bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multisite Clinical Utilization of Antibiotics among Hospitalized Patients with COVID‐19
Authors: Potter Pamela , Lam Martin , Wright Nathan , Meyer Emily , Rondon‐Clavo Carlos , Merrill Stevie , Samano Dannielle , Hammode Emad , Ihms Benjamin , Santarelli Anthony , Ashurst John , Huynh Megan 
Published: May 2022

IntroductionSevere acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has infected over 212,000,000 individuals worldwide with a mortality rate of 2.1% as of August 2021. A concerning trend in the treatment of COVID‐19 has emerged wherein hospitalized patients are administered broad spectrum antibiotics to stave off secondary bacterial infection. However, the clinical justification for the use of broad‐spectrum antibiotics for viral respiratory infection remains tenuous. Over administration of these therapies contributes to the growing frequency of antimicrobial resistance, which prior to the pandemic contributed to nearly 700,000 death per year.ObjectiveTo describe the clinical utilization and efficacy of broad‐spectrum antibiotics among hospitalized patients with SARS‐CoV‐2 within 3 hospital systems in the American southwest.MethodsA multisite retrospective chart review of patients admitted to inpatient care due SARS‐CoV‐2 infection from March 1st, 2020 through January 31st, 2021 was conducted. Abstracted data included patient demographics, laboratory culture results, administered antibiotics, and patient outcomes. Analysis was conducted using descriptive statistics, the Pearson chi‐square for categorical data, and the Mann‐Whitney U test for continuous data.ResultsA total of 489 patients with confirmed SARS‐CoV‐2 infection via nasopharyngeal sample were included in the analysis with 19.2% (94/489) diagnosed with a concurrent bacterial infection. Patients with concurrent bacterial infections were more likely to require critical care (50.0% vs 20.7%; p<0.001) and expire (28.7% vs 14.4%; p<0.001) while hospitalized. Though the rates of secondary bacterial infection were low, 83.4% of all patients were administered at least one broad spectrum antibiotic, with the most common being Azithromycin (60%; 297/489) followed by Ceftriaxone (46.6%; 228/489). Antibiotics were not preferentially administered to patients with concurrent bacterial infection (p=0.1619), nor did it show clinical efficacy for reducing mortality among the entire sample (p=0.190) or those with secondary infection (p=0.191).ConclusionThe COVID‐19 pandemic has contributed to non‐specific over administration of broad‐spectrum antibiotics, which failed to improve the rate of patient mortality even when afflicted with secondary infection. Over‐administration of these drugs will continue to exacerbate the growing rates of antimicrobial resistance. Clinicians are recommended to apply early empirical approaches when selecting to employ antibiotic therapies.
Characteristics and Outcomes of Patients Presenting to Rural or Urban Emergency Departments with COVID‐19
Authors: Potter Pamela , Sidhu Kamaldeep , Hailu Elon , Akramoff Ashley , Shah Bhairav , Merrill Stevie , Samano Dannielle , Colling Lindsey , Ihms Benjamin , Hammode Emad , Ashurst John , Santarelli Anthony 
Published: May 2022

BackgroundThe Coronavirus disease 2019 pandemic placed unprecedented strain on healthcare workers and hospital systems. While healthcare institutions across the nation all faced high census numbers, hospitals in rural settings are often burdened with less resources than their urban counterparts. Therefore, we hypothesized that receiving care in rural settings would be associated with poorer clinical outcomes.ObjectiveTo compare the characteristics and outcomes of patients with SARS‐CoV‐2 presenting to urban and rural emergency departments in the American southwest.MethodsA multisite retrospective chart review of patients admitted to inpatient care due SARS‐CoV‐2 infection from March 1st, 2020 through January 31st, 2021 was conducted at three participating hospitals. Abstracted data included patient demographics, intake laboratory values, and patient outcomes. Analysis was conducted using descriptive statistics, the Pearson chi‐square for categorical data, the Mann‐Whitney U test for continuous data, and Kaplan‐Myer for disease progression.ResultsA total of 489 patients with confirmed SARS‐CoV‐2 infection via nasopharyngeal sample were included in the analysis with 57.1% (279/489) presenting to an urban emergency department. Patients admitted in the rural and urban setting showed similar demographics in regard to age (p=0.710), sex (p=0.312), and majority/minority status (p=0.062). Upon presentation, patients in rural settings were more likely to have critically low white blood cell counts (p<0.001), abnormally high hematocrit (p=0.001), and abnormally high aspartate aminotransferase levels (p<0.001) than their urban counterparts. Following admission, urban patients were 2.53 times more likely than rural patients to be transferred to critical care (p<0.001) with the transfer contributing to a reduced hospitalization length of 2.7 days in the urban setting (p=0.002). Rural patients unable to transfer to critical care were 4.95 times more likely to expire than urban patients (p=0.014).ConclusionPatients receiving care for SARS‐CoV‐2 infection in the rural setting often present with more severe clinical profiles and are more likely to experience negative outcomes than their urban counterparts. Rural hospitals should attempt to reduce this discrepancy by developing robust prognostic procedures to minimize critical care bed utilization.
Imaging of Corticosteroids in Mouse Kidney Using Mass Spectrometry
Authors: Stasinopoulos Ioannis , Khan Shazia , MacKay C. Logan , Brown Roger W. , Andrew Ruth , Bailey Matthew A. 
Published: May 2022

Aldosterone regulates renal sodium reabsorption which is important for blood pressure homeostasis. Glucocorticoids may also contribute to this process although this is less well understood. Analysis of steroid hormones and the metabolites in the plasma and urine gives insights into corticosteroid biology but steroid concentrations at a cellular level are largely unknown, and the kidney remains a “black box”. Mass spectrometry imaging (MSI) permits localisation of steroids in histological zones based on regional markers. This approach has been previously applied to localise steroids in brain and testes, and here is applied to kidney. Our aim was to map and quantify glucocorticoids and aldosterone in different histological zones (cortex, medulla) of kidneys from mice receiving different dietary salt, to provide new information relevant to the physiological actions of these hormones.Cryosections kidney from male C57BL6 mouse (age 12 weeks, n=6: dietary salt low 0.03% vs normal 0.3% vs high 3%) were subject to MSI analysis following Girard T reagent derivatisation and α‐cyano‐4‐hydroxycinnamic acid matrix application. Matrix assisted laser desorption/ionisation (MALDI) was used as a sampling method, coupled to Fourier Transform Ion cyclotron mass spectrometry.Ions with m/z 458.3010 (Δppm=0.65), 460.3166 (Δppm=0.65), and 474.2957 (Δppm=1.05) were detected, using MALDI, in renal sections for derivatives of 11‐dehydrocorticosterone, corticosterone and aldosterone respectively. Untargeted evaluation of ions was conducted to find regional markers that would allow definition of kidney histological zones. Heat maps indicated that corticosterone intensity was higher in the inner cortex than the rest of the kidney. In contrast 11‐dehydrocorticosterone, a metabolite produced by the enzymic activity of 11β‐hydroxysteroid dehydrogenase type II, was detected at highest levels in the medulla. The aldosterone signal was equally strong in medulla and outer cortex. Steroid localisation after treatment with different salt intakes indicated that the intensity of the corticosterone signal increases in the outer cortex in kidneys from mice receiving low salt diet, while 11‐dehydrocorticosterone was not affected. The intensity of the aldosterone signal within the kidney was not changed by different salt intakes. Our approach shows that it is feasible to image corticosteroids at 75μm spatial resolution within the kidney. This technology provides new insights into the physiological control of sodium transport by steroids and opens doors to understanding changes in disorders of blood pressure.
Loss of protein stability and function caused by a single point mutation (P228L) in the Cytochrome P450 Oxidoreductase
Authors: Rojas Velazquez Maria Natalia , Noebauer Mathias , Pandey Amit V. 
Published: May 2022

Cytochrome P450 oxidoreductase (POR) is the obligatory redox partner of steroid and drug metabolizing cytochrome P450s located in the endoplasmic reticulum. Mutations in POR cause a broad range of disorders like congenital adrenal hyperplasia. Genome sequencing studies have revealed the existence of a POR missense variant P228L which was linked with reduced function of some P450 enzymes. We aimed to expand the enzymatic studies of POR variant P228L for its role in human metabolism.We expressed human wild type and the P228L variant POR in bacteria and purified the proteins by Affinity Chromatography. We tested the stability of the proteins using fast proteolysis and performed kinetics assays of POR activities using small molecules substrates. POR (WT or P228L) were mixed with purified cytochrome P450 proteins and activities of cytochrome P450 proteins were assayed.The single point mutation P228L had reduced thermal stability indicated by a lower melting point comparing to the WT. In the kinetics studies, the rates of the reactions with P228L were considerably lower than the WT but the Km did not show substantial changes. We observed a decrease in the enzymatic activities of CYP3A5 and CYP2C9 of more than 40% with P228L form of POR comparing to WT.A single change in the amino acid sequence can affect the protein stability and cause a severe reduction in POR activity. Molecular characterization of POR mutations is crucial to have a better understanding of the impact on the functionality of its redox Partners.
Pharmacology and pharmacokinetics of fentanyl toxicity reversal by anti‐fentanyl monoclonal antibodies in combination with naloxone
Authors: Baehr Carly A. , Pravetoni Marco 
Published: May 2022

AIMWidespread access to illicit fentanyl has contributed to an ongoing epidemic of fatal drug overdoses in the United States. The incidence of fatal overdoses in the United States accelerated during the COVID‐19 pandemic, with over 100,000 deaths recorded by April 2021. Fentanyl‐specific monoclonal antibodies (mAb) offer a prophylactic and therapeutic intervention against opioid overdose by binding and sequestering fentanyl in serum, and reducing distribution to the brain. Here, the kinetics of overdose reversal by anti‐fentanyl mAb alone or in combination with naloxone were explored, and the dose‐response relationship between naloxone and high doses of fentanyl in the presence of mAb was evaluated.METHODSTo evaluate the kinetics of fentanyl reversal, fentanyl 0.1 mg/kg was administered to male Sprague‐Dawley rats, and mAb or naloxone was administered fifteen minutes after exposure. Oxygen saturation was monitored constantly for ten minutes following administration of reversal agent. To evaluate duration and extent of protection from further fentanyl exposures, rats were pre‐treated with mAb, naloxone, or a combination, and challenged with increasing doses of fentanyl up to 0.5 mg/kg. Finally, to determine whether the presence of mAb would increase efficacy of naloxone against a lethal dose of fentanyl, 2.25 mg/kg fentanyl was administered, followed by naloxone 0.01 to 1.0 mg/kg.RESULTSThe most rapid reversal of fentanyl toxicity was achieved by intravenous administration of a combination of anti‐fentanyl mAb and naloxone (<1 min). Intravenous naloxone reversed fentanyl toxicity more quickly than subcutaneous naloxone, and intravenous mAb was effective against fentanyl within 4 minutes, similar to subcutaneous NLX. Against further challenges of fentanyl, both mAb and 0.1 mg/kg naloxone were effective against 0.1‐0.2 mg/kg fentanyl, and the combination of mAb and naloxone was effective against doses of 0.5 mg/kg fentanyl or higher. Prophylactic administration of mAb enhanced efficacy of naloxone in reversing a potentially lethal challenge of 2.25 mg/kg fentanyl. Finally, mAb sequestered high concentrations of both fentanyl and its metabolite norfentanyl in serum, and reduced brain concentrations of fentanyl in pre‐exposure scenarios.CONCLUSIONSThese results support translation of mAb as medical countermeasures to prevent and reverse opioid overdose related to fentanyl and its analogs.
Follow Your Nose: Ontogeny of the Olfactory Duct in Primates
Authors: Haynes Laura K. , Franklin Katheryn P. , Smith Timothy D. , DeLeon Valerie B. 
Published: May 2022

Most primates are characterized by orbital convergence, the displacement of the orbits toward the rostral midline. In platyrrhine primates and tarsiers, this convergence is so extreme that orbits meet in the midline at the apical interorbital septum. This produces a spatial separation of the anterior cranial fossa and the nasal cavity. The olfactory bulbs of the brain pass dorsal and then rostral to the orbits to reach the nasal cavity via a bony tube, the olfactory duct. Nerves are expected to constrain growth of musculoskeletal structures. We hypothesized that the network of olfactory nerves effectively tethers the olfactory bulbs to the mucosa of the nasal cavity, and the growth of facial structures in these primates results in rostral displacement of the olfactory bulbs through ontogeny. In addition, growth of the midface may be constrained by this functional relationship.This comparative analysis was based on 3D reconstructions of cranial structures in newborns and adults from representative platyrrhine species (e.g., Aotus nancymaae and Cebuella pygmaea) and tarsiers (Tarsius syrichta). Spatial relationships of the olfactory duct were estimated using endocasts based on conventional microCT scans. In addition, diffusion iodine contrast‐enhanced CT (diceCT) images were used to study Aotus nancymaae at multiple stages of ontogeny. DiceCT allowed us to reconstruct the actual position of olfactory bulbs relative to the olfactory duct and the distribution of olfactory nerves in the nasal cavity. 3DSlicer and Blender software were used to render 3D models. These data confirm our hypothesis that the rostral projection of the olfactory bulbs relative to the frontal lobes of the brain increases through ontogeny. In addition, the paths of olfactory nerves are diverted around the convergent eyes. The ontogenetic relationships occurring in platyrrhine and tarsier olfactory ducts have evolutionary implications for biological variation in the primate skull.
High Fat Diet and High Fructose Diet‐fed Male and Female Liv‐ARKO Mice Displayed Impair Glucose‐Stimulated Insulin Secretion
Authors: Falzarano Claire , Wilson Andre , Carr Kiana , Levey Josephine , Lofton Taylor , Andrisse Stanley 
Published: May 2022

Insulin resistance affects up to a third of the US adult population and polycystic ovary syndrome (PCOS) affects up to 10% of reproductive‐age adult women. The liver plays an essential component in the metabolism of insulin and androgen signaling. Hyperandrogenism in females can also increase predisposition to insulin resistance. In our study, we placed female and male liver androgen receptor knock‐out mice (Liv‐ARKO) on high fructose diets (HFrD) and high fat diets (HFD) to determine if Liv‐ARKO mice demonstrated altered glucose‐stimulated insulin secretion on special diets compared to a control diet.In this study, female and male Liv‐ARKO mice were placed on three distinct diets: Control (Research Diets Inc), High Fat (HFD), and High Fructose (HFrD). After one month and two months on these diets, Glucose‐Stimulated Insulin Secretion tests were performed: each group was injected with a 20% glucose solution at 2g of glucose/kg body mass and blood samples were taken via tail milking at 0 minutes, 15 minutes, and 30 minutes. Blood samples were immediately centrifuged and serum supernatant was extracted for further analysis via Sigma Insulin Assay.In the current study, after two months, female mice on HFrD demonstrated lower basal insulin levels compared to female mice fed a control diet. Interestingly, mice on a HFD showed insulin levels that were lower than the basal levels of both control mice and HFrD mice. Furthermore, compared to the control mice, the HFD mice demonstrated lower insulin levels at both basal level and 30 minutes post‐glucose administration.It was hypothesized that HFD and HFrD‐fed Liv‐ARKO mice would impair glucose‐stimulated insulin secretion, which our current study supports. These data suggest that diets high in fructose and fat both blunt insulin secretion following a meal, and to a greater extent in high fat diets. This dysfunction may ultimately play a role in the development of insulin resistance. More research is necessary in order to further investigate the effects of high fat and high fructose diets on glucose‐stimulated insulin secretion and consequent development of insulin resistance.
Cutaneous Microvascular Endothelial Function: Effects of Sex and Menopause Stage
Authors: Parr Shannon , Hammond Stephen , Sutterfield Shelbi L. , Ade Carl J. , Smith Joshua R. 
Published: May 2022

BackgroundEndothelial dysfunction and increased arterial stiffness are both associated with increased risk of cardiovascular events and mortality.Vascular aging has been characterized by deteriorating endothelial function accompanied by increasing vascular stiffness that occurs with increasing chronological age, with the onset of these changes varying by sex. Deteriorating large artery vascular function has been reported across the menopause transition in women, but it is unclear if this relationship extends to the cutaneous microvasculature, which may have critical implications for both thermal regulation and general cardiovascular health.Purpose & HypothesisThe primary purpose of this study was to determine the impact of sex and menopausal stage on cutaneous endothelial dependent (EDD) vasodilation. We hypothesized that cutaneous EDD vasodilation would decrease in women in a graded manner across the transition from pre, to peri, to postmenopause with differences compared to age matched men. Secondly, we hypothesized that there would be no differences in cutaneous EDD vasodilation between natural and surgical (i.e., hysterectomy) menopause.MethodsPremenopausal, (n=8, 44±5y), perimenopausal (n=6, 51±2y), and postmenopausal women (n=9, 60±7y) as well as men age matched to the postmenopausal group (n=6, 59±7y) volunteered for this study. Cutaneous EDD vasodilation was measured by local iontophoresis of Acetylcholine (Ach) administration into the forearm vasculature. Red blood cell flux was determined by laser Doppler flowmetry at baseline and after 200µL of Ach. CVC was calculated as the quotient of red blood cell flux and mean arterial pressure and expressed as the percentage increased from baseline (CVC%). Differences were determined using a 1‐way ANOVA. Data are presented as mean ± standard error.ResultsForearm microvascular CVC% was significantly different among groups (P=0.01) after Ach administration. Post hoc analyses revealed an attenuated CVC% response in postmenopausal women (691±150%; P=0.02) and men (733±127%; P=0.05) compared to premenopausal women (1398±247%). There were no differences detected between peri‐ and premenopausal women (1290±140% vs. 1398±247%; P=0.95). Further, we performed a subanalysis in our postmenopausal group which included surgical (n=3) and natural (n=8) postmenopausal women. No differences were present between surgical and natural postmenopausal women (P=0.87), while both the surgical (646±163%; P=0.08) and natural (713±221%; P=0.05) postmenopausal women appeared to have decreased CVC responses compared to premenopausal women (1398±247%).ConclusionsOur findings indicate that cutaneous EDD vasodilation decreases from pre‐ to postmenopause in healthy women. Our data suggests that decreases in microvascular function agrees with reported decrements in large vessel vascular function associated with the menopause transition.
Convolutional Neural Network Analysis to Predict Expiratory Flow Limitation During Exercise in Adults with Asthma
Authors: Haverkamp Hans C. , Petrics Greg 
Published: May 2022

OBJECTIVE and HYPOTHESISThe objective of this study was to assess the potential for using well‐known convolutional neural network (CNN) designs to accurately identify the presence of expiratory flow‐limitation (EFL) during exercise in adult asthmatics. We hypothesized that a CNN model would accurately identify spontaneous exercise tidal flow‐volume loops (eFVL) that exceed maximal airflow from the maximal forced expiration (i.e., EFL).METHODS and RESULTSThe expiratory portion of spontaneous eFVLs were placed within the pre‐exercise maximal volitional flow‐volume envelope. Inspiratory capacity maneuvers were performed to determine the correct lung volume for placement of the eFVLs. We assembled a collection of spontaneous eFVLs from one asthmatic subject consisting of an equal number of eFVLs that were flow‐limited and non‐flow‐limited. Subsequently, our overall approach followed standard deep learning practices. The eFVLs were manually labelled as EFL and non‐EFL. The sci‐kit learn train_test_split() method was used to split the eFVLs randomly into training and testing sets using a 67%/33% split. We trained both a one‐ (expired airflow only) and a two‐channel (expired volume and airflow) CNN model to predict the presence or absence of EFL as a response to an eFVL. The models were instantiated as sequential models using the TensorFlow 2.6.0 python API. After 100 training epochs on the training cases, the 1‐channel model was challenged to predict the labels of the previously unseen testing cases. The 1‐channel model achieved 93.3% accuracy at predicting the EFL/non‐EFL labels as a response to the eFVLs despite having not been trained on these data. Additionally, the 2‐channel model was 100% accurate on the unseen test cases. We then challenged the 2‐channel model on 45 unseen eFVLs from a different asthmatic subject; the eFVLs consisted of a balance of EFL and non‐EFL. The model performed poorly, accurately identifying only 57% of the eFVLs as EFL or non‐EFL. We then trained an additional 2‐channel model on a random sample of the combined data from the two subjects and challenged the model on the unseen eFVLs from the same two subjects. At 25 epochs and 100 epochs, the CNN was challenged with unseen testing subjects and achieved 88 and 92% accuracy, respectively, at distinguishing between EFL and non‐EFL.CONCLUSIONSThese proof‐of‐concept findings provide strong evidence that neural network analyses hold promise as a novel method for identifying either the presence or absence of EFL. Given the current, tedious and nuanced methods for determining EFL, such artificial intelligence analyses hold promise for automating the analysis and identification of exercise ventilatory constraints.