bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency of Optical Coherence Tomography Testing to Detect Progression in Glaucoma
Authors: Melchior Bruna , De Moraes Carlos G. , Paula Jayter S. , Cioffi George A. , Girkin Christopher A. , Fazio Massimo A. , Weinreb Robert N. , Zangwill Linda M. , Liebmann Jeffrey M.
Published: August 2022

Précis:

With high specificity and less variability than perimetry, more frequent testing resulted in shorter time to detect progression, though a 6-month testing interval provides a reasonable trade-off for following glaucoma patients using optical coherence tomography (OCT).

Purpose:

To investigate the time to detect progression in glaucomatous eyes using different OCT test intervals.

Materials and Methods:

Participants with manifest glaucoma from the African Descent and Glaucoma Evaluation Study (ADAGES), a multicenter, prospective, observational cohort study, were included. A total of 2699 OCT tests from 171 glaucomatous and 149 normal eyes of 182 participants, with at least 5 tests and 2 years of follow-up, were analyzed. Computer simulations (n=10,000 eyes) were performed to estimate time to detect progression of global circumpapillary retinal nerve fiber layer thickness (cpRNFL) measured with OCT tests. Simulations were based on different testing paradigms (every 4, 6, 12, and 24 mo) and different rates of change (µm/year). Time to detect significant progression (P<0.05) at 80% and 90% power were calculated for each paradigm and rate of cpRNFL change.

Results:

As expected, more frequent testing resulted in shorter time to detect progression. Although there was clear disadvantage for testing at intervals of 24 versus 12 months (~22.4% time [25 mo] increase in time to progression detection) and when testing 12 versus 6 months (~22.1% time [20 mo] increase), the improved time to detect progression was less pronounced when comparing 6 versus 4 months (~11.5% time [10 mo] reduction).

Conclusion:

With high specificity and less variability than perimetry, a 6-month testing interval provides a reasonable trade-off for following glaucoma patients using OCT.
Binocular Summation of Visual Acuity at High and Low Contrast in Early Glaucoma
Authors: Issashar Leibovitzh Galia , Trope Graham E. , Buys Yvonne M. , Tarita-Nistor Luminita
Published: August 2022

Précis:

This study examined the integrity of binocular summation function in patients with mild glaucoma. We found that binocular summation of visual acuity is preserved in these patients, despite their reduced monocular inputs.

Purpose:

Binocular summation represents superiority of binocular to monocular performance. In this study we examined the integrity of binocular summation function in patients with early glaucoma who had structural glaucomatous changes but otherwise had no significant interocular acuity asymmetry or other functional deficit detected with standard clinical measures.

Materials and Methods:

Participants included 48 patients with early glaucoma according to Hodapp, Anderson, and Parrish 2 (HAP2) criteria (age 65±12 y) and 42 healthy controls (age 60±12 y), matched for stereoacuity. Visual acuity was assessed binocularly and monocularly at high (95%) and low (25%) contrast using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts at 6 m. Binocular acuity summation was evaluated utilizing a binocular ratio (BR).

Results:

Overall, binocular and monocular visual acuity of the control group was better than that of the glaucoma group for both contrast levels, P=0.001. For the glaucoma group, there was a significant difference between BRs at high and low contrast, 0.01±0.05 and 0.04±0.06 (P=0.003), respectively. For the control group, the difference between BR at high and low contrast was not statistically significant, 0.00±0.07 and 0.02±0.06 (P=0.25), respectively.

Conclusion:

For patients with early glaucoma, binocular summation function for visual acuity was preserved at both contrast levels. This suggests an adaptation of the visual system in early stages of glaucoma that allows for normal binocular summation in the presence of reduced monocular visual input.
Impacts of a Parent-Implemented Language Intervention on Children's Language Development Within Home Visiting
Authors: Pentimonti Jill , Shaw Attaway Danielle , Harris Little Michael , Holod Aleksandra , Buysse Virginia , Walker Dale , Bigelow Kathryn
Published: August 2022

The purpose of this study was to conduct a pilot randomized controlled trial to evaluate the efficacy of an intervention for enhancing the language development of young children enrolled in home visiting programs. The participants were 59 children (18–30 months old) enrolled in one of three types of home visiting programs. Children's language skills were assessed pre- and post-intervention with the Preschool Language Scale. To estimate the impacts of the intervention on children's language scores, we conducted a two-level hierarchical linear model. Results from this model provide promising evidence for the benefits of using systematic parent-implemented language interventions.
Redistribution for Regular Texture Bites for Clinical Pediatric Feeding Cases In-Home
Authors: Taylor Tessa
Published: August 2022

Research has shown effectiveness of redistribution procedures for decreasing packing and increasing swallowing. Redistribution has been done using lower manipulated-texture foods on an infant gum brush in specialized U.S. hospitals. We extended this by using regular texture bites of food in a short-term (1–2 weeks) home-based program in Australia, showing decreased then absent use of the procedure, and following up. Two children with autism spectrum disorder participated. We used a modified withdrawal/reversal design. Latency to swallow decreased. Participants increased variety to 90 and 122 regular texture foods across food groups. All goals were met including increasing independence in self-feeding. Both parents were trained. Gains maintained to 6 months and redistribution was no longer needed.
Exploration of Grit, Self-Reflection and Insight, and Anxiety: A Multisite Study of Doctor of Physical Therapy Students
Authors: Costello Ellen , Huhn Karen , Healey William E. , Hilliard Marjorie Johnson , Plack Margaret M. , Maring Joyce
Published: August 2022

Introduction.

Physical therapist education is rigorous and challenging and reports of mental health concerns in college-aged students continue to rise.

Review of Literature.

Although the association between student mental health and behavioral characteristics has garnered interest, few researchers have examined the relationship across educational programs and years of study. This study aimed to investigate grit, self-reflection, and anxiety in Doctor of Physical Therapy (DPT) students.

Methods.

In this cross-sectional study, 535 DPT students (years 1, 2, 3) enrolled in 3 programs were invited to complete a demographic survey, Grit scale (Grit-S), State portion of the State-Trait Anxiety Inventory (STAI-S), and Self-Reflection and Insight Scale (SRIS). Data analysis summarized demographic variables and survey scores and explored differences and associations among schools, years of study, and demographic variables.

Results.

Two hundred fifty-four students (72.7% female; 76.8% Caucasian; 70.9% aged 20–25 years) participated; response rate of 47.5%. Mean survey scores for Grit-S (3.73; ± .52), SRIS composite (92.01; ± 12.54), and STAI-S (41.94; ± 11.66) showed no meaningful differences among schools. Grit scale scores were lowest in the second year and highest in year 3. Female participants scored higher than male participants on the SRIS engagement subscale. Higher Grit-S scores were associated with lower anxiety scores and higher composite SRIS scores. Higher SRIS composite scores were associated with less anxious students. Anxiety scores were inversely related to insight scores.

Discussion.

Doctor of Physical Therapy student grit scores were generally consistent with published means for health professional students. Self-Reflection and Insight Scale scores for DPT students were higher than nursing and medical students. Students exhibited higher state anxiety scores compared with the general population. Grit Scale changes over time may reflect curricular experiences and growing sense of competence. Relationships among grit, self-reflection, and anxiety may represent an important finding with potential to prompt proactive interventions or support. Further research is needed to understand the impact of demographic factors.
Early atherogenesis: new insights from new approaches
Authors: Scipione Corey A. , Cybulsky Myron I.
Published: August 2022

Purpose of review

To highlight recent conceptual and technological advances that have positioned the field to interrogate the cellular and molecular mechanisms contributing to the initiation of atherosclerosis, including intimal lipid accumulation, inflammation, and lesion growth.

Recent findings

Advances in the understanding of endothelial LDL transcytosis and rapid lipid uptake by intimal macrophages provide mechanistic insights into intimal LDL accumulation and the initiation of atherogenesis. Recent studies have used unbiased single-cell approaches, such as single-cell RNA sequencing and CyTOF, to characterize the cellular components of the normal intima and atherosclerotic lesions. In-vitro studies and high-resolution transcriptomic analysis of aortic intimal lipid-loaded versus lipid-poor myeloid populations in vivo suggest that lipid-loaded macrophages may not be the primary drivers of inflammation in atherosclerotic lesions.

A new perspective on the complex cellular landscape of the aorta, specifically the atherosclerosis-prone regions, confirm that intimal accumulation of lipid, monocyte recruitment, and macrophage accumulation are key events in atherogenesis triggered by hypercholesterolemia. Targeting these early events may prove to be a promising strategy for the attenuation of lesion development; however, the specific details of how hypercholesterolemia acts to initiate early inflammatory events remain to be fully elucidated.
A 2-Phase Survey to Assess a Facility's Readiness for Pediatric Essential Emergency and Critical Care in Resource-Limited Settings
Authors: Fung Jollee S.T. , Hwang Bella , Dunsmuir Dustin , Suiyven Elvis , Nwankwor Odiraa , Tagoola Abner , Trawin Jessica , Ansermino J. Mark , Kissoon Niranjan
Published: August 2022

Objective

Infectious diseases, including pneumonia, malaria, and diarrheal diseases, are the leading causes of death in children younger than 5 years worldwide. The vast majority of these deaths occur in resource-limited settings where there is significant variation in the availability and type of human, physical, and infrastructural resources. The ability to identity gaps in healthcare systems that may hinder their ability to deliver care is an important step to determining specific interventions for quality improvement. Our study objective was to develop a comprehensive, digital, open-access health facility survey to assess facility readiness to provide pediatric critical care in resource-limited settings (eg, low- and lower middle–income countries).

Methods

A literature review of existing facility assessment tools and global guidelines was conducted to generate a database of survey questions. These were then mapped to one of the following 8 domains: hospital statistics, services offered, operational flow, facility infrastructure, staff and training, medicines and equipment, diagnostic capacity, and quality of clinical care. A 2-phase survey was developed and an iterative review process of the survey was undertaken with 12 experts based in low- and middle-income countries. This was built into the REDCap Mobile Application for electronic data capture.

Results

The literature review process yielded 7 facility assessment tools and 7 global guidelines for inclusion. After the iterative review process, the final survey consisted of 11 sections with 457 unique questions in the first phase, “environmental scan,” focusing on the infrastructure, availability, and functionality of resources, and 3 sections with 131 unique questions in the second phase, “observation scan,” focusing on the level of clinical competency.

Conclusions

A comprehensive 2-phase survey was created to evaluate facility readiness for pediatric critical care. Results will assist hospital administrators and policymakers to determine priority areas for quality improvement, enabling them to implement a Plan-Do-Study-Act cycle to improve care for the critically ill child.
Lipid Emulsion Treatment for Drug Toxicity Caused by Nonlocal Anesthetic Drugs in Pediatric Patients
Authors: Lee Soo Hee , Kim Sunmin , Sohn Ju-Tae
Published: August 2022

Objective

Lipid emulsion (LE) has been used to treat children with cardiovascular collapse induced by toxic doses of nonlocal anesthetics with high lipid solubility. We aimed to analyze case reports on LE administration for resuscitation of toxicity induced by these drugs in pediatric patients.

Methods

Case reports involving pediatric patients undergoing LE treatment for toxicity caused by nonlocal anesthetic drugs until December 31, 2021, were searched through PubMed and Scopus using the following terms: “toxicity, or intoxication, or poisoning, or overdose” and “LE or intralipid.”

Results

Twenty-eight cases on LE treatment for toxicity induced by nonlocal anesthetic drugs in pediatric patients (younger than 19 years) were retrieved. The total number of patients was 31. Lipid emulsion treatment was carried out during toxicity caused by amitriptyline, flecainide, bupropion, propranolol, and lamotrigine, which was unresponsive to supportive treatment. These drugs are highly lipid-soluble and inhibit cardiac sodium channels, which is similar to pharmacological properties of the local anesthetic bupivacaine. The most frequent method of delivery involved bolus administration followed by continuous infusion; 1.5 mL/kg LE administration followed by 0.25 mL/kg/min LE was most frequently used. Lipid emulsion improved various symptoms of drug toxicity in 29 patients (29/31, 93.54%), and symptoms were improved in 14 patients (14/31, 45.16%) within an h after LE administration. The trend in frequency of improved symptoms after LE treatment was as follows: the cardiovascular symptom alone > symptoms of the central nervous system alone > symptoms of the cardiovascular and central nervous systems. The adverse effects of LE treatment in the reported cases were hypertriglyceridemia, mild pancreatitis, and elevated levels of aspartate and alanine aminotransaminases.

Conclusions

Lipid emulsion treatment may be effective in ameliorating intractable cardiovascular depression when systemic toxicity caused by drugs, including cardiac sodium channel blockers, is unresponsive to supportive treatments.
Relationships Between Serum Cortisol, RAGE-Associated s100A8/A9 Levels, and Self-Reported Cancer-Related Distress in Women With Nonmetastatic Breast Cancer
Authors: Taub Chloe J. , Diaz Alain , Blomberg Bonnie B. , Jutagir Devika R. , Fisher Hannah M. , Gudenkauf Lisa M. , Lippman Marc E. , Hudson Barry I. , Antoni Michael H.
Published: August 2022

Objective

Elevated inflammation and psychological distress in patients with breast cancer (BCa) have been related to poorer health outcomes. Regulation of the hypothalamic-pituitary-adrenal axis and signaling of the receptor for advanced glycation end products (RAGE) are important in the inflammatory response and have been associated with increased stress and poorer health outcomes in patients with cancer. This study examined relationships among circulating cortisol, a measure of hypothalamic-pituitary-adrenal axis activity and physiological stress; s100A8/A9, a RAGE ligand and emerging cancer-related biological measure; and self-reported cancer-related distress.

Methods

Patients with BCa (N = 183, stages 0–IIIb) were recruited 2 to 10 weeks after surgery but before receiving adjuvant therapies. Participants provided blood samples, from which serum cortisol and s100A8/A9 levels were determined, and completed a psychosocial questionnaire. Regression analyses, adjusting for age, cancer stage, time since surgery, race, and menopausal status, were conducted examining the relationships between cortisol, s100A8/A9, and cancer-related distress (Impact of Event Scale [IES]—Revised).

Results

Cortisol and s100A8/A9 levels were positively related (β = 0.218, t(112) = 2.332, p = .021), although the overall model was not significant. Cortisol levels were also positively associated with IES-Intrusions (β = 0.192, t(163) = 2.659, p = .009) and IES-Hyperarousal subscale scores (β = 0.171, t(163) = 2.304, p = .022).

Conclusions

Patients with higher cortisol levels also reported higher s100A8/A9 levels and more cancer-related distress. The relationship between cortisol and s100A8/A9 supports a link between the stress response and proinflammatory physiological processes known to predict a greater metastatic risk in BCa. Stress processes implicated in cancer biology are complex, and replication and extension of these initial findings are important.
Psychosocial Stress and Hypothalamic-Pituitary-Adrenal Axis Stress Reactivity: Variations by Race and Socioeconomic Status Among Adults at Risk of Diabetes
Authors: Kalesnikava Viktoryia A. , Clarke Philippa J. , Mukherjee Bhramar , Sen Srijan , Mezuk Briana
Published: August 2022

Objective

Although stress is posited to play a key role in health disparities, the extent to which commonly used self-report psychosocial stress measures are related to neurobiological stress processes, especially across diverse populations, is unresolved. This study examined how two measures of psychosocial stress, perceived stress and domain-specific stress, covary with the acute neurobiological stress response.

Methods

The Richmond Stress and Sugar Study includes a racially and socioeconomically diverse cohort of adults at risk for type 2 diabetes (n = 125; mean age = 57 years, 48% Black, and 61% high neighborhood socioeconomic status [SES]). Hypothalamic-pituitary-adrenal axis reactivity was assessed by salivary cortisol response to the Trier Social Stress Test (TSST), a laboratory stressor.

Results

Higher perceived stress was associated with a lower cortisol response to the TSST (−7.5%; 95% confidence interval [CI] = −13.1% to −1.5%) but was not associated with cortisol recovery after the TSST (3%; 95% CI = −0.6% to 6.8%). In contrast, domain-specific stress was not associated with cortisol response (−2.1%; 95% CI = −20.7% to 20.9%) but was inversely associated with cortisol recovery (3.7%; 95% CI = 0.6% to 7.0%). SES modified these associations: both perceived stress and domain-specific stress were associated with TSST cortisol response only among participants from high-SES neighborhoods. There was minimal evidence of effect modification by race.

Conclusions

Both self-report measures of psychosocial stress were associated with hypothalamic-pituitary-adrenal axis reactivity to an acute stressor. These associations varied by perceived versus domain-specific measurement scales and by neighborhood SES. Further efforts to refine stress measures and clarify biological linkages between social status and health are needed.
Biomarkers for Chronic Lung Allograft Dysfunction: Ready for Prime Time?
Authors: Verleden Stijn E. , Hendriks Jeroen M.H. , Lauwers Patrick , Yogeswaran Suresh Krishan , Verplancke Veronique , Kwakkel-Van-Erp Johanna M.
Published: August 2022

Chronic lung allograft dysfunction (CLAD) remains a major hurdle impairing lung transplant outcome. Parallel to the better clinical identification and characterization of CLAD and CLAD phenotypes, there is an increasing urge to find adequate biomarkers that could assist in the earlier detection and differential diagnosis of CLAD phenotypes, as well as disease prognostication. The current status and state-of-the-art of biomarker research in CLAD will be discussed with a particular focus on radiological biomarkers or biomarkers found in peripheral tissue, bronchoalveolar lavage‚ and circulating blood‚ in which significant progress has been made over the last years. Ultimately, although a growing number of biomarkers are currently being embedded in the follow-up of lung transplant patients, it is clear that one size does not fit all. The future of biomarker research probably lies in the rigorous combination of clinical information with findings in tissue, bronchoalveolar lavage‚ or blood. Only by doing so, the ultimate goal of biomarker research can be achieved, which is the earlier identification of CLAD before its clinical manifestation. This is desperately needed to improve the prognosis of patients with CLAD after lung transplantation.
Acceptability of transdermal antipsychotic patches by patients who refuse oral medication and their effectiveness in preventing recurrence of delirium: a retrospective observational study
Authors: Hatta Kotaro , Usui Chie , Nakamura Hiroyuki
Published: August 2022

Injectable antipsychotics had been used for patients who refuse oral medications in delirium practice. The objectives were to investigate acceptability of transdermal antipsychotic patches by patients who refuse oral medications and their effectiveness in preventing recurrence of delirium. In this retrospective observational study, data were collected between October 2019 and December 2021. The sample was represented by patients hospitalized because of acute diseases or elective surgery who had delirium on the night before the consultation and had refused oral therapy after consultation. Delirium has been diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Instead, a transdermal patch of blonanserin, a second-generation antipsychotic drug, was tried. The primary outcome was the rate of patients who accepted it. The secondary outcome was recurrence rates of delirium. As much as 95.1% of patients who refused oral medications (98/103 patients) accepted to receive the transdermal patch. Of these, 24 patients developed delirium again, whereas all five patients who refused it developed delirium again [24.5% (24/98) vs. 100% (5/5); P = 0.0014]. The present findings suggest that transdermal antipsychotic patches are more likely to be accepted by patients who refuse oral medications. Prospective studies are needed.
Two years of COVID-19: Excess mortality by age, region, gender, and race/ethnicity in the United States during the COVID-19 pandemic, March 1, 2020, through February 28, 2022
Authors: Faust Jeremy Samuel , Du Chengan , Renton Benjamin , Liang Chenxue , Chen Alexander Junxiang , Li Shu-Xia , Lin Zhenqiu , Nunez-Smith Marcella , Krumholz Harlan M.
Published: August 2022

Introduction

Excess mortality does not depend on labeling the cause of death and is an accurate representation of the pandemic population-level effects. A comprehensive evaluation of all-cause excess mortality in the United States during the first two years of the COVID-19 pandemic, stratified by age, sex, region, and race/ethnicity can provide insight into the extent and variation in harm.

Methods

With Centers for Disease Control and Prevention (CDC)/National Center for Health Statistics (NCHS) data from 2014-2022, we use seasonal autoregressive integrated moving averages (sARIMA) to estimate excess mortality during the pandemic, defined as the difference between the number of observed and expected deaths. We continuously correct monthly expected deaths to reflect the decreased population owing to cumulative pandemic-associated excess deaths recorded. We calculate excess mortality for the total US population, and by age, sex, US census division, and race/ethnicity.

Results

From March 1, 2020, through February 28, 2022, there were 1.17 million excess deaths in the United States. Overall, mortality was 20% higher than expected during the study period. Of the excess deaths, 799,477 (68%) were among residents aged 65 and older. The largest relative increase in all-cause mortality was 27% among adults ages 18-49 years. Males comprised most of the excess mortality (57%), but this predominance declined with age. A higher relative mortality occurred among non-Hispanic American Indian/Alaskan Native, non-Hispanic Black, non-Hispanic Native Hawaiian and Other Pacific Islander, Hispanic people. Excess mortality differed by region; the highest rates were in the South, including in the population ages ≥65 years. Excess mortality rose and fell contemporaneously with COVID-19 waves.

Conclusion

In the first two years of the pandemic, the US experienced 1.17 million excess deaths, with greater relative increases in all-cause mortality among men, in American Indian/Alaskan Native, Black and Hispanic people, and the South.
Assessment of pathogens in flood waters in coastal rural regions: Case study after Hurricane Michael and Florence
Authors: Usmani Moiz , Uprety Sital , Sano Daisuke , Shisler Joanna , Unnikrishnan Avinash , Nguyen Thanh H. , Jutla Antarpreet
Published: August 2022

The severity of hurricanes, and thus the associated impacts, is changing over time. One of the understudied threats from damage caused by hurricanes is the potential of cross-contamination of water bodies with pathogens in coastal agricultural regions. Using microbiological data collected after hurricanes Florence and Michael, this study shows a dichotomy in the presence of pathogens in coastal North Carolina and Florida. Salmonella Typhimurium was abundant in water samples collected in the regions dominated by the swine farms. A drastic decrease in Enterococcus spp. in Carolinas is indicative of pathogen removal with flooding waters. Except for the abundance presence of Salmonella, no significant changes in pathogens were observed after Hurricane Michael in the Florida panhandle. We argue that a comprehensive assessment of pathogens must be included in decision-making activities in the immediate aftermath of hurricanes to build resilience against risks of pathogenic exposure in rural agricultural and human populations in vulnerable locations.
Sirt3 enhanced Bufalin sensitivity of colorectal cancer cells through P53- dependent pathway of apoptosis
Authors: Li Lu , Liu Cui , Zhang Xinqing , Meng Xiao , Geng Yaxiao , Shi Zhigang , Zhang Yongzhi
Published: August 2022

Sirt3, one of class III histone deacetylase, is mainly localized in mitochondria and plays a significant role in the control of the metabolic activity, senescence and death [1]. Recently, Sirt3 emerged as a novel member of anticancer. However, the role of Sirt3 in colorectal cancer (CRC) has never been explained exactly. In this study, we found that sirt3 is down-regulated after Bufalin treatment. We also found that AC-P53 is up-regulated which induces Bax translocation to mitochondrion and open the mitochondrial permeability transition (mPTP) pores result in the release of cytochrome C lead to the activation of caspase-dependent apoptosis pathway. Collectively, our data suggests that Sirt3 may play an important role in CRC development and progression and may be a promising therapeutic target for CRC.
Chromosome-level genome of the three-spot damselfish, Dascyllus trimaculatus
Authors: Roberts May B. , Schultz Darrin T. , Gatins Remy , Escalona Merly , Bernardi Giacomo
Published: August 2022

Damselfishes (Family: Pomacentridae) are a group of ecologically important, primarily coral reef fishes that include over 400 species. Damselfishes have been used as model organisms to study recruitment (anemonefishes), the effects of ocean acidification (spiny damselfish), population structure and speciation (Dascyllus). The genus Dascyllus includes a group of small bodied species, and a complex of relatively larger bodied species, the Dascyllus trimaculatus species complex that comprises several species including D. trimaculatus itself. The three-spot damselfish, D. trimaculatus is a widespread and common coral reef fish species found across the tropical Indo-Pacific. Here we present the first genome assembly of this species. This assembly contains 910 Mb, 90% of the bases are in 24 chromosome-scale scaffolds, and the BUSCO score of the assembly is 97.9%. Our findings confirm previous reports of a karyotype of 2n = 47 in D. trimaculatus in which one parent contributes 24 chromosomes and the other 23. We find evidence that this karyotype is the result of a heterozygous Robertsonian fusion. We also find that the D. trimaculatus chromosomes are each homologous with single chromosomes of the closely related clownfish species, Amphiprion percula. This assembly will be a valuable resource in the population genomics and conservation of Damselfishes, and continued studies of the karyotypic diversity in this clade.
Noninvasive Proteomic Markers for Respiratory Tract Infections in Mechanically Ventilated Patients
Authors: Chen Dapeng , Mirski Marek A. , Chen Shuo , Devin Alese P. , Haddaway Caroline R. , Caton Emily R. , Bryden Wayne A. , McLoughlin Michael
Published: August 2022

Introduction

Early and accurate diagnosis of respiratory tract infections (RTI) in critical care settings is essential for appropriate antibiotic treatment and lowering mortality. The current diagnostic methods face critical challenges, including the lack of noninvasive specimens from the site of infection and molecular biomarkers that can predict disease progression and treatment effect. In this study, we addressed these critical challenges by developing a noninvasive method based on the characterization of truncated proteoforms contained in exhaled air collected from mechanically ventilated patients.

Methods

Exhaled air samples were collected from twenty-five intubated patients with RTI and twenty-two intubated patients without RTI, determined by clinical data and microbiological testing. Truncated proteoforms were identified using top-down proteomics. Feature selection algorithms were used to identify significant truncated proteoforms associated with RTI. A score system combining the significant truncated proteoforms was constructed and evaluated using multiple logistic regression to predict RTI.

Results

The results showed that six truncated proteoforms of lung structure and proteolytic proteins were statistically different between intubated patients with and without RTI. Specifically, the truncated proteoforms of collagen type VI alpha three chain protein, matrix metalloproteinase 9, and putative homeodomain transcription factor 2 were found to be independently associated with RTI. A score system named TrunScore was constructed by combining the three truncated proteoforms, and the diagnostic accuracy was significantly improved compared to individual truncated proteoforms.

Conclusions

In this study, we presented a noninvasive method to address the current challenges in diagnosing RTI in critical care settings, by characterizing truncated proteoforms contained in exhaled air from intubated patients. The method provides an accurate prediction for RTI in mechanically ventilated patients and can help diagnose other respiratory tract diseases.
Prediction of diabetic kidney disease risk using machine learning models: a population-based cohort study of Asian adults
Authors: Sabanayagam Charumathi , He Feng , Nusinovici Simon , Li Jialiang , Lim Cynthia , Tan Gavin , Cheng Ching-Yu
Published: August 2022

Background

Machine learning (ML) techniques improve disease prediction by identifying the most relevant features in multi-dimensional data. We compared the accuracy of ML algorithms for predicting incident diabetic kidney disease (DKD).

Methods

We utilized longitudinal data from 1365 Chinese, Malay and Indian participants aged 40-80 years with diabetes but free of DKD who participated in the baseline and 6-year follow-up visit of the Singapore Epidemiology of Eye Diseases Study (2004-2017). Incident DKD (11.9%) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 with at least 25% decrease in eGFR at follow-up from baseline. 339 features including participant characteristics, retinal imaging, genetic and blood metabolites were used as predictors. Performances of several ML models were compared to each other and to logic regression (LR) model based on established features of DKD (age, sex, ethnicity, duration of diabetes, systolic blood pressure, HbA1c, and body mass index) using area under the receiver operating characteristic curve (AUC).

Results

ML model, Elastic Net (EN) had the best AUC (95% confidence interval) of 0.851 (0.847-0.856), which was 7.0% relatively higher than by LR 0.795 (0.790-0.801). Sensitivity and specificity of EN were 88.2% and 65.9% vs. 73.0% and 72.8% by LR. The top-15 predictors included age, ethnicity, antidiabetic medication, hypertension, diabetic retinopathy, systolic blood pressure, HbA1c, eGFR and metabolites related to lipids, lipoproteins, fatty acids and ketone bodies.

Conclusions

Our results showed ML together with feature selection improves prediction accuracy of DKD risk in an asymptomatic stable population and identifies novel risk factors including metabolites.

Funding Support

This study was supported by the National Medical Research Council, NMRC/OFLCG/001/2017 and NMRC/HCSAINV/MOH-001019-00. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

None declared.
Non-invasive tumor probability maps developed using autopsy tissue identify novel areas of tumor beyond the imaging-defined margin
Authors: Bobholz Samuel A. , Lowman Allison K. , Connelly Jennifer M. , Duenweg Savannah R. , Kyereme Fitzgerald , Winiarz Aleksandra , Stebbins Margaret A. , Nath Biprojit , Brehler Michael , Bukowy John , Cochran Elizabeth J. , Coss Dylan , Lupo Janine M. , Phillips Joanna J. , Ellingson Benjamin M. , Krucoff Max , Mueller Wade M. , Agarwal Mohit , Banerjee Anjishnu , LaViolette Peter S.
Published: August 2022

Background

This study identified a clinically significant subset of glioma patients with tumor outside of contrast-enhancement present at autopsy, and subsequently developed a method for detecting non-enhancing tumor using radio-pathomic mapping. We tested the hypothesis that autopsy-based radio-pathomic tumor probability maps would be able to non-invasively identify areas of infiltrative tumor beyond traditional imaging signatures.

Methods

A total of 159 tissue samples from 65 subjects were aligned to MRI acquired nearest to death for this study. Demographic and survival characteristics for patients with and without tumor beyond the contrast-enhancing margin were computed. An ensemble algorithm was used to predict pixelwise tumor presence from pathological annotations using segmented cellularity (Cell), extracellular fluid (ECF), and cytoplasm (Cyt) density as input (6 train/3 test subjects). A second level of ensemble algorithms were used to predict voxel-wise Cell, ECF, and Cyt on the full dataset (43 train/22 test subjects) using 5-by-5 voxel tiles from T1, T1+C, FLAIR, and ADC as input. The models were then combined to generate non-invasive whole brain maps of tumor probability.

Results

Tumor outside of contrast was identified in 41.5 percent of patients, who showed worse survival outcomes (HR=3.90, p<0.001). Tumor probability maps reliably tracked non-enhancing tumor in the test set, external data collected pre-surgery, and longitudinal data to identify treatment-related changes and anticipate recurrence.

Conclusions

This study developed a multi-1 stage model for mapping gliomas using autopsy tissue samples as ground truth, which was able to identify regions of tumor beyond traditional imaging signatures.
Charge neutralization of the active site glutamates does not limit substrate binding and transport by EmrE
Authors: Spreacker Peyton J. , Brousseau Merissa , Hisao Grant S. , Soltani Mohammad , Davis James H. , Henzler-Wildman Katherine A.
Published: August 2022

EmrE, a small multidrug resistance (SMR) transporter from E. coli, confers broad-spectrum resistance to polyaromatic cations and quaternary ammonium compounds. Previous transport assays demonstrate that EmrE transports a +1 and a +2 substrate with the same stoichiometry of 2 protons:1 cationic substrate. This suggests that EmrE substrate binding capacity is limited to neutralization of the two essential glutamates, E14A and E14B (one from each subunit in the antiparallel homodimer), in the primary binding site. Here we explicitly test this hypothesis, since EmrE has repeatedly broken expectations for membrane protein structure and transport mechanism. We previously showed that EmrE can bind a +1 cationic substrate and proton simultaneously, with cationic substrate strongly associated with one E14 residue while the other remains accessible to bind and transport a proton. Here we demonstrate that EmrE can bind a +2 cation substrate and a proton simultaneously using NMR pH titrations of EmrE saturated with divalent substrates, for a net +1 charge in the transport pore. Further, we find that EmrE can alternate access and transport a +2 substrate and proton at the same time. Together, these results lead us to conclude that E14 charge neutralization does not limit the binding and transport capacity of EmrE.
Insane in the vembrane: filtering and transforming VCF/BCF files
Authors: Hartmann Till , Schröder Christopher , Kuthe Elias , Lähnemann David , Köster Johannes
Published: August 2022

Data from sequencing of DNA or RNA samples is routinely scanned for variation. Such variation data is stored in the standardized VCF/BCF format with additional annotations. Analyses of variants usually involve steps where filters are applied to narrow down the list of candidates for further analysis. A number of tools for this task exist, differing in functionality, speed, syntax and supported annotations. Thus, users have to switch between tools depending on the filtering task, and have to adapt to the respective filtering syntax. We present vembrane as a command line VCF/BCF filtering tool that consolidates and extends the filtering functionality of previous software to meet any imaginable filtering use case. To this end, vembrane exposes the VCF/BCF file type specification and its inofficial extensions by the annotation tools VEP and SnpEff as Python data structures. vembrane filter enables filtration by arbitrary Python expressions over (combinations of) annotations, requiring only basic knowledge of the Python programming language. vembrane table allows users to generate tables from subsets of annotations or functions thereof. Finally, it is fast, thanks to pysam, a Python wrapper around htslib, and by relying on Python’s lazy evaluation.

Availability and Implementation

Source code and installation instructions are available at github.com/vembrane/vembrane, DOI: 10.5281/zen-odo.7003981.
Clostridioides difficilePCR ribotype 151 is polyphyletic and includes pathogenic isolates from cryptic clade C-II with mono-toxin pathogenicity loci that can escape routine diagnostics
Authors: Ducarmon Quinten R. , van der Bruggen Tjomme , Harmanus Céline , Sanders Ingrid M.J.G. , Daenen Laura G.M. , Fluit Ad C. , Vossen Rolf H.A.M. , Kloet Susan L. , Kuijper Ed J. , Smits Wiep Klaas
Published: August 2022

We report a patient case with pseudomembranous colitis associated with a mono-toxin producingClostridioides difficilebelonging to the very rarely diagnosed PCR ribotype (RT) 151. The infection was difficult to diagnose, since the isolate and the feces sample tested negative for toxin-encoding genes using a routine commercial test. This prompted us to sequence n = 11 RT151s from various geographical regions to study their genomic characteristics and relatedness. By including whole genome sequence data from other sources, we could further place these isolates into the phylogenetic tree ofC. difficileand assign them to their respective clades. These analyses revealed that 1) RT151s are polyphyletic with isolates falling into clades 1, and cryptic clades C-I and C-II 2) RT151 contains both non-toxigenic and toxigenic isolates and 3) RT151 C-II isolates contained mono-toxin pathogenicity loci (PaLoc). Additional analysis with PacBio circular consensus sequencing revealed that the isolate from our patient case report contains a novel PaLoc insertion site, lackedtcdAand a had significantly divergenttcdBsequence that might explain the failure of the diagnostic test. The study is noteworthy as 1) RT151 encompasses both typical and cryptic clades and 2) conclusive evidence for CDI due to clade C-II isolates was hitherto lacking.
CRISPR Screens Identify Novel Regulators of cFLIP Dependency and Ligand-Independent, TRAIL-R1-Mediated Cell Death
Authors: Kuehnle Neil , Osborne Scout Mask , Liang Ziyan , Manzano Mark , Gottwein Eva
Published: August 2022

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). PEL cell lines require expression of the cellular FLICE inhibitory protein (cFLIP) for survival, although KSHV encodes a viral homolog of this protein (vFLIP). Cellular and viral FLIP proteins have several functions, including, most importantly, the inhibition of pro-apoptotic caspase 8 and modulation of NF-κB signaling. To investigate the essential role of cFLIP and its potential redundancy with vFLIP in PEL cells, we first performed rescue experiments with human or viral FLIP proteins known to affect FLIP target pathways differently. The long and short isoforms of cFLIP and molluscum contagiosum virus MC159L, which are all strong caspase 8 inhibitors, efficiently rescued the loss of endogenous cFLIP activity in PEL cells. KSHV vFLIP was unable to fully rescue the loss of endogenous cFLIP and is therefore functionally distinct. Next, we employed genome-wide CRISPR/Cas9 synthetic rescue screens to identify loss of function perturbations that can compensate for cFLIP knockout. Results from these screens and our validation experiments implicate the canonical cFLIP target caspase 8 and TRAIL receptor 1 (TRAIL-R1 or TNFRSF10A) in promoting constitutive death signaling in PEL cells. However, this process was independent of TRAIL receptor 2 or TRAIL, the latter of which is not detectable in PEL cell cultures. The requirement for cFLIP is also overcome by inactivation of the ER/Golgi resident chondroitin sulfate proteoglycan synthesis and UFMylation pathways, Jagunal homolog 1 (JAGN1) or CXCR4. UFMylation and JAGN1, but not chondroitin sulfate proteoglycan synthesis or CXCR4, contribute to TRAIL-R1 expression. In sum, our work shows that cFLIP is required in PEL cells to inhibit ligand-independent TRAIL-R1 cell death signaling downstream of a complex set of ER/Golgi-associated processes that have not previously been implicated in cFLIP or TRAIL-R1 function.
ΔNp63 Regulates Homeostasis, Stemness, and Suppression of Inflammation in the Adult Epidermis
Authors: Eyermann Christopher E. , Chen Xi , Somuncu Ozge S. , Li Jinyu , Joukov Alexander N. , Chen Jiang , Alexandrova Evguenia M.
Published: August 2022

The p63 transcription factor is critical for epidermis formation in embryonic development, but its role in the adult epidermis is poorly understood. Here we show that acute genetic ablation of ΔNp63, the main p63 isoform, in adult epidermis disrupts keratinocyte proliferation and self-maintenance and, unexpectedly, triggers an inflammatory psoriasis-like condition. Mechanistically, single-cell RNA sequencing revealed down-regulation of the cell cycle genes, up-regulation of differentiation markers, and induction of several pro-inflammatory pathways in ΔNp63-ablated keratinocytes. Intriguingly, ΔNp63-ablated cells disappear three weeks post-ablation, at the expense of the remaining non-ablated cells. This is not associated with active cell death mechanisms, but rather with reduced self-maintenance capacity. Indeed,in vivowound healing assay, a physiological readout of the epidermal stem cell function, is severely impaired in ΔNp63-ablated mice. We found that the Wnt signaling pathway (Wnt10a, Fzd6, Fzd10) and the AP1 factors (JunB, Fos, FosB) are the likely ΔNp63 effectors responsible for keratinocyte proliferation/stemness and suppression of differentiation, respectively, while interleukins IL-1a, IL-18, IL-24, and IL-36γ are the likely negative effectors responsible for the suppression of inflammation. These data establish ΔNp63 as a critical node that coordinates epidermal homeostasis, stemness, and suppression of inflammation in the adult epidermis, upstream of known regulatory pathways.
Loss of LRP1 in adult neural stem cells impairs migration to ischemic lesions
Authors: Dietert Kristi , Mahesula Swetha , Hegde Sheetal , Verschelde John , Reed Pamela , Sprague Shane , Kokovay Erzsebet , Sayre Naomi L.
Published: August 2022

After ischemia, cells in the brain parenchyma upregulate stromal derived factor 1 (SDF1), driving chemokine receptor CXCR4-mediated migration of adult neural stem cells from the subventricular zone (SVZ) to the ischemic injury. We discovered a novel regulator of CXCR4 in neural stem cells, low-density lipoprotein receptor related protein 1 (LRP1). We employed a tamoxifen-inducible Nestin-Cre to drive expression of a tdTomato reporter and also knockout floxed LRP1 in adult mice and then subjected mice to middle-cerebral artery occlusion. Examination 2 weeks post-stroke reveals a loss of tdTomato positive cells localizing from the SVZ to the lesion. We show that loss of LRP1 disrupts CXCR4-mediated neural stem cell migration in vitro, which is likely driven by LRP1-mediated loss of CXCR4 expression in vivo. Altogether, our results suggest that LRP1 is a novel regulator of CXCR4 in neural stem cells.

Highlights

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LRP1 KO in adult neural stem cells disrupts migration to ischemic lesions in vivo.

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LRP1 KO in adult neural stem cells disrupts migration towards SDF1 in vitro.

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LRP1 positively regulates expression of CXCR4 in adult neural stem cells.

eTOC blurb

Adult neural stem cells can home to ischemic brain injury and are considered an important part of the repair process after stroke. However, little is known about what molecules help drive this response. The authors discovered that LRP1 is a novel regulator of CXCR4, which is essential for neural stem cell migration to ischemic injury.
Behavioral entrainment to rhythmic auditory stimulation can be modulated by tACS depending on the electrical stimulation field properties
Authors: Cabral-Calderin Yuranny , Hinsberg Daniela van , Thielscher Axel , Henry Molly J.
Published: August 2022

Synchronization between auditory stimuli and brain rhythms is beneficial for perception. In principle, auditory perception could be improved by facilitating neural entrainment to sounds via brain stimulation. However, high inter-individual variability of brain stimulation effects questions the usefulness of this approach. Here we aimed to modulate auditory perception by modulating neural entrainment to frequency modulated (FM) sounds using transcranial alternating current stimulation (tACS). In addition, we evaluated the advantage of using tACS montages spatially optimized for each individual’s anatomy and functional data compared to a standard montage applied to all participants. Across two different sessions, 2-Hz tACS was applied targeting auditory brain regions. Concurrent with tACS, participants listened to FM stimuli with modulation rate matching the tACS frequency but with different phase lags relative to the tACS, and detected silent gaps embedded in the FM sound. We observed that tACS modulated the strength of behavioral entrainment to the FM sound in a phase-lag specific manner. Both the optimal tACS lag and the magnitude of the tACS effect were variable across participants and sessions. Inter-individual variability of tACS effects was best explained by the strength of the inward electric field, depending on the field focality and proximity to the target brain region. Although additional evidence is necessary, our results also provided suggestive insights that spatially optimizing the electrode montage could be a promising tool to reduce inter-individual variability of tACS effects. This work demonstrates that tACS effectively modulates entrainment to sounds depending on the optimality of the electric field. However, the lack of reliability on optimal tACS lags calls for caution when planning tACS experiments based on separate sessions.