bluuebunny/crossref_metadata_2025 huggingface dataset:
Dental eruption and adult dentition of the enigmatic ptolemaiid Qarunavus meyeri from the Oligocene of the Fayum Depression (Egypt) revealed by micro-computed tomography clarifies its phylogenetic position
Authors: Kampouridis Panagiotis , Hartung Josephina , Augustin Felix J , El Atfy Haytham , Ferreira Gabriel S
Published: August 2023

The Palaeogene is a very important time period for mammalian evolution because it documents the first occurrence of many groups. One such group is the enigmatic Ptolemaiida, best known from the Early Oligocene of the Fayum Depression in Egypt, where it is represented by three genera, Ptolemaia, Qarunavus, and Cleopatrodon, including five species. Among these, Qarunavus meyeri is especially rare, as it is only known from two partial juvenile mandibles. Herein, the affinities of this taxon are re-investigated by applying micro-computed tomography (μCT), thus enabling the study and comparison of its unerupted permanent dentition with that of other ptolemaiidans. The μCT analysis confirms that Q. meyeri is a valid species, distinct from all other ptolemaiidans. Both the comparison and a phylogenetic analysis suggest a closer relationship of Qarunavus to the genus Cleopatrodon than to Ptolemaia; thereby, placing Qarunavus in the family Ptolemaiidae. Furthermore, the μCT analysis enabled the assessment of the dental morphology of Q. meyeri revealing an unusual combination of traits, such as a very small single incisor next to a large canine. The eruption sequence of the permanent dentition in Q. meyeri implies a late dental eruption for the species, which would support the hypothesis of Ptolemaiida belonging to Afrotheria.
Association Between Neighborhood Deprivation and Child Cognition in Clinically Referred Youth
Authors: Kalb Luther , Lieb Rebecca , Ludwig Natasha , Peterson Rachel , Pritchard Alison , Ng Rowena , Wexler Danielle , Jacobson Lisa
Published: August 2023

Objective:

When socioeconomic status is measured at the individual and/or family level, it has long been associated with cognition in children. However, the association between neighborhood deprivation, an index of community-level socioeconomic status, and child cognition is not fully understood. The goal of this study was to investigate (1) the relationship between neighborhood deprivation and child cognitive functioning and (2) whether child age moderates the relationship between cognitive functioning and neighborhood deprivation.

Methods:

This study included 9878 children, ages 3 through 17 years (M = 10.4 yrs, SD = 3.4 yrs). Data were gathered from children referred for and evaluated at an urban, outpatient neuropsychology assessment clinic between 2006 and 2022, located in the Mid-Atlantic region of the United States. Neighborhood socioeconomic status was measured at the census block level using the Area Deprivation Index composite.

Results:

There was a 20-point median difference in overall intelligence between the neighborhoods with the lowest and highest levels of deprivation. Overall intelligence and verbal comprehension, compared with working memory, fluid reasoning, and processing speed, demonstrated the strongest negative association with neighborhood deprivation (all p < 0.05). Older children had lower overall intelligence scores compared with younger children in neighborhoods with high levels of deprivation (p < 0.01), suggesting a cumulative influence of poverty exposure.

Conclusion:

This study demonstrates the stark disparities in child cognitive functioning across levels of neighborhood deprivation. Findings support the importance of access to early interventions and services that promote intellectual growth and verbal capacity among children who live in neighborhoods with great deprivation.
Factors Associated with No-Show Rates in a Pediatric Audiology Clinic
Authors: Adkins David , Rojas-Ramirez Marcia V. , Shanker Anita , Burruss Clayton P. , Mirsky Becky , Westgate Philip , Shinn Jennifer B. , Bush Matthew L.
Published: August 2023

Objective

To evaluate factors associated with no-show rates in a pediatric audiology clinic.

Study Design

Retrospective review.

Setting

Tertiary referral center.

Participants

All pediatric patients younger than 18 years whose parents/guardians scheduled an appointment at a tertiary Audiology Clinic between June 1, 2015, and July 1, 2017.

Main Outcome Measure(s)

Data included whether the patient came to their appointment, patient age, sex, race, insurance type, appointment type, location, season of appointment, and day of the week of the appointment.

Results

Of the 7,784 pediatric appointments scheduled with audiology, the overall no-show rate was 24.3% (n = 1893). Lower age was significantly associated with no-shows (p = 0.0003). Black/African American children were more likely to no-show compared with White/Caucasians (p = 0.0001). Compared with self-pay/military/other insurance, those with Medicaid were more likely to no-show (p = 0.0001). The highest rate of no-shows occurred during summer (27%). On multivariate analysis, younger age, Black/African American race, and Medicaid insurance were associated with increased no-show rates.

Conclusion

A variety of factors influence no-show rates in a pediatric audiology setting. No-shows can affect treatment quality and affect overall hearing outcomes. Further investigation is necessary to assess barriers to appointment adherence and to develop interventions to improve adherence and care.
Incidence of Otalgia After Orthognathic Surgery
Authors: Sakamoto Yoshiaki , Wakabayashi Kenichiro , Ishii Takenobu , Kishi Kazuo
Published: August 2023

Background:

In orthognathic surgery, it is well known that maxillary osteotomies and displacements sometimes affect auditory function. Thus, this study examined the relationship between the direction of maxillary displacement and postoperative otalgia.

Methods:

Twenty consecutive patients underwent Le Fort I maxillary osteotomy using advancement, impaction, setback, or a combination of these procedures. The direction of movement and incidence of otalgia were investigated. Patients provided informed consent preoperatively, and postoperative reassurance was prudent.

Results:

Pure-tone average evaluation based on horizontal or vertical movements did not show significant differences, although vertical movements resulted in fewer changes in the hearing threshold. Specifically, no significant changes were observed in the hearing thresholds of patients after surgery. No significant difference was also observed between horizontal and vertical movements in the tympanometry results. Negative changes were found in the results of the Eustachian tube dysfunction test in vertical movements, which returned to preoperative values in the final test.

Conclusions:

The risk of minor changes in hearing function is probable during the first week after orthognathic surgery; however, these negative changes either completely disappear or remain negligible.
Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor
Authors: Reasoner Seth A. , Bernard Rachel , Waalkes Adam , Penewit Kelsi , Lewis Janessa , Sokolow Andrew G. , Brown Rebekah F. , Edwards Kathryn M. , Salipante Stephen J. , Hadjifrangiskou Maria , Nicholson Maribeth R.
Published: August 2023

The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores function of the pathogenic mutated CFTR channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in BMI, ppFEV1and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage ofStaphylococcus aureus, the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic-resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.

IMPORTANCE

Cystic fibrosis is an autosomal recessive disease with significant gastrointestinal symptoms in addition to pulmonary complications. Prior work has shown that the intestinal microbiome correlates with health outcomes in CF, particularly in children. Recently approved treatments for CF, CFTR modulators, are anticipated to substantially improve the care of patients with CF and extend their lifespans. Here, we study the intestinal microbiome of children with CF before and after the CFTR modulator, ELX/TEZ/IVA. We identify promising improvements in microbiome diversity, reduced measures of intestinal inflammation, and reduced antibiotic resistance genes. We present specific bacterial taxa and protein groups which change following ELX/TEZ/IVA. These results will inform future mechanistic studies to understand the microbial improvements associated with CFTR modulator treatment. This study demonstrates how the microbiome can change in response to a targeted medication that corrects a genetic disease.
The predictive and prognostic value of peripheral blood antigen-specific memory B cells in phospholipase A2 receptor-associated membranous nephropathy
Authors: Zhu Richard , Tang Hong , Howard Lilian , Waldman Meryl , Zhu Quansheng
Published: August 2023

Background

Phospholipase A2 receptor-associated membranous nephropathy (PLA2R-MN) is an anti-PLA2R antibody (PLA2R-Ab) mediated autoimmune kidney disease. Although antibody titer correlates closely with disease activity, whether it can provide longer-term predictions on disease course and progression is unclear. Rituximab, a B-cell depletion therapy, has become the first-line treatment option for PLA2R-MN; however, the response to Rituximab varies among patients.

Methods

We developed a flow cytometry-based test that detects and quantifies PLA2R antigen-specific memory B cells (PLA2R-MBCs) in peripheral blood, the primary source for PLA2R-Ab production upon disease relapse. We applied the test to 159 blood samples collected from 28 patients with PLA2R-MN (at diagnosis, during and after immunosuppressive treatment, immunological remission, and relapse) to evaluate the relationship between circulating PLA2R-MBC levels and disease activity.

Results

The level of PLA2R-MBCs in healthy controls (n=56) is less than or equal to 1.5% of the total MBC compartment. High circulating PLA2R-MBC levels were detected in two patients post-Rituximab despite achieving immunologic and proteinuric remission, as well as in two patients with negative serum autoantibody but increasing proteinuria. Elimination of these cells with Rituximab improved clinical outcomes. Moreover, five patients exhibited elevated PLA2R-MBC levels before disease relapse, followed by a rapid decline to baseline when relapse became clinically evident. COVID-19 vaccination or SARS-CoV-2 infection significantly affected the dynamics of circulating PLA2R-MBCs.

Conclusions

This study suggests that monitoring PLA2R-MBC levels in patients with PLA2R-MN may help refine and individualize immunosuppressive therapy and predict disease course and progression. The technology and findings may also have broader applications in the clinical management of other autoimmune diseases.
Cost-Effectiveness of Systematic Screening and Treatment of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in Patients with Heart Failure with Preserved Ejection Fraction (HFpEF) in United States
Authors: Lau Anson TC , DiDomenico Robert J. , Kim Kibum
Published: August 2023

Background

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure in clinical practice.99mTc-pyrophosphate scintigraphy (PYP-scan) improves the accuracy of ATTR-CM detection, enabling timely initiation of tafamidis, a drug that slows the progression of ATTR-CM and lowers the risk of adverse cardiac events. We assessed the cost-effectiveness of universal systematic screening (USS) using PYP-scans in patients aged 60 years or older with heart failure with preserved ejection fraction (HFpEF) and ventricular wall thickness of at least 12mm.

Methods

Two screening strategies, USS of ATTR-CM with PYP-scan versus selected clinical referrals for PYP-scan in standard-of-care (SoC), were compared in a model-based assessment. Treatment decisions were based upon the accuracy of each screening strategy, which was followed by Markov state transitions across NYHA functional classes and death. Model inputs were identified from a literature review. We calculated lifetime cost in 2022 US dollars and quality adjusted life-years (QALYs) of each strategy. The primary outcome was the incremental cost-effectiveness ratio (ICER).

Results

The USS was associated with a significant increase in lifetime costs ($124,380 vs. $70,412) and modest improvement in QALYs (4.42 QALYs vs 4.36 QALYs). The ICER for the USS was $919,509 per QALY gained. ICER was sensitive to the age at the time of ATTR-CM diagnosis, true prevalence rate of ATTR-CM, and daily cost of tafamidis.

Conclusions

Owing to the high cost of treatment with tafamidis, USS along with PYP scan for ATTR-CM in older HFpEF patients with ventricular wall thickening is unlikely to become a cost-effective strategy at a liberal WTP threshold.

What is Known

- ATTR-CM is a rare but serious condition that leads to a restrictive cardiomyopathy with symptoms that mimic heart failure from other causes (e.g., HFpEF).

- PYP-scan, when it is used along with the other conventional diagnostic tests, is a non-invasive diagnostic tool that sensitively and specifically detect ATTR-CM followed by a timely treatment with tafamidis.

- Tafamidis can slow down ATTR-CM progression and improve survival.

What the Study Adds

- This is the first attempt to evaluate the cost-effectiveness of universal systematic screening of ATTR-CM using PYP-scans in older HFpEF patients with ventricular wall thickening.

- The study found that the universal systematic screening is not cost-effective compared to standard-of-care at a liberal WTP threshold, mainly due to the costly treatment option.

- The study identified the key parameters that affect the cost-effectiveness of screening, such as age, prevalence, and drug cost.
Quercetin alleviates intestinal oxidative stress in Jilin White geese
Authors: Yingkun Liu , Wei Guo , Fangyuan Jia , Kai Wang , Zhichao Li , Tao Zhang , Mo Liu , Haizhu Zhou
Published: August 2023

Oxidative stress can occur during all stages of geese breeding, frequently damaging the intestinal tract and various tissues and organs. Quercetin is a flavonoid that exerts potential therapeutic effects against oxidative stress-induced cell damage and mitochondrial dysfunction. Herein, we investigated the alleviating effects of quercetin against lipopolysaccharide (LPS)-induced intestinal inflammation and oxidative stress in Jilin White geese. We selected 120 healthy male 7-d-old geese of similar BW and randomly divided them into six treatment groups, with five replicates each and four geese in each replicate. The groups were as follows: C (fed basal diet, i.p. injection of 0.5 mg/kg normal saline); L (fed basal diet, i.p. injection of 0.5 mg/kg LPS); Q1, Q2, Q3, and Q4 (diet + 150, 300, 450, or 600 mg/kg quercetin, respectively, i.p. injection of 0.5 mg/kg LPS). Samples were collected after experimental d 21. Our results showed that adding 300 mg/kg quercetin to the diet significantly improved growth performance after oxidative stress and reduced serum low-density lipoprotein and glutathione aminotransferase activities. Adding 450 mg/kg quercetin significantly increased the intestinal expression of downstream genes of the nuclear factor E2-related factor 2 pathway, heme oxygenase 1 (HO-1), reduced coenzyme/quinone oxidoreductase (NQO1), and glutathione oxidase (GSTP) in Jilin White geese. Considering production, adding 300 mg/kg quercetin to the diet could alleviate LPS-induced oxidative stress and reduce costs. These findings provide a reference hypothesis for the oxidative stress damage during geese production, which may help reduce the economic loss owing to geese mortality.
Stable recurrent dynamics in heterogeneous neuromorphic computing systems using excitatory and inhibitory plasticity
Authors: Maryada  , Soldado-Magraner Saray , Sorbaro Martino , Laje Rodrigo , Buonomano Dean V. , Indiveri Giacomo
Published: August 2023

Abstract

Many neural computations emerge from self-sustained patterns of activity in recurrent neural circuits, which rely on balanced excitation and inhibition. Neuromorphic electronic circuits that use the physics of silicon to emulate neuronal dynamics represent a promising approach for implementing the brain’s computational primitives, including self-sustained neural activity. However, achieving the same robustness of biological networks in neuromorphic computing systems remains a challenge, due to the high degree of heterogeneity and variability of their analog components.

Inspired by the strategies used by real cortical networks, we apply a biologically-plausible cross-homeostatic learning rule to balance excitation and inhibition in neuromorphic implementations of spiking recurrent neural networks. We demonstrate how this learning rule allows the neuromorphic system to work in the presence of device mismatch and to autonomously tune the spiking network to produce robust, self-sustained, fixed-point attractor dynamics with irregular spiking in an inhibition-stabilized regime. We show that this rule can implement multiple, coexisting stable memories, with emergent soft-winner-take-all (sWTA) dynamics, and reproduce the so-called “paradoxical effect” widely observed in cortical circuits. In addition to validating neuroscience models on a substrate that shares many similar properties and limitations with biological systems, this work enables the construction of ultra-low power, mixed-signal neuromorphic technologies that can be automatically configured to compute reliably, despite the large on-chip and chip-to-chip variability of their analog components.
Valvular Prostaglandins are Elevated in Severe Human Aortic Valve Stenosis
Authors: Cayer Lucien G.J. , Surendran Arun , Karakach Tobias , Aukema Harold M. , Ravandi Amir
Published: August 2023

Introduction

Aortic valve stenosis (AVS) is the most common valvular disease in the developed world. AVS involves the progressive fibro-calcific remodeling of the aortic valve (AV), which impairs function and can ultimately lead to heart failure. Due to gaps in our understanding of the underlying mechanisms of AVS, there are no pharmacological treatments nor dietary interventions known to slow AVS progression. Recent studies have begun to suggest oxylipins, a class of bioactive lipid, may be dysregulated in the valves of AVS-patients.

Methodology

We utilized HPLC-MS/MS to conduct a targeted oxylipin analysis on human AV tissue and plasma from a cohort of 110 patients undergoing AV surgery.

Results

We identified 36 oxylipins in human AV tissue with all showing significant increase in patients with severe AVS. A multivariate model including patient characteristics and valvular oxylipins identified arachidonic acid-cyclooxygenase (COX) pathway derived prostanoids to be the most associated with AVS severity. Plasma oxylipin levels were measured in a subset of aortic surgery patients and compared to a control group of healthy participants, showing distinct oxylipin profiles between control and disease.

Conclusion

Our comprehensive analysis of oxylipins in the human AV to date and identified the inflammatory and osteogenic regulating prostanoids to be positively correlated with AVS severity. This elucidation of prostanoid dysregulation warrants further research into COX inhibition to mitigate AVS.
Effects of high-intensity interval training and moderate-intensity continuous training on non-motor symptoms in patients with Parkinson’s disease: a randomized pilot trial
Authors: Kim Ryul , Choi Seohee , Kang Nyeonju , Park Kiwon , Shin Heehyun , Lee Hanall , Lee Hyungwoo , Jun Jin-Sun , Jeon Beomseok , Byun Kyeongho
Published: August 2023

Objective

To explore whether high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) have different effects on non-motor symptoms in patients with Parkinson’s disease (PD).

Methods

In this 24-week, randomized, controlled, investigator–blinded pilot trial, 33 participants with PD (Hoehn and Yahr stages 1–2; aged 50–80 years) were allocated to HIIT (3 days/week, 60% maximum aerobic power for 30–50 seconds with 1 minute rest intervals), MICT (3 days/week, 50% peak oxygen consumption), or control (usual care) groups. The primary clinical outcome was a 24-week change in the Non-Motor Symptoms Scale (NMSS) score. The secondary clinical outcomes were 24-week changes in the scores of specific non-motor questionnaires covering neuropsychiatric, sleep-related, autonomic, and sensory symptoms.

Results

NMSS score changes did not differ significantly among the three groups (Bonferroni-adjustedp>0.6 in all). In the secondary clinical outcome analyses, the MICT group showed a greater improvement in Beck Depression Inventory scores (median difference, 3.5 points; 95% confidence interval [CI], 1.4 to 6.0; Bonferroni-adjustedp=0.016) and, to a lesser extent, Beck Anxiety Inventory scores (median difference, 2.0 points; 95% CI, 0.0 to 10.8; Bonferroni-adjustedp=0.054) compared with those of the control group. However, these trends were not observed in the HIIT group when compared with the control group (Bonferroni-adjustedp>0.9 in all). There were no significant differences in the other secondary outcomes between the groups.

Conclusion

This trial did not show the potential benefits of HIIT or MICT on overall non-motor symptoms in patients with PD. However, MICT may be more effective than HIIT in alleviating mood symptoms, which requires further large-scale investigation.

Trial registration

CRIS (cris.nih.go.kr) identifier: KCT0007130
Modelling the risk ecosystem of depression using machine learning in a population of young adults
Authors: Fraser H. , Kwong A.S.F. , Brooks M. , Davidson B.I. , McConville R. , Pearson R. M.
Published: August 2023

Understanding what is predictive of early adulthood depression could help inform resource targeting and direction of approaches aiming to alleviate the personal, cultural, and economic burden of depression and similar disorders. This work uses multivariate longitudinal data (n=3487) measured from conception to adulthood from a UK based birth cohort of young adults (Avon Longitudinal Study of Parents and Children (ALSPAC)) and a machine learning approach to a) investigate whether episodes of early adulthood depression can be predicted from various risk factors across early life and adolescence, and b) interpret which factors are most important for predicting episodes of early adulthood depression. Here, we build four models to predict participants having an episode of early adulthood depression and show that the highest performing model can predict if people experienced symptoms of depression with an F1-score of 0.66, using a range of biological, behavioural, and early life experience related risk factors.
PCSK9genetic variants and risk of vascular and non-vascular diseases in Chinese and UK populations
Authors: Holmes Michael V , Kartsonaki Christiana , Boxall Ruth , Lin Kuang , Reeve Nicola , Yu Canqing , Lv Jun , Bennett Derrick A , Hill Michael R , Yang Ling , Chen Yiping , Du Huaidong , Turnbull Iain , Collins Rory , Clarke Robert J , Tobin Martin D , Li Liming , Millwood Iona Y , Chen Zhengming , Walters Robin G
Published: August 2023

Background

Lowering low-density lipoprotein cholesterol (LDL-C) through PCSK9 inhibition represents a new therapeutic approach to preventing and treating cardiovascular disease (CVD). Phenome-wide analyses ofPCSK9genetic variants in large prospective biobanks can help to identify unexpected effects of PCSK9 inhibition.

Methods

The prospective China Kadoorie Biobank genotyped >100,000 participants with follow-up for fatal and non-fatal disease events. APCSK9genetic score (PCSK9-GS) was constructed using three single nucleotide polypmorphisms at thePCSK9locus associated with directly-measured LDL-C, including a loss-of-function variant (rs151193009). Logistic regression gave estimated odds ratios (ORs) forPCSK9-GS associations with CVD and non-CVD outcomes, scaled to 1-standard deviation (SD) lower LDL-C.

Results

PCSK9-GS was associated with lower apolipoprotein B, and with lower risks of carotid plaque (n=8340 cases; OR=0.61 [95%CI: 0.45-0.83]; P=0.0015), major occlusive vascular events (n=15,752; 0.80 [0.67-0.95]; P=0.011), and ischaemic stroke (n=11,467; 0.80 [0.66-0.98]; P=0.029). However,PCSK9-GS was also associated with higher risk of hospitalisation with chronic obstructive pulmonary disease (COPD: n=6836; 1.38 [1.08-1.76]; P=0.0089), and with even higher risk of fatal exacerbations among individuals with pre-existing COPD (n=730; 3.61 [1.71-7.60]; P=7.3×10−4). Risk of acute upper respiratory tract infection (URTI) was also increased (n=1,095; 2.18 [1.34-3.53]; P=0.0016), as previously reported in UK Biobank, with a pooled OR after meta-analysis of 1.87 ([1.38-2.54]; P=5.4×10−5). We also replicated a previously-reported association with self-reported asthma (pooled OR 1.17 ([1.04-1.30]; P=0.0071). There was heterogeneity between the associations ofPCSK9-GS and a polygenic LDL-C score for each of COPD hospitalisation (P-het=0.015), fatal COPD exacerbation (P-het=0.0012), and URTI (P-het=0.013).

Conclusions

LDL-C-loweringPCSK9genetic variants are associated with lower risk of subclinical and clinical atherosclerotic vascular disease, but higher risks of respiratory diseases which appear unrelated to LDL-C. Pharmacovigilance studies may be required to monitor patients treated with therapeutic PCSK9 inhibitors for exacerbations of respiratory diseases or respiratory tract infections.
Cervicovaginal and anal self-sampling for HPV testing in a transgender and gender diverse population assigned female at birth: comfort, difficulty, and willingness to use
Authors: Welsh Erin F , Andrus Emily C. , Sandler Claire B. , Moravek Molly B. , Stroumsa Daphna , Kattari Shanna K. , Walline Heather M. , Goudsmit Christine M. , Brouwer Andrew F.
Published: August 2023

Background

Transgender and gender diverse (TGD) people assigned female at birth (AFAB) face numerous barriers to preventive care, including for HPV and cervical cancer screening. Self-sampling options may expand access to HPV testing for TGD people AFAB.

Methods

We recruited TGD individuals AFAB to collect cervicovaginal and anal specimens at-home using self-sampling for HPV testing, and individuals reported their perceptions of self-sampling. Associations between demographic and health characteristics and each of comfort of use, ease of use, and willingness to use self-sampling were estimated using robust Poisson regression.

Results

The majority of the 101 participants who completed the study reported that the cervicovaginal self-swab was not uncomfortable (68.3%) and not difficult to use (86.1%), and nearly all (96.0%) were willing to use the swab in the future. Fewer participants found the anal swab to not be uncomfortable (47.5%), but most participants still found the anal swab to not be difficult to use (70.2%) and were willing to use the swab in the future (89.1%). Participants were more willing to use either swab if they had not seen a medical professional in the past year. About 70% of participants who reported negative experiences with either self-swab were still willing to use that swab in the future.

Conclusions

TGD AFAB individuals were willing to use and preferred self-sampling methods for cervicovaginal and anal HPV testing. Developing clinically approved self-sampling options for cancer screening could expand access to HPV screening for TGD AFAB populations.
Machine learning for the prediction of in-hospital mortality in patients with spontaneous intracerebral hemorrhage
Authors: Mao Baojie , Zhang Rui , Pan Yuhang , Zheng Ruzi , Shen Yanfei , Lu Wei , Lu Yuning , Xu Shanhu , Wu Jiong , Wang Ming , Wan Shu
Published: August 2023

Backgrounds

Early and accurate identification of patients with spontaneous intracerebral hemorrhage(sICH) who are at high risk of in-hospital death can help intensive care unit (ICU) physicians make optimal clinical decisions. The aim of this study was to develop a machine learning(ML)-based tool to predict the risk of in-hospital death in patients with sICH in ICU.

Methods

We conducted a retrospective administrative database study using the MIMIC-IV and Zhejiang Hospital database. The outcome of the study was in-hospital mortality. To develop and validate the final model, we employed the LASSO regression to screen and select relevant variables. Five algorithms, namely Logistic Regression (LR), K-Nearest Neighbors (KNN), Adaptive Boosting (AdaBoost), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost), were utilized. The selection of the best model was based on the area under the curve (AUC) in the validation cohort. Furthermore, we employ the SHapley Additive exPlanations (SHAP) methodology to elucidate the contributions of individual features to the model and analyze their impact on the model’s outputs. To facilitate accessibility, we also created a visual online calculation page for the model.

Results

In the final cohort comprising 1596 patients from MIMIC-IV and Zhejiang Hospital, 367 individuals (23%) experienced in-hospital mortality during the inpatient follow-up period. After extracting 46 variables from the database, LASSO regression identified 14 predictor variables for further analysis. Among the five evaluated models, the XGBoost model demonstrated superior discriminative power in both the internal validation set (AUC = 0.907) and the external validation set (AUC = 0.787). Furthermore, through the SHAP technique, we identified the top 5 predictors in the feature importance rankings: Glasgow Coma Scale (GCS), Sequential Organ Failure Assessment (SOFA), anticoagulant medication, mannitol medication and oxygen saturation.

Conclusions

Among the five models, the XGBoost model exhibited superior performance in predicting mortality for patients with sICH in the ICU, indicating its potential significance in the development of early warning systems.
Detection of regularities in auditory sequences before and at term-age in human neonates
Authors: Panzani Marine , Mahmoudzadeh Mahdi , Wallois Fabrice , Dehaene-Lambertz Ghislaine
Published: August 2023

During the last trimester of gestation, fetuses and preterm neonates begin to respond to sensory stimulation and to discover the structure of their environment. Yet, neuronal migration is still ongoing. This late migration notably concerns the supra-granular layers neurons, which are believed to play a critical role in encoding predictions and detecting regularities. In order to gain a deeper understanding of how the brain processes and perceives regularities during this stage of development, we conducted a study in which we recorded event-related potentials (ERP) in 31-wGA preterm and full-term neonates exposed to alternating auditory sequences (e.g. “ba ga baga ba”), when the regularity of these sequences was violated by a repetition (e.g., "ba ga baga ga"). We compared the ERPs in this case to those obtained when violating a simple repetition pattern (“ga ga gaga ga” vs “ga ga gaga ba”). Our results indicated that both preterm and full-term neonates were able to detect violations of regularity in both types of sequences, indicating that as early as 31 weeks gestational age, human neonates are sensitive to the conditional statistics between successive auditory elements. Full-term neonates showed an early and similar mismatch response (MMR) in the repetition and alternating sequences. In contrast, 31-wGA neonates exhibited a two-component MMR. The first component which was only observed for simple sequences with repetition, corresponded to sensory adaptation. It was followed much later by a deviance-detection component that was observed for both alternation and repetition sequences. This pattern confirms that MMRs detected at the scalp may correspond to a dual cortical process and shows that deviance detection computed by higher-level regions accelerates dramatically with brain maturation during the last weeks of gestation to become indistinguishable from bottom-up sensory adaptation at term.

Highlights

Starting at 31 wGA, neonates are sensitive to conditional statistics between successive events.

The MisMatch Response detected at the scalp may correspond to a dual cortical process

The prediction error signal accelerates during the third trimester of gestation

It overlaps with the phenomenon of sensory adaptation at term age
Osteoclast-Cancer Cell Metabolic Symbiosis Renders PARP Inhibitor Therapy Resistance in Bone Metastasis
Authors: Fan Huijuan , Xu Zhanao , Yao Ke , Zheng Bingxin , Zhang Yuan , Wang Xuxiang , Zhang Tengjiang , Li Xuan , Hu Haitian , Yue Bin , Hu Zeping , Zheng Hanqiu
Published: August 2023

Seventy percent of patients with late-stage breast cancer develop distal bone metastases; however, the mechanism by which the metabolic microenvironment affects resistance to therapy remains unknown. We investigated the metabolic bone microenvironment and identified glutathione metabolism as the top pathway in osteoclasts, which provides feedback to tumor cells to help neutralize oxidative stress and generate PARP inhibitor (PARPi) therapy resistance. GPX4, the critical enzyme responsible for glutathione oxidation, was upregulated during PARPi therapy through stress-induced ATF4-dependent transcriptional programming. The increased absorption of glutamine and the upregulation of GPX4 expression work in concert to enhance glutathione metabolism in cancer cells. Human clinical sample analysis of paired primary breast tumor and bone metastasis samples revealed that GPX4 was significantly induced in bone metastases. Combination therapy utilizing PARPi and zoledronate, which blocks osteoclast activity and thereby reduces the microenvironmental glutamine supply, generates a synergistic effect in reducing bone metastasis. Thus, our results identified an essential metabolic symbiosis between bone-resident cells and metastatic cancer cells during PARPi therapy.

SIGNIFICANCE

Osteoclast-derived glutamine is taken up by tumor cells to synthesize glutathione and neutralize the ROS generated by PARPi. This is the first example of “metabolic symbiosis” in therapeutic resistance of bone metastasis.
Development and characterization of pFluor50, a fluorogenic-based kinetic assay system for high-throughput inhibition screening and characterization of time-dependent inhibition and inhibition type for six human CYPs
Authors: Shriwas Pratik , Revnew Andre , Roo Sarah , Bender Alex , Lane Thomas R. , Ekins Sean , McElroy Craig A.
Published: August 2023

1

Cytochrome P450 enzymes (CYPs) play an integral role in drug and xenobiotic metabolism in humans and thus understanding CYP inhibition or activation by new therapeutic candidates is an important step in the drug development process. Ideally, CYP inhibition/activation assays should be high-throughput, use commercially available components, allow for analysis of metabolism by the majority of human CYPs, and allow for kinetic analysis of inhibition type and time-dependent inhibition. Here, we developed pFluor50, a 384-well microtiter plate-based fluorogenic kinetic enzyme assay system using substrates metabolized by six human CYPs to generate fluorescent products and determined the Michaelis-Menten kinetics constant (KM) and product formation rate (Vmax) for each substrate-CYP pair. The substrate-CYP pairs were as follows: resorufin ethyl ether for CYP1A2 (KM= 0.8 μM), CYP2C9 (KM= 0.6 μM), and CYP2D6 (KM= 2.7 μM); resorufin benzyl ether for CYP2B6 (KM= 46 μM); 3-O-methyl fluorescein for CYP2C19 (KM= 3.0 μM); and dibenzyl fluorescein for CYP3A4 (KM= 2.9 μM). We then validated each assay using known inhibitors: α-naphthoflavone for CYP1A2 (IC50= 13.5 nM); sertraline for CYP2B6 (IC50= 410 nM) and CYP2D6 (IC50= 2.4 μM); sulfaphenazole for CYP2C9 (IC50= 1 μM); ticlopidine for CYP2C19 (IC50= 1.2 μM); and CYP3cide for CYP3A4 (IC50= 56 nM). pFluor50 was also used to elucidate inhibition type and time-dependent inhibition for some inhibitors demonstrating its utility for characterizing the observed inhibition, even mechanism-based inhibition. The pFluor50 assay system developed in this study using commercially available components should be very useful for high-throughput screening and further characterization of potential therapeutic candidates for inhibition/activation with the most prevalent human CYPs.
A robust ultrasensitive transcriptional switch in noisy cellular environments
Authors: Jeong Eui Min , Kim Jae Kyoung
Published: August 2023

Ultrasensitive transcriptional switches enable sharp transitions between on and off states of transcription and are essential for cells to respond to environmental cues precisely. However, conventional switches, relying on direct repressor-DNA binding, are extremely sensitive to noise. Here, we discovered an alternative design combining three indirect transcriptional repression mechanisms, sequestration, blocking, and displacement, to generate a noise-resilient ultrasensitive switch. Although sequestration alone can generate an ultrasensitive switch, it remains sensitive to noise because the unintended transcriptional state induced by noise can persist for long periods. However, by jointly utilizing blocking and displacement, these noise-induced transitions can be rapidly restored to the original transcriptional state. Because this transcriptional switch is effective in noisy cellular contexts, it goes beyond previous synthetic transcriptional switches utilizing direct repression mechanisms, making it particularly valuable for robust synthetic system design. Our findings also provide insights into the evolution of robust ultrasensitive switches in real cells. Specifically, the concurrent use of seemingly redundant indirect repression mechanisms in diverse biological systems appears to be a strategy to achieve noise-resilience of ultrasensitive switches.

GRAPHICAL ABSTRACT
The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production andde novolipogenesis
Authors: Acevedo Aracely , Jones Anthony E. , Danna Bezawit T. , Turner Rory , Montales Katrina P. , Benincá Cristiane , Reue Karen , Shirihai Orian S. , Stiles Linsey , Wallace Martina , Wang Yibin , Bertholet Ambre M. , Divakaruni Ajit S.
Published: August 2023

Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation ofBckdkin specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly five-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in loweringde novolipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.
Effect of Tokenization on Transformers for Biological Sequences
Authors: Dotan Edo , Jaschek Gal , Pupko Tal , Belinkov Yonatan
Published: August 2023

Deep learning models are transforming biological research. Many bioinformatics and comparative genomics algorithms analyze genomic data, either DNA or protein sequences. Examples include sequence alignments, phylogenetic tree inference and automatic classification of protein functions. Among these deep learning algorithms, models for processing natural languages, developed in the natural language processing (NLP) community, were recently applied to biological sequences. However, biological sequences are different than natural languages, such as English, and French, in which segmentation of the text to separate words is relatively straightforward. Moreover, biological sequences are characterized by extremely long sentences, which hamper their processing by current machine-learning models, notably the transformer architecture. In NLP, one of the first processing steps is to transform the raw text to a list of tokens. Deep-learning applications to biological sequence data mostly segment proteins and DNA to single characters. In this work, we study the effect of alternative tokenization algorithms on eight different tasks in biology, from predicting the function of proteins and their stability, through nucleotide sequence alignment, to classifying proteins to specific families. We demonstrate that applying alternative tokenization algorithms can increase accuracy and at the same time, substantially reduce the input length compared to the trivial tokenizer in which each character is a token. Furthermore, applying these tokenization algorithms allows interpreting trained models, taking into account dependencies among positions. Finally, we trained these tokenizers on a large dataset of protein sequences containing more than 400 billion amino acids, which resulted in over a three-fold decrease in the number of tokens. We then tested these tokenizers trained on large-scale data on the above specific tasks and showed that for some tasks it is highly beneficial to train database-specific tokenizers. Our study suggests that tokenizers are likely to be a critical component in future deep-network analysis of biological sequence data.
Dopamine Release Plateau and Outcome Signals in Dorsal Striatum Contrast with Classic Reinforcement Learning Formulations
Authors: Kim Min Jung , Gibson Daniel J. , Hu Dan , Mahar Ara , Schofield Cynthia J. , Sompolpong Patlapa , Yoshida Tomoko , Tran Kathy T. , Graybiel Ann M.
Published: August 2023

We recorded dopamine release signals in medial and lateral sectors of the striatum as mice learned consecutive visual cue-outcome conditioning tasks including cue association, cue discrimination, reversal, and probabilistic discrimination task versions. Dopamine release responses in medial and lateral sites exhibited learning-related changes within and across phases of acquisition. These were different for the medial and lateral sites. In neither sector could these be accounted for by classic reinforcement learning as applied to dopamine-containing neuron activity. Cue responses ranged from initial sharp peaks to modulated plateau responses. In the medial sector, outcome (reward) responses during cue conditioning were minimal or, initially, negative. By contrast, in lateral sites, strong, transient dopamine release responses occurred at both cue and outcome. Prolonged, plateau release responses to cues emerged in both regions when discriminative behavioral responses became required. In most sites, we found no evidence for a transition from outcome to cue signaling, a hallmark of temporal difference reinforcement learning as applied to midbrain dopamine activity. These findings delineate reshaping of dopamine release activity during learning and suggest that current views of reward prediction error encoding need review to accommodate distinct learning-related spatial and temporal patterns of striatal dopamine release in the dorsal striatum.
Estrogen regulates myogenic tone in hippocampal arterioles by enhanced basal release of nitric oxide and endothelial SKCachannel activity
Authors: Jeffrey Danielle A. , Russell Abigail , Guerrero Mayra Bueno , Fontaine Jackson T. , Romero Phinea , Rosehart Amanda C. , Dabertrand Fabrice
Published: August 2023

Arteries and arterioles exhibit myogenic tone, a partially constricted state that allows further constriction or dilation in response to moment-to-moment fluctuations in blood pressure. The vascular endothelium that lines the internal surface of all blood vessels controls a wide variety of essential functions, including the contractility of the adjacent smooth muscle cells by providing a tonic vasodilatory influence. Studies conducted on large (pial) arteries on the surface of the brain have shown that estrogen lowers myogenic tone in female mice by enhancing nitric oxide (NO) release from the endothelium, however, whether this difference extends to the intracerebral microcirculation remains ambiguous. The existing incomplete picture of sex differences in cerebrovascular physiology combined with a deficiency in treatments that fully restore cognitive function after cerebrovascular accidents places heavy emphasis on the necessity to investigate myogenic tone regulation in the microcirculation from both male and female mice. We hypothesized that sex-linked hormone regulation of myogenic tone extends its influence on the microcirculation level, and sought to characterize it in isolated arterioles from the hippocampus, a major cognitive brain area. Using diameter measurements bothin vivo(acute cranial window vascular diameter) andex vivo(pressure myography experiments), we measured lower myogenic tone responses in hippocampal arterioles from female than male mice. By using a combined surgical and pharmacological approach, we found myogenic tone in ovariectomized (OVX) female mice matches that of males, as well as in endothelium-denuded arterioles. Interestingly, eNOS inhibition induced a larger constriction in female arterioles but only partially abolished the difference in tone. We identified that the remnant difference was mediated by a higher activity and expression of the small-conductance Ca2+-sensitive K+(SK) channels. Collectively, these data indicate that eNOS and SK channels exert greater vasodilatory influence over myogenic tone in female mice at physiological pressures.
Engineered 3D Immuno-Glial-Neurovascular Human miBrain Model
Authors: Stanton Alice E. , Bubnys Adele , Agbas Emre , James Benjamin , Park Dong Shin , Jiang Alan , Pinals Rebecca L. , Liu Liwang , Truong Nhat , Loon Anjanet , Staab Colin , Cerit Oyku , Wen Hsin-Lan , Kellis Manolis , Blanchard Joel W. , Langer Robert , Tsai Li-Huei
Published: August 2023

Patient-specific, human-based cellular models integrating a biomimetic blood-brain barrier (BBB), immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. By engineering a novel brain-mimicking 3D hydrogel and co-culturing all six major brain cell types derived from patient iPSCs, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model within vivo-like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer’s Disease pathologies associated withAPOE4genetic risk.APOE4miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic GFAP. Unlike the co-emergent fate specification of glia and neurons in organoids, miBrains integrate independently differentiated cell types, a feature we harnessed to identify thatAPOE4in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.