bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Retrospective and Anatomical Study Describing the Injection of Botulinum Neurotoxins in the Depressor Anguli Oris
Authors: Moradi Amir , Shirazi Azadeh 
Published: February 2022

Summary:
The depressor anguli oris acts to lower the lateral corners of the mouth and can cause an individual to appear sad or angry and contribute to the development of the labiomental folds. Many patients can benefit from the injection of small amounts of botulinum neurotoxin into the depressor anguli oris to enable the lip elevators to reposition the corners of the mouth. Although effective, the procedure is off-label, and the proximity of the depressor anguli oris to the depressor labii inferioris, particularly inferiorly, can lead to inadvertent treatment of the latter, resulting in lip asymmetry. The authors have taken a threefold approach to establish a depressor anguli oris injection technique that provides optimal aesthetic outcomes with a low incidence of adverse events. This involved, first, reviewing the limited existing literature for studies discussing depressor anguli oris anatomy and botulinum neurotoxin treatment technique; second, supplementing information from the published literature with information from cadaver dissections to demonstrate the relationship between the depressor anguli oris and surrounding anatomical structures; and third, performing a retrospective chart review of 275 patients treated with the authors’ three-point injection technique. Combining data from published studies, cadaver dissections, and clinical experience, the authors demonstrate that a three-point technique performed in the upper half of the depressor anguli oris is associated with good clinical outcome and avoids common side effects related to injection or spread of neurotoxin to adjacent muscles.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, IV.
National Surgical Quality Improvement Program Adverse Events Combined With Clavien-Dindo Scores Can Direct Quality Improvement Processes in Surgical Patients
Authors: Ghannam Alexander D. , Crandall Marie L. , Woodruff Grant , Ra Jin , Kerwin Andrew J. , Awad Ziad T. , Tepas Joseph 
Published: February 2022

Objective
The burden of postoperative adverse events (AE) weighs immediately on the patient as unanticipated stress and on the healthcare system as unreimbursed cost. Applying the Clavien-Dindo (C-D) system of AE gradation as a surrogate of cost, we analyzed 4 years’ data from a single-state National Surgical Quality Improvement Program (NSQIP) collaboration, hypothesizing that trends of AE were consistent over time and that more frequently performed cases would be associated with less and more minor AE.

Methods
The NSQIP defined AEs, consisting of 21 listed postoperative occurrences, which were analyzed using deidentified 30-day postoperative data for 2015 to 2018. Each AE was graded using (C-D) severity (1, lowest; 4, highest with survival). The C-D severity weight, as defined in previous multi-institutional studies, was used as a surrogate for cost and unplanned patient burden. Adverse event incidence was calculated as sum AE/case volume, and population burden as total AE burden/case volume.

Results
There were 12,567 surgical cases recorded by members of the state collaborative. The overall data demonstrated no significant difference in AE incidence; however, the burden of AE increased by 18.8%. The 8 most common Current Procedural Terminology codes had approximately 50% lower AE incidence compared with overall cases; however, the incidence increased by 56.0% and the AE burden/case increased by 48.0%.

Conclusions
Although the 8 most common Current Procedural Terminology codes showed a 50% lower AE incidence compared with overall cases, the incidence increased over the study period. Surgical quality initiatives should be patient centered and focus on high burden AE.
Virtual Noncontrast Imaging of the Liver Using Photon-Counting Detector Computed Tomography
Authors: Sartoretti Thomas , Mergen Victor , Higashigaito Kai , Eberhard Matthias , Alkadhi Hatem , Euler André 
Published: February 2022

Objectives
The aim of this study was to assess the accuracy of virtual noncontrast (VNC) images of the liver in a phantom and patients using dual-source photon-counting detector computed tomography (PCD-CT).

Materials and Methods
An anthropomorphic abdominal phantom with a liver insert containing liver parenchyma (1.4 mgI/mL) and 19 liver lesions (iodine content 0–5 mgI/mL) was imaged on a clinical dual-source PCD-CT (tube voltage 120 kV) and in the dual-energy mode on a dual-source energy-integrating detector (EID) CT (tube voltage combinations, 80/Sn150 kV, 90/Sn150 kV, and 100/Sn150 kV). Rings of fat-equivalent material were added to the phantom to emulate 3 sizes (small, medium, large). Each setup was imaged at 3 different radiation doses (volume CT dose index: 5, 10, and 15 mGy). Virtual noncontrast images were reconstructed and CT attenuation was measured in each lesion and liver parenchyma. The absolute error of CT attenuation (VNCerror) was calculated using the phantom specifications as reference. In addition, 15 patients with hypodense liver lesions who were clinically scanned on PCD-CT were retrospectively included. Attenuation values in lesions and liver parenchyma in VNC images reconstructed from portal venous phase CT were compared with true noncontrast images. Statistical analysis included analysis of variance with post hoc t tests and generalized linear models to assess the impact of various variables (dose, patient size, base material, iodine content, and scanner/scan mode) on quantification accuracy.

Results
In the phantom, the overall mean VNCerror for PCD-CT was 4.1 ± 3.9 HU. The overall mean VNCerror for EID-CT was 7.5 ± 5, 6.3 ± 4.7, and 6.7 ± 4.8 HU for 80/Sn150 kV, 90/Sn150 kV, and 100/Sn150 kV, respectively, with the VNCerror of EID-CT being significantly higher at all tube voltage settings (P < 0.001), even after adjusting for dose, size, iodine content of the lesion, and attenuation of base material. For PCD-CT, a smaller phantom size was associated with higher quantification accuracy (P = 0.007–0.046), whereas radiation dose did not impact accuracy (P > 0.126). For EID-CT, but not for PCD-CT, VNCerror increased with lesion iodine content (P < 0.001). In patients, there was no difference in attenuation measured on true noncontrast and VNC images (P = 0.093), with a mean VNCerror of 3.7 ± 2.2 HU.

Conclusions
Photon-counting detector CT allows for the reconstruction of VNC images of the liver both in a phantom and in patients with accurate attenuation values, being independent of dose, attenuation of base material, and liver iodine content.
The Combined Roles of Race/Ethnicity and Substance Use in Predicting Likelihood of Kidney Transplantation
Authors: DeBlasio Richelle N. , Myaskovsky Larissa , DiMartini Andrea F. , Croswell Emilee , Posluszny Donna M. , Puttarajappa Chethan , Switzer Galen E. , Shapiro Ron , DeVito Dabbs Annette J. , Tevar Amit D. , Hariharan Sundaram , Dew Mary Amanda 
Published: February 2022

Background.Racial/ethnic minorities face known disparities in likelihood of kidney transplantation. These disparities may be exacerbated when coupled with ongoing substance use, a factor also reducing likelihood of transplantation. We examined whether race/ethnicity in combination with ongoing substance use predicted incidence of transplantation.Methods.Patients were enrolled between March 2010 and October 2012 at the time of transplant evaluation. Substance use data were retrieved from transplant evaluations. Following descriptive analyses, the primary multivariable analyses evaluated whether, relative to the referent group (White patients with no substance use), racial/ethnic minority patients using any substances at the time of evaluation were less likely to receive transplants by the end of study follow-up (August 2020).Results.Among 1152 patients, 69% were non-Hispanic White, 23% non-Hispanic Black, and 8% Other racial/ethnic minorities. White, Black, and Other patients differed in percentages of current tobacco smoking (15%, 26%, and 18%, respectively;P= 0.002) and illicit substance use (3%, 8%, and 9%;P< 0.001) but not heavy alcohol consumption (2%, 4%, and 1%;P= 0.346). Black and Other minority patients using substances were each less likely to receive transplants than the referent group (hazard ratios ≤0.45,P≤ 0.021). Neither White patients using substances nor racial/ethnic minority nonusers differed from the referent group in transplant rates. Additional analyses indicated that these effects reflected differences in waitlisting rates; once waitlisted, study groups did not differ in transplant rates.Conclusions.The combination of minority race/ethnicity and substance use may lead to unique disparities in likelihood of transplantation. To facilitate equity, strategies should be considered to remove any barriers to referral for and receipt of substance use care in racial/ethnic minorities.
Defining An Expanded RAS Conformational Landscape Based on Over 700 Experimentally Determined Structures of KRAS, NRAS, and HRAS
Authors: Parker Mitchell I. , Meyer Joshua E. , Golemis Erica A. , Dunbrack Roland L. 
Published: February 2022

ABSTRACTFor many human cancers and tumor-associated diseases, mutations in the RAS isoforms (KRAS, NRAS, and HRAS) are the most common oncogenic alterations, making these proteins high-priority therapeutic targets. Effectively targeting the RAS isoforms requires an exact understanding of their active, inactive, and druggable conformations. However, there is no structure-guided catalogue of RAS conformations to guide therapeutic targeting or examining the structural impact of RAS mutations. We present an expanded classification of RAS conformations based on analyzing their catalytic switch 1 (SW1) and switch 2 (SW2) loops. From all 721 available human KRAS, NRAS, and HRAS structures in the Protein Data Bank (PDB) (206 RAS-protein complexes, 190 inhibitor-bound, and 325 unbound, including 204 WT and 517 mutated structures), we created a broad conformational classification based on the spatial positions of residue Y32 in SW1 and residue Y71 in SW2. Subsequently, we defined additional conformational subsets (some previously undescribed) by clustering all well modeled SW1 and SW2 loops using a density-based machine learning algorithm with a backbone dihedral-based distance metric. In all, we identified three SW1 conformations and nine SW2 conformations, each which are associated with different nucleotide states (GTP-bound, nucleotide-free, and GDP-bound) and specific bound proteins or inhibitor sites. The GTP-bound SW1 conformation can be further subdivided based on the hydrogen (H)-bond type made between residue Y32 and the GTP γ-phosphate: water-mediated, direct, or no H-bond. Further analyzing these structures clarified the catalytic impact of the G12D and G12V RAS mutations, and the inhibitor chemistries that bind to each druggable RAS conformation. To facilitate future RAS structural analyses, we have created a web database, called Rascore, presenting an updated and searchable dataset of human KRAS, NRAS, and HRAS structures in the PDB, and which includes a page for analyzing user uploaded RAS structures by our algorithm (http://dunbrack.fccc.edu/rascore/).SignificanceAnalyzing >700 experimentally determined RAS structures helped define an expanded landscape of active, inactive and druggable RAS conformations, the structural impact of common RAS mutations, and previously uncharacterized RAS-inhibitor binding modes.
Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade
Authors: Mehta Arnav , Rucevic Marijana , Sprecher Emmett , Parikh Milan , Chen Jiajia , Frederick Dennie T. , Woods Elliot , Bi Lynn , Lieb David , Hultin-Rosenberg Lina , Guess Jamey , Park Ryan J. , Schneider Alexis , Michaud William , Miao Benchun , Kasumova Gyulnara , Kim Michelle S. , Bai Xue , Jenkins Russell W. , Klempner Samuel J. , Gonye Anna L. K. , Yizhak Keren , Sade-Feldman Moshe , Liu David , Sullivan Ryan J. , Flaherty Keith T. , Hacohen Nir , Boland Genevieve M. 
Published: February 2022

AbstractMost patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Therefore, there is a critical need to identify early non-invasive biomarkers of response. We performed plasma proteomic analysis (>700 proteins) at three timepoints on 174 metastatic melanoma patients treated with ICB. We leverage independent training and testing cohorts to build a predictor of immunotherapy response that outperforms several tissue-based approaches. We found 217 differentially expressed proteins between ICB responders (R) and non-responders (NR), including a co-regulated module of proteins enriched in certain NR patients. By analyzing single-cell RNA-sequencing data of tumor biopsies from 32 patients, we dissected the relative contribution of cells in the tumor to proteins in circulation. The majority of proteins in the co-regulated NR module derived from tumor and myeloid cells. Amongst myeloid cells, we identified a subset of tumor-associated macrophages (TAMs) with a suppressive phenotype that expressed high levels of the co-regulated NR module, thus suggesting they are key drivers of non-response signatures. Together, our data demonstrates the utility of plasma proteomics in biomarker discovery and in understanding the biology of host response to tumors.
High-performance Flexible Microelectrode Array with PEDOT:PSS Coated 3D Micro-cones for Electromyographic Recording
Authors: Lu Jiaao , Zia Muneeb , Williams Matthew J. , Jacob Amanda L. , Chung Bryce , Sober Samuel J. , Bakir Muhannad S. 
Published: February 2022

AbstractHigh signal-to-noise ratio (SNR) electromyography (EMG) recordings are essential for identifying and analyzing single motor unit activity. While high-density electrodes allow for greater spatial resolution, the smaller electrode area translates to a higher impedance and lower SNR. In this study, we developed an implantable and flexible 3D microelectrode array (MEA) with low impedance that enables high-quality EMG recording. With polyimide micro-cones realized by standard photolithography process and PEDOT:PSS coating, this design can increase effective surface area by up to 250% and significantly improve electrical performance for electrode sites with various geometric surface areas, where the electrode impedance is at most improved by 99.3%. Acute EMG activity from mice was recorded by implanting the electrodes in vivo, and we were able to detect multiple individual motor units simultaneously and with high resolution (SNR ≫ 100). The charge storage capacity was measured to be 34.2 mC/cm2, indicating suitability of the electrodes for stimulation applications as well.
A heterogeneous drug tolerant persister state in BRAF-mutant melanoma is characterized by ion channel dysregulation and susceptibility to ferroptosis
Authors: Hayford Corey E. , Stauffer Philip E. , Baleami Blake , Paudel B. Bishal , Tyson Darren R. , Al’Khafaji Aziz , Johnson Kaitlyn E. , Harris Leonard A. , Brock Amy , Quaranta Vito 
Published: February 2022

ABSTRACTThere is increasing interest in cancer cell subpopulations that can withstanding treatment via non-genetic mechanisms, such as tumor cell plasticity and adaptation. These cell populations may be comprised of cells with diverse phenotypes, e.g., quiescent or slow cycling. Such populations have been broadly termed “drug-tolerant persisters” (DTPs) and may be responsible for minimal residual disease following anticancer treatment and acquired resistance. Understanding molecular mechanisms that drive emergence of DTPs could lead to new strategies to improve therapeutic outcomes. Recently, we reported that BRAF-mutant melanoma cells under prolonged BRAF inhibition enter a DTP state with balanced cell death and division, which we termed “idling.” Here, we apply single cell barcoding to show that idling DTP populations emerge via cell state transitions, rather than selection of a few pre-existing drug-tolerant clones. Within the time frame of our experiments, DTPs exhibit varying proportions of fast- and slow-cycling cells within each lineage, suggesting that entry into the DTP state is a stochastic process. Furthermore, single-cell transcriptomics and bulk epigenomics reveal common gene expression and ontology signatures in DTP lineages that are consistent with rebalancing of ion channels. Calcium flux experiments uncover a reduction of divalent cation reserves in intracellular organelles, likely leading to endoplasmic reticulum stress. Accordingly, idling DTPs are more prone to ferroptotic cell death, as indicated by increased sensitivity to inhibition of glutathione peroxidase 4 (GPX4), which prevents removal of toxic lipid peroxides. In summary, we propose that ion channel homeostasis is a central process underlying idling DTP emergence in BRAF-mutated melanoma. Future studies will investigate translational aspects of this insight.
Laboratory and field trials reveal the potential of a gel formulation of entomopathogenic nematodes as biocontrol against the fall armyworm (Spodoptera frugiperda)
Authors: Fallet Patrick , Bazagwira Didace , Guenat Julie , Bustos-Segura Carlos , Karangwa Patrick , Mukundwa Ishimwe Primitive , Kajuga Joelle , Degen Thomas , Toepfer Stefan , Turlings Ted C.J. 
Published: February 2022

1.AbstractThe fall armyworm (FAW), Spodoptera frugiperda (Lepidoptera: Noctuidae) can cause tremendous yield losses in maize. Its invasion into Africa and Asia has led to an enormous influx of insecticides into maize agro-ecosystems. Safe, effective and readily available alternatives are desperately needed. Entomopathogenic nematodes (EPN) are commonly used against soil insect pests, but can also control some above-ground pests. We explored the possibility to control FAW by incorporating EPN into a formulation that can be easily applied into the whorl of maize plants, where the caterpillars mostly feed. We tested this approach in laboratory cage experiments as well as in field trials. In the laboratory, treating maize plants with a low dose of EPN in a carboxymethyl cellulose (CMC) gel formulation (about 3000 infective juveniles per plant), caused 100% mortality of FAW caterpillars and prevented plant damage considerably, whereas EPN applied in water or a surfactant-polymer-formulation (SPF) caused 72% and 94% mortality, respectively. Under field conditions, one-time treatments with EPN applied in water, SPF or CMC gel were all able to prevent significant plant damage, but only the EPN-gel formulation significantly reduced FAW infestation. Notably, the gel formulation was as effective as a standard dose of cypermethrin, an insecticide commonly used against FAW. Repeated applications may be needed to reduce re-infestations by FAW across a whole cropping season depending on the local maize phenology and pest dynamics. These findings demonstrate that EPN are excellent candidates for the biological control of FAW and are a safe and sustainable alternative to chemical insecticides.HighlightsEntomopathogenic nematodes are highly lethal to fall armyworm caterpillars.Appropriate formulation of the nematodes is crucial for above-ground application.A gel formulation of entomopathogenic nematodes was as effective as chemical insecticides.Entomopathogenic nematodes can be used for the control of fall armyworm in maize.
The GLasses Against transmission of SARS-CoV-2 in the communitY (GLASSY) trial: A pragmatic randomized trial (study protocol)
Authors: Fretheim Atle , Hemkens Lars G. , Helleve Arnfinn , Elgersma Ingeborg Hess , Elstrøm Petter , Kacelnik Oliver 
Published: February 2022

AbstractBackgroundA systematic review of observational studies indicated that eye protection may be an effective measure to prevent SARS-CoV-2 infections. Randomized trials are needed to assess whether the observed associations are caused by protection of the eye or confounding factors such as other systematic differences between users and non-users of eye protection, co-interventions, or changes in COVID-19 incidence when comparisons were done over time.MethodsPragmatic, virtual, parallel group, 1:1 randomized, superiority trial. We will recruit and randomize participants via an online portal. The trial will be fully remote and virtual without any personal interaction between investigators and participants. All members of the public are eligible who confirm that they are at least 18 years of age, do not regularly wear glasses, have not contracted COVID-19 since December 15th 2021, and are willing to be randomized to wear, or not wear glasses in public when close to other people, for a 2-week period. Persons who are dependent on visual aids but typically use contact lenses are eligible. The participants will be randomized (1:1) to wear glasses (sunglasses or other types of glasses) in public spaces when close to others (public transport, shopping centers etc.), or to the control group. The control group will be asked not to wear glasses in public spaces when close to others. The primary outcome is positive test for COVID-19. We aim to include about 25,000 participants to have a statistical power of 80% to detect a relative risk reduction of 25% for the primary outcome.DiscussionMany have easy access to sunglasses or other glasses. Wearing glasses may provide eye protection and repurposing sunglasses for infection control could be a simple, readily available, environmentally friendly, safe, and sustainable infection prevention measure.Trial registrationNCT05217797 (Clinicaltrials.gov)
Estimating the incidence and key risk factors of cardiovascular disease in patients at high risk of imminent fracture using routinely collected real-world data from the UK
Authors: Pineda-Moncusí Marta , El-Hussein Leena , Delmestri Antonella , Cooper Cyrus , Alireza Moayyeri , Libanati Cesar , Toth Emese , Prieto-Alhambra Daniel , Khalid Sara 
Published: February 2022

AbstractThe objective of this work was to estimate the incidence rate of cardiovascular disease (CVD) events (myocardial infarction, stroke or CVD-death) at 1 year among 3 cohorts of patients at high risk of fracture (osteoporosis; previous fracture; and anti-osteoporosis medication), and to identify the key risk factors of CVD events in these three cohorts. To do so, this prospective cohort study used data from the Clinical Practice Research Datalink, a primary care database from United Kingdom. MACE events (a composite outcome for the occurrence of either myocardial infarction (MI), stroke or CVD death) were identified in patients aged fifty or over at high or imminent fracture risk identified in three different cohorts (not mutually exclusive): recently diagnosed with osteoporosis (OST, n=65,295), incident fragility fracture (IFX, n=80,587), and starting oral bisphosphonates (OBP, n=145,959). MACE incidence rates (cases/1000 person-years) were: 19.63 (18.54;20.73) in OST, 51.09 (49.39;52.80) in IFX, and 26.26 (25.41;27.12) in OBP cohorts. Candidate risk factors from QRISK tool, and candidates from literature selected by lasso regression, were fitted into prediction models to estimate 1-year risk of MACE for each cohort. OST and OBP models had a discrimination of ≥ 70% and IFX cohort ≥ 60%. Calibration plots showed good internal validity of the models. Generally, models from lasso regression were better than QRISK. Main risk factors common in all MACE models were sex, alcohol, atrial fibrillation, anti-hypertensive medication, age, prior MI/stroke, established CVD, glomerular filtration rate, systolic blood pressure, and number of GP visits and concomitant medicines. Incidence of MACE in the studied populations was 4.35% or lower, with IFX as the cohort with the higher risk. Identified key risk factors highlight the differences of patients at high risk of fracture versus general population. Proposed models could improve prediction of CVD events in patients with osteoporosis in primary care settings.