bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Validation of the Clinician Reported and Patient Reported Photonumeric Scales to Assess Buttocks Cellulite Severity
Authors: Cohen Joel L. , Sadick Neil S. , Kirby M. Todd , McLane Michael P. , Lenderking William R. , Bender Randall H. , Chen Jun , Hurley David , Knoble Naomi B. , Liu Genzhou , Xiang Qinfang , Davidson Jeffrey A. , Goldman Mitchel P.
Published: October 2020

BACKGROUND

The Clinician Reported Photonumeric Cellulite Severity Scale (CR-PCSS) and Patient Reported PCSS (PR-PCSS) are newly developed tools for assessing cellulite severity.

OBJECTIVE

To report on the reliability, validity, and ability to detect a change in cellulite severity on the buttocks of adult women with the CR-PCSS and PR-PCSS.

MATERIALS AND METHODS

Content validity of both scales was established through concept elicitation and cognitive interviews. Test–retest reliability was evaluated, and intra-rater (both scales) and inter-rater (CR-PCSS only) reliability were estimated using intraclass correlation coefficients (ICCs) for agreement and consistency. Ability to detect a change was determined using the Subject–Global Aesthetic Improvement Scale (GAIS) or Investigator-GAIS as anchors.

RESULTS

For the CR-PCSS (n = 6) at baseline and Day 2, the mean interrater ICCs were ≥0.70 and mean intrarater ICCs (95% confidence interval [CI]) were ≥0.81 (0.72–0.90) for both buttocks. For the PR-PCSS (n = 99) at baseline and Day 14, the mean test–retest reliability ICCs (95% CI) were ≥0.86 (0.79–0.91) for both buttocks. A clinically meaningful change was 1.0 point on the PR-PCSS and 1.0 on the CR-PCSS.

CONCLUSION

The CR-PCSS and PR-PCSS reliably assess cellulite severity of the buttocks and can detect a clinically meaningful change after treatment for cellulite.
Postoperative pain therapy with hydromorphone; comparison of patient-controlled analgesia with target-controlled infusion and standard patient-controlled analgesia
Authors: Wehrfritz Andreas , Ihmsen Harald , Fuchte Tobias , Kim Michael , Kremer Sven , Weiß Alexander , Schüttler Jürgen , Jeleazcov Christian
Published: October 2020

BACKGROUND

The challenge of managing acute postoperative pain is the well tolerated and effective administration of analgesics with a minimum of side effects. The standard therapeutic approach is patient-controlled analgesia (PCA) with systemic opioids. To overcome problems of oscillating opioid concentrations, we studied patient-controlled analgesia by target-controlled infusion (TCI-PCA) as an alternative.

OBJECTIVE

To compare efficacy, safety and side effects of standard PCA with TCI-PCA for postoperative pain therapy with hydromorphone.

DESIGN

Single-blinded, randomised trial.

SETTING

University Hospital, Germany from December 2013 to April 2015.

PARTICIPANTS

Fifty adults undergoing cardiac surgery.

INTERVENTIONS

Postoperative pain therapy on the ICU was managed with intravenous (i.v.) hydromorphone and patients randomised to TCI-PCA with target plasma concentrations between 0.8 and 10 ng ml−1, or PCA with bolus doses of 0.2 mg. Pain was regularly assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, oxygen saturation and cardiac output were continuously monitored, and adverse events were registered throughout the study.

MAIN OUTCOME MEASURES

NRS pain ratings, hydromorphone doses, haemodynamic effects and side effects.

RESULTS

NRS pain ratings, total doses of hydromorphone and haemodynamic data did not differ significantly between TCI-PCA and PCA. The number of bolus doses during PCA was significantly higher than the number of target increases during TCI-PCA (P = 0.006). The number of negative requests was also significantly higher during PCA than during TCI-PCA (P = 0.02). The respiratory rate on the first postoperative morning was 25 ± 6 min−1 during TCI-PCA, compared with 19 ± 4 min−1 during PCA (P = 0.022). Nausea occurred in 30% after TCI-PCA and 24% after PCA (P = 0.46).

CONCLUSION

TCI-PCA was effective and well tolerated in acute postoperative pain management after cardiac surgery. Further studies are needed to evaluate this approach in clinical practice.

TRIAL REGISTRATION

EudraCT Number: 2013-002875-16, and ClinicalTrials.gov Identifier: NCT02035709.
Investigation into the Energy and Scatter Response of OSLDs at Diagnostic Energies Using a C-arm System
Authors: Liu Kevin
Published: October 2020

Optically stimulated luminescent dosimeters (OSLDs) are radiation detectors commonly used in a clinical setting to monitor the dose to patients undergoing imaging or interventional procedures, especially those involving fluoroscopy. In dose tracking using OSLDs, it is important to consider that photons at the diagnostic energy range are prone to energy spectrum shifts from scattering interactions in the medium and that OSLDs have been reported to yield a somewhat strong energy-dependent response in the diagnostic energy range. This study examines the response of OSLDs exposed to a spectrum of photons in the diagnostic energy range (60-120 kVp), both free-in-air and on the surface of a PMMA phantom, within and just outside of the exposure field. From these measurements, it was observed that the response differs substantially (as high as 30%) in OSLDs irradiated under identical exposure settings but with differences in beam quality and scattering conditions. Furthermore, this study devises a method of weighted averages to calculate the calibration factors for OSLDs exposed to both primary and scatter photons, which were approximately 2-5% less than their corresponding measured values. This study emphasizes the need to develop different calibration factors in the clinical use of OSLDs for diagnostic imaging procedures, especially for procedures in which more precise dose measurements may be necessary.
Improving Atraumatic Chest Pain Evaluation in an Urban, Safety-net Hospital Through Incorporation of a Modified HEART Score
Authors: Trent Stacy A. , Stella Sarah , Skinner Alisha , Salame Gerard , Hanratty Rebecca L. , Prandi-Abrams Mara , French Andrew , Krantz Mori J.
Published: October 2020

Atraumatic chest pain is a common emergency department (ED) presentation and the American College of Cardiology and American Heart Association recommends stress testing within 72 hours. The HEART score predicts major adverse cardiac events (MACE) in ED populations and does not require universal stress testing. An evaluation based solely on history, electrocardiography, and biomarkers, therefore, is an attractive approach to risk stratification in resource-limited settings. The HEART score has not been previously evaluated in a safety net hospital setting. We therefore implemented an interdisciplinary clinical care guideline utilizing the HEART score to stratify patients presenting to our inner-city hospital. During a 6-month study period, 1170 patients were evaluated (521 before and 649 after implementation). Among the 998 patients with confirmed follow-up 6-weeks after the index ED encounter, the prevalence of MACE (all-cause mortality, acute myocardial infarction, or coronary revascularization) was 0% [95% confidence interval (CI), 0%–1%] for low, 9% (95% CI, 7%–12%) for moderate, and 52% (95% CI, 39%–65%) for high-risk groups. Guideline implementation significantly increased admissions (+12%, 95% CI, 7%–17%) primarily in the moderate risk group (+38%, 95% CI, 29%–47%), but significantly decreased median ED length of stay (−37 minutes, 95% CI, 17–58). It also led to an increase in stress testing among moderate and high-risk patients (+10%, 95% CI, 0%–19%). In conclusion, the HEART score effectively stratified risk of MACE in a safety net population, improved evaluation consistency, and decreased ED length of stay. However, implementation was associated with an increase in hospitalizations and stress testing. Although the American Heart Association/American College of Cardiology guideline regarding atraumatic chest pain in the ED recommends universal noninvasive testing, the value of this approach, particularly in conjunction with the HEART score is uncertain in safety net hospitals. Further evaluation of the costs and clinical advantages of this approach are warranted.
Adjuvant External Beam Radiotherapy Following Enucleation of Eyes With Extraocular Extension From Uveal Melanoma
Authors: Roelofs Kelsey A. , Cohen Victoria M.L. , Sagoo Mandeep S. , Plowman P. Nicholas , Negretti Guy S. , O’Day Roderick , Hay Gordon , Arora Amit K. , Damato Bertil
Published: October 2020

Purpose:

To report local disease control and all-cause mortality in patients with extraocular extension (EOE) of uveal melanoma undergoing enucleation followed by observation or external beam radiotherapy (EBRT).

Methods:

Charts of patients enucleated between January 1, 1997 and December 31, 2019, with histopathological evidence of EOE of uveal melanoma were reviewed.

Results:

The cohort comprised 51 patients with a mean age of 67 ± 15 years, 22 (43%) of whom underwent adjuvant postenucleation EBRT. Risk factors for metastasis included presence of epithelioid cells (29/45; 88%), closed loops (20/43; 47%), monosomy 3 (16/25; 64%), and gain of 8q (20/22; 91%). Patients undergoing EBRT had more extensive EOE (median: 5.1 mm vs. 2.6 mm, p = 0.008) and surgical excision was less likely to be histologically complete (2/20; 10% vs. 14/25; 56%, p = 0.002). Local side effects following EBRT were seen in 64% (14/22). At latest follow up, 59% of patients (30/51) were alive, with a median follow up of 1.8 years (interquartile range: 2.9; range: 0.1–6.5]. By Kaplan-Meier survival analysis, the 5- and 10-year overall survival rates were 56% and 12%, respectively. There was no difference in all-cause mortality between those receiving adjuvant EBRT and those who were observed (log rank, p = 0.273). No cases of orbital recurrence were documented.

Conclusions:

Orbital EBRT causes significant morbidity. Cases with relatively small EOE undergoing enucleation can be safely observed, without adjuvant EBRT. Multicenter studies are required to better assess the role of EBRT when EOE is more extensive.
A review of current controversies in determining death by neurologic criteria in children
Authors: Virupakshaiah Akash , Ichord Rebecca , Topjian Alexis A. , Kirschen Matthew P.
Published: October 2020

Purpose of review

Death by neurologic criteria (DNC) is the irreversible cessation of all functions of the entire brain, including the brainstem. It is legally recognized as equivalent to cardiopulmonary death. Legal and ethical controversies surrounding DNC have emerged as a result of several highly publicized cases that have eroded public trust in our ability to declare DNC accurately. In this review, we focus on recently published primary data about DNC and address some of these controversies.

Recent findings

Approximately 21% of children who die in pediatric intensive care units (PICU) are declared DNC. Although 60% of physicians report that they have been asked to maintain organ support after DNC declaration, less than 1% of patients remain physically present in the PICU more than 5 days after DNC declaration. We discuss strategies for safely conducting the apnea test, indications and prevalence of ancillary testing, and objections to DNC, including issues of consent and requests for ongoing organ support.

In order to maintain public trust, published guidelines must be followed to accurately and consistently diagnose DNC. We must develop strategies to respond to objections to DNC determination. Ongoing research is needed to improve the safety of apnea testing and indications for and interpretation of ancillary testing.
The Influence of Functional Shoulder Biomechanics as a Mediator of Patient-Reported Outcomes following Mastectomy and Breast Reconstruction
Authors: Leonardis Joshua M. , Lyons Daniel A. , Kidwell Kelley M. , Giladi Aviram M. , Lipps David B. , Momoh Adeyiza O.
Published: October 2020

Background:

Postmastectomy breast reconstruction techniques differentially influence patient-reported physical and psychosocial well-being. Objective measures of shoulder biomechanics, which are uniquely influenced by reconstruction technique, may provide insight into the influence of reconstruction technique on patient-reported outcomes.

Methods:

Robot-assisted measures of shoulder strength and stiffness, and five validated patient-reported outcomes surveys were obtained from 46 women who had undergone mastectomy and a combined latissimus dorsi flap plus subpectoral implant, subpectoral implant, or DIEP flap breast reconstruction. Mediation analyses examined the role of functional shoulder biomechanics as a mediator between reconstruction technique and patient-reported outcomes.

Results:

Reconstruction technique affected shoulder biomechanics, with latissimus dorsi flap plus subpectoral implant patients exhibiting reduced shoulder strength and stiffness compared with subpectoral implant and DIEP flap patients. Increasing external rotation strength was predictive of improved upper extremity function (p = 0.04). Increasing shoulder stiffness while at rest was predictive of worsened upper extremity function (p = 0.03). Increasing shoulder stiffness at rest and during contraction was indicative of worsened psychosocial well-being (all p ≤ 0.02). Reconstruction technique did not predict survey scores of function directly, or when mediated by functional shoulder biomechanics.

Conclusions:

In the current cohort, latissimus dorsi plus subpectoral implant breast reconstructions significantly reduced shoulder strength and stiffness when compared with the other techniques. In addition, objective measures of shoulder biomechanics were predictive of patient-reported physical and psychosocial well-being. The results emphasize the need for improved perioperative screening for shoulder functional deficits in patients undergoing breast reconstruction.

CLINICAL QUESITON/LEVEL OF EVIDENCE:

Therapeutic, II.
Repair of Alar Defects Using the Alar Rotation Flap: Our Experience with 394 Patients
Authors: Mitkov Mario , Griffith James , Dyson Mary , Kimyai-Asadi Arash
Published: October 2020

Background:

The purpose of this study was for the authors to describe their patient selection, surgical technique, and results with the alar rotation flap for surgical defects of the nasal ala.

Methods:

The authors performed a retrospective analysis of all alar rotation flaps performed between June of 2006 and February of 2019. Three hundred ninety-four patients were identified, and follow-up encounters were reviewed to assess for complications and need for revision procedures.

Results:

The alar rotation flap was performed on 394 patients over a 13-year period. The mean defect size was 9.3 ± 2.8 mm by 7.2 ± 2.3 mm. Three hundred nineteen patients (81 percent) were evaluated postoperatively, with a mean average duration of follow-up of 2.3 years (range, 6 days to 11.9 years). Complications included hemorrhagic crust along the incision line [n = 9 (3 percent)], flap edema [n = 7 (2 percent)], internal nasal valve dysfunction [n = 3 (1 percent)], depressed surgical scar [n = 2 (1 percent)], hematoma [n = 1 (0.5 percent)], and paresthesia [n = 1 (0.5 percent)].

Conclusion:

The alar rotation flap is a reliable one-stage flap for small- to medium-size partial-thickness defects of the nasal ala that can produce topographic restoration with minimal risk of aesthetic or functional complication.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
The role of new antimicrobials for Gram-negative infections in daily clinical practice
Authors: Bassetti Matteo , Vena Antonio , Battaglini Denise , Pelosi Paolo , Giacobbe Daniele Roberto
Published: October 2020

Purpose of review

To discuss a possible clinical reasoning for treating resistant Gram-negative bacteria (GNB) infections in daily clinical practice, as well as developing a research agenda for the field.

Recent findings

Novel agents, both belonging to β-lactams and to other classes of antimicrobials, have recently become available, likely replacing polymyxins or polymyxin-based combination regimens as the preferred choices for the first-line treatment of severe resistant GNB infections in the near future.

The peculiar characteristics of novel agents for severe resistant GNB infections have abruptly made the structure of previous therapeutic algorithms somewhat obsolete, in view of the differential activity of most of them against different classes of carbapenemases. Furthermore, other agents showing activity against resistant GNB are in late phase of clinical development. Optimizing the use of novel agents in order both to guarantee the best available treatment to patients and to delay the emergence and spread of resistance is an important task that cannot be postponed, especially considering the unavailability of well tolerated and fully efficacious options for treating resistant GNB infections that we faced in the last 15 years.
Relationship of Bladder Pain With Clinical and Urinary Markers of Neuroinflammation in Women With Urinary Urgency Without Urinary Incontinence
Authors: Soriano Alex , Andy Uduak , Hassani Daisy , Whitmore Kristene , Harvie Heidi , Malykhina Anna P. , Arya Lily
Published: October 2020

Purpose

The pathogenesis of bladder pain is poorly understood. Our hypothesis is that in women with urinary urgency without incontinence, bladder pain is associated with the presence of neurogenic inflammation in the bladder wall and neuroinflammatory biomarkers in the urine.

Methods

We conducted a prospective cross-sectional study of women with urinary urgency without incontinence. Urinary symptoms were measured using Female Genitourinary Pain Index. Neuropathic pain, a clinical biomarker of neuroinflammation, was measured using the PainDETECT questionnaire. Inflammatory neuropeptides measured in the urine included nerve growth factor (NGF), brain-derived neurotrophic factor, vascular endothelial growth factor, and osteopontin. Neuropathic pain scores and urinary neuropeptide levels were compared between patients with and without bladder pain using univariable and multivariable analyses.

Results

In 101 women with urinary urgency without incontinence, 62 (61%) were in the bladder pain group (visual analog scale score, ≤ 3), whereas 39 (39%) were in the no bladder pain group. Urinary symptom scores (5.0 ± 3.1 versus 3.5 ± 2.4, P < 0.001) and neuropathic pain scores (13.3 ± 8.6 vs 5.1 ± 4.8, P < 0.001) were significantly higher for the bladder pain group than for the no bladder pain group. On multivariable analysis after controlling for age, body mass index, and severity of urinary urgency, bladder pain score was significantly associated with elevated urinary levels of vascular endothelial growth factor (P = 0.04) and osteopontin (P = 0.02), whereas the neuropathic pain score was significantly associated with an increased NGF level (P = 0.03).

Conclusions

In women with urinary urgency without incontinence, bladder pain is associated with the presence of clinical and urinary biomarkers of neuroinflammation.
Biomarkers of Cytokine Release Syndrome Predict Disease Severity and Mortality From COVID-19 in Kidney Transplant Recipients
Authors: Benotmane Ilies , Perrin Peggy , Vargas Gabriela Gautier , Bassand Xavier , Keller Nicolas , Lavaux Thomas , Ohana Mickael , Bedo Dimitri , Baldacini Clément , Sagnard Mylene , Bozman Dogan-Firat , Chiesa Margaux Della , Cognard Noëlle , Olagne Jérôme , Delagreverie Héloïse , Marx David , Heibel Françoise , Braun Laura , Moulin Bruno , Fafi-Kremer Samira , Caillard Sophie
Published: October 2020

Background.

Data on coronavirus disease 2019 (COVID-19) in immunocompromised kidney transplant recipients (KTR) remain scanty. Although markers of inflammation, cardiac injury, and coagulopathy have been previously associated with mortality in the general population of patients with COVID-19, their prognostic impact amongst KTR with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has not been specifically investigated.

Methods.

We conducted a cohort study of 49 KTR who presented with COVID-19. Clinical and laboratory risk factors for severe disease and mortality were prospectively collected and analyzed with respect to outcomes. The study participants were divided into 3 groups: (1) mild disease manageable in an outpatient setting (n = 8), (2) nonsevere disease requiring hospitalization (n = 21), and (3) severe disease (n = 20).

Results.

Gastrointestinal manifestations were common at diagnosis. The 30-day mortality rate in hospitalized patients was 19.5%. Early elevations of C-reactive protein (>100 mg/L) and interleukin-6 (>65 ng/L) followed by increases in high-sensitivity troponin I (>30 ng/L) and D-dimer (>960 ng/mL) were significantly associated with severe disease and mortality. Viral load did not have prognostic significance in our sample, suggesting that outcomes were chiefly driven by a cytokine release syndrome (CRS).

Conclusions.

Regular monitoring of CRS biomarkers in KTR with COVID-19 is paramount to improve clinical outcomes.
Synergistic interactions between detritivores disappear under reduced rainfall
Authors: Joly François-Xavier , McAvoy Euan , Subke Jens-Arne
Published: October 2020

Understanding the consequences of altered rainfall patterns on litter decomposition is critical to predicting the feedback effect of climate change on atmospheric CO2concentrations. While their effect on microbial decomposition received considerable attention, their effect on litter fragmentation by detritivores, the other dominant decomposition pathway, remains largely unexplored. Particularly, it remains unclear how different detritivore species and their interactions respond to changes in rainfall quantity and frequency. To fill this knowledge gap, we determined the contribution to litter decomposition of two detritivore species (millipede and isopod), separately and in combination, under contrasting rainfall quantity and frequency in a temperate forest. Although halving rainfall quantity and frequency decreased top-soil moisture by 7.8 and 13.1%, respectively, neither millipede- nor isopod-driven decomposition were affected by these changes. In contrast, decomposition driven by both detritivore species in combination was 65.5% higher than expected based on monospecific treatments under high rainfall quantity, but unchanged or even lower under low rainfall quantity. This indicates that while detritivore activity is relatively insensitive to changes in rainfall patterns, large synergistic interactions between detritivore species may disappear under future rainfall patterns. Incorporating interspecific interactions between decomposers thus seems critical to evaluate the sensitivity of decomposition to altered rainfall patterns.
The Nature ofEspeletiaSpecies
Authors: Pineda Yam M. , Cortés Andrés J. , Madriñán Santiago , Jiménez Iván
Published: October 2020

Species are often regarded as basic units of study in biology, following the presumption that they are real and discrete natural entities. But several biologists wonder if species are arbitrary divisions that do not correspond to discrete natural groups of organisms. Two issues must be addressed to solve this controversy, but few studies seem to do so. The first is whether organisms form sympatric and synchronic groups that are distinct in terms of phenotypes and genome-wide allele frequencies, often called “good species.” Alternatives to “good species” include “cryptic species,” syngameons and, more generally, cases in which phenotypes and genome-wide allele frequencies reflect contrasting evolutionary histories. The second issue is the degree to which species taxa (i.e., taxonomic classification at the species level) reflect natural groups of organisms or constitute arbitrary divisions of biological diversity. Here, we empirically addressed both issues by studying plants of the Andean genusEspeletia(Asteraceae). We collected a geographically dense sample of 538 specimens from the paramo de Sumapaz, in the Cordillera Oriental of Colombia. Additionally, we examined 165 herbarium specimens previously collected by other researchers in this region, or from taxa known to occur there. We tested for the existence of phenotypic groups using normal mixture models and data on 13 quantitative characters. Among 307 specimens with all 13 measurements, we found six distinct phenotypic groups in sympatry. We also tested for the existence of groups defined by genome-wide allele frequencies, using ancestry models and data on 2,098 single nucleotide polymorphisms. Among 77 specimens with complete genomic data, we found three groups in sympatry, with high levels of admixture. Concordance between groups defined by phenotype and genome-wide allele frequencies was low, suggesting that phenotypes and genome-wide allele frequencies reflect contrasting evolutionary histories. Moreover, the high levels of admixture suggest thatEspeletiaplants form a syngameon in the paramo de Sumapaz. To determine the extent to which species taxa corresponded to phenotypic and genomic groups, we used data on 12 phenotypic characters to assign 307 specimens to species taxa, according to descriptions of species taxa in the most recent monograph ofEspeletia. This sample included 27 specimens cited in the monograph. Remarkably, only one out of 307 specimens in our sample fell inside any of the phenotypic ranges reported in the monograph for the species taxa known to occur in the paramo de Sumapaz. These results show that species taxa inEspeletiaare delineations of largely empty phenotypic space that miss biological diversity.
A chaotic viewpoint-based approach to solve haplotype assembly using hypergraph model
Authors: Olyaee Mohammad Hossein , Khanteymoori Alireza , Khalifeh Khosrow
Published: October 2020

Decreasing the cost of high-throughput DNA sequencing technologies, provides a huge amount of data that enables researchers to determine haplotypes for diploid and polyploid organisms. Although various methods have been developed to reconstruct haplotypes in diploid form, their accuracy is still a challenging task. Also, most of the current methods cannot be applied to polyploid form. In this paper, an iterative method is proposed, which employs hypergraph to reconstruct haplotype. The proposed method by utilizing chaotic viewpoint can enhance the obtained haplotypes. For this purpose, a haplotype set was randomly generated as an initial estimate, and its consistency with the input fragments was described by constructing a weighted hypergraph. Partitioning the hypergraph specifies those positions in the haplotype set that need to be corrected. This procedure is repeated until no further improvement could be achieved. Each element of the finalized haplotype set is mapped to a line by chaos game representation, and a coordinate series is defined based on the position of mapped points. Then, some positions with low qualities can be assessed by applying a local projection. Experimental results on both simulated and real datasets demonstrate that this method outperforms most other approaches, and is promising to perform the haplotype assembly.
The stage specific plasticity of descending modulatory controls in a rodent model of cancer induced bone pain
Authors: Kucharczyk Mateusz Wojciech , Derrien Diane , Dickenson Anthony Henry , Bannister Kirsty
Published: October 2020

Pain resulting from metastatic bone disease is a major unmet clinical need. Studying spinal processing in rodent models of cancer pain is desirable since the percept of pain is influenced in part by modulation at the level of the transmission system in the dorsal horn of the spinal cord. Here a rodent model of cancer induced bone pain (CIBP) was generated following syngenic rat mammary gland adenocarcinoma cell injection in the tibia of male Sprague Dawley rats. Disease progression was classified as ‘early’ or ‘late’ stage according to bone destruction. Even though wakeful CIBP rats showed progressive mechanical hypersensitivity, subsequentin vivoelectrophysiological measurement of mechanically evoked deep dorsal horn spinal neuronal responses revealed no change. Rather, a dynamic reorganization of spinal neuronal modulation by descending controls was observed, and this was maladaptive only in the early stage of CIBP. Interestingly, this latter observation corresponded with the degree of damage to the primary afferents innervating the cancerous tissue. Plasticity in the modulation of spinal neuronal activity by descending control pathways reveals a novel opportunity for targeting CIBP in a stage-specific manner. Finally, the data herein has translational potential since the descending control pathways measured are present also in man.

Simple Summary

The mechanisms that underlie pain resulting from metastatic bone disease remain elusive. This translates to a clinical and socioeconomic burden; targeted therapy is not possible, and patients do not receive adequate analgesic relief. Complicating matters is the heterogeneous nature of metastatic bone disease. Early stage cancers are molecularly very different to their late stage counterparts and so too is the pain associated with infant and advanced tumours. Thus, analgesic approaches should differ according to disease stage. In this article we demonstrate that a unique form of brain inhibitory control responsible for modulation of incoming pain signals at the level of the spinal cord changes with the progression of bone tumours, This corresponds with the degree of damage to the primary afferents innervating the cancerous tissue. Plasticity in the modulation of spinal neuronal activity by descending control pathways reveals a novel opportunity for targeting bone cancer pain in a stage-specific manner.
SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitorsin vitro
Authors: Hsu Alan C-Y. , Wang Guoqiang , Reid Andrew T. , Veerati Punnam Chander , Pathinayake Prabuddha S. , Daly Katie , Mayall Jemma R. , Hansbro Philip M. , Horvat Jay C. , Wang Fang , Wark Peter A.
Published: October 2020

SARS-CoV-2 infection causes an inflammatory cytokine storm and acute lung injury. Currently there are no effective antiviral and/or anti-inflammatory therapies. Here we demonstrate that 2019 SARS-CoV-2 spike protein subunit 1 (CoV2-S1) induces high levels of NF-κB activations, production of pro-inflammatory cytokines and mild epithelial damage, in human bronchial epithelial cells. CoV2-S1-induced NF-κB activation requires S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, and associated unfolded protein response (UPR), and MAP kinase signalling pathways. We developed an antagonistic peptide that inhibits S1-ACE2 interaction and CoV2-S1-induced productions of pro-inflammatory cytokines. The existing FDA-approved ER stress inhibitor, 4-phenylburic acid (4-PBA), and MAP kinase inhibitors, trametinib and ulixertinib, ameliorated CoV2-S1-induced inflammation and epithelial damage. These novel data highlight the potentials of peptide-based antivirals for novel ACE2-utilising CoVs, while repurposing existing drugs may be used as treatments to dampen elevated inflammation and lung injury mediated by SARS-CoV-2.
SC-JNMF: Single-cell clustering integrating multiple quantification methods based on joint non-negative matrix factorization
Authors: Shiga Mikio , Seno Shigeto , Onizuka Makoto , Matsuda Hideo
Published: October 2020

Abstract

Unsupervised cell clustering is important in discovering cell diversity and subpopulations. Single-cell clustering using gene expression profiles is known to show different results depending on the method of expression quantification; nevertheless, most single-cell clustering methods do not consider the method.

In this article, we propose a robust and highly accurate clustering method using joint non-negative matrix factorization (joint NMF) based on multiple gene expression profiles quantified using different methods. Matrix factorization is an excellent method for dimension reduction and feature extraction of data. In particular, NMF approximates the data matrix as the product of two matrices in which all factors are non-negative. Our joint NMF can extract common factors among multiple gene expression profiles by applying each NMF to them under the constraint that one of the factorized matrices is shared among the multiple NMFs. The joint NMF determines more robust and accurate cell clustering results by leveraging multiple quantification methods compared to the conventional clustering methods, which uses only a single quantification method. In conclusion, our study showed that our clustering method using multiple gene expression profiles is more accurate than other popular methods.
Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape
Authors: Mijnheer Gerdien , Lutter Lisanne , Mokry Michal , van der Wal Marlot , Fleskens Veerle , Scholman Rianne , Pandit Aridaman , Tao Weiyang , Wekking Mark , Vervoort Stephin , Roberts Ceri , Petrelli Alessandra , Peeters Janneke G.C. , Knijff Marthe , de Roock Sytze , Vastert Sebastiaan , Taams Leonie S. , van Loosdregt Jorg , van Wijk Femke
Published: October 2020

Treg are critical regulators of immune homeostasis, and increasing evidence demonstrates that environment-driven Treg differentiation into effector (e)Treg is crucial for optimal functioning. However, human Treg programming under inflammatory conditions remains poorly understood. Here, we combine transcriptional and epigenetic profiling to identify the human eTreg core signature. Functional autoimmune inflammation-derived Treg display a unique transcriptional profile characterized by upregulation of both a core Treg (FOXP3, CTLA-4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identified a specific human eTreg signature that includes the vitamin D receptor (VDR) as predicted key-regulator in eTreg differentiation. H3K27ac/H3K4me1 occupancy revealed pronounced changes in the (super-)enhancer landscape, including enrichment of the binding motif for VDR and BATF. The observed Treg profile showed striking overlap with tumor-infiltrating Treg. Our data demonstrate that human inflammation-derived Treg acquire a specific eTreg profile guided by epigenetic changes. The core eTreg profile is conserved, and fine-tuned by environment-specific adaptations.
FANCD2 Alleviates Physiologic Replication Stress in Fetal Liver HSC
Authors: Mochizuki-Kashio Makiko , me Yoon Young , Menna Theresa , Grompe Markus , Kurre Peter
Published: October 2020

Bone marrow failure (BMF) in Fanconi Anemia (FA) results from exhaustion of hematopoietic stem cells (HSC), but the physiological role of FA proteins in HSC pool integrity remains unknown. Herein we demonstrate that FANCD2, a core component of the FA pathway, counters replication stress during developmental HSC expansion in the fetal liver (FL). Rapid rates of proliferation and FANCD2 deficient result in excess RPA-coated ssDNA, and provoke pChk1 activation andCdkn1a(p21)nuclear localization in fetalFancd2−/−HSC. Checkpoint mediated S-phase delays induced byCdkn1a(p21)are rescued by Tgf-βinhibition, but pChk1 activation is further aggravated. Our observations reveal the mechanism and physiological context by which FANCD2 safeguards HSC pool formation during development.
Transcriptional differences for COVID-19 Disease Map genes between males and females indicate a different basal immunophenotype relevant to the disease
Authors: Liu Tianyuan , Nogueira Leandro Balzano , Lleo Ana , Conesa Ana
Published: October 2020

Worldwide COVID-19 epidemiology data indicate clear differences in disease incidence among sex and age groups. Specifically, male patients are at a higher death risk than females. However, whether this difference is the consequence of a pre-existing sex-bias in immune genes or a differential response to the virus has not been studied yet. We created DeCovid, an R shiny app that combines gene expression data of different human tissue from the Genotype-Tissue Expression (GTEx) project and the COVID-19 Disease Map gene collection to explore basal gene expression differences across healthy demographic groups. We used this app to study differential gene expression between men and women for COVID-19 associated genes. We identified that healthy women present higher levels in the expression of interferon genes and the JAK-STAT pathway leading to cell survival.
Proteoglycan 4 (PRG4) expression and function in dry eye associated inflammation
Authors: Menon Nikhil G. , Goyal Ruchi , Lema Carolina , Woods Paige S. , Jay Gregory D. , Shapiro Linda H. , Redfern Rachel L. , Ghosh Mallika , Schmidt Tannin A.
Published: October 2020

Purpose

Dry eye disease (DED) affects hundreds of millions worldwide. Proteoglycan 4 (PRG4) has been shown to improve signs and symptoms of DED in humans. The objectives of this study were to characterize endogenous PRG4 expression by telomerase-immortalized human corneal epithelial (hTCEpi) cells, examine how exogenous recombinant human PRG4 (rhPRG4) modulates cytokine and chemokine secretion in response to TNFα and IL-1β, explore rhPRG4 as a potential substrate and/or inhibitor of MMP-9, and to understand how experimental dry (EDE) in mice affects PRG4 expression.

Methods

PRG4 secretion was quantified by Western blotting and PRG4 expression by immunocytochemistry. Cytokine/chemokine release was measured by ELISA, and MMP-9 inhibition was quantified using an MMP-9 inhibitor kit. EDE was induced in mice, and PRG4 was visualized by immunohistochemistry in the cornea and Western blotting in lacrimal gland lysate.

Results

hTCEpi cells synthesize and secrete PRG4in vitro, which is inhibited by TNFα and IL-1β. TNFα and IL-1β significantly increased secretion of cytokine IL-6 and chemokines IL-8, IP-10, RANTES, and ENA-78, and several of these chemokines were downregulated after cotreatment with rhPRG4. Fluorescently-labelled rhPRG4 was internalized by hTCEpi cells. rhPRG4 was not digested by MMP-9 and inhibitedin vitroactivity of exogenous MMP-9 both in solution and in the presence of human tears. Finally, EDE decreased corneal and lacrimal gland expression of PRG4.

Conclusions

These results demonstrate rhPRG4’s anti-inflammatory properties in the corneal epithelium and its contribution to ocular surface homeostasis, furthering our understanding of PRG4’s immunomodulatory properties in the context of DED inflammation.
Indexing All Life’s Known Biological Sequences
Authors: Karasikov Mikhail , Mustafa Harun , Danciu Daniel , Zimmermann Marc , Barber Christopher , Rätsch Gunnar , Kahles André
Published: October 2020

The amount of biological sequencing data available in public repositories is growing exponentially, forming an invaluable biomedical research resource. Yet, making it full-text searchable and easily accessible to researchers in life and data science is an unsolved problem. In this work, we take advantage of recently developed, very efficient data structures and algorithms for representing sequence sets. We make Petabases of DNA sequences across all clades of life, including viruses, bacteria, fungi, plants, animals, and humans, fully searchable. Our indexes are freely available to the research community. This highly compressed representation of the input sequences (up to 5800×) fits on a single consumer hard drive (≈100 USD), making this valuable resource cost-effective to use and easily transportable. We present the underlying methodological framework, called MetaGraph, that allows us to scalably index very large sets of DNA or protein sequences using annotated De Bruijn graphs. We demonstrate the feasibility of indexing the full extent of existing sequencing data and present new approaches for efficient and cost-effective full-text search at an on-demand cost of $0.10 per queried Mpb. We explore several practical use cases to mine existing archives for interesting associations and demonstrate the utility of our indexes for integrative analyses.
High Definition transcranial Direct Current Stimulation (HD-tDCS) for chronic tinnitus: outcomes from a prospective longitudinal large cohort study
Authors: Jacquemin Laure , Mertens Griet , Shekhawat Giriraj Singh , Van de Heyning Paul , Vanderveken Olivier M. , Topsakal Vedat , De Hertogh Willem , Michiels Sarah , Beyers Jolien , Moyaert Julie , Van Rompaey Vincent , Gilles Annick
Published: October 2020

Background

Transcranial Direct Current Stimulation (tDCS) aims to induce cortical plasticity by modulating the activity of brain structures. The broad stimulation pattern, which is one of the main limitations of tDCS, can be overcome with the recently developed technique called High-Definition tDCS (HD-TDCS).

Objective

Investigation of the effect of HD-tDCS on tinnitus in a large patient cohort.

Methods

This prospective study included 117 patients with chronic, subjective, non-pulsatile tinnitus who received six sessions of anodal HD-tDCS of the right Dorsolateral Prefrontal Cortex (DLPFC). Therapy effects were assessed by use of a set of standardized tinnitus questionnaires filled out at the pre-therapy (Tpre), post-therapy (T3w) and follow-up visit (T10w). Besides collecting the questionnaire data, the perceived effect (i.e. self-report) was also documented at T10w.

Results

The Tinnitus Functional Index (TFI) and Tinnitus Questionnaire (TQ) total scores improved significantly over time (pTFI < .01; pTQ < .01), with the following significant post-hoc comparisons: Tpre vs. T10w (pTFI < .05; pTQ < .05) and T3w vs. T10w (pTFI < .01 ; pTQ < .01). The percentage of patients reporting an improvement of their tinnitus at T10w was 47%. Further analysis revealed a significant effect of gender with female patients showing a larger improvement on the TFI and TQ (pTFI < .01; pTQ < .05).

Conclusions

The current study reported the effects of HD-tDCS in a large tinnitus population. HD-tDCS of the right DLPFC resulted in a significant improvement of the tinnitus perception, with a larger improvement for the female tinnitus patients.
Sex differences in lifespan trajectories and variability of human sulcal and gyral morphology
Authors: Díaz-Caneja Covadonga M. , Alloza Clara , Gordaliza Pedro M. , Pena Alberto Fernández , de Hoyos Lucía , Santonja Javier , Buimer Elizabeth E.L. , van Haren Neeltje E.M. , Cahn Wiepke , Arango Celso , Kahn René S. , Hulshoff Pol Hilleke E. , Schnack Hugo G. , Janssen Joost
Published: October 2020

Sex differences in development and aging of human sulcal morphology have been understudied. We charted sex differences in trajectories and inter-individual variability of global sulcal depth, width, and length, pial surface area, exposed (hull) gyral surface area, unexposed sulcal surface area, cortical thickness, and cortex volume across the lifespan in a longitudinal sample (700 scans, 194 participants two scans, 104 three scans, age range: 16-70 years) of neurotypical males and females. After adjusting for brain volume, females had thicker cortex and steeper thickness decline until age 40 years; trajectories converged thereafter. Across sexes, sulcal shortening was faster before age 40, while sulcal shallowing and widening were faster thereafter. While hull area remained stable, sulcal surface area declined and was more strongly associated with sulcal shortening than with sulcal shallowing and widening. Males showed greater variability for cortex volume and thickness and lower variability for sulcal width. Across sexes, variability decreased with age for all measures except for cortical volume and thickness. Our findings highlight the association between loss of sulcal area, notably through sulcal shortening, with cortex volume loss. Studying sex differences in lifespan trajectories may improve knowledge of individual differences in brain development and the pathophysiology of neuropsychiatric conditions.
Novel approaches for the lipid sponge phase crystallization of the Rhodobacter sphaeroides photosynthetic reaction center
Authors: Selikhanov Georgii , Fufina Tatiana , Vasilieva Lyudmila , Betzel Christian , Gabdulkhakov Azat
Published: October 2020

With the recent developments in the field of free-electron-laser-based serial femtosecond crystallography, the necessity to obtain a large number of high-quality crystals has emerged. In this work crystallization techniques were selected, tested and optimized for the lipid mesophase crystallization of the Rhodobacter sphaeroides membrane pigment-protein complex, known as the photosynthetic reaction center (RC). Novel approaches for lipid sponge phase crystallization in comparatively large volumes using Hamilton gas-tight glass syringes and plastic pipetting tips are described. An analysis of RC crystal structures obtained by lipid mesophase crystallization revealed non-native ligands that displaced the native electron-transfer cofactors (carotenoid spheroidene and a ubiquinone molecule) from their binding pockets. These ligands were identified and were found to be lipids that are major mesophase components. The selection of distinct co-crystallization conditions with the missing cofactors facilitated the restoration of spheroidene in its binding site.
Evaluation of SAR sensor design parameters on remote sensing missions
Authors: Sharifi Alireza
Published: October 2020

Purpose

The purpose of this study is to investigate the design parameters of an optimal SAR satellite sensor on remote sensing missions. Synthetic aperture radar (SAR) satellite missions, with the advantages of using all weather conditions, repetition of a pass, high spatial resolution and adequate balance, can not only provide timely coverage in disaster areas but also environmental monitoring and accident assessment. It also provides resources. The product of images depicts the needs of government organizations not only before and after the crisis but also during the crisis. Therefore, low-cost SAR satellite loading efforts have begun with SAR satellites and key technologies.

Design/methodology/approach

Information about the basic parameters of SAR satellites such as antenna dimensions, image resolution, pulse and relationship repetition, as well as the tradeoff between required parameters and design needs’ evaluation was achieved. In this paper, the tradeoff methods between some technical requirements are presented, and the limitations in the design of a SAR prototype sensor in the X band are examined. Diagrams can provide a complete overview of the predicted fluctuations and tradeoffs between them for a designer.

Findings

Analysis of findings reveals that data transmission rate with PRFmin is independent of antenna incidence angle, but in contrast, it is dependent on PRFmax, and afterward its relationship was analyzed. Drawn diagrams approved presented design and calculations. Other important parameters in the design of the SAR sensor such as antenna dimensions, tilt angle, amplitude and resolution of azimuth can be achieved as significant elements in systematic design according to the results of this paper. Regarding the displayed diagrams, it can be understood that the angle of the antenna should not be from 15 to 60 degrees.

Originality/value

This paper provides an overview of the new observational capability offered by the second generation of SAR sensors, especially in the field of remote sensing applications. The built-in antenna is built for the small SAR sensor. This array antenna is designed with a parallel screen to work in X-frequency with vertical polarity.
Predicting formulae for effective length of counterpoise wires buried in ionized, dispersive and inhomogeneous soils
Authors: Sajjadi Seyyed Sajjad , Ostadzadeh Saeed Reza
Published: October 2020

Purpose

The purpose of this paper is to investigate the ionization and dispersion effects in combination with the inhomogeneity of soil simultaneously on the effective lengths of counterpoise wires.

Design/methodology/approach

Improved multi-conductor transmission line model is used for computing effective length of counterpoise wires considering all aspects of soils.

Findings

The simulation results show that the ionization and dispersion effects simultaneously results in placing the effective length between situations where only one effect is considered. Also, predicting formulae for effective length of counterpoise wires considering all effects are proposed.

Originality/value

A sensitivity analysis on the effective lengths of counterpoise wires considering all aspects of soils is carried out.