsta valve. The Pulsta valve consistently demonstrated favorable clinical and hemodynamic outcomes over a 2.4-year period. Pulsta valve showed adaptability in the diverse native right ventricular outflow tract geometries from the compact shape of Pulsta valve.
The Antiviral Mechanism of Action of Molnupiravir in Humans with COVID-19
Authors: Sheahan Timothy P. , Stevens Laura J. , Narowski Tara M. , Krajewski Taylor J. , Lee Chanhwa , Mollan Katie R. , Gribble Jennifer , Moreira Fernando R. , Castillo Izabella N. , Cuadra Edwing , Alabanza Paul , Loftis Amy James , Coombs Robert W. , Goecker Erin A. , Greninger Alexander L. , Chappell James D. , Brown Ariane J. , Won John , Lipansky Felicia , Holman Wayne , Szewczyk Laura J. , Baric Ralph S. , Painter Wendy P. , Eron Joseph J. , Premkumar Lakshmanane , Denison Mark R. , Fischer William A.
Published: November 2023

Meaningful metrics of antiviral activity are essential for determining the efficacy of therapeutics in human clinical trials. Molnupiravir (MOV) is a broadly acting antiviral nucleoside analog prodrug that acts as a competitive alternative substrate for the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). We developed an assay, Culture-PCR, to better understand the impact of MOV therapy on infectious SARS-CoV-2. Culture-PCR revealed MOV eliminated infectious virus within 48 hours in the nasopharyngeal compartment, the upper airway location with the greatest levels of infectious virus. MOV therapy was associated with increases in mutations across the viral genome but select regions were completely unaffected, thus identifying regions where mutation likely abrogates infectivity. MOV therapy did not alter the magnitude or neutralization capacity of the humoral immune response, a documented correlate of protection. Thus, we provide holistic insights into the function of MOV in adults with COVID-19.
Predicting postoperative delirium assessed by the Nursing Screening Delirium Scale in the recovery room for non-cardiac surgeries without craniotomy: A retrospective study using a machine learning approach
Authors: Giesa Niklas , Haufe Stefan , Menk Mario , Weiß Björn , Spies Claudia , Piper Sophie K. , Balzer Felix , Boie Sebastian D.
Published: November 2023

Background

Postoperative delirium (POD) contributes to severe outcomes such as death or development of dementia. Thus, it is desirable to identify vulnerable patients in advance during the perioperative phase. Previous studies mainly investigated risk factors for delirium during hospitalization and further used a linear logistic regression (LR) approach with time-invariant data. Studies have not investigated patients’ fluctuating conditions to support POD precautions.

Objective

In this single-center study, we aimed to predict POD in a recovery room setting with a non-linear machine learning (ML) technique using pre-, intra-, and postoperative data.

Methods

The target variable POD was defined with the Nursing Screening Delirium Scale (Nu-DESC) ≥ 1. Feature selection was conducted based on robust univariate test statistics and L1regularization. Non-linear multi-layer perceptron (MLP) as well as tree-based models were trained and evaluated – with the receiver operating characteristics curve (AUROC), the area under precision recall curve (AUPRC), and additional metrics – against LR and published models on bootstrapped testing data.

Results

The prevalence of POD was 8.2% in a sample of 73,181 surgeries performed between 2017 and 2020. Significant univariate impact factors were the preoperative ASA status, the intraoperative amount of given remifentanil, and the postoperative Aldrete score. The best model used pre-, intra-, and postoperative data. The tree-based model achieved a mean AUROC of 0.854 and a mean AUPRC of 0.418 outperforming linear LR, well as best applied and retrained baseline models.

Conclusions

Overall, non-linear machine learning models using data from multiple perioperative time phases were superior to traditional ones in predicting POD in the recovery room. Class imbalance was seen as a main impediment for model application in clinical practice.

Author Summary

Currently, the pathophysiology of postoperative delirium (POD) is unknown. Hence, there is no dedicated medication for treatment. Patients who experience POD are oftentimes mentally disturbed causing pressure on related family members, clinicians, and the health system. With our study, we want to detect POD before onset trying to give decision support to health professionals. Vulnerable patients could be transferred to delirium wards mitigating the risk of severe outcomes such as permanent cognitive decline. We also provide insides into clinical parameters - recorded before, during, and after the surgery - that could be adapted for reducing POD risk. Our work is openly available, developed for clinical implementation, and could be transferred to other clinical institutions.
Prevalence of Coronary Atherosclerosis in Master Female Endurance Athletes
Authors: Papatheodorou Efstathios , Aengevaeren Vincent L. , Eijsvogels Thijs M.H. , Fakih Khaled Al , Hughes Rebecca Kathryn , Merghani Ahmed , Kissel Christine K. , Fyyaz Saad , Bakalakos Athanasios , Wilson Mathew G. , Dey Damini , Finocchiaro Gherardo , Parry-Williams Gemma , Torlasco Camilla , Papadakis Michael , Moon James C. , Sharma Sanjay
Published: November 2023

BACKGROUND

Studies in ostensibly healthy male master athletes have revealed a greater prevalence of coronary artery calcification (CAC) and coronary plaques compared with relatively sedentary counterparts. In contrast, data relating to potentially adverse coronary remodelling in female master athletes is sparse and conflicting. We investigated the prevalence of coronary atherosclerosis in a cohort of predominantly post-menopausal female master athletes with a low atherosclerotic risk profile.

METHODS

196 female athletes with a mean age of 55±7 years-old and median exercise duration of 33 years (25-39) and 59 relatively sedentary females of similar age underwent cardiovascular investigations including a coronary computed tomogram angiography with assessment of CAC scores, coronary plaques, and pericoronary adipose tissue attenuation. 70% of the athletes and 68% of the control group were post-menopausal.

RESULTS

Athletes and controls had a similarly low Framingham 10-year risk (1.49% versus 2.1%; P=0.68), but body mass index and blood pressure were lower and HDL-C was higher in the athletes. The prevalence of CAC score >0 Agatston units (AU) was low and did not differ between athletes and controls (21%versus32%;P=0.073). Female athletes had a lower prevalence of a CAC score >50thcentile (19%versus32%;P<0.03) and >75thcentile (14%versus25%;P=0.045) for age compared with controls, but the prevalence of a CAC score >100 AU did not differ between the groups (3.6%versus8.5%;P=0.12). There were also no differences between the groups in the prevalence of individuals with coronary plaques (21%versus32%;P=0.09), total plaque volume (16 mm3[IQR 3-56]versus49 [5-142] mm3;P=0.08), or plaque burden (10.8% [2.8-21]versus15.4% [4.6-28];P=0.46). Coronary plaques were predominantly calcified in both athletes and controls (80%versus63%;P=0.08). Age, blood pressure and HDL-C were independent predictors for a CAC score >0 AU among athletes.

CONCLUSIONS

In contrast with previous studies in male master athletes, lifelong exercise in female counterparts does not appear to be associated with increased CAC score, coronary plaque burden or any qualitative differences in coronary plaque compared with relatively sedentary healthy counterparts. Coronary atherosclerosis in master female athletes is mainly driven by traditional risk factors.
Large Language Models and Medical Knowledge Grounding for Diagnosis Prediction
Authors: Gao Yanjun , Li Ruizhe , Croxford Emma , Tesch Samuel , To Daniel , Caskey John , W. Patterson Brian , M. Churpek Matthew , Miller Timothy , Dligach Dmitriy , Afshar Majid
Published: November 2023

While Large Language Models (LLMs) have showcased their potential in diverse language tasks, their application in the healthcare arena needs to ensure the minimization of diagnostic errors and the prevention of patient harm. A Medical Knowledge Graph (KG) houses a wealth of structured medical concept relations sourced from authoritative references, such as UMLS, making it a valuable resource to ground LLMs’ diagnostic process in knowledge. In this paper, we examine the synergistic potential of LLMs and medical KG in predicting diagnoses given electronic health records (EHR), under the framework of Retrieval-augmented generation (RAG). We proposed a novel graph model: Dr.Knows, that selects the most relevant pathology knowledge paths based on the medical problem descriptions. In order to evaluate Dr.Knows, we developed the first comprehensive human evaluation approach to assess the performance of LLMs for diagnosis prediction and examine the rationale behind their decision-making processes, aimed at improving diagnostic safety. Using real-world hospital datasets, our study serves to enrich the discourse on the role of medical KGs in grounding medical knowledge into LLMs, revealing both challenges and opportunities in harnessing external knowledge for explainable diagnostic pathway and the realization of AI-augmented diagnostic decision support systems.
Effects of Maternal Fortified Balanced Energy-Protein Supplementation on the Mother-Infant Gut Microbiome: A Sub-Study of the MISAME-III Randomized Controlled Trial
Authors: Deng Lishi , Taelman Steff , Olm Matthew R. , Toé Laéticia Céline , Balini Eva , Ouédraogo Lionel , Bastos-Moreira Yuri , Argaw Alemayehu , Tesfamariam Kokeb , Sonnenburg Erica D. , Ouédraogo Moctar , Ganaba Rasmané , van Criekinge Wim , Kolsteren Patrick , Stock Michiel , Lachat Carl , Sonnenburg Justin L. , Dailey-Chwalibóg Trenton
Published: November 2023

Biological pathways, including individual gut microbiome are potential barriers for maternal nutritional supplementation to improvement in infant growth. We evaluated the impact of balanced energy-protein (BEP) supplementation during pregnancy and the first six months of lactation on the composition and functionality of gut microbiome in mothers and their infants in rural Burkina Faso. Our findings reveal that BEP supplementation led to a significant increase in microbiome diversity during pregnancy. In the second trimester, there was a notable decrease in the abundance of anOscillospiraceaespecies, while postpartum, the abundance ofBacteroides fragilisincreased. We identified concerted enriched or depleted microbial pathways associated with BEP supplementation, including the phosphotransferase system, a critical mechanism for bacterial carbohydrates uptake, which exhibited enrichment in infants born to BEP-supplemented mothers. Despite these observations, the intricate biological connections with other omics necessitate further analysis to fully elucidate the underlying comprehensive biological pathways.
Deep learning-based patient stratification for prognostic enrichment of clinical dementia trials
Authors: Birkenbihl Colin , de Jong Johann , Yalchyk Ilya , Fröhlich Holger ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2023

Dementia probably due to Alzheimer’s disease (AD) is a progressive condition that manifests in cognitive decline and impairs patients’ daily life. Affected patients show great heterogeneity in their symptomatic progression, which hampers the identification of efficacious treatments in clinical trials. Using artificial intelligence approaches to enable clinical enrichment trials serves a promising avenue to identify treatments.

In this work, we used a deep learning method to cluster the multivariate disease trajectories of 283 early dementia patients along cognitive and functional scores. Two distinct subgroups were identified that separated patients into ‘slow’ and ‘fast’ progressing individuals. These subgroups were externally validated and independently replicated in a dementia cohort comprising 2779 patients. We trained a machine learning model to predict the progression subgroup of a patient from cross-sectional data at their time of dementia diagnosis. The classifier achieved a prediction performance of 0.70 ± 0.01 AUC in external validation.

By emulating a hypothetical clinical trial conducting patient enrichment using the proposed classifier, we estimate its potential to decrease the required sample size. Furthermore, we balance the achieved enrichment of the trial cohort against the accompanied demand for increased patient screening. Our results show that enrichment trials targeting cognitive outcomes offer improved chances of trial success and are more than 13% cheaper compared to conventional clinical trials. The resources saved could be redirected to accelerate drug development and expand the search for remedies for cognitive impairment.
gQuant: A Robust and Generalizable Algorithm for Identifying Normalizer Genes in qRT-PCR Data: A Case Study on Urinary Exosomal miRNAs
Authors: Pathak Abhay Kumar , Kural Sukhad , Singh Shweta , Kumar Lalit , Yadav Mahima , Gupta Manjari , Das Parimal , Jain Garima
Published: November 2023

The emergent role of nucleic acid-based biomarkers, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs), is becoming increasingly prominent in the realms of disease diagnostics and risk assessment. Quantitative reverse transcription PCR (qRT-PCR) is the primary analytical method for quantitative measurement of biomarkers. Yet, the relative infancy of non-coding RNAs’ (ncRNAs) recognition as biomarkers poses a challenge due to the absence of a consensus on a universally accepted normalizer gene, which is pivotal for accurate quantification. Current tools for selecting normalizer genes in qRT-PCR are fraught with limitations, including inadequate handling of null values, reliance on elementary statistical tools, use of a biased integrated approach, outlier sensitivity, and suboptimal graphical user interface for data visualization. These deficiencies underscore the necessity for a more nuanced and algorithmically balanced tool tailored to handle qRT-PCR datasets and facilitate the discernment of the most appropriate normalizer gene for specific datasets.

Addressing the identified challenges, we have developed ‘gQuant,’ a tool crafted to address the limitations present in existing methods. In ‘gQuant’ we employed voting classifiers as an ensemble technique that combines predictions from multiple statistical methods to make more accurate rankings than any individual statistical measures. The tool’s efficacy was substantiated through rigorous validation against datasets from the Gene Expression Omnibus (GEO) database and corroborated with experimental data derived from urinary exosomal miRNAs. Comparative analysis with existing tools revealed that their integrated methodologies could skew the ranking of normalizer genes, whereas ‘gQuant’ consistently yielded rankings characterized by lower standard deviation, reduced covariance, and enhanced kernel density estimation (KDE) values. Given ‘gQuant’s’ promising performance, normalizer gene identification will be greatly improved, improving the precision of gene expression quantification in a variety of research scenarios.
At matched loads, aging does not alter ankle, muscle, or tendon stiffness
Authors: Jakubowski Kristen L. , Ludvig Daniel , Lee Sabrina S.M. , Perreault Eric J.
Published: November 2023

Older adults have difficulty maintaining balance when faced with postural disturbances, a task that is influenced by the stiffness of the triceps surae and Achilles tendon. Age-related changes in Achilles tendon stiffness have been reported at matched levels of effort, but measures typically have not been made at matched loads, which is important due to age-dependent changes in strength. Moreover, age-dependent changes in muscle stiffness have yet to be tested. Here, we investigate how age alters muscle and tendon stiffness and their influence on ankle stiffness. We hypothesized that age-related changes in muscle and tendon contribute to reduced ankle stiffness in older adults and evaluated this hypothesis when either load or effort were matched. We used B-mode ultrasound with joint-level perturbations to quantify ankle, muscle, and tendon stiffness across a range of loads and efforts in seventeen healthy younger and older adults. At matched loads, there was no significant difference in ankle, muscle, or tendon stiffness between groups (all p>0.13). However, at matched effort, older adults exhibited a significant decrease in ankle (27%; p=0.008), muscle (37%; p=0.02), and tendon stiffness (22%; p=0.03) at 30% of maximum effort. This is consistent with our finding that older adults were 36% weaker than younger adults in plantarflexion (p=0.004). Together these results indicate that, at the loads tested in this study, there are no age-dependent changes in the mechanical properties of muscle or tendon, only differences in strength that result in altered ankle, muscle, and tendon stiffness at matched levels of effort.

New andNoteworthy

We provide the first simultaneous estimates of ankle, muscle, and tendon stiffness in younger and older adults. In contrast to earlier conclusions, we found that muscle and tendon mechanical properties are unaffected by age when compared at matched loads. However, due to age-related decreases in strength, mechanical properties do differ at matched efforts. As such, it is important to assess the relevance of the comparisons being made relative to the functional tasks under consideration.
Mitigating inflammatory bone loss in post-menopausal osteoporosis via targeting the IL-9 producing osteoclastogenic Th9 cells
Authors: Sapra Leena , Saini Chaman , Mishra Pradyumna K. , Chattopadhya Naibedya , Srivastava Rupesh K.
Published: November 2023

Recent discoveries have established the pivotal role of IL-9-secreting Th9 cells in a wide spectrum of inflammatory and autoimmune diseases. However, little is known about how Th9 cells contribute to the etiology of inflammatory bone loss in post-menopausal osteoporosis (PMO). We observed that IL-9 has a pathological impact on inflammatory bone loss in ovariectomized (Ovx) mice. Our in vivo temporal kinetics analysis further revealed that estrogen deprivation increased the release of IL-9 from Th which in turn enhances the IL-17-producing Th17 cells. Both ex vivo and in vivo studies corroborated these findings in Ovx mice, as estrogen diminishes IL-9’s effect on the differentiation of Th17 cells as well as the potential of Th9 cells to produce IL-9. Mechanistically, Th9 cells in an IL-9-dependent manner enhance osteoclastogenesis and thereby establish themselves as a novel and independent osteoclastogenic Th subset. Blocking IL-9 improves bone health in Ovx mice by inhibiting the differentiation and function of both osteoclasts and Th9/Th17 cells. Our clinical findings further attested to the osteoporotic role of Th9 cells in post-menopausal osteoporotic human subjects. Collectively, our study establishes IL-9-secreting Th cells as the critical regulator of bone loss observed in PMO and highlights the fundamental implications of IL-9/Th9 targeted immunotherapies as an innovative approach for the treatment of inflammatory bone loss observed in osteoporosis.
Qualitative Observations of Transgenically Individualized Serotonergic Fibers in the Mouse Telencephalon
Authors: Haiman Justin H. , Mays Kasie C. , Roostaeyan Helen A. , Elyasi Nasim , Janušonis Skirmantas
Published: November 2023

The matrix of serotonergic axons (fibers) is a constant feature of neural tissue in vertebrate brains. Its fundamental role appears to be associated with the spatiotemporal control of neuroplasticity. The densities of serotonergic fibers vary across brain regions, but their development and maintenance remain poorly understood. A specific fiber concentration is achieved as the result of the dynamics of a large number of individual fibers, each of which can make trajectory decisions independently of other fibers. Bridging these processes, operating on very different spatial scales, remains a challenge in neuroscience. The study provides the first qualitative description of individually-tagged serotonergic axons in four selected telencephalic regions (cortical and subcortical) of the mouse brain. Based on our previous implementation of the Brainbow toolbox in this system, serotonergic fibers were labeled with random intensity combinations of three fluorophores and imaged with high-resolution confocal microscopy. All examined regions contained serotonergic fibers of diverse identities and morphologies, often traveling in close proximity to one another. Some fibers transitioned among several morphologies in the same imaged volume. High fiber densities appeared to be associated with highly tortuous fiber segments produced by some individual fibers. This study supports efforts to predictively model the self-organization of the serotonergic matrix in all vertebrates, including regenerative processes in the adult human brain.
Habitat selection during dispersal reduces the energetic cost of transport when making large displacements
Authors: de Boer Tullio , Farine Damien R. , Klarevas-Irby James A.
Published: November 2023

When dispersing, individuals typically have to make large displacements. While previously thought to be costly, recent work has suggested that individuals can largely mitigate these costs by expressing distinct movement strategies—moving faster and straighter—during dispersal. Several studies have also found that individuals express differences in their habitat preferences during dispersal. These preferences often involve an increased use of open habitats relative to their non-dispersing habitat selection, within which individuals typically achieve larger displacements per unit of time. As a result, it has been suggested, but never explicitly tested, that changes in habitat selection could reflect an increased preference for habitats that facilitate greater energetic efficiency in terms of movement. Here, we combine step-selection analysis with models of the energetics of movement to determine whether actively dispersing vulturine guineafowl (Acryllium vulturinum) select different habitats relative to their non-dispersing counterparts, and whether their habitat preferences correspond to a decrease in the cost of transport. Our results confirm that fine-scale differences in habitat preferences expressed when making large displacements during the transient stage of dispersal correspond with an increase in the energetic efficiency of movement. These findings highlight the ability for animals to exhibit adaptive movement strategies across different axes of decision-making (e.g., where and how to move) to overcome different ecological challenges.