bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrasound and MR muscle imaging in new onset idiopathic inflammatory myopathies at diagnosis and after treatment: a comparative pilot study
Authors: Walter Anne W , Lim Johan , Raaphorst Joost , Smithuis Frank F , den Harder J Michiel , Eftimov Filip , Potters Wouter , Saris Christiaan G J , de Visser Marianne , van Schaik Ivo N , de Haan Rob J , van der Kooi Anneke J , Verhamme Camiel
Published: May 2022

Objectives

To prospectively compare ultrasound (US) and whole-body MRI for detection of muscle abnormalities compatible with idiopathic inflammatory myopathies (IIM).

Methods

Newly diagnosed IIM patients underwent US (14 muscles) and MRI (36 muscles) at diagnosis and after nine weeks monotherapy with intravenous immunoglobulin. Muscles were compatible with IIM when quantitative US echo-intensity (EI) z scores was ≥1.5, semi-quantitative US Heckmatt score was ≥2, qualitative US was abnormal, or when MRI showed oedema on T2-weighted images. At patient level, findings were classified as abnormal when quantitative US EI z scores was >1.5 (n = 3 muscles), >2.5 (n = 2 muscles) or >3.5 (n = 1 muscle), or if ≥3 muscles showed abnormalities as described above for the other diagnostic methods.

Results

At diagnosis, in 18 patients US of 252 muscles revealed abnormalities in 36 muscles (14%) with quantitative, in 153 (61%) with semi-quantitative and in 168 (67%) with qualitative analysis. MRI showed oedema in 476 out of 623 muscles (76%). Five patients (28%) reached abnormal classification with quantitative US, 16 (89%) with semi-quantitative and qualitative US, and all patients (100%) with MRI. Nine-week follow-up of 12 patients showed no change over time with quantitative US or MRI, and a decrease in abnormalities with semi-quantitative US (P <0.01), and qualitative US (P <0.01).

Conclusion

At diagnosis, MRI was more sensitive than US to detect muscle abnormalities compatible with IIM. Semi-quantitative US and qualitative US detected abnormalities in the majority of the patients while evaluating fewer muscles than MRI and showed change over time after nine weeks of treatment.
Identification and functional characterization of imbalanced osteoarthritis-associated fibronectin splice variants
Authors: van Hoolwerff Marcella , Tuerlings Margo , Wijnen Imke J L , Suchiman H Eka D , Cats Davy , Mei Hailiang , Nelissen Rob G H H , van der Linden–van der Zwaag Henrike M J , Ramos Yolande F M , Coutinho de Almeida Rodrigo , Meulenbelt Ingrid
Published: May 2022

Objective

To identify FN1 transcripts associated with OA pathophysiology and investigate the downstream effects of modulating FN1 expression and relative transcript ratio.

Methods

FN1 transcriptomic data was obtained from our previously assessed RNA-seq dataset of lesioned and preserved OA cartilage samples from the Research osteoArthritis Articular Cartilage (RAAK) study. Differential transcript expression analysis was performed on all 27 FN1 transcripts annotated in the Ensembl database. Human primary chondrocytes were transduced with lentiviral particles containing short hairpin RNA (shRNA) targeting full-length FN1 transcripts or non-targeting shRNA. Subsequently, matrix deposition was induced in our 3D in vitro neo-cartilage model. Effects of changes in the FN1 transcript ratio on sulphated glycosaminoglycan (sGAG) deposition were investigated by Alcian blue staining and dimethylmethylene blue assay. Moreover, gene expression levels of 17 cartilage-relevant markers were determined by reverse transcription quantitative polymerase chain reaction.

Results

We identified 16 FN1 transcripts differentially expressed between lesioned and preserved cartilage. FN1-208, encoding migration-stimulating factor, was the most significantly differentially expressed protein coding transcript. Downregulation of full-length FN1 and a concomitant increased FN1-208 ratio resulted in decreased sGAG deposition as well as decreased ACAN and COL2A1 and increased ADAMTS-5, ITGB1 and ITGB5 gene expression levels.

Conclusion

We show that full-length FN1 downregulation and concomitant relative FN1-208 upregulation was unbeneficial for deposition of cartilage matrix, likely due to decreased availability of the classical RGD (Arg-Gly-Asp) integrin-binding site of fibronectin.
ESTABLISHMENT OF REGIONAL DIAGNOSTIC REFERENCE LEVELS IN ADULT COMPUTED TOMOGRAPHY FOR FOUR AFRICAN COUNTRIES: A PRELIMINARY SURVEY
Authors: Uushona Vera , Boadu Mary , Nyabanda Rose , Diagne Magatte , Inkoom Stephen , Issahaku Shiraz , Hasford Francis , Haiduwa Paulus , Koteng Arthur , Omondi Bob , Diop Adji Yaram , Gilley Debbie Bray
Published: May 2022

This preliminary study aims towards the establishment of regional diagnostic reference levels (DRLs) for routine adult computed tomography (CT) examinations. The study was performed on 54 CT facilities from four African countries (Ghana, Kenya, Namibia and Senegal) and the results compared with international DRLs. Data were collected from facilities using a structured questionnaire provided by the International Atomic Energy Agency. Dose descriptors (volume computed tomography dose index [CTDIvol] and dose length product [DLP]) evaluations were performed on CT head and body phantoms for head, chest and abdomen CT examination protocols using standard methods. The estimated dose indices were compared with console-displayed dose values. Experienced radiologists accepted the diagnostic image quality of the images as per departmental imaging requirements. Median CTDIvol and DLP data from each facility were compiled to estimate the typical dose in each country. National DRLs were established based on the 75th percentile of median values, whereas the regional DRLs were based on the median of the national DRLs. Comparison of measured CTDIvol with console values of all facilities in all four countries was within 20% as recommended. The established CTDIvol DRLs for head CT, chest CT and abdomen CT were 60.9 mGy, 15.2 mGy and 15.7 mGy, respectively. Similarly, that of DLP, DRLs were 1259 mGy.cm, 544 mGy.cm and 737 mGy.cm, respectively for head CT, chest CT and abdomen CT. The established DRLs from this study were comparable to DRLs from other countries with some variations. This study would serve as baseline for establishment of a more generalized regional adult CT DRLs for Africa.
FATCA, CRS and Public BO registers: a report on the direction of travel—the next 12 months
Authors: Noseda Filippo
Published: May 2022

The author represents a number of clients in ongoing litigation against the excessive nature of public registers of beneficial ownership, the US Foreign Account Tax Compliance Act (FATCA) and the Common Reporting Standard (CRS). Cases are pending before the courts in Austria, Germany, Luxembourg and the UK. The question relating to the compatibility of public registers of beneficial ownership with individuals’ fundamental rights to privacy and data protection is currently before the Court of Justice of the European Union (CJEU). The European Union’s Advocate General has already issued his opinion and a judgment is expected in the coming months.
Effects of a multicomponent microbial feed additive containing prebiotics and probiotics on health, immune status, metabolism, and performance of newly weaned beef steers during a 35-d receiving period
Authors: Idowu Modoluwamu D , Taiwo Godstime , Pech Cervantes Andres , Bowdridge Scott A , Ogunade Ibukun M
Published: May 2022

We examined the effects of dietary supplementation of a multicomponent blend of prebiotics and probiotics on health, immune status, metabolism, and performance of newly weaned beef steers during a 35-d receiving period. Eighty newly weaned crossbred steers (12-hour postweaning; 206 ± 12 kg of body weight [BW]) from a single source were stratified by BW into four pens (20 steers per pen) such that each pen had similar BW at the beginning of the experiment. The pens were randomly assigned to receive a corn silage-based diet with no additive (CON; two pens; n = 40 steers) or a basal diet supplemented with SYNB feed additive at an average of 28 g/steer/d (SYNB; two pens; n = 40 steers). The SYNB additive is a blend of live Saccharomyces cerevisiae and the fermentation products of S. cerevisiae, Enterococcus lactis, Bacillus licheniformis, and Bacillus subtilis and was supplemented for the first 21 d only. Percentage of steers treated for bovine respiratory disease (BRD) was calculated for each dietary treatment. Daily dry matter intake (DMI) and meal events (meal frequency and duration) were measured. Weekly BWs were measured to calculate average daily gain (ADG). Blood samples collected on days 0, 14, 21, 28, and 35 were used for ex-vivo tumor necrosis factor alpha (TNF-α) release assay following lipopolysaccharides (LPS) stimulation, plasma metabolome analysis, and mRNA expression analysis of 84 innate and adaptive immune-related genes. Compared with CON, supplemental SYNB increased (P ≤ 0.05) ADG, DMI, and meal events during the first 7 d. At d 21, there was no treatment effect (P > 0.05) on final BW, DMI, ADG, and meal events; however, beef steers fed supplemental SYNB had greater (P = 0.02) meal duration. Over the entire 35-d receiving period, beef steers fed supplemental SYNB had greater (P = 0.01) ADG and feed efficiency, tended to have greater (P = 0.08) meal duration, and had lower percentage (35 vs. 50%) of animals treated for BRD and lower percentage of sick animals treated for BRD more than once (7.15 vs. 45%). Whole blood expression of pro-inflammatory genes was downregulated while that of anti-inflammatory genes was upregulated in beef steers fed supplemental SYNB. Beef steers fed supplemental SYNB had lower (P = 0.03) plasma concentration of TNF-α after LPS stimulation. Six nutrient metabolic pathways associated with health benefits were enriched (false discovery rate ≤ 0.05) in beef steers fed supplemental SYNB. This study demonstrated that dietary supplementation of SYNB during the first 21 d of arrival reduced BRD morbidity, improved the performance, immune, and metabolic status of beef steers over a 35-d receiving period thereby extending the SYNB effect by a further 14 days post supplementation.
Intake of corn stover botanical parts by growing and finishing beef steers
Authors: Karls Caleb W , Shinners Kevin J , Schaefer Daniel M
Published: May 2022

Single-pass corn stover harvest is a method whereby combine harvester tailings consisting of cob, stalk, leaf, husk, and tassel fractions are collected and baled without coming into contact with soil. The objective was to feed beef steers diets that included a roughage component consisting of harvested corn residue in chopped form from conventional corn stover bales (CST) or single-pass bales (SPB) to assess intake selectivity of corn stover fractions and estimate net energy values of these corn stovers. Whole plant corn silage served as the control roughage in the control diet (CSIL). Steers (n = 90, 5 pens per treatment) were fed during Grow (84 d) and Finish (66 d) trials. Steers sorted through corn stover during both trials and consumed 52.5% of corn stover offered and 40% of cob offered. Intake of SPB cob was 2.6-fold and 3.3-fold greater than CST cob intake (P < 0.01) in Grow and Finish trials, respectively, indicating that when more cob was available, cattle consumed more. During the Grow trial, stover intake tended (P = 0.07) to be lower for SPB and diet dry matter intake (DMI) was less (P ≤ 0.05) for SPB, which may be due to the elevated cob intake by SPB steers. Across treatments, stover DMI was similar in the Grow (1.10 kg per steer per d) and Finish (1.11 kg per steer per d) trials. The proportion (65%) of Fines (<8 mm) consumed from the Grow diet (40% neutral detergent fiber, aNDF) was greater than the Finish diet (25% aNDF; 18% to 31%) and gleaning of concentrate feeds from orts seemed to be more extensive in the Grow diet. Steers consuming Finish diets containing SPB and CST had DMI that were 17% and 18%, respectively, greater (P ≤ 0.05) than CSIL, an indication of compensatory intake. The physical effectiveness factors for stovers fed in the Grow and Finish diets were 0.85 and 0.95, respectively. Estimates for net energy maintenance and net energy gain (NEg), respectively, using National Research Council methods from 2001 were as follows for consumed stovers: SPB (1.09 and 0.54 Mcal/kg) and CST (0.98 and 0.44 Mcal/kg) in the Grow trial, and SPB (0.96 and 0.42 Mcal/kg) and CST (0.95 and 0.40 Mcal/kg) in the Finish trial. Although SPB and CST differ in botanical fraction composition and net intakes of botanical fractions, their energetic contributions to steer performance were very similar. Steers fed the Finish diet (1.25 Mcal performance-adjusted NEg per kg) selected stover botanical components to achieve a diet composition of 25% aNDF.
Mechanistic Considerations and Pharmacokinetic Implications on Concomitant Drug Administration During CytoSorb Therapy
Authors: Scheier Joerg , Nelson Peter J. , Schneider Antoine , Colombier Sébastien , Kindgen-Milles Detlef , Deliargyris Efthymios N. , Nolin Thomas D.
Published: May 2022

OBJECTIVE:

The CytoSorb hemoadsorption device (CytoSorbents Inc, Monmouth Junction, NJ) is increasingly used in many critical disease states. The potential impact on the pharmacokinetic (PK) of concomitantly administered drugs must be considered in clinical practice. The current review summarizes relevant mechanistic principles, available preclinical and clinical data, and provides general guidance for the management of concomitant drug administration during CytoSorb therapy.

DATA SOURCES:

Detailed search strategy using the PubMed and OVID MEDLINE databases, as well as presented congress abstracts for studies on drug removal by the CytoSorb device.

STUDY SELECTION:

Human, animal, and bench-top studies with PK or drug-removal data during CytoSorb therapy were selected for inclusion. Publications reporting on CytoSorb treatments for drug overdose were not considered.

DATA EXTRACTION:

Relevant PK data were examined and synthesized for narrative review.

DATA SYNTHESIS:

To date, PK data during CytoSorb hemoadsorption are available for more than 50 drugs, including analgesics, antiarrhythmics, anticonvulsants, antidepressants, antihypertensives, antiinfectives, antithrombotics, anxiolytics, and immunosuppressants. Based on available PK data, drugs were categorized into low (<30%), moderate (30–60%), or high rates of removal (>60%), or, alternatively, according to clearance increase relative to endogenous clearance: negligible (<25%), low (25–100%), moderate (100–400%), or high (>400%). In most reports, additional impact of the extracorporeal platform where CytoSorb was integrated was not available. Based on available data and considering drug, patient, and setup-specific aspects, general dosing guidance for clinical practice was developed.

CONCLUSIONS:

CytoSorb therapy may increase drug elimination through active removal. However, the extent of removal is heterogeneous, and its clinical significance, if any, depends on the broader clinical context, including a patient’s specific endogenous drug clearance and the underlying extracorporeal platform used. The available data, although not definitive, allow for general guidance on dosing adjustments during CytoSorb therapy; however, any treatment decisions should always be complemented by clinical judgment and therapeutic drug monitoring, when available.
Elderly Runners and Osteoarthritis: A Systematic Review
Authors: Migliorini Filippo , Marsilio Emanuela , Oliva Francesco , Hildebrand Frank , Maffulli Nicola
Published: May 2022

Purpose:

The impact of running on the onset of osteoarthritis (OA) is controversial. This study compared the incidence of OA in elderly runners versus nonrunners.

Material and Methods:

This systematic review was conducted according to the PRISMA guidelines. PubMed, Google scholar, Embase, and Web of Science databases were accessed in January 2022. All the published clinical studies investigating OA onset in runners versus non-runners were considered. Studies reporting data on OA and participants in other sports were excluded. Only studies investigating patients with a mean age older than 55 years were considered. The methodological quality of the articles was evaluated using the Newcastle-Ottawa Scale (NOS).

Results:

Data from 3001 participants and 6674 joints were retrieved. The mean age was 59.4±2.7 years. The mean body mass index was 24.6±2.5 kg/m2. The 5 included articles (963 runners, 2038 nonrunners) did not report significant differences in runners compared with controls.

Conclusion:

Middle aged runners did not present greater imaging or clinical signs of OA compared with nonrunner controls. Running at elite or recreational level did not increase the rate of OA progression in individuals older than 50 years.
A Theoretical Framework of Home-Based Professional Nursing Practice
Authors: Hinck Susan M.
Published: May 2022

The purpose of this article is to introduce a descriptive middle-range theoretical framework unique to professional nursing practice provided in the patient's home. The variety of care models provided in the home, ranging from nonskilled home maintenance service to hospital-at-home programs, reinforces the need to clearly define and describe home-based professional nursing practice. This framework includes six concepts (primacy of home, patient authority, patient self-management, caregivers as collaborators, interprofessional clinical team collaboration, nurse autonomy), and four relational statements of the concepts that describe the experience of patients in their homes and home-based providers. The four theoretical statements are: (1) The patient's beliefs, habits, and self-management actions in the home are shaped by the meaning of home and the physical home environment. (2) The patient has ultimate decision-making control and authority over his/her own health-related behaviors in the home. (3) Home-based care includes interprofessional teams to provide holistic care and maximize self-management ability. (4) The home-based nurse is autonomous when working in the home with the patient/caregiver and has primary responsibility for holistic assessment and intervention. Knowledge of this theoretical framework can help nurses maintain the integrity and purpose of the professional nurse's role in home-based care as well as provide guidance for nursing education and organizational structures. Recommendations for research to test and validate the framework are provided.
Geometric microcanonical theory of two-dimensional truncated Euler flows
Authors: van Kan A. , Alexakis A. , Brachet M.
Published: May 2022

This paper presents a geometric microcanonical ensemble perspective on two-dimensional truncated Euler flows, which contain a finite number of (Fourier) modes and conserve energy and enstrophy. We explicitly perform phase space volume integrals over shells of constant energy and enstrophy. Two applications are considered. In the first part, we determine the average energy spectrum for highly condensed flow configurations and show that the result is consistent with Kraichnan’s canonical ensemble description, despite the fact that no thermodynamic limit is invoked. In the second part, we compute the probability density for the largest-scale mode of a free-slip flow in a square, which displays reversals. We test the results against numerical simulations of a minimal model and find excellent agreement with the microcanonical theory, unlike the canonical theory, which fails to describe the bimodal statistics.

This article is part of the theme issue ‘Mathematical problems in physical fluid dynamics (part 2)’.
Spontaneous symmetry breaking for extreme vorticity and strain in the three-dimensional Navier–Stokes equations
Authors: Schorlepp Timo , Grafke Tobias , May Sandra , Grauer Rainer
Published: May 2022

We investigate the spatio-temporal structure of the most likely configurations realizing extremely high vorticity or strain in the stochastically forced three-dimensional incompressible Navier–Stokes equations. Most likely configurations are computed by numerically finding the highest probability velocity field realizing an extreme constraint as solution of a large optimization problem. High-vorticity configurations are identified as pinched vortex filaments with swirl, while high-strain configurations correspond to counter-rotating vortex rings. We additionally observe that the most likely configurations for vorticity and strain spontaneously break their rotational symmetry for extremely high observable values. Instanton calculus and large deviation theory allow us to show that these maximum likelihood realizations determine the tail probabilities of the observed quantities. In particular, we are able to demonstrate that artificially enforcing rotational symmetry for large strain configurations leads to a severe underestimate of their probability, as it is dominated in likelihood by an exponentially more likely symmetry-broken vortex-sheet configuration.

This article is part of the theme issue ‘Mathematical problems in physical fluid dynamics (part 2)’.
Editorial: Mathematical problems in physical fluid dynamics: part II
Authors: Goluskin D. , Protas B. , Thiffeault J.-L.
Published: May 2022

Fluid dynamics is a research area lying at the crossroads of physics and applied mathematics with an ever-expanding range of applications in natural sciences and engineering. However, despite decades of concerted research efforts, this area abounds with many fundamental questions that still remain unanswered. At the heart of these problems often lie mathematical models, usually in the form of partial differential equations, and many of the open questions concern the validity of these models and what can be learned from them about the physical problems. In recent years, significant progress has been made on a number of open problems in this area, often using approaches that transcend traditional discipline boundaries by combining modern methods of modelling, computation and mathematical analysis. The two-part theme issue aims to represent the breadth of these approaches, focusing on problems that are mathematical in nature but help to understand aspects of real physical importance such as fluid dynamical stability, transport, mixing, dissipation and vortex dynamics.

This article is part of the theme issue ‘Mathematical problems in physical fluid dynamics (part 2)’.
Assessment of Alzheimer-related Pathologies of Dementia Using Machine Learning Feature Selection
Authors: Rajab Mohammed D , Jammeh Emmanuel , Taketa Teruka , Brayne Carol , Matthews Fiona E , Su Li , Ince Paul G , Wharton Stephen B , Wang Dennis
Published: May 2022

Although a variety of brain lesions may contribute to the pathological diagnosis of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remain uncertain. Systematically assessing neuropathological measures in relation to the cognitive and functional definitions of dementia may enable the development of better diagnostic systems and treatment targets. The objective of this study is to apply machine learning approaches for feature selection to identify key features of Alzheimer-related pathologies associated with dementia. We applied machine learning techniques for feature ranking and classification as an unbiased comparison of neuropathological features and assessment of their diagnostic performance using a cohort (n=186) from the Cognitive Function and Ageing Study (CFAS). Seven feature ranking methods using different information criteria consistently ranked 22 out of the 34 neuropathology features for importance to dementia classification. Braak neurofibrillary tangle stage, Beta-amyloid and cerebral amyloid angiopathy features were the most highly ranked, although were highly correlated with each other. The best performing dementia classifier using the top eight ranked neuropathology features achieved 79% sensitivity, 69% specificity, and 75% precision. A substantial proportion (40.4%) of dementia cases was consistently misclassified by all seven algorithms and any combination of the 22 ranked features. These results highlight the potential of using machine learning to identify key indices of plaque, tangle and cerebral amyloid angiopathy burdens that may be useful for the classification of dementia.
Longitudinal analyses of depression and anxiety highlight greater prevalence during COVID-19 lockdowns in the Dutch general population and a continuing increase in suicidal ideation in young adults
Authors: Ori Anil P. S. , Wieling Martijn ,   Lifelines Corona Research Initiative, van Loo Hanna M.
Published: May 2022

Objective

The pandemic of the coronavirus disease 2019 (COVID-19) has led to an increased burden on mental health. This study therefore investigated the development of major depressive disorder (MDD), generalized anxiety disorder (GAD), and suicidal ideation in the Netherlands during the first fifteen months of the pandemic and three nation-wide lockdowns.

Methods

Participants of the Lifelines Cohort Study –a Dutch population-based sample-reported current symptoms of MDD and GAD, including suicidal ideation, according to DSM-IV criteria using a digital structured questionnaire. Between March 2020 and June 2021, 36,106 participants (aged 18-96) filled out a total of 629,811 questionnaires across 23 time points. Trajectories over time were estimated using generalized additive models and analyzed in relation to age, sex, and lifetime history of MDD/GAD to identify groups at risk.

Results

We found non-linear trajectories for MDD and GAD with a higher number of symptoms and prevalence rates during periods of lockdown. The point prevalence of MDD and GAD peaked during the third hard lockdown at 2.88% (95% CI: 2.71%–3.06%) and 2.92% (95% CI: 2.76%-3.08%), respectively, in March 2021. Women, younger adults, and participants with a history of MDD/GAD reported significantly more symptoms. For suicidal ideation, we found a linear increase over time in younger participants which continued even after the lockdowns ended. For example, 4.63% (95% CI: 3.09%-6.96%) of 20-year-old participants reported suicidal ideation at our last measured time point in June 2021, which represents a 4.14x increase since the start of the pandemic.

Conclusions

Our study showed greater prevalence of MDD and GAD during COVID-19 lockdowns suggesting that the pandemic and government enacted restrictions impacted mental health in the population. We furthermore found a continuing increase in suicidal ideation in young adults. This warrants for alertness in clinical practice and prioritization of mental health in public health policy.
Multi-ancestry genome-wide analysis identifies effector genes and druggable pathways for coronary artery calcification
Authors: Kavousi Maryam , Bos Maxime M. , Barnes Hanna J. , Lino Cardenas Christian L. , Wong Doris , O’Donnell Christopher J. , Bielak Lawrence F. , Peyser Patricia A. , Malhotra Rajeev , van der Laan Sander W. , Miller Clint L.
Published: May 2022

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts symptomatic coronary artery disease. Identifying genetic risk factors for CAC may point to new therapeutic avenues for preventing clinical disease. Here, we conducted a multi-ancestry genome-wide association study in 26,909 individuals of European ancestry and 8,867 individuals of African American ancestry. We identified 11 independent risk loci, of which 8 are novel for CAC. Some novel loci harbor candidate causal genes supported by multiple lines of functional evidence. Together, these findings help refine the genetic architecture of CAC, extend our understanding of the biological pathways underlying CAC formation, as well as identify druggable targets for CAC.
Assessment of Standard HIV Testing Services Delivery to Injured Persons Seeking Emergency Care in Nairobi, Kenya: A Prospective Observational Study
Authors: Aluisio Adam R. , Sugut Janet , Kinuthia John , Bosire Rose , Ochola Eric , Ngila Beatrice , Ojuka Daniel K. , Lee J. Austin , Maingi Alice , Guthrie Kate M. , Liu Tao , Mugambi Mary , Katz David A. , Farquhar Carey , Mello Michael J.
Published: May 2022

Emergency departments (EDs) in Africa are contact points for key groups for HIV testing services (HTS) but understanding of ED-testing delivery is limited which may impeded program impacts. This study evaluated the offering and uptake of standard HTS among injured persons seeking ED care at Kenyatta National Hospital (KNH) in Nairobi, Kenya.

An ED population of adult injured persons was prospectively enrolled (1 March - 25 May 2021) and followed through ED disposition. Participants requiring admission were followed through hospital discharge and willing participants were contacted at 28-days for follow up. Data on population characteristics and HTS were collected by personnel distinct from clinicians responsible for standard HTS. Descriptive analyses were performed and prevalence values with 95% confidence intervals (CI) were calculated for HIV parameters.

The study enrolled 646 participants. The median age was 29 years with the majority male (87.8%). Most ED patients were discharged (58.9%). A prior HIV diagnosis was reported by 2.3% of participants and 52.7% reported their last testing as >6 months prior. Standard ED-HTS were offered to 49 or 8.6% of participants (95% CI: 5.8-9.9%), among which 89.8% accepted. For ED-tested participants 11.4% were newly diagnosed with HIV (95% CI: 5.0-24.0%). Among 243 participants admitted, testing was offered to 6.2% (95% CI: 3.9-9.9%), with 93.8% accepting. For admitted participants tested 13.3% (95% CI: 4.0-35.1%) were newly diagnosed (all distinct from ED cases). At 28-day follow up an additional 22 participants reported completing testing since ED visitation, with three newly diagnosed. During the full follow-up period the HIV prevalence in the population tested was 10.3% (95% CI: 5.3-19.0%); all being previously undiagnosed.

Offering of standard HTS was infrequent, however, when offered, uptake and identification of new HIV diagnoses were high. These data suggest that opportunities exist to improve ED-HTS which could enhance identification of undiagnosed HIV.
Correlation of Suspected COVID-19 Symptoms with COVID-19 Positivity in Children
Authors: Satoskar Sanika A. , Hindman Daniel , Husain Amyna , Prichett Laura , Badaki Oluwakemi B. , Kane Ann
Published: May 2022

Background

Early in the pandemic, COVID-19 was found to infect adults at higher rates than children, leaving limited data on disease presentation in children. Further understanding of the epidemiology of COVID-19 symptoms among children is needed. Our aim was to explore how symptoms vary between children testing positive for COVID-19 infection versus children testing negative.

Methods

Data analysis of symptom prevalence among pediatric patients presenting to emergency departments (ED) in the Johns Hopkins Health System (JHHS) with concern for COVID-19 who subsequently received COVID-19 testing. Inclusion criteria included patients 0-17 years-of-age, ED evaluation between March 15th, 2020 - May 11th, 2020, and those who were ordered for COVID-19 testing. Chart review was performed to document symptoms using ED provider notes. Comparisons were made using chi-squared t-tests and Student’s t-tests.

Results

Fever (62.6%) and cough (47.9%) were the most prevalent symptoms among children with suspected COVID-19 infection. Compared to children with a negative COVID-19 test, children who tested positive had higher prevalence of myalgia (21.7% vs 6.0%) and loss of taste/smell (15.2% vs 0.9%). Over half of the children who tested positive for COVID-19 had public insurance (52.2%) and 58.7% of the positive tests occurred among children with Hispanic ethnicity.

Conclusions

Myalgia and loss of taste/smell were found to be significantly more prevalent among COVID-19 positive children compared to children testing negative. Additionally, children with public insurance and those with Hispanic ethnicity were more likely to test positive, emphasizing the importance of social factors in the screening and decision-making process.
Dog Size and Patterns of Disease History Across the Canine Age Spectrum: Results from the Dog Aging Project
Authors: Nam Yunbi , White Michelle , Karlsson Elinor K. , Creevy Kate E. , Promislow Daniel , McClelland Robyn L. ,   The Dog Aging Project Consortium
Published: May 2022

Age in dogs is associated with the risk of many diseases, and canine size is a major factor in that risk. However, the size effect is not as simple as the age effect. While small size dogs tend to live longer, some diseases are more prevalent among small dogs. Utilizing owner-reported data on disease history from a substantial number of companion dogs, we investigate how body size, as measured by weight, associates with the prevalence of a reported condition and its pattern across age for various disease categories. We found significant positive associations between weight and prevalence of skin, bone/orthopedic, gastrointestinal, ear/nose/throat, cancer/tumor, brain/neurologic, endocrine, and infectious diseases. Similarly, weight was negatively associated with the prevalence of eye, cardiac, liver/pancreas, and respiratory disease categories. Kidney/urinary disease prevalence did not vary by weight. We also found that the association between age and disease prevalence varied by dog size for many conditions including eye, cardiac, orthopedic, ear/nose/throat, and cancer. Controlling for sex, purebred/mixed breed, and geographic region made little difference in all disease categories we studied. Our results align with the reduced lifespan in larger dogs for most of the disease categories but suggest potential avenues for further examination.
Biochemical Characterization of a Fungal Bifunctional Type I Diterpene Synthase Brings a Cryptic Natural Product to Light
Authors: Zhang Peng , Wu Guangwei , Heard Stephanie C. , Niu Changshan , Bell Stephen A. , Li Fengli , Ye Ying , Zhang Yonghui , Winter Jaclyn M.
Published: May 2022

We report the identification of the tnd biosynthetic cluster from the marine-derived fungal strain Aspergillus flavipes CNL-338 and in vivo characterization of a cryptic type I diterpene synthase. Heterologous expression of the bifunctional terpene synthase TndC in Saccharomyces cerevisiae led to the discovery of a new diterpene backbone, talarodiene, harboring a benzo[a]cyclopenta[d]cyclooctane tricyclic fused ring system. The cyclization mechanism that converts geranylgeranyl diphosphate to the tricyclic hydrocarbon skeleton was investigated using 13C-labeling studies and stable isotope tracer experiments showed the biotransformation of talarodiene into talaronoid C.
Within- and between-subject reproducibility and variability in multi-modal, longitudinal brain networks
Authors: Nakuci Johan , Wasylyshyn Nick , Cieslak Matthew , Elliot James C. , Bansal Kanika , Giesbrecht Barry , Grafton Scott T. , Vettel Jean M. , Garcia Javier O. , Muldoon Sarah F.
Published: May 2022

Network analysis provides new and important insights into the function of complex systems such as the brain by examining structural and functional networks constructed from diffusion Magnetic Resonance Imaging (dMRI), functional MRI (fMRI) and Electro/Magnetoencephalography (E/MEG) data. Although network models can shed light on cognition and pathology, questions remain regarding the importance of these findings, due in part to the reproducibility of the core measurements and subsequent modeling strategies. In order to ensure that results are reproducible, we need a better understanding of within- and between-subject variability over long periods of time. Here, we analyze a longitudinal, 8 session, multi-modal (dMRI, and simultaneous EEG-fMRI), and multiple task imaging data set. We first investigate the reproducibility of individual brain connections and network measures and find that across all modalities, within-subject reproducibility is higher than between-subject reproducibility, reaffirming the ability to detect individual differences in network structure in both structural and functional human brain networks. We see high variability in the reproducibility of pairwise connections between brain regions, but observe that in EEG-derived networks, during both rest and task, alpha-band connectivity is consistently more reproducible than networks derived from other frequency bands. Further, reproducible connections correspond to strong connections. Structural networks show a higher reliability in network statistics than functional networks, and certain measures such as synchronizability and eigenvector centrality are consistently less reliable than other network measures across all modalities. Finally, we find that structural dMRI networks outperform functional networks in their ability to identify individuals using a fingerprinting analysis. Our results highlight that functional networks likely reflect state-dependent variability not present in structural networks, and that the analysis of either structural or functional networks to study individual differences should depend on whether or not one wants to take into account state dependencies of the observed networks.
An actomyosin-polarized membrane reservoir mediates the unequal divisions ofDrosophilaneural stem cells
Authors: LaFoya Bryce , Prehoda Kenneth E.
Published: May 2022

The asymmetric divisions ofDrosophilaneural stem cells (NSCs) produce unequally sized siblings, with most volume directed into the sibling that retains the NSC fate. Sibling size asymmetry results from preferential expansion of the NSC sibling surface during division. Here we show that a polarized membrane reservoir constructed by the NSC in early mitosis provides the source for expansion. The reservoir is formed from membrane domains that contain folds and microvilli that become polarized by apically-directed cortical flows of actomyosin early in mitosis. When furrow ingression begins and internal pressure increases, the stores of membrane within the apical reservoir are rapidly consumed. Expansion is significantly diminished in NSCs that lack a reservoir, and membrane expansion equalizes when the reservoir is not polarized. Our results suggest that the cortical flows that remodel the plasma membrane during asymmetric cell division function to satisfy the dynamic surface area requirements of unequally dividing cells.
A DNase T6SS effector requires its MIX domain for secretion
Authors: Fridman Chaya Mushka , Jana Biswanath , Ben-Yaakov Rotem , Bosis Eran , Salomon Dor
Published: May 2022

ABTRACT

Gram-negative bacteria often employ the type VI secretion system (T6SS) to deliver diverse cocktails of antibacterial effectors into rival bacteria. In many cases, even when the identity of the delivered effectors is known, their toxic activity and mechanism of secretion are not. Here, we investigate VPA1263, aVibrio parahaemolyticusT6SS effector that belongs to a widespread class of polymorphic effectors containing a MIX domain. We reveal a C-terminal DNase toxin domain belonging to the HNH nuclease superfamily, and we show that it mediates the antibacterial toxicity of this effector during bacterial competition. Furthermore, we demonstrate that the VPA1263 MIX domain is necessary for T6SS-mediated secretion and intoxication of recipient bacteria. These results are the first indication of a functional role for MIX domains in T6SS secretion.

IMPORTANCE

Specialized protein delivery systems are used during bacterial competition to deploy cocktails of toxins that target conserved cellular components. Although numerous toxins have been revealed, the activity of many remains unknown. In this study, we investigated such a toxin from the pathogenVibrio parahaemolyticus. Our findings indicated that the toxin employs a DNase domain to intoxicate competitors. We also showed that a domain used as a marker for secreted toxins is required for secretion of the toxin via a type VI secretion system.
Human papilloma virus E6 regulates therapy responses in oropharyngeal cancer by repressing the PGC-1α/ERRα axis
Authors: Sannigrahi Malay K. , Rajagopalan Pavithra , Lai Ling , Liu Xinyi , Sahu Varun , Nakagawa Hiroshi , Jalaly Jalal , Brody Robert M. , Morgan Iain M. , Windle Bradford E. , Wang Xiaowei , Gimotty Phyllis A. , Kelly Daniel P. , White Elizabeth A. , Basu Devraj
Published: May 2022

Therapy with radiation plus cisplatin kills human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) by increasing reactive oxygen species beyond cellular antioxidant capacity. To explore why some patients fail these standard treatments, we evaluated whether the variation in HPV oncoprotein levels among HPV+ OPSCCs impacts mitochondrial metabolism, a source of antioxidant capacity. In cell line and patient-derived xenograft models, levels of HPV full-length E6 (fl-E6) inversely correlated with oxidative phosphorylation, antioxidant capacity, and therapy resistance, and fl-E6 was the only HPV oncoprotein to display such correlation. Ectopically expressing fl-E6 in models with low levels reduced mitochondrial mass, depleted antioxidant capacity, and sensitized to therapy. In this setting, fl-E6 repressed the PGC-1α/ERRα pathway for mitochondrial biogenesis by reducing p53-dependent PGC-1α transcription. Concordant observations were made in three clinical cohorts, where expression of mitochondrial components was higher in tumors of patients with reduced survival. These tumors contained the lowest fl-E6 levels, highest p53 target gene expression, and an activated PGC-1α/ERRα pathway. Our findings demonstrate that E6 can potentiate treatment responses by depleting mitochondrial antioxidant capacity and provide evidence for low E6 negatively impacting patient survival. E6’s interaction with the PGC-1α/ERRα axis has implications for predicting and targeting treatment resistance in OPSCC.
A heterogeneous pool of tumor precursor cells with self-replenishing and tumor-originating properties in early pathogenesis of Chronic Lymphocytic Leukemia
Authors: Budeus Bettina , Dampmann Maria , Kibler Artur , Faßbender Bianca , Brauser Martina , Bronischewski Kevin , Homp Ekaterina , Taudien Sarah , Johansson Patricia , Bloehdorn Johannes , Stilgenbauer Stephan , von Tresckow Julia , Dürig Jan , Reinhardt Hans Christian , Küppers Ralf , Dietrich Sascha , Seifert Marc
Published: May 2022

Intratumor heterogeneity (ITH) refers to the coexistence of distinct cancer cell subpopulations within a single tumor, each with unique molecular and functional properties. Understanding the dynamics and evolution of ITH is crucial for predicting tumor progression and the development of therapy resistance.

Here, we conducted a comprehensive investigation of ITH in Chronic Lymphocytic Leukemia (CLL) and identified a subpopulation that carried the CLL B-cell receptor rearrangement but contrasted from the CLL main population by low CD5 and high CD20 expression and highly mutated Ig-genes. This CLL-related memory B-cell population shared somatic driver mutations with the main CLL population but also exhibited exclusive somatic mutations. Phylogenetic analysis suggested a pathogenically early generation of these CLL-related B cells before monoclonal B lymphocytosis or CLL manifestation. Our data indicated that CLL-related B cells have self-replenishing potential, as they diminish upon treatment but recover indistinguishably on relapse. This contrasts with the main CLL population, which mostly represents a selective and novel expansion of the CLL-related B cells. This differentiation capacity into conventional CLL cells, and the expression of leukemic stem cell signatures further supported their tumorigenic capacity.

We propose that these CLL-related B cells represent a pool of highly diversified, early-stage CLL precursor cells, which persist in the shape of “malignant memory B cells”. Longitudinal analyses of these CLL precursor cells suggested that they form a reservoir of malignant, leukemia-originating cells which contribute during disease progression to CLL outgrowth and clonal evolution.
Behavioral and brain responses to verbal stimuli reveal transient periods of cognitive integration of external world in all sleep stages
Authors: Türker Başak , Musat Esteban Munoz , Chabani Emma , Fonteix-Galet Alexandrine , Maranci Jean-Baptiste , Wattiez Nicolas , Pouget Pierre , Sitt Jacobo , Naccache Lionel , Arnulf Isabelle , Oudiette Delphine
Published: May 2022

Sleep has long been considered as a state of disconnection from the environment, with absent reactivity to external stimuli. Here, we questioned this sleep disconnection dogma by directly investigating behavioral responsiveness in 49 napping subjects (27 with narcolepsy and 22 healthy volunteers) engaged in a lexical decision task. Participants were instructed to frown or smile depending on the stimulus type (words vs pseudo-words). We found accurate behavioral responses, visible via contractions of the corrugator or zygomatic muscles, in all sleep stages in both groups (except slow-wave sleep for healthy volunteers). Stimuli presented during states with high (vs. low) values of neural markers indexing rich cognitive states more often yielded responses. Our findings suggest that transient windows of reactivity to external stimuli exist in all sleep stages, even in healthy individuals. Such windows of reactivity could be used to probe sleep-related mental and cognitive processes in real-time across all sleep stages.
Cardiopulmonary bypass activates classical monocytes via shear-mediated activation of Store-Operated Calcium Entry
Authors: Li Weiming , Tu Lan N. , Hsieh Lance , Smith Julian R. , Yeh Yi-Ting , Sinyagin Anthony , Ghassemian Majid , Timms Andrew , Charette Kevin , Mauchley David , McMullan Michael , Bohuta Lyubomyr , Greene Christina , Regier Mary C. , del Alamo Juan Carlos , Savan Ram , Nigam Vishal
Published: May 2022

Patients undergoing cardiac surgery face significant inflammatory induced by exposure to cardiopulmonary bypass (CPB), contributing to heightened morbidity and mortality. The molecular and cellular mechanisms that underpin this inflammatory process remain unknown. To address this knowledge gap, we performed snRNA/ATAC-Sequencing on leukocytes from neonatal CPB patients. Classical monocytes become more prevalent and have dysregulation of inflammatory genes after CPB, indicating their role in CPB-associated inflammation. A genome-wide CRISPR screen andin vitroexperiments in non-adherent monocytic cells identified two novel genes, SPTAN1 and RAF1, as effectors of hemodynamic stress. SPTAN1 and RAF1 activate store-operated calcium entry that results inflammation and cell death. snATAC-Seq revealed dynamically changing patterns of chromatin accessibility and AP-1 transcription factor binding after CPB exposure. These findings provide novel insights into the pathogenesis of CPB-associated inflammation, with broad implications for understanding the early stages of sterile inflammation and how non-adherent cells sense shear stress.
Retinoic acid-gated BDNF synthesis in neuronal dendrites drives presynaptic homeostatic plasticity
Authors: Thapliyal Shruti , Arendt Kristin L. , Lau Anthony G. , Chen Lu
Published: May 2022

Homeostatic synaptic plasticity is a non-Hebbian synaptic mechanism that adjusts synaptic strength to maintain network stability while achieving optimal information processing. Among the molecular mediators shown to regulate this form of plasticity, synaptic signaling through retinoic acid (RA) and its receptor, RARα, has been shown to be critically involved in the homeostatic adjustment of synaptic transmission in both hippocampus and sensory cortices. In this study, we explore the molecular mechanism through which postsynaptic RA and RARα regulates presynaptic neurotransmitter release during prolonged synaptic inactivity at excitatory synapses. We show that RARα binds to a subset of dendritically sorted brain-derived neurotrophic factor (BDNF) mRNA splice isoforms and represses their translation. The RA-mediated translational de-repression of postsynaptic BDNF results in the retrograde activation of presynaptic Tropomyosin receptor kinase B (TrkB) receptors, facilitating presynaptic homeostatic compensation through enhanced presynaptic release. Together, our study illustrates a RA-mediated retrograde synaptic signaling pathway through which postsynaptic protein synthesis during synaptic inactivity drives compensatory changes at presynaptic site.