bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Heat Inactivation of Blood Samples on Therapeutic Drug Monitoring of 5 Second-Generation Antipsychotics and Their Metabolites
Authors: Ding Jing , Yang Liu , Zhang Yan , Zhang Suo , Meng Zhuocheng
Published: April 2022

Background:

The severe acute respiratory syndrome coronavirus 2 outbreak has been classified as a pandemic. Because many coronaviruses are heat sensitive, heat inactivation of patient samples at 56°C before testing reduces the risk of transmission. The aim of this study is to assess the impact of heat inactivation of patient blood samples on plasma concentrations of 5 second-generation antipsychotics and their metabolites.

Methods:

Blood samples were collected during routine clinical therapeutic drug monitoring examination between April 3, 2021, and April 19, 2021. Samples were divided into 2 groups: group A, noninactivated raw sample, and group B, inactivated samples. Inactivation was performed by a 30-minute incubation at 56°C. The levels of the 5 drugs and their metabolites before and after sample heat inactivation were measured using liquid chromatography-tandem mass spectrometry and compared. Furthermore, correlation and Bland–Altman analyses were conducted.

Results:

No statistically significant difference was observed between the levels of the 5 drugs and their metabolites (ie, risperidone, 9-OH-risperidone, aripiprazole, dehydroaripiprazole, olanzapine, quetiapine, norquetiapine, clozapine, and norclozapine) in the noninactivated group A and the inactivated group B (P > 0.05). Each drug's concentration values in inactivated and noninactivated treatments correlated (Spearman r
s > 0.98; P < 0.001). The results of the noninactivated treatment methods and samples alone showed good consistency via Bland–Altman analysis.

Conclusions:

Blood sample heat inactivation had no significant effect on the therapeutic drug monitoring of 5 second-generation antipsychotics and their metabolites. This inactivated treatment method should be recommended to effectively protect laboratory staff from virus contamination.
Efficacy of interventions to manage sexual dysfunction in women with cancer: a systematic review
Authors: Febrina Fiorentina , Triyoga Ichsan Fauzi , White Michelle , Marino Jennifer L. , Peate Michelle
Published: April 2022

Importance:

Cancer and its treatment negatively affect female sexual health and function. The prevalence of female sexual dysfunction after cancer is between 33% and 43%. Numerous studies have addressed treatment options for sexual dysfunction in women with cancer, but it still remains a challenge to select the most efficacious option for patients.

Objective:

To compile and appraise recent evidence of any interventions for managing sexual dysfunction in female cancer survivors.

Evidence Review:

A literature search of the electronic databases MEDLINE, EMBASE, PsycINFO, and Cochrane Central Register of Controlled Trials (January 2011 to February 2021) was conducted using general search terms of “women”, “cancer”, “intervention”, “sexual dysfunction”. We included randomized controlled trials (RCTs) and uncontrolled before-after studies that evaluated the efficacy of intervention for female sexual dysfunction in women with history of cancer. Methodological quality of studies was assessed using Risk of Bias (RoB) 2.0 for RCTs and National Institutes of Health (NIH) assessment tools for uncontrolled before-after studies.

Findings:

Thirty-six studies were included for qualitative synthesis (14 RCTs (n = 1284), 17 uncontrolled trials (n = 589), and 5 cohort studies (n = 497). Only four studies were at low risk of bias. Topical interventions (vaginal gels or creams) were able to alleviate vaginal dryness and dyspareunia, with intravaginal dehydroepiandrosterone (DHEA) (6.5 mg) gel showing evidence of improved sexual function. Evidence for estriol-lactobacilli vaginal tablets was unreliable due to a small-scale study. Psychoeducational therapy (internet-based cognitive behavioral therapy [CBT]) studies typically were at high risk of bias, but all displayed significant improvements of sexual function. Both laser therapy (fractional CO2 and erbium) and multimodal approach studies were at concerning risk of bias, although suggesting beneficial effects on sexual function.

Conclusions and Relevance:

The most reliable evidence for improvement was from a study of DHEA vaginal gel, but in general, gels or creams were useful in reducing dyspareunia. Pharmacological, psychoeducational, laser therapy, and multimodal approaches demonstrated potential in managing cancer-related sexual issues, but most were small in size (10-70 participants), with moderate to high risk of bias. Therefore, large-scale, double-blind, RCTs with long-period follow-up, and at low risk of bias are needed to show efficacy for these interventions.

Video Summary:
http://links.lww.com/MENO/A912.
Health Literacy, Cognitive Impairment, and Diabetes Knowledge Among Incarcerated Persons Transitioning to the Community
Authors: Todd Sarah , Reagan Louise , Laguerre Rick
Published: April 2022

Purpose

The purpose of this study was to evaluate the relationships of health literacy (HL; Short Test of Functional Health Literacy), cognitive impairment (CI), and diabetes knowledge (DK) among incarcerated persons transitioning to the community.

Methods

Using preintervention data from a quasi-experimental nonequivalent control group study evaluating the feasibility of a six-session literacy-tailored Diabetes Survival Skills intervention for incarcerated men transitioning to the community, we conducted correlational analyses among the Short Test of Functional Health Literacy, Montreal Cognitive Assessment, and Spoken Knowledge in Low Literacy in Diabetes Scale using the SPSS PROCESS macro and bias-corrected bootstrapping to test the meditational hypothesis: HL mediates the relationship between CI and DK.

Results

Participants (N = 73) were incarcerated for 1–30 years with a mean age of 47 (9.9) years, 40% Black, 19% White, and 30% Hispanic, with 78% having high school/GED or less education. Most (70%) screened positive for CI and had low DK, and 20% had marginal or inadequate HL. HL, CI, and DK were positively associated with each other. Controlling for race, age, and group (control/experimental), cognitive function had a significant direct effect on HL (b = 0.866, p = 0.0003) but not on DK (b = 0.119, p = 0.076). Results indicated a significant indirect effect of cognitive functioning on DK via HL, 95% confidence interval [0.300, 0.1882].

Conclusion

Intervention approaches aimed at increasing HL or tailored to low HL in the presence of CI may be effective in increasing DK in this population.

Implications

Given the low risk to high benefit of implementing literacy-tailored approaches to persons in prison and the population demographics from studies supporting a high degree of CI, nurses should consider implementing literacy-tailored approaches and screening for CI before participation in all educational programs.
A Comparison of the Effects of Pin and Vacuum-Assisted Suspension Systems in Individuals With Transtibial Amputation
Authors: Çerezci Duygu Senay , Anaforoğlu Bahar , Erbahçeci Fatih
Published: April 2022

Introduction

Suspension systems are essential components for a lower-limb prosthesis, as they provide sufficient prosthetic fit. Although various adverse and positive effects have been reported for suspension systems, it is important to determine the effects on the prosthesis users in detail.

Objective

The aim of this study was to compare the pin suspension system (PSS) with the vacuum-assisted suspension system (VASS) in terms of parameters including walking capacity, functional mobility, weight bearing on the operated side, prosthesis satisfaction, and body image perception.

Study Design

This is an original research report.

Methods

Nine individuals with transtibial amputation were evaluated. Both suspension systems were applied consecutively. Initially, participants used the PSS for 3 months after fabrication and adjustment of the prosthesis and a prosthetic training period. They then used the VASS for 3 months after a similar training period. After both prosthetic systems had been adjusted, L.A.S.A.R. Posture was used to determine weight bearing on the prosthetic side. The 6-minute walk test was applied for walking capacity, the timed up-and-go test was used to determine functional mobility, the Prosthetic Satisfaction Index was used for prosthetic satisfaction, and the Amputee Body Image Scale was used for body image perception.

Results

Significant differences were observed between PSS and VASS in terms of prosthetic side weight-bearing ratios, walking capacity, functional mobility, and prosthetic satisfaction (P < 0.05), all in favor of VASS. No significant difference was determined in terms of body image scores (P > 0.05).

Conclusion

In terms of function and prosthetic satisfaction in individuals with transtibial amputation, VASS was determined to be superior. The available evidence suggests that if there is no contraindication for the use of VASS, it may contribute to the individual with amputation functionally and increase the satisfaction with the prosthesis.

Clinical Relevance

Vacuum systems can make a positive contribution to reaching the goals for prosthesis users who are targeted to have high physical activity levels. This positive contribution includes increased weight transfer to the prosthetic side, an increase in mobility determinants, and increased prosthesis satisfaction, which has many dimensions.
What a Patient Sees in the Mirror: Validation of the Truncal Anterior Asymmetry Scoliosis Questionnaire
Authors: Lonner Baron S. , Toombs Courtney S. , Shah Suken A. , Bastrom Tracey , Penn Phedra , Bright Kristin , Stern Carrie Scharf , Roy-Beaudry Marjolaine , Beausejour Marie , Neiss Geraldine , Castillo Andrea , Parent Stefan
Published: April 2022

Introduction

Self-image and body shape are important to adolescent idiopathic scoliosis (AIS) patients. The impact of scoliosis on anterior trunk shape has been incompletely studied. The Truncal Anterior Asymmetry Scoliosis Questionnaire (TAASQ) was developed to assess anterior truncal appearance concerns and mental preoccupation and behavioral modification related to those concerns. The purpose of this study is to validate TAASQ in AIS.

Methods

A total of 105 female surgical AIS patients (average age, 14.9 years; mean Cobb, 53°) completed the TAASQ, Spinal Appearance Questionnaire (SAQ), and Scoliosis Research Society Questionnaire (SRS-22) questionnaires. TAASQ was developed with breast cancer researchers and piloted in 13 perioperative adolescent and adult idiopathic scoliosis patients. TAASQ contains 14 questions, both response scale and free response. Questions are categorized into three domains: breast, appearance, and clothing. Internal consistency/reliability (Cronbach's α) and concurrent validity were determined.

Results

Internal consistency was 0.86, 0.77, and 0.84 for clothing, appearance, and breast domains, respectively (good to excellent). Domains and subdomains of the TAASQ correlate well with the image domain of the SRS-22 but not with the SAQ.

However, given that the TAASQ was designed to assess concerns with anterior appearance, the correlation with the image domain establishes concurrent validity of the questionnaire.

Conclusions

TAASQ is a reliable and valid measure of the concerns and behavioral modifications related to anterior truncal appearance in female AIS patients. Further study of TAASQ will help clinicians counsel patients on the impact of surgery on anterior truncal deformity.

Clinical Relevance

There is a clinical lack of knowledge about the significant self-image and anterior body shape concerns of adolescent females with AIS. The TAASQ has been developed to assess concerns related to anterior truncal appearance and mental preoccupation and behavioral modification.
The Nursing Professional Development Practice Model
Authors: Rainford Melanie , Uland Cari , Youl Zoe
Published: April 2022

In the nursing professional development (NPD) specialty, the NPD practice model visually represents the NPD scope of practice and reflects a growing, vibrant specialty. It delineates the who, what, when, why, where, and how of the specialty practice and is approved by the American Nurses Association. This column reflects upon the evolution of the NPD practice model and delineates its updates in the fourth edition of the Nursing Professional Development: Scope and Standards of Practice.
Brief Report: Previous Preexposure Prophylaxis Use Among Men Who Have Sex With Men Newly Diagnosed With HIV Infection in King County, WA
Authors: Cannon Chase A. , Ramchandani Meena S. , Buskin Susan , Dombrowski Julia , Golden Matthew R.
Published: April 2022

Background:

Preexposure prophylaxis (PrEP) discontinuations are common and are associated with subsequent HIV acquisition. The population-level impact of PrEP discontinuations is unknown.

Methods:

Public health staff routinely asked men who have sex with men (MSM) with newly diagnosed HIV infection about their history of PrEP use as part of partner notification interviews in King County, WA, from 2013 to 2021. We assessed trends in the proportion of MSM who ever took PrEP and described reasons for PrEP discontinuation.

Results:

A total of 1098 MSM were newly diagnosed with HIV during the study period; of whom, 797 (73%) were interviewed, and 722 responded to questions about their history of PrEP use. Ninety-four (13%) reported ever taking PrEP. The proportion of MSM who ever used PrEP before HIV diagnosis increased from 2.3% in 2014 to 26.6% in 2020–2021 (P < 0.001 for trend). The median time from PrEP discontinuation to HIV diagnosis was 152 days, and median duration on PrEP was 214 days. Common reasons for stopping PrEP included self-assessment as being at low risk for HIV, side effects, and insurance issues. Nineteen men were on PrEP at the time of HIV diagnosis; mutations conferring emtricitabine/tenofovir resistance were identified in 8 (53%) of 15 men with available genotype data.

Conclusion:

More than 25% of MSM with newly diagnosed HIV from 2020 to 2021 had ever used PrEP. More than 50% who discontinued PrEP were diagnosed <6 months after stopping. Strategies to preempt PrEP discontinuations, enhance retention, and facilitate resumption of PrEP are critical to decrease new HIV diagnoses.
First-in-Man Noninvasive Initial Diagnostic Approach of Primary CNS Lymphoma Versus Glioblastoma Using PET With 18F-Fludarabine and l-[methyl-11C]Methionine
Authors: Postnov Andrey , Toutain Jérôme , Pronin Igor , Valable Samuel , Gourand Fabienne , Kalaeva Diana , Vikhrova Nina , Pyzhik Elena , Guillouet Stéphane , Kobyakov Grigoriy , Khokholova Ekaterina , Pitskhelauri David , Usachev Dmitry , Maryashev Sergey , Rizhova Marina , Potapov Alexander , Derlon Jean-Michel
Published: April 2022

Objectives

This study sought to assess 18F-fludarabine (18F-FLUDA) PET/CT’s ability in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastoma multiformes (GBMs).

Patients and Methods

Patients harboring either PCNSL (n = 8) before any treatment, PCNSL treated using corticosteroids (PCNSLh; n = 10), or GBM (n = 13) were investigated with conventional MRI and PET/CT, using 11C-MET and 18F-FLUDA. The main parameters measured with each tracer were SUVT and T/N ratios for the first 30 minutes of 11C-MET acquisition, as well as at 3 different times after 18F-FLUDA injection. The early 18F-FLUDA uptake within the first minute of injection was equally considered, whereas this parameter was combined with the later uptakes to obtain R FLUDA 2 and R FLUDA 3 ratios.

Results

No significant differences in 11C-MET uptakes were observed among PCNSL, PCNSLh, and GBM. With 18F-FLUDA, a clear difference in dynamic GBM uptake was observed, which decreased over time after an early maximum, as compared with that of PCNSL, which steadily increased over time, PCNSLh exhibiting intermediate values. The most discriminative parameters consisting of R FLUDA 2 and R FLUDA 3 integrated the early tracer uptake (first 60 seconds), thereby provided 100% specificity and sensitivity.

Conclusions

18F-FLUDA was shown to likely be a promising radiopharmaceutical for differentiating PCNSL from other malignancies, although a pretreatment with corticosteroids might compromise this differential diagnostic ability. The diagnostic role of 18F-FLUDA should be further investigating, along with its potential of defining therapeutic strategies in patients with PCNSL, while assessing the treatments’ effectiveness.
Implication of Exercise for Healthy Longevity in Older People
Authors: Yamada Minoru , Arai Hidenori
Published: April 2022

As the aging population is increasing substantially worldwide, extending the healthy life expectancy of older people has become a challenging issue. The structure and function of skeletal muscle decline with age, and this change has been shown to be involved in the development of various adverse health outcomes. In recent years, sarcopenia, a disease that is associated with age-related skeletal muscle mass loss and muscle weakness, has been attracting attention, and disuse muscle atrophy is also an important condition. For these diseases, it is recommended to increase exercise and physical activity, especially resistance exercise. In addition to conducting further research, it is necessary to widely disseminate information regarding the significance of exercise and physical activity as cost-effective interventions to the general public as well as health care professionals.
Walking Promotes Physical Fitness of Community-Dwelling Older Adults
Authors: Sithichoksakulchai Siriluk , Chen Meng-Chin , Chen Kuei-Min
Published: April 2022

Physical activity is positively associated with the health of older adults. Walking is a simple activity that can be applied to older adults. This article aims to systematically review and meta-analyze the effects of walking on physical fitness in older adults. Studies were searched from 13 databases. Results showed that walking could improve aerobic endurance (21.04, 95% CI [13.82, 28.27]), lower body strength (2.77, 95% CI [1.46, 4.09]), static balance (6.07, 95% CI [3.34, 8.79]), and agility and dynamic balance (1.52, 95% CI [0.23, 2.80]). Walking is effective and should be promoted to improve the physical function of older adults.
The Influence of a New Intervention Model of Community-Based Physical Fitness Exercise on the Older Adults' Adherence to Physical Activity and the Improvement of Functional Fitness
Authors: Hsu Hui-Chu , Liang Jing-Min , Chu I-Hua , Chang Jyh-Jong , Wu Wen-Lan
Published: April 2022

Purpose:

This single-arm clinical study aimed to design a new exercise intervention strategy based on the transtheoretical model and discuss its influence for elders at different stages of the behavior change.

Methods:

Fifteen participants in the maintenance stage (MP) and 15 participants under the maintenance stage (MPb) participated in a 12-week structured exercise and a 12-week autonomous group class training.

Results and Conclusions:

The new intervention model successfully improved the amount, efficiency, and adherence of physical activity, and enhanced the functional fitness for both groups. The exercise behavior for MPb group successfully progressed to the next stage.
The Effectiveness of Short-Term Lifestyle Intervention Programs on Physical Function, Cognition, and Quality of Life Among Community Older Adults
Authors: Tsai Athena Yijung , Sun Ting-Shiuan , Chen Ming-De , Kuo Chang-Chih , Su Pei-Chi , Chou Ying-Chun
Published: April 2022

The objective of this study was to explore whether (1) the 2 short-term lifestyle intervention programs (ie, lifestyle modification for the elderly [LiME] and prescription for a healthy life [PHL]) increase behavioral outcome in meaningful activity participation, and health outcomes in physical function, cognition, and health-related quality of life and (2) the multimodule program (LiME) has better outcomes? Twenty-one community older adults were recruited to join the 2 programs: 9 in LiME and 12 in PHL. Both programs conducted 12 weekly group sessions, including 1 outing. LiME showed positive within-group outcomes in physical, mental, and quality of life. PHL did not demonstrate any significant health outcome. Neither program had noted behavior outcome. The results of LiME and PHL at any time point did not show a significant between-group difference. LiME was a rarely seen short-term (3 months) lifestyle intervention program that demonstrated positive outcomes on physical function, cognition, and quality of life among community older adults.
White Matter, Behavioral Neurology, and the Influence of Corticocentrism
Authors: Filley Christopher M.
Published: April 2022

White matter in the human brain occupies roughly the same volume as gray matter but has received far less attention in behavioral neurology and related disciplines. In particular, the cerebral cortex has long dominated thinking about the organization of brain–behavior relationships. As a result, subcortical structures, including deep gray matter and, most notably, white matter, have been accorded relatively little neuroscientific study compared with the extensive work devoted to the cerebral cortex. The influence of corticocentrism can be explained by several factors, including historical precedent in neurology strongly emphasizing the importance of the cortex, a preponderance of investigative methods that selectively target this structure, and a misinterpretation of comparative neuroanatomic data gathered from normal brains. This paper will describe the background of the corticocentric bias and emphasize that white matter merits its own place within the study of the higher functions. Although corticocentrism continues to exert a powerful impact on behavioral neurology, considerable progress is being made in the study of white matter—a development that promises to expand our knowledge of the normal brain and lead to an improved understanding of how it mediates behavior. In turn, a range of vexing neurologic and psychiatric disorders may become better illuminated by considering pathology within, or dysfunction of, white matter tracts. A complete appreciation of brain–behavior relationships requires an understanding not only of the outermost layer of the cerebral hemispheres, but also of white matter connectivity that links gray matter regions into distributed neural networks that subserve cognition and emotion.
Patient Experience with Amputation or Limb Loss: Literature Review
Authors: Isworo Atyanti , Pandin Moses Glorino Rumambo
Published: April 2022

Backgrounds

Amputation which is the removal of body parts, the reality faced by patients who must be amputated raises various responses ranging from rejection to acceptance. The process of each patient is certainly different according to the experience experienced by each patient.

Methods

This literature review uses articles published from 2018-2022 with source from databased ScienceDirect, Pubmed, Scopus, Sage Journals, EBSCO-Host, BMC Journal, Springer Link, Taylor and Francis, and ProQuest. The keywords used are patient experience, perspectives of patients, amputations, limb loss, low extremity amputation, qualitative, qualitative study. Article selection follows “PRISMA” flow.

Results

This systematic review have a total of 6 articles meet the criteria for analysis. Respondents involved in this qualitative research amounted to 109 respondents who had undergone the amputation process. There are several themes that are used to explore the patient’s experience, the themes used are divided into several aspects in the form of aspects of physical changes, aspects of psychological changes, and also aspects of social adaptation that patients must go through after undergoing the amputation process.

Conclusion

Through a qualitative study, it was found that the average patient expressed feelings of worry, fear, anxiety, feeling useless, no longer liking his body, feeling lost in self-confidence, and no longer wanting to interact socially because of the negative response from the surrounding environment towards the patients.
Striatal dopamine gene network moderates the effect of early adversity on the risk for adult psychiatric and cardiometabolic comorbidity
Authors: Barth Barbara , Arcego Danusa Mar , de Mendonça Filho Euclides José , Merscher Sobreira de Lima Randriely , Parent Carine , Dalmaz Carla , Portella André Krumel , Pokhvisneva Irina , Meaney Michael J , Silveira Patricia Pelufo
Published: April 2022

Cardiometabolic and psychiatric disorders often co-exist and share common early life risk factors, such as low birth weight. However, the biological pathways linking early adversity to adult cardiometabolic/psychiatric comorbidity remain unknown. Dopamine (DA) neurotransmission in the striatum is sensitive to early adversity and influences the development of both cardiometabolic and psychiatric diseases. Here we show that a co-expression based polygenic score (ePGS) reflecting individual variations in the expression of the striatal dopamine transporter gene (SLC6A3) network significantly interacts with birth weight to predict psychiatric and cardiometabolic comorbidities in both adults (UK Biobank, N= 225,972) and adolescents (ALSPAC, N= 1188). Decreased birth weight is associated with an increased risk for psychiatric and cardiometabolic comorbidities, but the effect is dependent on a striatalSLC6A3ePGS, that reflects individual variation in gene expression of genes coexpressed with the SLC6A3 gene in the striatum. Neuroanatomical analyses revealed that SNPs from the striatumSLC6A3ePGS were significantly associated with prefrontal cortex gray matter density, suggesting a neuroanatomical basis for the link between early adversity and psychiatric and cardiometabolic comorbidity. Our study reveals that psychiatric and cardiometabolic diseases share common developmental pathways and underlying neurobiological mechanisms that includes dopamine signaling in the prefrontal cortex.
Octreotide may improve pharyngocutaneous fistula healing through downregulation of cystatins: a pilot study
Authors: Cohen Jonathan , Reed William , Foster Matthew W. , Kahmke Russel , Rocke Daniel , Watts Tammara , Puscas Liana , Cannon Trinitia , Lee Walter T.
Published: April 2022

Objective

Pharyngocutaneous fistula (PCF) and salivary leaks are well known complications of head and neck surgery. The medical management of PCF has included the use of octreotide without a well-defined understanding of its therapeutic mechanism. We hypothesized that octreotide induces alterations in the saliva proteome and that these alterations may provide insight into the mechanism of action underlying improved PCF healing. We undertook an exploratory pilot study in healthy controls that involved collecting saliva before and after a subcutaneous injection of octreotide and performing proteomic analysis to determine the effects of octreotide.

Materials and Methods

Four healthy adult participants provided saliva samples before and after subcutaneous injection of octreotide. A mass-spectrometry based workflow optimized for the quantitative proteomic analysis of biofluids was then employed to analyze changes in salivary protein abundance after octreotide administration.

Results

There were 3,076 human, 332 S. mitis, 102 G. haemolyans and 42 G. adiacens protein groups quantified in saliva samples. A paired statistical analysis was performed using the generalized linear model (glm) function in edgeR. There were and ∼300 proteins that had a p<0.05 between the pre-and post-octreotide groups ∼50 proteins with an FDR-corrected p<0.05 between pre-and post-groups. These results were visualized using a volcano plot after filtering on proteins quantified by 2 more or unique precursors. Both human and bacterial proteins were among the proteins altered by octreotide treatment. Notably, four isoforms of the human cystatins, belonging to a family of cysteine proteases, that had significantly lower abundance after treatment.

Conclusion

This pilot study demonstrated octreotide-induced downregulation of cystatins. By downregulation of cystatins in the saliva, there is decreased inhibition of cysteine proteases such as Cathepsin S. This results in increased cysteine protease activity that has been linked to enhanced angiogenic response, cell proliferation and migration that have resulted in improved wound healing. These insights provide first steps at furthering our understanding of octreotide’s effects on saliva and reports of improved PCF healing.
Multi-omics Characterization of Neutrophil Extracellular Trap Formation in Severe and Mild COVID-19 Infections
Authors: Bramer Lisa M. , Hontz Robert D. , Eisfeld Amie J. , Sims Amy C. , Kim Young-Mo , Stratton Kelly G. , Nicora Carrie D. , Gritsenko Marina A. , Schepmoes Athena A. , Akasaka Osamu , Koga Michiko , Tsutsumi Takeya , Nakamura Morio , Nakachi Ichiro , Baba Rie , Tateno Hiroki , Suzuki Shoji , Nakajima Hideaki , Kato Hideaki , Ishida Kazunari , Ishii Makoto , Uwamino Yoshifumi , Mitamura Keiko , Paurus Vanessa L. , Nakayasu Ernesto S. , Attah Isaac K. , Letizia Andrew G. , Waters Katrina M. , Metz Thomas O. , Corson Karen , Kawaoka Yoshihiro , Gerbasi Vincent R.
Published: April 2022

The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics analysis of an immunologically naïve SARS-CoV-2 clinical cohort from the plasma of uninfected controls, mild, and severe infections. A comparison of healthy controls and patient samples showed activation of neutrophil degranulation pathways and formation of neutrophil extracellular trap (NET) complexes that were activated in a subset of the mild infections and more prevalent in severe infections (containing multiple NET proteins in individual patient samples). As a potential mechanism to suppress NET formation, multiple redox enzymes were elevated in the mild and severe symptom population. Analysis of metabolites from the same cohort showed a 24- and 60-fold elevation in plasma L-cystine, the oxidized form of cysteine, which is a substrate of the powerful antioxidant glutathione, in mild and severe patients, respectively. Unique to patients with mild infections, the carnosine dipeptidase modifying enzyme (CNDP1) was up-regulated. The strong protein and metabolite oxidation signatures suggest multiple compensatory pathways working to suppress oxidation and NET formation in SARS-CoV-2 infections.
Single cell RNA-seq identifies inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma
Authors: Chen Ling , Hoefel Gabriela Araujo , Pathinayake Prabuddha S. , Reid Andrew , Kelly Coady , HuiYing Tan , Kim Richard Y , Hansbro Philip M , Brody Steven L , Foster Paul S , Horvat Jay C , Riveros Carlos , Wark Peter AB , Kaiko Gerard E
Published: April 2022

Asthma is the most common chronic airways disease worldwide and the severe treatment resistant subtype of asthma is responsible for the majority of disease burden. Asthma is heterogeneous in nature and can be classified according to airway infiltrates as eosinophilic or non-eosinophilic (sometimes referred to as Type 2 low), which is further divided into paucigranulocytic (low levels of granulocytes), or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in airway tissue, sputum, and bronchoalveolar lavage. Severe non-eosinophilic asthma currently has fewer effective treatment options and many of these patients fail to qualify for newer biologic monoclonal therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is a key protein whose function is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease (COPD) and has proven a valuable therapeutic target. Using human bronchial epithelial cells (hBECs) isolated differentiated at air-liquid interface we demonstrated a reduced function of the CFTR in non-eosinophilic asthma. Characterization of the cell and molecular differences in airway epithelial cells between severe asthma subtypes using single cell RNA-sequencing (scRNAseq) revealed that airway epithelial cells from non-eosinophilic asthma, and in particular neutrophilic asthma patients, fail to differentiate into CFTR-expressing ionocytes compared with eosinophilic asthma or healthy donors. We identified a novel ionocyte transcriptional signature, which was present in both bronchial and tracheal airway epithelial samples indicating conserved anatomical gene regulation. Using protein markers and immunofluorescent quantification loss of ionocytes was confirmed in non-eosinophilic asthma hBECs. Similarly, ioncytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic allergen asthma models. Furthermore, treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture, but not IL-13, led to loss of ionocytes primarily due to IFN-γ. Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target for this difficult-to-treat disease.
Mechanisms regulating the frequency of inhibition-based gamma oscillations in primate prefrontal and parietal cortices
Authors: Gonzalez-Burgos Guillermo , Miyamae Takeaki , Reddy Nita , Dawkins Sidney , Chen Chloe , Hill Avyi , Enwright John , Ermentrout G Bard , Lewis David A.
Published: April 2022

In primates, the dorsolateral prefrontal (DLPFC) and posterior parietal (PPC) cortices are critical nodes in the network mediating cognitive functions including attention and working memory. Notably, during working memory tasks, gamma oscillations, usually prominent in layer 3 (L3), are induced in both DLPFC and PPC but exhibit higher frequency in DLPFC. These oscillation frequency differences might be crucial for working memory function, but the mechanisms producing different oscillation frequencies in monkey DLPFC and PPC remain poorly understood.

To investigate the basis of the DLPFC-PPC differences in oscillation frequency we studied GABAAR-mediated inhibition, which plays a crucial role in gamma oscillation production, in L3 pyramidal neurons (L3 PNs) from the rhesus monkey DLPFC or PPC. Recordings of GABAAR-mediated synaptic currents from L3 PNs, while suggesting a contribution to network synchronization in both areas, revealed no DLPFC-PPC differences in the strength or kinetics of GABAAR-mediated inhibition. Likewise, the expression of GABAAR genes in L3 PNs did not differ between regions.

In the absence of differences in inhibition, DLPFC L3 PNs showed greater dendritic spine density and higher expression of AMPAR and NMDAR subunit genes relative to PPC L3 PNs, suggesting that the excitatory synaptic drive onto L3 PNs could be stronger in the DLPFC. Simulations in computational models of the cortical microcircuit showed that, with constant synaptic inhibition, increasing the strength of recurrent excitatory synaptic drive increased the network oscillation frequency. Hence, the DLPFC-PPC differences in gamma oscillation frequency could depend on stronger recurrent excitation in the DLPFC relative to PPC.

Significance statement

Gamma oscillations may contribute to the neural substrate of working memory and exhibit a higher frequency in the prefrontal (DLPFC) than parietal (PPC) areas of primate cortex. To investigate the basis of these oscillation frequency differences which may be crucial for working memory encoding, we studied GABAAR-mediated inhibition on L3 pyramidal neurons (L3 PNs) from rhesus monkey DLPFC or PPC. Our data revealed no DLPFC-PPC differences in GABAAR-mediated inhibition but showed greater dendritic spine density in DLPFC L3 PNs, suggesting stronger excitatory synaptic drive. Simulations in computational network models showed that stronger recurrent excitatory synaptic drive increased the network oscillation frequency, suggesting that the higher oscillation frequency could depend on stronger recurrent excitation in the DLPFC relative to PPC.
Bacterial lipopolysaccharide modulates immune response in the colorectal tumor microenvironment
Authors: Sulit A.K. , Daigneault M. , Allen-Vercoe E. , Silander O.K. , Hock B. , McKenzie J. , Pearson J. , Frizelle F.A. , Schmeier S. , Purcell R.
Published: April 2022

Immune responses can have opposing effects in colorectal cancer (CRC), the balance of which may determine whether a cancer regresses, progresses, or potentially metastasizes. These effects are evident in CRC consensus molecular subtypes (CMS) where both CMS1 and CMS4 contain immune infiltrates yet have opposing prognoses. The microbiome has previously been associated with CRC and immune response in CRC but has largely been ignored in the CRC subtype discussion. Using CMS subtyping, we aimed to determine the contributions of the microbiome to the pleiotropic effects evident in immune-infiltrated subtypes. We integrated host gene-expression and meta-transcriptomic data to determine the link between immune characteristics and microbiome contributions in these subtypes and identified lipopolysaccharide (LPS) binding as a potential functional mechanism. We identified candidate bacteria with LPS properties that could affect immune response, focusing onFusobacterium periodonticumandBacteroides fragilisin CMS1, andPorphyromonas asaccharolyticain CMS4. Treatment of peripheral blood mononuclear cells (PBMCs) with LPS isolated from these bacteria showed thatF. periodonticumstimulates cytokine production in PBMCs while bothB. fragilisandP. asaccharolyticahad an inhibitory effect. Furthermore, LPS from the latter two species can inhibit the immunogenic properties ofF. periodonticumLPS when co-incubated with PBMCs. We propose that different microbes in the CRC tumor microenvironment can alter the local immune activity, with important implications for prognosis and treatment response.
Expression of cell-wall related genes is highly variable and correlates with sepal morphology
Authors: Hartasánchez Diego A. , Kiss Annamaria , Battu Virginie , Soraru Charline , Delgado-Vaquera Abigail , Massinon Florian , Brasó-Vives Marina , Mollier Corentin , Martin-Magniette Marie-Laure , Boudaoud Arezki , Monéger Françoise
Published: April 2022

Control of organ morphology is a fundamental feature of living organisms. There is, however, observable variation in organ size and shape within a given genotype. Taking the sepal of Arabidopsis as a model, we investigated whether we can use variability of gene expression alongside variability of organ morphology to identify gene regulatory networks potentially involved in organ size and shape determination. We produced a dataset composed of morphological parameters and genome-wide transcriptome obtained from 27 individual sepals from wild-type plants with nearly identical genetic backgrounds, environment, and developmental stage. Sepals exhibited appreciable variability in both morphology and transcriptome, with response to stimulus genes and cell-wall related genes displaying high variability in expression. We additionally identified five modules of co-expressed genes which correlated significantly with morphology, revealing biologically relevant gene regulatory networks. Interestingly, cell-wall related genes were overrepresented in two of the top three modules. Overall, our work highlights the benefit of using coupled variation in gene expression and phenotype in wild-type plants to shed light on the mechanisms underlying organ size and shape determination. Although causality between gene expression and sepal morphology has not been established, our approach opens the way to informed analysis for mutant characterization and functional studies.
Weak seed banks influence the signature and detectability of selective sweeps
Authors: Korfmann Kevin , Awad Diala Abu , Tellier Aurélien
Published: April 2022

Seed banking (or dormancy) is a widespread bet-hedging strategy, generating a form of population overlap, which decreases the magnitude of genetic drift. The methodological complexity of integrating this trait implies it is ignored when developing tools to detect selective sweeps. But, as dormancy lengthens the ancestral recombination graph (ARG), increasing times to fixation, it can change the genomic signatures of selection. To detect genes under positive selection in seed banking species it is important to 1) determine whether the efficacy of selection is affected, and 2) predict the patterns of nucleotide diversity at and around positively selected alleles. We present the first tree sequence-based simulation program integrating a weak seed bank to examine the dynamics and genomic footprints of beneficial alleles in a finite population. We find that seed banking does not affect the probability of fixation and confirm expectations of increased times to fixation. We also confirm earlier findings that, for strong selection, the times to fixation are not scaled by the inbreeding effective population size in the presence of seed banks, but are shorter than would be expected. As seed banking increases the effective recombination rate, footprints of sweeps appear narrower around the selected sites and due to the scaling of the ARG are detectable for longer periods of time. The developed simulation tool can be used to predict the footprints of selection and draw statistical inference of past evolutionary events in plants, invertebrates, or fungi with seed banks.
Elongated Hypocotyl 5 (HY5) regulates BRUTUS (BTS) to maintain Iron homeostasis in Arabidopsis thaliana
Authors: Mankotia Samriti , Singh Dhriti , Monika Kumari , Meena Himani , Meena Varsha , Yadav Ram Kishor , Pandey Ajay Kumar , Satbhai Santosh B.
Published: April 2022

Iron (Fe) is an essential micronutrient for both plants and animals. Fe limitation significantly reduces crop yield and therefore has adverse impacts on human nutrition. Owing to limited bioavailability of Fe, plants have adapted different strategies that regulate Fe uptake and homeostasis. Particularly, modifications of root growth traits are a key for the survival of plants on Fe-deficient soils. Understanding the molecular basis for these root growth responses will have critical implications for plant breeding. Fe uptake is regulated by a cascade of basic helix-loop-helix (bHLH) transcription factors. In our study, we show that HY5 (Elongated Hypocotyl 5), a member of the basic leucine zipper (bZIP) family of transcription factors plays an important role in the Fe deficiency signalling pathway in Arabidopsis thaliana. The hy5 mutant plants failed to mount an optimum Fe deficiency response and showed severe root growth defects under Fe limitation that could be partially reverted by complementation of hy5 mutant. qRT-PCR analysis revealed that the induction of the genes involved in Fe uptake pathway [FER-like iron deficiency-induced transcription factor (FIT), Ferric Reduction Oxidase 2 (FRO2) and Iron-Regulated Transporter1 (IRT1)] is significantly reduced in the hy5 mutants as compared to the wild-type plants under Fe deficiency. Moreover, we also found that HY5 function is critical for activating the expression of coumarin biosynthesis genes (F6’H1, S8H, PDR9 and BGLU42) under Fe deficiency. Interestingly, our results showed that HY5 acts as a negative regulator of BRUTUS (BTS) which is known to negatively regulate Fe deficiency response. Chromatin Immunoprecipitation followed by qPCR revealed direct binding of HY5 to the promoter of BTS. Altogether, our results showed that HY5 plays an important role in regulation of Fe deficiency responses in Arabidopsis.
Differentiation of thermal reaction norms between marginal and core populations of a northward expanding parasitoid
Authors: Delava Emilie , Fleury Frederic , Gibert Patricia
Published: April 2022

Understanding the speed of and the type of mechanisms that species use to adapt to rapid change is a central question in evolutionary biology. Classically, the two mechanisms denoted in the literature that allow individuals to address these environmental changes are either phenotypic plasticity or rapid evolutionary changes. However, phenotypic plasticity itself can evolve rapidly. In this study, we investigated the genetic differentiation between marginal and core populations of a high-trophic level insect,Leptopilina boulardi, aDrosophilaparasitoid, which has exhibited a very rapid progression northward of its geographical range. Several life history traits have been investigated in different populations according to four fluctuating thermal regimes that mimic the thermal conditions in the field. We found that at low developmental temperature, the two northern marginal populations that have to face a colder winter, survive longer than the two core populations. In addition, the northernmost populations exhibit a higher potential fecundity, a higher starvation resistance and a larger amount of energy at low temperatures. These significant genetic differentiations with genotype-by-environment interactions show that a rapid genetic differentiation of the shape of thermal reaction norms is possible when populations have to cope with new environments.
Voltammetry in the spleen assesses real-time anti-inflammatory norepinephrine release elicited by autonomic neurostimulation
Authors: Mughrabi Ibrahim T. , Gerber Michael , Jayaprakash Naveen , Palandira Santhoshi P. , Al-Abed Yousef , Datta-Chaudhuri Timir , Smith Corey , Pavlov Valentin A. , Zanos Stavros
Published: April 2022

Background

The noradrenergic innervation of the spleen is implicated in the autonomic control of inflammation and has been the target of neurostimulation therapies for inflammatory diseases. However, there is no real-time marker of its successful activation, which hinders the optimization of anti- inflammatory neurostimulation therapies and mechanistic studies in anti-inflammatory neural circuits.

Methods

In mice, we performed fast-scan cyclic voltammetry (FSCV) in the spleen during intravascular injections of norepinephrine (NE), or during stimulation of the vagus, splanchnic, or splenic nerves. We defined the stimulus-elicited charge generated at the oxidation potential for NE (∼0.8 V) as the “NE voltammetry signal” and quantified the dependence of the signal on NE or nerve stimulation dose. We correlated the NE voltammetry signal in response to splenic nerve stimulation (SpNS) with the latter’s anti-inflammatory effect in a model of lipopolysaccharide- (LPS) induced endotoxemia, quantified as suppression of TNF release.

Results

We found that the NE voltammetry signal is proportional to injected amount and estimated peak NE concentration, with 0.3 μM detection threshold. In response to SpNS, the signal increases within seconds, returns to baseline minutes later and is blocked by interventions that deplete NE or inhibit NE release. The signal is elicited by efferent, but not afferent, electrical or optogenetic vagus nerve stimulation, and by splanchnic nerve stimulation. The magnitude of the signal during SpNS is inversely correlated with subsequent TNF suppression in endotoxemia and explains 40% of the variance in TNF measurements.

Conclusion

FSCV in the spleen provides a marker for real-time monitoring of anti-inflammatory activation of the splenic innervation during autonomic stimulation.