bluuebunny/crossref_metadata_2025 huggingface dataset:
Reliability and Validity of the Student Version of the Oldenburg Burnout Inventory in Physical Therapist Students
Authors: Smith Allison , Ellison Jennifer , Bogardus Jennifer , Gleeson Peggy
Published: February 2022

Introduction.

Limited research exists on burnout in physical therapists (PTs) and PT students. The prevalence of PT student burnout is unknown and few outcome measures exist to study burnout in students. The purpose of this study was to assess the test–retest reliability and internal consistency of the Oldenburg Burnout Inventory for Students (OLBI-S) and convergent validity of the OLBI-S with the Maslach Burnout Inventory General Survey for Students (MBI-GSS) in Doctor of Physical Therapy (DPT) students.

Review of Literature.

Most authors studying burnout have used the MBI, which has been criticized in recent years. The OLBI was developed in response to the criticisms and psychometric limitations of the MBI. The OLBI-S has not yet been validated in PT students.

Subjects.

Participants included a convenience sample of DPT students attending Texas Woman's University in Houston during the fall semester of 2020.

Methods.

Students completed the OLBI-S and MBI-GSS and completed the OLBI-S a second time 1 week later. Intraclass correlation coefficients (ICCs) were calculated to examine test–retest reliability, Cronbach's α was calculated to assess internal consistency, and convergent validity was assessed by calculating Pearson's correlations comparing corresponding subscales for the OLBI-S and MBI-GSS.

Results.

Test–retest reliability was excellent for both the OLBI-S exhaustion subscale (ICC = .916, P < .001) and the OLBI-S disengagement subscale (ICC = .955, P < .001). Internal consistency was good for both the exhaustion subscale (Cronbach's α = .833) and the disengagement subscale (Cronbach's α = .784). Convergent validity was found to be good between the OLBI-S and MBI-GSS exhaustion subscales (r = .741, P < .001) as well as the disengagement subscale of the OLBI-S and cynicism subscale of the MBI-GSS (r = .766, P < .001).

Discussion and Conclusion.

The OLBI-S has excellent reliability, good validity, and is a free alternative outcome measure to the MBI-GSS to measure burnout in DPT students.
Infant Carrying in the United States: A Survey of Current Practices, Physical and Mental Health Benefits, and Challenges of Babywearing
Authors: Havens Kathryn L. , Johnson Eileen V. , Day Elizabeth N. , Holdener Caleb J. , Starnes Catherine P.
Published: February 2022

Background:

Parents carry their infants, toddlers, and young children every day. An ergonomic aid to carry (ie, babywearing) has been used for generations by caregivers of young children worldwide. While the benefits of close physical contact for infants are well documented, little is known on how this additional load impacts the health of the caregiver.

Objective:

An understanding of how babies are carried during their early years, especially how this behavior affects the musculoskeletal and mental health of the caregiver, is the first step to understanding this dynamic and is the objective of this research.

Study Design:

Cross-sectional observational study.

Methods:

A survey was designed to provide insight into current practices in the United States and the self-perceived physical and mental health benefits or challenges to babywearing.

Results:

A total of 3758 babywearing enthusiasts with a high level of experience and frequent babywearing responded. Respondents reported babywearing to allow for multitasking (97%) and for bonding/attachment (87%). Increased babywearing frequency was associated with improvements in fatigue, insomnia, and interest in sex among caregivers. Most respondents had experienced back pain (82%). Urinary incontinence and pelvic organ prolapse appear more prevalent than other research reports, although strong relationships were not found with babywearing. Finally, respondents had mild symptoms of stress, anxiety, and depression. Surprisingly, no relationships were identified between mental health scales and babywearing frequency or experience.

Conclusions:

Taken together, this data provides a better understanding of physical and mental health of caregivers in the United States, especially as they relate to babywearing.

See the Video, Supplemental Digital Content A (available at: http://links.lww.com/JWHPT/A72).
Academic-Practice Partnership Pivot During COVID-19 Pandemic Surge
Authors: Harper Doreen C. , Poe Terri L. , Stewart Jill , Powers Summer , Watts Penni , McLain Rhonda , Shirey Maria R.
Published: February 2022

Health care systems continue to experience the sequential aftermath of the COVID-19 pandemic, with major care access, quality, safety, financial sustainability, and workforce considerations. Yet, academic-clinical partnership opportunities exist for transformational change, even when efforts to respond to a pandemic seem insurmountable. A nursing partnership between an academic health center nursing school and university health system provided short- and long-term support for the nursing workforce shortage during a COVID-19 surge. An academic-clinical integration framework guided planning, clinical support activities, outcomes achieved, technology innovations, and shared lessons associated with these efforts. The COVID-19 surge response steps included a call to action, preparation for surge support by the academic and clinical partners, and a team approach for clinical service delivery by faculty, students, and staff. Through the 6-week COVID-19 surge response, more than 10 000 hours of hospital nurse staffing were provided by nursing school faculty and students; over 770 worked shifts that provided approximately 30% of the full surge hospital supplemental staffing and approximately 46 000 vaccine encounters. Well-established academic-clinical nursing partnerships allow for quick pivots in the rapidly changing COVID-19 environment that can enhance nursing clinical proficiency and competency, augment clinically immersive learning, and reinforce analytics to measure health outcomes, lower costs, improve access, quality, safety, and workforce conditions.
Three-Dimensional Changes in the Mandibular Proximal Segment After Using a Surgery-First Approach in Patients With Class III Malocclusion and Facial Asymmetry
Authors: Kim MyungSu , Jha Nayansi , Choi Jae-Hong , Kim Yoon-Ji , Lee Uilyong , Cevidanes Lucia , Choi Jin-Young , Baek Seung-Hak
Published: February 2022

This study was performed to evaluate condylar position and angulation after asymmetric mandibular setback between a conventional (CA) and surgery-first approach (SFA) using three-dimensional analysis. The condylar positions of 30 patients with skeletal Class III malocclusion and facial asymmetry who underwent 1-jaw (sagittal split ramus osteotomy) or 2-jaw orthognathic surgery (Le Fort I osteotomy and sagittal split ramus osteotomy) with CA (n = 18) or SFA (n = 12) from 2 university hospitals were studied. The three-dimensional assessment of condylar changes was performed using computed tomography images at the initial time point (T0) and at least 6 months after surgery (T1). Segmentation of condyles and cranial base assessment from cone-beam computed tomography images were performed using ITK-SNAP software (version 3.4.0). Condylar position and angulation changes were calculated using 3D Slicer software (version 4.10.2), and statistical analysis was performed. No significant translational or rotational condylar changes were observed between the deviated and non-deviated sides in each group or between the CA and SFA groups except yaw (p = 0.014). Linear mixed-model analysis and multi-variate analysis showed no significant difference between the CA and SFA groups. Surgery-first approach might not be associated with more harmful effects on the condylar position and angulation changes as compared with CA.
The Clinical Features and Molecular Mechanism of Pituitary Adenoma Associated With Vestibular Schwannoma
Authors: Zhu Haibo , Wang Dawei , Miao Yazhou , Guo Jing , Shen Yutao , Zhang Yazhuo , Li Chuzhong
Published: February 2022

Objectives:

To explore the clinical features and mechanism of pituitary adenoma associated with vestibular schwannoma (PAVS).

Patients and Methods:

The authors retrospectively reviewed pituitary adenoma patients in Beijing Tiantan Hospital from January 1, 2008 to December 31, 2016. A total of two pituitary adenoma samples, 1 vestibular schwannoma sample and one paired pituitary adenoma/blood sample were subjected next-generation sequencing and sanger sequence.

Results:

A total of 5675 pituitary adenoma patients from January 1, 2008 to December 31, 2016, were retrospectively analyzed; of these, 4 (7%) patients met the criteria of PAVS. Clinical variable analyses revealed significant correlations between PAVS and older age when compared with sporadic pituitary adenoma (SPA) or sporadic vestibular schwannoma (SVS). The authors found that there were 2 germline mutations of XKR3 in 2/4 PAVS patients. Therefore, the authors speculated that XKR3 might be a genetic predisposition factor. The result also showed that there was no NF2 mutation and NF2-related symptom in the 4 PAVS samples.

Conclusions:

PAVS had a significant correlation with older age when compared with SPA and SVS. XKR3 may be a genetic predisposition factor for PAVS, it represents a therapeutic target for PAVS in the future.
Subjective and Objective Evaluation of Speech in Adult Patients with Unrepaired Cleft Palate
Authors: Lou Qun , Wang Xudong , Jiang Liping , Wang Guomin , Chen Yang , Liu Qiong
Published: February 2022

Objective:

To explore the speech outcomes of adult patients through subjective perception evaluation and objective acoustic analysis, and to compare the differences in pronunciation characteristics between speakers with adult patients with unrepaired cleft palate and their non-cleft peers.

Participants and Intervention:

Subjective evaluation indicators included speech intelligibility, nasality, and consonant missing rate, whereas objective acoustic parameters included normalized vowel formants, voice onset time, and the analysis of three-dimensional spectrogram and spectrum, were carried out on speech samples produced by 2 groups of speakers: (a) speakers with unrepaired cleft palate (n = 65, mean age = 25.1 years) and (b) typical speakers (n = 30, mean age = 23.7 years).

Results:

Compared with typical speakers, individuals with unrepaired cleft palate exhibited a lower speech intelligibility with higher nasality and consonant missing rate, the missing rate is highest for the 6 consonants syllables The acoustic parameters are mainly manifested as differences in vowel formants and voice onset time.

Conclusions:

The results revealed important acoustical differences between adult patients with unrepaired cleft palate and typical speakers. The trend of spectral deviation may have contributed to the difficulty in producing pressure vowels and aspirated consonants in individuals with speech disorders related to cleft palate.
Development and Validation of a Nomogram to Predict the Risk of Blood Transfusion in Orthognathic Patients
Authors: Jiang Fengli , He Jingjing , Wu Huanhuan , Wu Lingsong , Sun Na , Li Mixue , Xing Jiahua , Li Yan , Xu Yujian , Zheng Yang , Chen Youbai , Zhan Sien
Published: February 2022

Objective:

This study aims to establish a nomogram to predict the probability of blood transfusion in patients with preoperative autologous blood donation before orthognathic surgery.

Methods:

The authors conducted a retrospective case-control study on consecutive orthognathic patients with preoperative autologous blood donation from January 2014 to December 2020. The outcome variable was the actual transfusion of autologous blood (ATAB). Predictors included patients’ demographics, preoperative blood cell test, vital signs, American Society of Anesthesiologists classification, surgical procedure, operation duration, and blood loss. Univariable and multivariable logistic regressions were performed to identify independent risk factors associated with ATAB. A nomogram was constructed to predict the risk for ATAB. The performance of the nomogram was evaluated using the area under the receiver operating characteristic curve, calibration curve and the consistency index.

Results:

A total of 142 patients (75 males and 67 females) with an average age of 22.72 ± 5.34 years donated autologous blood before their orthognathic surgery. Patients in the transfusion group (n = 56) had significantly lower preoperative red blood cell counts (4.74 ± 0.55 × 109/L versus 4.98 ± 0.45 × 109/L, P = 0.0063), hemoglobin (141.48 ± 15.18g/dL versus 150.33 ± 14.73g/dL, P = 0.0008), and hematocrit (41.05% ± 4.03% versus 43.32% ± 3.42%, P= 0.0006), more bimaxillary osteotomies (92.86% versus 56.98%, P < 0.001), longer operation duration (348.4 ± 111.10 minutesversus261.6 ± 115.44 minutes, P < 0.001), and more intraoperative blood loss (629.23±273.06 ml versus 359.53 ± 222.84 ml, P < 0.001) than their counterparts (n = 86) in the non– transfusion group. Univariable and multivariable logistic regression demonstrated that only hemoglobin (adjusted odds ratio [OR] 0.864, 95% confidence interval [CI]:0.76–0.98, P= 0.026), operation procedures (adjusted OR 8.14, 95% CI:1.69–39.16, P = 0.009), and blood loss (adjusted OR 1.006, 95% CI:1.002–1.009, P < 0.001) were independent risk factors for ATAB. The area under the receiver operating characteristic curve of the nomogram was 0.823. The consistency index of the nomogram was 0.823. The calibration curve illustrated that the nomogram was highly consistent with the actual observation.

Conclusions:

The nomogram is a simple and useful tool with good accuracy and performance in predicting the risk for blood transfusion.
A Survey of Factors Influencing Specialization in Plastic Surgery Among Chinese Surgeons
Authors: Liang Xuebing , Sun Sijie , Gu Tianyi , Ma Jiguang , Wang Keming
Published: February 2022

In recent years, more Chinese surgeons have left other fields to enter plastic surgery. The factors influencing this respe-cialization have not been elicited. The authors aim to elucidate Chinese surgeons’ experience and career satisfaction in this specialty change. Between July and September 2020, the authors conducted an online survey of nonplastic surgeons who received plastic surgery training at an academic center. The survey evaluated their motivation for pursuing their field, practice patterns, and career satisfaction. Responses were compared those who respecialized in plastic surgery with those who did not. A total of 251 nonplastic surgeons completed the survey. The most frequent reasons for pursuing plastic surgery were lifestyle (61.1%), desire to help others (44.4%), and higher compensation (37.3%). Among those who changed fields, employment in academic centers declined from 85% to 51.7%, 70% devoted at least half of their practice to aesthetic surgery, and the median nights on call decreased from 1.54 to 0.38 per week after specializing in plastic surgery. Overall career satisfaction in plastic surgery was significantly higher compared with their former specialties (78.3% versus 28.3%, P 0.05). The authors’ study showed that outflow of surgeons from other specialties to plastic surgery is mainly due to burnout, which erodes physicians’ satisfaction level and the quality of care they are able to provide. The authors highlight the need for reducing burnout in other surgical fields as well as rigorous plastic and aesthetic surgery training for those changing fields to ensure high-quality patient care.
Quantification of the Bimodal Plate-Specific Complication Profile Associated With Reconstruction of Segmental Mandibular Defects With Reconstruction Plate and Soft Tissue Flap: Evidence From Systematic Review
Authors: Rymer Ben C.
Published: February 2022

Reconstruction of segmental mandibular defects with a mandibular reconstruction plate and separate soft tissue flap can be indicated in certain patients. Whilst this technique can provide acceptable results, its exact longevity and timing of associated complications is poorly understood. This study was designed to quantify and plot in time the complication profile associated with this technique of mandibular reconstruction.

A search of the Medline and PubMed Central databases was conducted using the terms “Mandibulectomy” and “Reconstruction Plate.” Articles reporting total number of plate extrusions and fractures and their postoperative timing were included.

Nine articles were included, representing 265 patients with mandibulectomy defects reconstructed using mandibular reconstruction plates. Of these, 135 were male (62%) and 82 were female (38%). The mean age was 59 years. The predominant pathology was oral cavity Squamous Cell Carcinoma (SCC) (80%). Seventy-three patients (28%) experienced complications (mean follow-up: 24 months), with median time to complication of 3 months. Forty-three plate extrusions (16%), 20 plate fractures (8%) and 10 cases of loosened screws (4%) were reported. A bimodal temporal distribution of complications was found.

Overall, a plate-specific complication rate of 28% was found, confirming a higher incidence of complications in comparison to osseous free flap reconstruction. These occur over a bimodal time distribution, with extrusion occurring earlier than fracture. interference with speech, swallow and dental rehabilitation, and delay of adjuvant therapy are potential consequences. These findings indicate that patients may be better served by more complex reconstructive procedures, to minimize exposure to a frequent and prolonged complication profile.
Variational phylodynamic inference using pandemic-scale data
Authors: Ki Caleb , Terhorst Jonathan
Published: February 2022

The ongoing global pandemic has sharply increased the amount of data available to researchers in epidemiology and public health. Unfortunately, few existing analysis tools are capable of exploiting all of the information contained in a pandemic-scale data set, resulting in missed opportunities for improved surveillance and contact tracing. In this paper, we develop the variational Bayesian skyline (VBSKY), a method for fitting Bayesian phylodynamic models to very large pathogen genetic data sets. By combining recent advances in phylodynamic modeling, scalable Bayesian inference and differentiable programming, along with a few tailored heuristics, VBSKY is capable of analyzing thousands of genomes in a few minutes, providing accurate estimates of epidemiologically relevant quantities such as the effective reproduction number and overall sampling effort through time. We illustrate the utility of our method by performing a rapid analysis of a large number of SARS-CoV-2 genomes, and demonstrate that the resulting estimates closely track those derived from alternative sources of public health data.
Effectiveness and safety of PRP on persistent olfactory dysfunction related to COVID-19: towards a new therapeutic hope
Authors: Steffens Younès , Le Bon Serge , Prunier Léa , Rodriguez Alexandra , Lechien Jérôme R. , Saussez Sven , Horoi Mihaela
Published: February 2022

Olfactory dysfunction (OD) is a well know symptom of coronavirus disease 2019 (COVID-19), accounting for 48 to 85% of patients. In 1 to 10% of cases, patients develop a chronic olfactory dysfunction (COD,) lasting more than 6 months. Recently, platelet-rich plasma (PRP) was used in patients with non-COVID-19 COD and authors reported encouraging results. In the present study, we investigated the usefulness and safety of PRP injection in 56 patients with COVID-19 COD.

Our results showed that PRP in the olfactory cleft can increase the olfactory threshold one month after the injection. Moreover, our results suggest that timing of treatment may be an important factor and that PRP is a safe treatment because no adverse effects were reported throughout the study
Microbiome Toolbox: Methodological approaches to derive and visualize microbiome trajectories
Authors: Banjac Jelena , Sprenger Norbert , Dogra Shaillay Kumar
Published: February 2022

The gut microbiome changes rapidly under the influence of different factors such as age, dietary changes or medications to name just a few. To analyze and understand such changes we present a microbiome analysis toolbox. We implemented several methods for analysis and exploration to provide interactive visualizations for easy comprehension and reporting of longitudinal microbiome data. Based on abundance of microbiome features such as taxa as well as functional capacity modules, and with the corresponding metadata per sample, the toolbox includes methods for 1) data analysis and exploration, 2) data preparation including dataset-specific preprocessing and transformation, 3) best feature selection for log-ratio denominators, 4) two-group analysis, 5) microbiome trajectory prediction with feature importance over time, 6) spline and linear regression statistical analysis for testing universality across different groups and differentiation of two trajectories, 7) longitudinal anomaly detection on the microbiome trajectory, and 8) simulated intervention to return anomaly back to a reference trajectory.

Availability and implementation

The software tools are open source and implemented in Python. The link to the interactive dashboard is https://microbiome-toolbox.herokuapp.com/. For developers interested in additional functionality of the toolbox, the Python package can be downloaded from https://pypi.org/project/microbiome-toolbox/. The toolbox is modular allowing for further extension with custom methods and analysis. The code is available on Github https://github.com/JelenaBanjac/microbiome-toolbox.

Contact

ShaillayKumar.Dogra@rd.nestle.com

Supplementary Information

Supplementary data are available at Bioinformatics online.
GMMchi: Gene Expression Clustering Using Gaussian Mixture Modeling
Authors: Liu Ta-Chun , Kalugin Peter N. , Wilding Jennifer L. , Bodmer Walter F.
Published: February 2022

Motivation

Cancer evolution consists of a stepwise acquisition of genetic and epigenetic changes, which alter the gene expression profiles of cells in a particular tissue and result in phenotypic alterations acted upon by natural selection. The recurrent appearance of specific genetic lesions across individual cancers and cancer types suggests the existence of certain “driver mutations,” which likely make up the major contribution to tumors’ selective advantages over surrounding normal tissue and as such are responsible for the most consequential aspects of the cancer cells’ gene expression patterns and phenotypes. We hypothesize that such mutations are likely to cluster with specific dichotomous shifts in the expression of the genes they most closely control, and propose GMMchi, a Python package that leverages Gaussian Mixture Modeling to detect and characterize bimodal gene expression patterns across cancer samples, as a tool to analyze such correlations using 2x2 contingency table statistics.

Results

We confirm that GMMchi robustly and reliably extracts bimodal patterns from both colorectal cancer (CRC) cell line-derived microarray and tumor-derived RNA-Seq data and verify previously reported gene expression correlates of some well-characterized CRC phenotypes. Using well-defined simulated data, we were able to confirm the robust performance of GMMchi, reaching 85% accuracy with a sample size of n = 90. We were also able to demonstrate a few examples of the application of GMMchi with respect to its capacity to characterize background florescent signal in microarray data, filter out uninformative background probe sets, as well as uncover novel genetic interrelationships and tumor characteristics. Our approach to analysing gene expression analysis in cancers provides an additional lens to supplement traditional continuous-valued statistical analysis by maximizing the information that can be gathered from bulk gene expression data.

Availability

The Python package GMMchi and our cell line microarray data used in this paper is available for downloading on GitHub at https://github.com/jeffliu6068/GMMchi

Contact

ta-chun.liu@oncology.ox.ac.uk, peter.kalugin@hms.harvard.edu, walter.bodmer@hertford.ox.ac.uk
Robust statistical evaluation of tumor incidences in long-term rodent carcinogenicity studies: the reformulated poly-k trend test
Authors: Hothorn Ludwig A.
Published: February 2022

Mortality-adjusted tumor rates in long-term carcinogenicity rodent bioassays are commonly evaluated by means of the poly-k=3 Armitage trend test. However, this assumes exactly a linear dose-response curve and the Weibull parameter of k=3 for all tumor sites. These unrealistic assumptions can be circumvented by multiple testing across multiple possible dose-response shapes, multiple Weibull parameters, multiple effect sizes, multiple correlated tumors as well as pairwise and trend tests using the multiple marginal models approach. Based on data examples, different multiple tests are demonstrated using the CRAN R packages multcomp, tukeytrend, coin, MCPAN and multfisher.
Clonally heritable gene expression imparts a layer of diversity within cell types
Authors: Mold Jeff E. , Weissman Martin H. , Ratz Michael , Hagemann-Jensen Michael , Hård Joanna , Eriksson Carl-Johan , Toosi Hosein , Berghenstråhle Joseph , von Berlin Leonie , Martin Marcel , Blom Kim , Lagergren Jens , Lundeberg Joakim , Sandberg Rickard , Michaëlsson Jakob , Frisén Jonas
Published: February 2022

Cell types can be classified based on shared patterns of transcription. Variability in gene expression between individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. We asked whether long-term, heritable differences in transcription can impart diversity within a cell type. Studying clonal human lymphocytes and mouse brain cells, we uncover a vast diversity of heritable transcriptional states among different clones of cells of the same type in vivo. In lymphocytes we show that this diversity is coupled to clone specific chromatin accessibility, resulting in distinct expression of genes by different clones. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging and disease.
Genomic Surveillance of Salmonella spp. in the Philippines, 2013-2014
Authors: Lagrada Marietta L. , Argimón Silvia , Borlasa Janice B. , Abad Jaywardeen P. , Gayeta June M. , Masim Melissa L. , Olorosa Agnettah M. , Cohen Victoria , Jeffrey Benjamin , Abudahab Khalil , Sia Sonia B. , Hufano Charmian M. , Stelling John , Holden Matthew T.G. , Aanensen David M. , Carlos Celia C. ,   the Philippines Antimicrobial Resistance Surveillance Program
Published: February 2022

Increasing antimicrobial resistance (AMR) in Salmonella has been observed in the Philippines. This study aims to utilize whole genome sequencing (WGS) to characterize the population and AMR mechanisms of Salmonella captured by the Philippine Antimicrobial Resistance Surveillance Program (ARSP) and contrast to traditional laboratory methods.

We sequenced the whole genomes of 148 Salmonella Typhi (S. Typhi) and 65 non-typhoidal Salmonella (NTS) collected in the Philippines in 2013–2014. From the genome sequences, we determined the serotype, multilocus sequence type, presence of determinants of antimicrobial resistance and relatedness between isolates. We also compared the genotypic predictions of serotype and AMR to the phenotypic data.

AMR rates in S. Typhi were low, with sparse acquisition of mutations associated with reduced susceptibility to fluoroquinolones or extended-spectrum beta-lactamases (ESBL) genes. In contrast, three quarters of NTS isolates were insusceptible to at least one antimicrobial, with more than half carrying mutations and/or genes linked to resistance to fluoroquinolones. ESBL genes were detected in five genomes that also carried other AMR determinants. The population of S. Typhi was dominated by the likely endemic genotype 3.0, which also caused of a putative local outbreak susceptible to antibiotics. The main NTS clades were global epidemic S. Enteritidis ST11 and the monophasic variant of S. Typhimurium (I 4,[5],12:i:-) ST34, which had frequently been serotyped as S. Typhimurium in the laboratory.

This was the first time that Salmonella isolated from the Philippines were characterized by WGS and we provide evidence of its utility for ongoing surveillance at the ARSP.
Neurovascular Uncoupling: Multimodal Imaging Delineates the Acute Effects of MDMA
Authors: Ionescu Tudor M. , Amend Mario , Watabe Tadashi , Hatazawa Jun , Maurer Andreas , Reischl Gerald , Pichler Bernd J. , Wehrl Hans F. , Herfert Kristina
Published: February 2022

Psychedelic compounds have attracted increasing interest in recent years due to their therapeutic potential for psychiatric disorders. Methylenedioxymethamphetamine (MDMA) is currently being investigated in clinical trials to treat post-traumatic stress disorder. To understand the acute effects of psychedelic drugs in vivo, functional MR imaging (fMRI) has been widely used in recent years. Notably, fMRI studies have shown that MDMA leads to inhibition of brain activity, challenging earlier hypotheses indicating mainly excitatory effects. However, interpretation of hemodynamic changes induced by psychedelics is challenging because of the potent vascular effects associated with this class of substances. Therefore, this study aimed to investigate the acute effects of MDMA using simultaneous positron emission tomography (PET)/fMRI in rats. For this purpose, hemodynamic changes measured by BOLD-fMRI were related to alterations in glucose utilization and serotonin transporter (SERT) occupancy, investigated using [18F]FDG functional PET (fPET) and [11C]DASB PET.

We demonstrate that MDMA induces global hemodynamic decreases accompanied by localized metabolic increases. Elevated metabolism was found primarily in limbic projection areas involved in emotion processing. Concurrent BOLD-fMRI decreases, also found in extracerebral areas, indicate that the BOLD-fMRI reductions observed in the brain are of vascular, non-neuronal origin. We further show that higher SERT occupancy strongly correlates with regional BOLD-fMRI reductions. Therefore, increased serotonin levels induced by SERT blockage may cause a neurovascular uncoupling.

Correct understanding of the in vivo mechanism of MDMA not only supports ongoing research but also warrants a reassessment of previous studies on neuronal effects of psychedelics relying on neurovascular coupling.
Lin28b specifies an innate-like lineage of CD8+ T cells in early life
Authors: Watson Neva B. , Patel Ravi K. , Oyesola Oyebola O. , Laniewski Nathan , Grenier Jennifer K. , Wang Jocelyn , Tabilas Cybelle , Yee Mon Kristel J. , Peng Seth P. , Wesnak Samantha P. , Nzingha Kito , Smith Norah L. , Davenport Miles P. , Tait Wojno Elia D. , Scheible Kristin M. , Grimson Andrew , Rudd Brian D.
Published: February 2022

The immune system is stratified into layers of specialized cells with distinct functions. Recently, Lin28b was shown to serve as a master regulator of fetal lymphopoiesis, programming the development of more innate-like lymphocytes in early life. However, it remains unclear whether Lin28b specifies innate functions in more conventional adaptive lymphocytes. In this report, we discovered that Lin28b promotes the development of a more innate-like lineage of CD8+ T cells that is capable of protecting the host against a wide variety of pathogens in the absence of TCR stimulation. Using RNA-seq and ATAC-seq, we found that Lin28b transcriptionally and epigenetically programs CD8+ T cells to be highly responsive to innate cytokines. We also performed scRNAseq and found that the shift from innate-like CD8+ T cells in early life to adaptive CD8+ T cells in adulthood is mediated by changes in the abundance of distinct subsets of cells. Remarkably, the innate CD8+ T cell subset predominates in early life but is also present in adult mice and humans. Collectively, our findings demonstrate that neonatal CD8+ T cells are a distinct lineage of lymphocytes that provide the host with innate defense in early life.

One sentence Summary

High-dimensional analysis reveals how Lin28b programs neonatal CD8+ T cells for innate defense.
Novel ERR pan-agonists ameliorate heart failure through boosting cardiac fatty acid metabolism and mitochondrial function
Authors: Xu Weiyi , Billon Cyrielle , Li Hui , Hayes Matthew , Yu Keyang , Losby McKenna , Hampton Carissa S. , Adeyemi Christiana M. , Graves Andrea , Nasiotis Eleni , Fu Chen , Welch Ryan , Evans Ronald M. , Pei Liming , Walker John K. , Milosavljevic Aleksandar , Burris Thomas , Zhang Lilei
Published: February 2022

Cardiac metabolic dysfunction is a hallmark of heart failure. Estrogen related receptors ERRα and ERRγ are essential regulators for cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for heart failure. However, no natural or synthetic ERR agonist is available to demonstrate their pharmacological effectin vivo. Using a structure-based design approach, we designed and synthesized two structurally distinct pan-ERR agonists, SLU-PP-332 (332) and SLU-PP-915 (915), which significantly improved ejection fraction and ameliorated fibrosis against pressure overload-induced heart failure without affecting cardiac hypertrophy. Mechanistically, a broad-spectrum of metabolic genes were transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function, which were mainly mediated by ERRγ. Metabolomics analysis showed significant normalization of metabolic profiles in fatty acid/lipid and TCA/OXPHOS metabolites by 915 in the mouse heart with 6-week pressure overload. Autophagy was also induced by ERR agonists in cardiomycoyte. On the other hand, ERR agonism led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocyte. In summary, ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced heart failurein vivo. Our results provided direct pharmacological evidence supporting the further development of ERR agonists as novel heart failure therapeuticsin vivo.
Hoisted with his own petard: how sex-ratio meiotic drive in Drosophila affinis creates resistance alleles that limit its spread
Authors: Ma Wen-Juan , Knoles Emma M. , Patch Kistie B. , Shoaib Murtaza M. , Unckless Robert L.
Published: February 2022

Meiotic drivers are selfish genetic elements that tinker with gametogenesis to bias their own transmission into the next generation of offspring. Such tinkering can have significant consequences on gametogenesis and end up hampering the spread of the driver. In Drosophila affinis, sex-ratio meiotic drive is caused by an X-linked complex that, when in males with a susceptible Y chromosome, results in broods that are typically more than 95% female. Interestingly, D. affinis males lacking a Y chromosome (XO) are fertile and males with the meiotic drive X and no Y produce only sons - effectively reversing the sex-ratio effect. Here, we show that meiotic drive dramatically increases the rate of nondisjunction of the Y chromosome (at least 750X), meaning that the driver is creating resistant alleles through the process of driving. We then model how the O might influence the spread, dynamics and equilibrium of the sex-ratio X chromosome. We find that the O can prevent the spread or reduce the equilibrium frequency of the sex-ratio X chromosome and it can even lead to oscillations in frequency. Finally, with reasonable parameters, the O is unlikely to lead to the loss of the Y chromosome, but we discuss how it might lead to sex-chromosome turnover indirectly.
ScRNA-seq Identified the Metabolic Reprogramming of Human Colonic Immune Cells in Different Locations and Disease States
Authors: Zhao Qiuchen , Zhang Tong , Yang Hao
Published: February 2022

Different regions and states of the human colon are likely to have a distinct influence on immune cell functions. Here we studied the immunometabolic mechanisms for the spatial immune specialization and the dysregulated immune response during ulcerative colitis at single-cell resolution. We revealed that the macrophages and CD8+ T cells in the lamina propria (LP) of the human colon possessed an effector phenotype and were more activated, while their lipid metabolism was suppressed compared with those in the epithelial (Epi). Also, IgA+ plasma cells accumulated in lamina propria of the sigmoid colon were identified to be more metabolically activated versus those in the cecum and transverse colon, and the improved metabolic activity was correlated with the expression of CD27. In addition to the immunometabolic reprogramming caused by spatial localization colon, we found dysregulated cellular metabolism was related to the impaired immune functions of macrophages, dendritic cells, regulatory T cells, and ILCs in patients with ulcerative colitis. The cluster of OSM+ inflammatory monocytes was also identified to play its role in resistance to anti-TNF treatment, and we explored targeted metabolic reactions that could reprogram them to a normal state. Altogether, this study revealed a landscape of metabolic reprogramming of human colonic immune cells in different locations and disease states, and offered new insights into treating ulcerative colitis by immunometabolic modulation.
Functional and effective connectivity between dorsolateral prefrontal and subgenual anterior cingulate cortex depends on the timing of transcranial magnetic stimulation relative to the phase of prefrontal alpha EEG
Authors: Pantazatos Spiro P. , Mclntosh James R. , Saber Golbarg T. , Sun Xiaoxiao , Doose Jayce , Faller Josef , Lin Yida , Teves Joshua B. , Blankenship Aidan , Huffman Sarah , Goldman Robin I. , George Mark S. , Sajda Paul , Brown Truman R.
Published: February 2022

BACKGROUND

The communication through coherence model posits that brain rhythms are synchronized across different frequency bands and that effective connectivity strength between interacting regions depends on their phase relation. Evidence to support the model comes mostly from electrophysiological recordings in animals while evidence from human data is limited.

METHODS

Here, an fMRI-EEG-TMS (fET) instrument capable of acquiring simultaneous fMRI and EEG during noninvasive single pulse TMS applied to dorsolateral prefrontal cortex (DLPFC) was used to test whether prefrontal EEG alpha phase moderates TMS-evoked top-down influences on subgenual, rostral and dorsal anterior cingulate cortex (ACC). Results in healthy volunteers (n=11) were compared to those from patients with major depressive disorder (MDD) (n=17) collected as part of a ongoing clinical trial investigation.

RESULTS

In both groups, TMS-evoked functional connectivity between DLPFC and subgenual ACC (sgACC) depended on the EEG alpha phase. TMS-evoked DLPFC to sgACC effective connectivity (EC) was moderated by EEG alpha phase in healthy volunteers, but not in the MDD patients. Top-down EC was inhibitory for TMS onsets during the upward slope of the alpha wave relative to TMS timed to the downward slope of the alpha wave. Prefrontal EEG alpha phase dependent effects on TMS-evoked fMRI BOLD activation of the rostral anterior cingulate cortex were detected in the MDD patient group, but not in the healthy volunteer group.

DISCUSSION

Results demonstrate that TMS-evoked top-down influences vary as a function of the prefrontal alpha rhythm, and suggest clinical applications whereby TMS is synchronized to the brain’s internal rhythms in order to more efficiently engage deep therapeutic targets.
Validation of the RT-LAMP assay in a large cohort of nasopharyngeal swab samples shows that it is a useful screening method for detecting SARS-CoV-2 and its VOC variants
Authors: Cisneros-Villanueva Mireya , Blancas Sugela , Cedro-Tanda Alberto , Ríos-Romero Magdalena , Hurtado-Córdova Eduardo , Almaraz-Rojas Oscar , Ortiz-Soriano Diana R. , Álvarez-Hernández Víctor , Arriaga-Guzmán Ivonne E. , Tolentino-García Laura , Sánchez-Vizcarra Antonia , Lozada-Rodríguez Laura F. , Peralta-Arrieta Irlanda , Pérez-Aquino José E. , Andonegui-Elguera Marco A. , Cendejas-Orozco Mariana , Mendoza-Vargas Alfredo , Reyes-Grajeda Juan P. , Campos-Romero Abraham , Alcantar-Fernández Jonathan , Luis Moreno-Camacho José , Gallegos-Rodriguez Jorge , Esparza-Luna-Ruiz Marco , Ortiz-Ramirez Jesus , Gonzalez Mariana Benitez , Uribe-Figueroa Laura , Ruiz Rosaura , Angulo Ofelia , Herrera Luis A. , Hidalgo-Miranda Alfredo
Published: February 2022

The COVID-19 pandemic is challenging the global supply chain and equipment needed for mass testing with RT-qPCR, the gold standard for SARS-CoV-2 diagnosis. Here, we propose the RT-LAMP assay as an additional strategy for rapid virus diagnosis. However, its validation as a diagnostic method remains uncertain. In this work, we validated the RT-LAMP assay in 1,266 nasopharyngeal swab samples with confirmed diagnosis by CDC 2019-nCoV RT-qPCR. Our cohort was divided, the first (n=984) was used to evaluate two sets of oligonucleotides (S1 and S3) and the second (n=281) to determine whether RT-LAMP could detect samples with several types of variants. This assay can identify positive samples by color change or fluorescence within 40 minutes and shows high concordance with RT-qPCR in samples with CT ≤35. Also, S1 and S3 are able to detect SARS-CoV-2 with a sensitivity of 68.4% and 65.8%, and a specificity of 98.9% and 97.1%, respectively. Furthermore, RT-LAMP assay identified 279 sequenced samples as positive (99.3% sensitivity) corresponding to the Alpha, Beta, Gamma, Delta, Epsilon, Iota, Kappa, Lambda, Mu and Omicron variants. In conclusion, RT-LAMP is able to identify SARS-CoV-2 with good sensitivity and excellent specificity, including all VOC, VOI, VUM and FMV variants.
Sequential increase of PHGDH expression with Alzheimer’s pathology and symptoms
Authors: Chen Xu , Calandrelli Riccardo , Girardini John , Yan Zhangming , Tan Zhiqun , Xu Xiangmin , Hiniker Annie , Zhong Sheng
Published: February 2022

We report consistent increases in phosphoglycerate dehydrogenase (PHGDH) expression in mouse models of Alzheimer’s disease (AD) (3xTg-AD) and related tauopathy (PS19), particularly in hippocampal astrocytes. Human single-cell RNA-sequencing data reveal a sequential increase of PHGDH expression in people with no, early, and late AD pathology, which is corroborated by protein mass spectrometry and immunohistochemical analyses of three independent cohorts. A sequential increase of PHGDH expression also correlates with increasing clinical AD symptoms and worsening cognitive decline in patients. The consistent increase of PHGDH expression in six AD cohorts (Mayo, ROSMAP, Mount Sinai, Baltimore, Amsterdam, and UCSD/UCI) corroborates with the recent report of PHGDH extracellular RNA in blood plasma as a candidate biomarker for early diagnosis of AD and offers a caution to the suggested use of L-serine as a potential therapy of AD.
Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation
Authors: Petrauskas Arnas , Fortunati Daniel L. , Singh Amanjot , Kandi Arvind Reddy , Pothapragada Sai Shruti , Agrawal Khushboo , Huelsmeier Joern , Hillebrand Jens , Brown Georgia , Chaturvedi Dhananjay , Lee Jongbo , Lim Chunghun , Auburger Georg , VijayRaghavan K. , Ramaswami Mani , Bakthavachalu Baskar
Published: February 2022

Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments onDrosophilaand human Ataxin-2 proteins. Results of Targets of RNA-Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Transgenic experiments inDrosophilaindicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.
International spread of emerging multidrug-resistant Rhodococcus equi
Authors: Val-Calvo Jorge , Darcy Jane , Gibbons James , Creighton Alan , Egan Claire , Buckley Thomas , Schmalenberger Achim , Fogarty Ursula , Scortti Mariela , Vázquez-Boland José A.
Published: February 2022

The recently characterized multidrug-resistant clone of the animal and human zoonotic pathogen Rhodococcus equi, MDR-RE 2287, has been circulating among horse farms in the United States (US) since the early 2000’s. Here, we report the first documented detection of the MDR-RE 2287 clone outside the US. The finding highlights the risk of MDR-RE spreading internationally with the movement of horses.
Contribution of individual excitatory synapses on dendritic spines to electrical signalling
Authors: Weng Ju-Yun , Ceballos Cesar , Zecevic Dejan
Published: February 2022

Dendritic spines, small (∼1 µm) membrane protrusions from neuronal dendrites which receive most of the excitatory synaptic inputs in the mammalian brain, are widely considered the elementary computational units of the brain. Our understanding of electrical signalling in spines is currently being debated, primarily for methodological reasons. We combined the standard techniques of whole-cell recording and voltage imaging methods to study excitatory postsynaptic potentials evoked by two-photon glutamate uncaging (uEPSPs) on individual dendritic spines on basal dendrites in rat cortical slices. We analyzed the initiation, temporal summation, and propagation of uEPSPs from the spine head to the parent dendrites in three principal neocortical pyramidal neuron classes. Our measurements show no significant attenuation of uEPSPs across the spine neck in most tested mushroom spines on basal dendrites. This result implies that spine synapses are not electrically isolated from parent dendrites and that these spines do not serve a meaningful electrical role. Using the same high-sensitivity voltage imaging techniques, we characterized the temporal summation of uEPSPs induced by repetitive glutamate uncaging mimicking burst activity of presynaptic neurons. We found that responses to high-frequency repetitive quantal EPSPs are strictly limited in amplitude and waveform. This finding reveals a biophysical mechanism for preventing synaptic saturation.

Significance Statement

We used an electrochromic voltage-sensitive dye, which acts as a transmembrane optical voltmeter, to define the electrical role of dendritic spines, small membrane protrusions that receive most of the excitatory synaptic inputs in the brain. The data argue that investigated spine synapses of principal neurons are not electrically isolated from the parent dendrites. We also found that the amplitude of temporal uEPSP summation during repetitive synaptic activation is restricted at the site of origin, preventing synaptic saturation. These results facilitate our understanding of how a complex assembly of receptors and ion channels in spines generates and processes electrical signals and mediate plasticity in response to the quantal release of chemical transmitters caused by patterned activity in presynaptic axons.