bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost saving in primary versus tertiary level of reproductive health services in Sana’a, Yemen
Authors: Nassar Abdulkareem Ali Hussein , Raja’a Yahia Ahmed , Bahubaishi Najia Saleh
Published: August 2021

Introduction

In Yemen, women tend to bypass the nearby primary health level facilities (PHLF) for using vaginal delivery (VD), antenatal care (ANC) and intrauterine device (IUD) services. This study aimed to estimate the cost saving for utilization of VD, ANC and IUD services at PHLF instead of tertiary health level facilities (THLF) in Sana’a.

Methods

A comparative cross sectional study design was conducted in 2013. It was used to estimate the costs from the patient’s perspective. A structured questionnaire was used to collect data. Descriptive analyses were performed. P value <0.05 was considered as the cut point for significance. The SPSS version 17 was used.

Results

A total of 180 women were found. The median of DMC of VD, ANC and IUD services were US$43.9, US$14.8 and US$9.1 at THLF compared with US$19.5, US$0.9 and US$11.2 at PHLF, respectively. The DMC difference of VD, ANC and IUD services between THLF and PHLF was US$24.4, US$13.9 and US$-2.1, respectively. Regarding the DNMC, the median of VD, ANC and IUD services were US$43.1, US$19.1 and US$17.3 at THLF compared with US$14.0, US$0.0 and US$0.0 at PHLF, respectively. The DNMC difference of VD, ANC and IUD service between THLF and PHLF was US$29.1, US$19.1 and US$17.3, respectively. Moreover, the median of INDC for VD, ANC and IUD services were US$23.9, US$9.5 and US$10.4 at THLF compared with US$7.9, US$1.6 and US$1.1 at PHLF, respectively. The INDC difference of VD, ANC and IUD service between THLF and PHLF was US$16.0, US$7.9 and US$9.3.

Conclusion

The study found the utilization of VD, ANC and IUD services at PHLF instead of THLF is a considerable cost saving for families. Therefore, shifting the utilization of services from THLF to PHLF reduces the financial burden affecting individuals, families and their productivity. Implementation of the health referral system is recommended.

Key questions

What is already known?

➢

Women tend remarkably to bypass the nearby primary reproductive health services that are rising the expenses and increasing the burden borne by individuals, families and their productivity.

➢

Few studies have estimated the cost saving for utilization of primary instead tertiary level of reproductive health services in the world, while no such study was conducted in Yemen.

What are the new findings?

➢

A significant difference in the expenses on reproductive health services between the primary and tertiary health level facilities.

➢

A significant cost is saved for women and families as a result of utilization of primary instead tertiary level of reproductive health services.

What do the new findings imply?

➢

The primary health level facilities reduce the financial burden affecting individuals, families and their productivity.

➢

This study provides evidence for decision-makers to implement the health referral system and protect the families from incurring the high expenditure.
Profile of Mucormycosis Cases from a Network of Hospitals in North India Amidst COVID-19 Pandemic
Authors: Budhiraja Sandeep , Aggarwal Mona , Mahajan Monica , Indrayan Abhaya , Jha Vinita , Mittal Ambrish , Sachdeva Sanjay , Mrig Sumit , Jain Anurag , Gera Ravinder , Aggarwal Rahul , Kalra Suven , Ramalingam WVPS , Deka Anupal , Das Arjun , Jijina D , Mansingh Ajit , Singhal Anuj , Reddi Rajashekhar , Aggarwal Puneet , Kumar Mukesh , Mukherjee JD , Nangia Vivek , Lall Ajay , Singh Omender , Dewan Arun , Jain Ajay , Shrivastava Gita G , Bhattacharjee Mala , Nihalani Meena , Kumar Manoj , Jain Meenakshi , Mehra Mukesh , Arora Vijay , Mehta Viresh Prashant , Bhalla Dilip , Batra Amit , Gupta Rajesh , Kumar Vivek , Dua Sanjeev , Pandey Praveen , Singh Y P , Mathur Mohit , Singh Ashok , Arora Sanjeev , Gupta Ajay Kumar , Choudhary Pankaj Nand , Singh Manoj , Kaul Namita , Pathak Sitla Prasad , Joshi Sharad , Gupta Manish , Mishra Rajesh , Joshi Alok , Aggarwal Manoj , Gupta Rajiv , Boobna Vandana , Chhabra Yogesh Kumar , Chugh Inder Mohan , Garg Sandeep , Mittal Vikas , Sood Neha , Kumar Anil , Pande Rajesh Kumar , Singh V P , Khan Iram , Garg Nitin , Tyagi Puneet , Belwal Shantanu , Roy Anup Kumar , Bhasin Deepak , Pandove Sachin , Bahl Ravikant , Soni Prateek
Published: August 2021

Incidence of mucormycosis suddenly surged in India after the second wave of COVID-19. This is a crippling disease and needs to be studied in detail to understand the disease, its course, and the outcomes.

Between 1st March and 15th July 2021, our network of hospitals in North India received a total of 155 cases of COVID-associated mucormycosis cases as all of them reported affliction by COVID-19 earlier or concurrent. Their records were retrieved from the Electronic Health Records system of the hospitals and their demographics, clinical features, treatments, and outcomes were studied. More than 80% (125 cases) had proven disease and the remaining 30 were categorized as ‘possible’ mucormycosis as per the EORTC criteria.

More than two-thirds (69.0%) of the cases were males and the mean age was 53 years for either sex. Nearly two-thirds (64.5%) had symptoms of nose and jaws and 42.6% had eye involvement. Some had multiple symptoms. As many as 78.7% had diabetes and 91.6% gave history of use of steroids during COVID-19 treatment. The primary surgery was functional endoscopic sinus surgery (FESS) (83.9%). Overall mortality was 16.8%, which is one-and-a-half times the mortality in hospitalized COVID-19 patients in the corresponding population. Occurrence of mucormycosis was associated with diabetes and use of steroids, but mortality was not associated with either of them. Cases undergoing surgery and on antifungal had steeply lower mortality (11.9% vs. 50.0%, P < 0.001) than those who were exclusively on antifungal drugs. Treatment by different drugs did not make much of a difference in mortality.
Behavioral and neural dissociation of social anxiety and loneliness
Authors: Lieberz Jana , Shamay-Tsoory Simone G. , Saporta Nira , Kanterman Alisa , Gorni Jessica , Esser Timo , Kuskova Ekaterina , Schultz Johannes , Hurlemann René , Scheele Dirk
Published: August 2021

Background

Loneliness is a public health concern with detrimental effects on physical and mental well-being. Given phenotypical overlaps between loneliness and social anxiety, cognitive behavioral interventions targeting social anxiety might be adopted to reduce loneliness. However, it is still elusive whether social anxiety and loneliness share the same underlying neurocognitive mechanisms. The current study aimed at investigating to what extent known behavioral and neural correlates of social avoidance in social anxiety are evident in loneliness.

Methods

We used a pre-stratified approach involving 42 participants with high and 40 control participants with low loneliness scores. During functional magnetic resonance imaging, the participants completed a social gambling task to measure the subjective value of engaging in a social situation and responses to positive and negative social feedback.

Results

Uni- and multivariate analyses of behavioral and neural data replicated known task effects across groups. However, although lonely participants were characterized by increased social anxiety, loneliness was associated with a response pattern clearly distinct from social anxiety. Specifically, Bayesian analyses revealed moderate evidence for equal subjective values of engaging in social situations and comparable amygdala responses to social decision-making and striatal responses to positive social feedback in both groups. Conversely, lonely participants showed significantly altered behavioral responsiveness to negative feedback and reduced striatal activity, whereas striatal-hippocampal connectivity was increased compared to controls.

Conclusion

Our findings suggest that loneliness is associated with altered emotional reactivity to social situations rather than behavioral tendencies to withdraw from social interactions. Thus, established interventions for social anxiety should be adjusted when targeting loneliness.
Father absence and trajectories of offspring mental health across adolescence and young adulthood: findings from a UK-birth cohort
Authors: Culpin Iryna , Heuvelman Hein , Rai Dheeraj , Pearson Rebecca M , Joinson Carol , Heron Jon , Evans Jonathan , Kwong Alex S F
Published: August 2021

Background

High prevalence of parental separation and resulting biological father absence raises important questions regarding its impact on offspring mental health across the life course. However, few studies have examined prospective associations between biological father absence in childhood and risk of offspring depression and depressive symptoms trajectories across adolescence and young adulthood. We specifically examined whether these relationships vary by sex and the timing of exposure to father absence (early or middle childhood).

Methods

This study is based on up to 8,409 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants provided self-reports of depression (Clinical Interview Schedule-Revised) at age 24 years and depressive symptoms (Short Mood and Feelings Questionnaire) between the ages of 10 and 24 years. Biological father absence in childhood was assessed through maternal questionnaires at regular intervals from birth to 10 years. We used logistic regression to examine the association between biological father absence and depression/depressive symptoms at age 24. We estimated the association between biological father absence and trajectories of depressive symptoms using multilevel growth-curve modelling.

Results

Early but not middle childhood father absence was strongly associated with increased odds of offspring depression and greater depressive symptoms at age 24 years. Early childhood father absence was associated with higher trajectories of depressive symptoms during adolescence and early adulthood compared with father presence. Differences in the level of depressive symptoms between middle childhood father absent and father present groups narrowed into early adulthood. Girls whose father was absent in early childhood, compared with present, manifested higher levels of depressive symptoms throughout adolescence, but this difference narrowed by early adulthood. In contrast, boys who experienced father absence in early childhood had similar trajectories of depressive symptoms compared to the father present group but experienced a steep increase in early adulthood. Girls whose fathers were absent in middle childhood manifested higher trajectories across middle adolescence into young adulthood compared to the father present group.

Conclusions

We found evidence that father absence in childhood is persistently associated with offspring depression in adolescence and early adulthood and that this relationship varies by sex and timing of father’s departure. Further research is needed to examine whether this relationship is causal and to identify mechanisms that could inform preventative interventions to reduce the risk of depression in children who experience father absence.
Clinical Evaluation of the Novel Rapid Nucleic Acid Amplification Point-of-Care Test (Smart Gene SARS-CoV-2) in the analysis of Nasopharyngeal and Anterior Nasal samples
Authors: Kiyasu Yoshihiko , Owaku Masato , Akashi Yusaku , Takeuchi Yuto , Narahara Kenji , Mori Sunao , Nagano Takashi , Notake Shigeyuki , Ueda Atsuo , Nakamura Koji , Ishikawa Hiroichi , Suzuki Hiromichi
Published: August 2021

Introduction

Smart Gene is a point-of-care (POC)-type automated molecular testing platform that can be performed with 1 minute of hands-on-time. Smart Gene SARS-CoV-2 is a newly developed Smart Gene molecular assay for the detection of SARS-CoV-2. The analytical and clinical performance of Smart Gene SARS-CoV-2 has not been evaluated.

Methods

Nasopharyngeal and anterior nasal samples were prospectively collected from subjects referred to the local PCR center from March 25 to July 5, 2021. Two swabs were simultaneously obtained for the Smart Gene SARS-CoV-2 assay and the reference real-time RT-PCR assay, and the results of Smart Gene SARS-CoV-2 were compared to the reference real-time RT-PCR assay.

Results

Among a total of 1150 samples, 68 of 791 nasopharyngeal samples and 51 of 359 anterior nasal samples were positive for SARS-CoV-2 in the reference real-time RT-PCR assay. In the testing of nasopharyngeal samples, Smart Gene SARS-CoV-2 showed the total, positive and negative concordance of 99.2% (95% confidence interval [CI]: 98.4–99.7%), 94.1% (95% CI: 85.6–98.4%) and 99.7% (95% CI: 99.0–100%), respectively. For anterior nasal samples, Smart Gene SARS-CoV-2 showed the total, positive and negative concordance of 98.9% (95% CI: 97.2–99.7%), 98.0% (95% CI: 89.6–100%) and 99.0% (95% CI: 97.2–99.8%), respectively. In total, 5 samples were positive in the reference real-time RT-PCR and negative in Smart Gene SARS-CoV-2, whereas 5 samples were negative in the reference real-time RT-PCR and positive in Smart Gene SARS-CoV-2.

Conclusion

Smart Gene SARS-CoV-2 showed sufficient analytical performance for the detection of SARS-CoV-2 in nasopharyngeal and anterior nasal samples.
Willingness and influential factors of parents to vaccinate their children against the COVID-19: a systematic review and meta-analysis
Authors: Galanis Petros , Vraka Irene , Siskou Olga , Konstantakopoulou Olympia , Katsiroumpa Aglaia , Kaitelidou Daphne
Published: August 2021

Background

Coronavirus disease 2019 (COVID-19) vaccine uptake among children will be critical in limiting the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease. Parents are key decision-makers for whether their children will receive a COVID-19 vaccine.

Objective

To estimate parents’ willingness to vaccinate their children against the COVID-19, and to investigate the predictors for their decision.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines for this systematic review and meta-analysis. We searched Scopus, Web of Science, Medline, PubMed, ProQuest, and CINAHL from inception to August 11, 2021. The review protocol was registered with PROSPERO (CRD42021273125). We applied a random effect model to estimate pooled effects since the heterogeneity was very high. We used subgroup analysis and meta-regression analysis to explore sources of heterogeneity.

Results

We found 17 studies including 45,783 parents. The overall proportion of parents that intend to vaccinate their children against the COVID-19 was 56.8% (95% confidence interval: 51.8-61.8%). Parents’ willingness ranged from 29% to 72.7%. Studies quality, sample size, data collection time, and the continent that studies were conducted did not affect the results. The main predictors of parents’ intention to vaccinate their children against COVID-19 were male gender, older age of parents and children, higher socio-economic status, white race, positive attitudes toward vaccination, higher levels of knowledge, and higher levels of perceived threat from the COVID-19, worry, fear, and anxiety.

Conclusions

Parents’ willingness to vaccinate their children against the COVID-19 is moderate and several factors affect this decision. Understanding parental COVID-19 vaccine hesitancy does help policy makers to change the stereotypes and establish broad community COVID-19 vaccination. Identification of the factors that affect parents’ willingness to vaccinate their children against COVID-19 will provide opportunities to enhance parents trust in the COVID-19 vaccines and optimize children’s uptake of a COVID-19 vaccine.
Novel Electrode Architecture for Subgaleal Electroencephalography: A Feasibility Study
Authors: Ahnood Arman , Truong Nhan Duy , Fleiss Bobbi , Nikpour Armin , Kavehei Omid
Published: August 2021

Abstract

Electroencephalography (EEG) has been widely used to understand the nervous system and as a clinical diagnostic tool. In the case of neurological conditions with intermittent episodes, such as epilepsy, long-term EEG monitoring outside the clinics and in the community setting is vital. Subgaleal EEG (sgEEG) has emerged as an essential tool for long-term monitoring over several years. Current sgEEG solutions share a need for at least a 10 cm long lead wire, resulting in a bulky and invasive device. This work introduces a novel electrode architecture for subgaleal EEG recording, which forgoes the need for lead wires. A back-to-back electrode configuration with an electrode spacing of less than 1 mm is proposed. Compared to the current side-by-side approaches with an electrode spacing of several cm, our proposed approach results in at least one order of magnitude reduction in volume. The efficacy of the proposed electrode architecture is investigated through finite element modeling, phantom measurements, and cadaver studies. Our results suggest that compared to the conventional side-by-side electrode configuration, the source signal can be recorded reliably. Lead wires have posed a significant challenge from a device reliability and measurement quality perspective. Moreover, lead wires and the associated feedthrough connectors are bulky. Our proposed lead-free EEG recording solution may lead to a less invasive surgical placement through volume reduction and improve EEG recording quality.
Comprehensive genetic and functional analysis of FcγRs in rituximab therapy for autoimmunity reveals a key role for FcγRIIIa on NK cells
Authors: Robinson James I , Md Yusof Md Yuzaiful , Davies Vinny , Wild Dawn , Morgan Michael , Taylor John C , El-Sherbiny Yasser , Morris David L , Liu Lu , Rawstron Andy C , Buch Maya H , Plant Darren , Cordell Heather J , Isaacs John D , Bruce Ian N , Emery Paul , Barton Anne , Vyse Timothy J , Barrett Jennifer H , Vital Edward M , Morgan Ann W ,   MASTERPLANS Consortia
Published: August 2021

B cell depletion using rituximab is widely used to treat autoimmune diseases, but patient response varies. The efficacy of rituximab is limited by the efficiency of depletion. Strategies to improve response include altering rituximab dosing, switching anti-CD20-mAb, alternative B cell targets, or non-B cell targeted therapies. Implementing an appropriate strategy requires understanding of the mechanism(s) of resistance to depletion and, if this varies between individuals, a means to test for it. Rituximab kills B cells via a variety of Fcγ receptor (FcγR)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), as well as non-FcγR mechanisms. We conducted a longitudinal cohort study in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) using two national registries. Qualitative and quantitative FCGR functional variants were measured using multiplexed ligation-dependent probe amplification, supplemented by novel FCGR2C assays.

We provide consistent evidence that FCGR3A, specifically increased number of copies of the FCGR3A-158V allele, was the major FcγR gene associated with rituximab response, including clinical response in RA and SLE and depth of B cell depletion in the combined cohort. In SLE, we provide preliminary data suggesting increased FCGR2C ORF copies were also associated with improved clinical response. Furthermore, we demonstrated the impact of disease status and concomitant therapies on both natural killer cell FcγRIIIa expression and rituximab-induced ADCC; demonstrating increased FcγRIIIa expression and FCGR3A genotype were independently associated with clinical response and B cell depletion. Our findings highlight the importance of enhancing FcγR-effector functions, may help stratify patients, and support ongoing development of next-generation CD20 depleting therapeutics.

One Sentence Summary

The high affinity FcγRIIIa allotype on NK cells explains depth of B cell depletion and clinical response in rituximab therapy for autoimmune disease
Imputing cognitive impairment in SPARK, a large autism cohort
Authors: Shu Chang , Snyder LeeAnne Green , Shen Yufeng , Chung Wendy K.
Published: August 2021

Background

Diverse large cohorts are necessary for dissecting subtypes of autism, and intellectual disability is one of the most robust endophenotypes for analysis. However, current cognitive assessment methods are not feasible at scale.

Methods

We developed five commonly used machine learning models to predict cognitive impairment (FSIQ<80 and FSIQ<70) and FSIQ scores among 521 children with autism using parent-reported online surveys in SPARK, and evaluated them in an independent set (n=1346) with a missing data rate up to 70%. We assessed accuracy, sensitivity and specificity by comparing predicted cognitive level against clinical IQ data.

Results

The elastic-net model has good performance (AUC=0.876, sensitivity=0.772, specificity=0.803) using 129 predictive features to impute cognitive impairment (FSIQ<80). Top ranked predictive features included parent-reported language and cognitive levels, age at autism diagnosis, and history of services. Prediction of FSIQ<70 and FSIQ scores also showed good prediction performance.

Conclusions

We show cognitive levels can be imputed with high accuracy for children with autism, using commonly collected parent-reported data and standardized surveys. The current model offers a method for large scale autism studies seeking estimates of cognitive ability when standardized psychometric testing is not feasible.

Lay summary

Children with autism who have more severe learning challenges or cognitive impairment have different needs that are important to consider in research studies. When children in our study were missing standardized cognitive testing scores, we were able to use machine learning with other information to correctly “guess” when they have cognitive impairment about 80% of the time. We can use this information in research in the future to develop more appropriate treatments for children with autism and cognitive impairment.
Causal and Associational Language in Observational Health Research: A systematic evaluation
Authors: Haber Noah A. , Wieten Sarah E. , Rohrer Julia M. , Arah Onyebuchi A. , Tennant Peter W.G. , Stuart Elizabeth A. , Murray Eleanor J. , Pilleron Sophie , Lam Sze Tung , Riederer Emily , Howcutt Sarah Jane , Simmons Alison E. , Leyrat Clémence , Schoenegger Philipp , Booman Anna , Dufour Mi-Suk Kang , O’Donoghue Ashley L. , Baglini Rebekah , Do Stefanie , Rosa Takashima Mari De La , Evans Thomas Rhys , Rodriguez-Molina Daloha , Alsalti Taym M. , Dunleavy Daniel J. , Meyerowitz-Katz Gideon , Antonietti Alberto , Calvache Jose A. , Kelson Mark J. , Salvia Meg G. , Parra Camila Olarte , Khalatbari-Soltani Saman , McLinden Taylor , Chatton Arthur , Seiler Jessie , Steriu Andreea , Alshihayb Talal S. , Twardowski Sarah E. , Dabravolskaj Julia , Au Eric , Hoopsick Rachel A. , Suresh Shashank , Judd Nicholas , Peña Sebastián , Axfors Cathrine , Khan Palwasha , Aguirre Ariadne E. Rivera , Odo Nnaemeka U. , Schmid Ian , Fox Matthew P.
Published: August 2021

We estimated the degree to which language used in the high profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality.

We searched and screened for 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, three reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations.

Reviewers rated the causal implication of exposure/outcome linking language as None (no causal implication) in 13.8%, Weak 34.2%, Moderate 33.2%, and Strong 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was “associate” (45.7%). Reviewer’s ratings of linking word roots were highly heterogeneous; over half of reviewers rated “association” as having at least some causal implication.

This research undercuts the assumption that avoiding “causal” words leads to clarity of interpretation in medical research.
Temporal Trends in Racial and Ethnic Disparities in Multimorbidity Prevalence in the United States, 1999–2018
Authors: Caraballo César , Mahajan Shiwani , Massey Daisy , Lu Yuan , Ndumele Chima D. , Drye Elizabeth E. , Herrin Jeph , Krumholz Harlan M.
Published: August 2021

Background

Disparities in multimorbidity prevalence indicate health inequalities. This study sought to determine if gaps in multimorbidity prevalence by race and ethnicity are decreasing over time.

Methods and findings

Serial cross-sectional analysis of the National Health Interview Survey from years 1999 to 2018. The study included individuals ≥18 years old, categorized by self-reported race, ethnicity, age, and income. The main outcomes were temporal trends in multimorbidity prevalence based on the self-reported presence of ≥2 of 9 chronic conditions. The study sample included 596,355 individuals (4.7% Asian, 11.8% Black, 13.8% Latino/Hispanic, and 69.7% White). In 1999, the estimated prevalence of multimorbidity was 5.9% among Asian, 17.4% among Black, 10.7% among Latino/Hispanic, and 13.5% among White individuals. Prevalence increased for all racial/ethnic groups during the study period (P<0.005 for each), with no significant change in the differences between them. In 2018, when compared with White people, multimorbidity was more prevalent among Black individuals (+2.5 percent points [95% CI: +0.5, +4.6]) and less prevalent among Asian and Latino individuals (−6.6 points [-8.8, -4.4] and -2.1 points [-4.0, -0.2], respectively). The estimated prevalence of reporting at least 1, 2, 3, or 4 conditions all increased with age across all groups, with Black individuals having the greatest prevalence in each age category. Among those aged ≥30 years, Black people had multimorbidity rates equivalent to those of Latino/Hispanic and White people aged 5 years older, and Asian people aged 10 years older. Notably, the prevalence of multimorbidity diverged between Black people and White people among those aged 30 years, reached its maximum difference of 10.1 percentage points (95% CI: 8.2, 12.1) among those aged 60, and converged to reach similar rates among those aged ≥80.

Conclusions

From 1999 to 2018, a period of increasing multimorbidity prevalence for all the groups studied, there has not been any significant progress in eliminating disparities between Black and White people. The disparity began among young adults. Public health interventions that prevent the onset of chronic conditions in early life may be needed to eliminate these disparities.
The indoleamine 2,3 dioxygenase pathway drives intratumoral B cell maintenance
Authors: Johnson Burles A. , Aragaki Adam K. , Williams Donna M. , Rogers Ophelia , Mountain Jack , Luo Li , Zhang Wenhao , Xian Lingling , Feng Mingxiao , Chia Lionel , Dordai Dominic , Hahn Noah M. , Desiderio Stephen , Johnson Theodore S. , McConkey David J. , Resar Linda M.S.
Published: August 2021

B cells have been implicated as central regulators of immune responses in settings as diverse as mammalian pregnancy, mucosal tolerance, chronic infection states, autoimmunity, and the tumor microenvironment. Despite the established importance of B cells in these environments, the mechanisms by which B cells are maintained in these contexts remain undefined. Here, we report that IDO1 pathway inhibition with D-1-methyl-tryptophan (D-1MT) and linrodostat significantly decreases tumor infiltrating B (TIL-B) cells in a preclinical model of melanoma. Single cell RNA sequencing (scRNAseq) of murine melanoma demonstrate TIL-B cells are heterogeneous but primarily express markers consistent with an immune stimulatory phenotype. D-1MT decreases splenic B cells and bone marrow derived B cell precursors in tumor-bearing mice, suggesting that IDO1 pathway inhibition impedes B cell maturation. D-1MT decreases intratumoral myeloid derived suppressor cells (MDSCs), which are essential for maintenance of TIL-B cells. Unlike D-1MT, genetic deletion of tumor Ido1 does not impact TIL-B or MDSC numbers. In human solid tumors, intratumoral IDO1 expression consistently associates with high expression of a pan-B cell gene signature, and in patients with melanoma, scRNAseq analysis of tumor samples revealed most TIL-B cells express IDO1. Collectively, our data reveal the impact of pharmacologic IDO1 inhibition on B cells, which may have therapeutic implications for patients with solid tumors by informing the design of future oncology clinical trials.
M-CAMP™: A cloud-based web platform with a novel approach for species-level classification of 16S rRNA microbiome sequences
Authors: Schriefer Andrew E. , Kumar Brajendra , Zolti Avihai , Preetam R , Didier Adam , Nirmal MG , Nadiv Nofar , Perez Michael , Mahankuda Santosh Kumar , Kumar Pankaj , Greeshma G T , Tenney Aaron , Bourner Maureen , Lezer Shira , Zhong Fei , Daniely Michal , Liu Yang
Published: August 2021

The M-CAMP™ (Microbiome Computational Analysis for Multiomic Profiling) Cloud Platform was designed to provide users with an easy-to-use web interface to access best in class microbiome analysis tools. This interface allows bench scientists to conduct bioinformatic analysis on their samples and then download publication-ready graphics and reports. The core pipeline of the platform is the 16S-seq taxonomic classification algorithm which provides species-level classification of Illumina 16s sequencing. This algorithm uses a novel approach combining alignment and kmer based taxonomic classification methodologies to produce a highly accurate and comprehensive profile. Additionally, a comprehensive proprietary database combining reference sequences from multiple sources was curated and contains 18056 unique V3-V4 sequences covering 11527 species. The M-CAMP™ 16S taxonomic classification algorithm was validated on 52 sequencing samples from both public and in-house standard sample mixtures with known fractions. Compared to current popular public classification algorithms, our classification algorithm provides the most accurate species-level classification of 16S rRNA sequencing data.
Adduction Induces Large Optic Nerve Head Deformations in Subjects with Normal Tension Glaucoma
Authors: Chuangsuwanich Thanadet , Tun Tin A. , Braeu Fabian A. , Wang Xiaofei , Chin Zhi Yun , Panda Satish K. , Buist Martin , Milea Dan , Strouthidis Nicholas , Perera Shamira A. , Nongpiur Monisha E. , Aung Tin , Girard Michael JA
Published: August 2021

Purpose: To assess optic nerve head (ONH) deformations and strains during adduction, abduction, and intraocular pressure (IOP) elevation in subjects with high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). Design: Clinic-based cross-sectional study. Participants: 114 HTG subjects and 114 NTG subjects. Methods. We recruited 228 subjects (114 subjects with HTG [pre-treatment IOP > 21mmHg] and 114 with NTG [pre-treatment IOP < 21mmHg]). For each subject, we imaged the ONH using spectral-domain optical coherence tomography (OCT) under the following conditions: (1) primary gaze, (2) 20 degree adduction, (3) 20 degree abduction, and (4) primary gaze with acute IOP elevation (to approximately 33 mmHg) achieved through ophthalmodynamometry. For each OCT volume, we automatically segmented the prelaminar tissue (PLT), the choroid, the sclera and the lamina cribrosa (LC) using a deep learning algorithm. We also digitally aligned the OCT volumes obtained from (2)-(4) to the primary gaze volume (1) before performing digital volume correlation (DVC) analysis to quantify IOP- and gaze-induced ONH tissues three-dimensional displacements and effective strain (a local measure of tissue deformation) for all scenarios. Main Outcome Measures: Three-dimensional ONH displacements and strains. Results: Across all subjects, adduction generated high effective strain (4.2 ± 1.4%) in the ONH tissues with no significant difference (p>0.05) with those induced by IOP elevation (4.5 ± 1.5%); while abduction generated significantly lower (p = 0.014) effective strain (3.8 ± 1.1%). Interestingly, the LC of HTG subjects exhibited significantly higher effective strain than those of NTG subjects under IOP elevation (HTG:4.6 ± 1.7% vs NTG:4.1 ± 1.5%, p = 0.047). Conversely, the LC tissue of NTG subjects exhibited significantly higher effective strain than those of HTG subjects under adduction (NTG: 4.9 ± 1.9% vs HTG: 4.0 ± 1.4%, p = 0.041). Conclusion: We found that adduction produced comparable strains and displacements as IOP elevation. We also found that NTG subjects experienced higher strains due to adduction than HTG subjects, while HTG subjects experienced higher strain due to IOP elevation than NTG subjects - and that these differences were most pronounced in the LC tissue.
Signaling and transcriptional networks governing late synovial joint development
Authors: Bian Qin , Cheng Yu-Hao , Su Emily Y. , Tan Yuqi , Kim Dong Won , Wang Hong , Yoo Sooyeon , Blackshaw Seth , Cahan Patrick
Published: August 2021

Background

During synovial joint development, cavitation marks the end of the emergence of new cell types and the onset of the consolidation of cell type specific programs. However, the transcriptional programs that regulate this crucial stage prior to joint maturation are incompletely characterized. Gdf5-lineage cells give rise to the majority of joint constituents such as articular cartilage, meniscus, ligament, and tendon. Therefore, to explore pre-maturation of the synovial joint, we performed single cell RNA-Seq analysis of 1,306 Gdf5-lineage cells from the murine knee joint at E17.5.

Results

Using computational analytics and in situ hybridization, we identified nine sub-states contributing to articular cartilage, meniscus, cruciate ligament, synovium, lining, and surrounding fibrous tissue. We identified a common progenitor population that is predicted to give rise to ligamentaocytes, articular chondrocytes, and lining cells. We further found that while a large number of signaling pathways orchestrate the differentiation of this progenitor to either ligamentocytes or to lining cells, only continued FGF signaling guides these cells to a default chondrocyte fate.

Conclusions

Our single cell transcriptional atlas is a resource that can be used to better understand and further study synovial joint development and the reactivation of embryonic programs in diseases such as osteoarthritis.
Oxo-M and 4-PPBP Delivery via Multi-Domain Peptide Hydrogel Toward Tendon Regeneration
Authors: Park Ga Young , Tarafder Solaiman , Lewis Samantha , Park Soomin , Park Ryunhyung , Siddiqui Zain , Kumar Vivek , Lee Chang H.
Published: August 2021

We have recently identified novel small molecules, Oxo-M and 4-PPBP, which specifically stimulates endogenous tendon stem/progenitor cells (TSCs) leading to potential regenerative healing of fully-transected tendons. Here we investigated an injectable, multi-domain peptide (MDP) hydrogel providing a controlled delivery of the small molecules for regenerative tendon healing. We investigated the release kinetics of Oxo-M and 4-PPBP from MDP hydrogels and the effect of MDP-released small molecules on tenogenic differentiation of TSCs and in vivo tendon healing. In vitro, MDP showed a sustained release of Oxo-M and 4-PPBP and a slower degradation compared to fibrin. In addition, tenogenic gene expression was significantly increased in TSC with MDP-released Oxo-M and 4-PPBP as compared to the fibrin-released. In vivo, MDP releasing Oxo-M and 4-PPBP significantly improved tendon healing, likely associated with prolonged effects of Oxo-M and 4-PPBP on suppression of M1 macrophages and promotion of M2 macrophages. Comprehensive analyses including histomorphology, digital image processing, and modulus mapping with nanoindentation consistently suggested that Oxo-M and 4-PPBP delivered via MDP further improved tendon healing as compared to fibrin-based delivery. In conclusion, MDP delivered with Oxo-M and 4-PPBP may serve as an efficient regenerative therapeutic for in situ tendon regeneration and healing.
Optical mini-stroke of thalamic networks impairs sleep stability, topography and cognition
Authors: Lenzi I , Borsa M , Czekus C , Rusterholz T , Bassetti C. L. , Gutierrez Herrera C
Published: August 2021

Modelling stroke in animals remains a challenge for translational research, especially for the infraction of small subcortical arteries. Using combined fibre optics and photothrombosis technologies, we developed a novel model of optically-induced infarcts (Opto-STROKE). Combining our model with electrophysiological recordings in freely-behaving mice, we studied early and late consequent patho-physiological changes in the dynamics of sleep-wake circuits and cognitive performance. Here, focusing on inducing Opto-STROKE lesions in the intralaminar thalamus (IL), which in humans cause severe impairments of arousal, cognition, and affective symptoms, our model recapitulated important deficits on sleep disorders presented in humans including arousal instability, concurrent to an augmented slow-wave activity and a reduction gamma power bands during wakefulness. Moreover, during NREM sleep, spindle density was decreased and topographically shifted to frontal cortices when compared to control animals. Remarkably, gamma power and spindle density were correlated with decreased pain threshold and impaired prefrontal cortex-dependent working memory in Opto-STROKE mice relative to controls. Collectively, our combined method influences both anatomical and functional outcomes of the classical stroke procedures and offers new insights on the fundamental role of the media thalamus as a hub for the regulation of both sleep-wake architecture and cognition.
Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct
Authors: Li Zhenzhou , McConnell Heather L. , Stackhouse Teresa L. , Pike Martin M. , Zhang Wenri , Mishra Anusha
Published: August 2021

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by ∼75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-HETE, either by inhibiting its synthetic enzyme CYP450 ω-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of ω-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of EP4 receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of ω-hydroxylases normalized 20-HETE levelsin vivoand increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying neurovascular coupling impairment after stroke. Our results suggest that the brain’s energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that ω-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.
Reorganizations of latency structure within white matter from wakefulness to sleep
Authors: Guo Bin , Zhou Fugen , Zou Guangyuan , Jiang Jun , Zou Qihong , Gao Jiahong
Published: August 2021

Previous studies based on resting-state fMRI (rsfMRI) data have revealed the existence of highly reproducible latency structure, reflecting the propagation of BOLD fMRI signals, in white matter (WM). Here, based on simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data collected from 35 healthy subjects who were instructed to sleep, we explored the alterations of propagations in WM across wakefulness and nonrapid eye movement (NREM) sleep stages. Lagged cross-covariance was computed among voxel-wise time series, followed by parabolic interpolation to determine the actual latency value in-between. In WM, regions including cerebellar peduncle, internal capsule, posterior thalamic radiation, genu of corpus callosum, and corona radiata, were found to change their temporal roles drastically, as revealed by applying linear mixed-effect model on voxel-wise latency projections across wakefulness and NREM sleep stages. Using these regions as seeds, further seed-based latency analysis revealed that variations of latency projections across different stages were underlain by inconsistent temporal shifts between each seed and the remaining part of WM. Finally, latency analysis on resting-state networks (RSNs), obtained by applying k-means clustering technique on group-level functional connectivity matrix, identified a path of signal propagations similar to previous findings in EEG during wakefulness, which propagated mainly from the brainstem upward to internal capsule and further to corona radiata. This path showed inter-RSN temporal reorganizations depending on the paired stages between which the brain transitioned, e.g., it changed, between internal capsule and corona radiata, from mainly unidirectional to clearly reciprocal when the brain transitioned from wakefulness to N3 stage. These findings suggested the functional role of BOLD signals in white matter as a slow process, dynamically modulated across wakefulness and NREM sleep stages, and involving in maintaining different levels of consciousness and cognitive processes.
The effects of the NMDAR co-agonist D-serine on the structure and function of the optic tectum
Authors: Chorghay Zahraa , Li Vanessa J. , Ghosh Arna , Schohl Anne , Ruthazer Edward S.
Published: August 2021

The N-methyl-D-aspartate type glutamate receptor (NMDAR) is a molecular coincidence detector which converts correlated patterns of neuronal activity into cues for the structural and functional refinement of developing circuits in the brain. D-serine is an endogenous co-agonist of the NMDAR. In this study, we investigated the effects of potent enhancement of NMDAR-mediated currents by chronic administration of saturating levels of D-serine on the developing Xenopus retinotectal circuit. Chronic exposure to the NMDAR co-agonist D-serine resulted in structural and functional changes to the optic tectum. D-serine administration affected synaptogenesis and dendritic morphology in recently differentiated tectal neurons, resulting in increased arbor compaction, reduced branch dynamics, and higher synapse density. These effects were not observed in more mature neurons. Calcium imaging to examine retinotopic map organization revealed that tectal neurons of animals raised in D-serine had sharper visual receptive fields. These findings suggest that the availability of endogenous NMDAR co-agonists like D-serine at glutamatergic synapses may regulate the refinement of circuits in the developing brain.

Significance statement

N-methyl-D-aspartate receptors (NMDAR) are implicated in activity-dependent circuit plasticity. We used administration of the NMDAR co-agonist D-serine to further examine the role of the NMDAR in circuit development in vivo. D-serine stabilised dendritic arbors specifically of recently differentiated neurons, promoted synaptogenesis, and led to sharper retinotopic receptive fields in the optic tectum. Together, these results support the idea that signaling in response to synaptic current through NMDARs promotes the maturation of developing brain circuits.
Cerebrovascular super-resolution 4D Flow MRI – using deep learning to non-invasively quantify velocity, flow, and relative pressure
Authors: Ferdian E. , Marlevi D. , Schollenberger J. , Aristova M. , Edelman E.R. , Schnell S. , Figueroa C.A. , Nordsletten D.A. , Young A.A.
Published: August 2021

The development of cerebrovascular disease is tightly coupled to changes in cerebrovascular hemodynamics, with altered flow and relative pressure indicative of the onset, development, and acute manifestation of pathology. Image-based monitoring of cerebrovascular hemodynamics is, however, complicated by the narrow and tortuous vasculature, where accurate output directly depends on sufficient spatial resolution. To address this, we present a method combining dedicated deep learning and state-of-the-art 4D Flow MRI to generate super-resolution full-field images with coupled quantification of relative pressure using a physics-driven image processing approach. The method is trained and validated in a patient-specificin-silicocohort, showing good accuracy in estimating velocity (relative error: 12.0 ± 0.1%, mean absolute error (MAE): 0.07 ± 0.06 m/s at peak velocity), flow (relative error: 6.6 ± 4.7%, root mean square error (RMSE): 0.5 ± 0.1 mL/s at peak flow), and with maintained recovery of relative pressure through the circle of Willis (relative error: 11.0 ± 7.3%, RMSE: 0.3 ± 0.2 mmHg). Furthermore, the method is applied to anin-vivovolunteer cohort, effectively generating data at <0.5mm resolution and showing potential in reducing low-resolution bias in relative pressure estimation. Our approach presents a promising method to non-invasively quantify cerebrovascular hemodynamics, applicable to dedicated clinical cohorts in the future.
Image classification and cognition using contour curvature statistics
Authors: Marantan Andrew , Tolkova Irina , Mahadevan L.
Published: August 2021

Although the higher order mechanisms behind object representation and classification in the visual system are still not well understood, there are hints that simple shape primitives such as “curviness” might activate neural activation and guide this process. Drawing on elementary invariance principles, we propose that a statistical geometric object, the probability distribution of the normalized contour curvatures (NCC) in the intensity field of a planar image, has the potential to represent and classify categories of objects. We show that NCC is sufficient for discriminating between cognitive categories such as animacy, size and type, and demonstrate the robustness of this metric to variation in illumination and viewpoint, consistent with neurobiological constraints and psychological experiments. A generative model for producing artificial images with the observed NCC distributions highlights the key features that our metric captures and just as importantly, those that it does not. More broadly, our study points to the need for statistical geometric approaches to cognition that build in both the statistics and the natural invariances of the sensory world.