bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐cell RNA sequencing redefines the mesenchymal cell landscape of mouse endometrium
Authors: Kirkwood Phoebe M. , Gibson Douglas A. , Smith James R. , Wilson‐Kanamori John R. , Kelepouri Olympia , Esnal‐Zufiaurre Arantza , Dobie Ross , Henderson Neil C. , Saunders Philippa T. K.
Published: March 2021

The endometrium is a dynamic tissue that exhibits remarkable resilience to repeated episodes of differentiation, breakdown, regeneration, and remodeling. Endometrial physiology relies on a complex interplay between the stromal and epithelial compartments with the former containing a mixture of fibroblasts, vascular, and immune cells. There is evidence for rare populations of putative mesenchymal progenitor cells located in the perivascular niche of human endometrium, but the existence of an equivalent cell population in mouse is unclear. We used the Pdgfrb‐BAC‐eGFP transgenic reporter mouse in combination with bulk and single‐cell RNA sequencing to redefine the endometrial mesenchyme. In contrast to previous reports we show that CD146 is expressed in both PDGFRβ + perivascular cells and CD31 + endothelial cells. Bulk RNAseq revealed cells in the perivascular niche which express the high levels of Pdgfrb as well as genes previously identified in pericytes and/or vascular smooth muscle cells (Acta2, Myh11, Olfr78, Cspg4, Rgs4, Rgs5, Kcnj8, and Abcc9). scRNA‐seq identified five subpopulations of cells including closely related pericytes/vascular smooth muscle cells and three subpopulations of fibroblasts. All three fibroblast populations were PDGFRα+/CD34 + but were distinct in their expression of Ngfr/Spon2/Angptl7 (F1), Cxcl14/Smoc2/Rgs2 (F2), and Clec3b/Col14a1/Mmp3 (F3), with potential functions in the regulation of immune responses, response to wounding, and organization of extracellular matrix, respectively. Immunohistochemistry was used to investigate the spatial distribution of these populations revealing F1/NGFR + cells in most abundance beside epithelial cells. We provide the first definitive analysis of mesenchymal cells in the adult mouse endometrium identifying five subpopulations providing a platform for comparisons between mesenchymal cells in endometrium and other adult tissues which are prone to fibrosis.
FilGAP, a GAP protein for Rac, regulates front‐rear polarity and tumor cell migration through the ECM
Authors: Saito Koji , Mori Mamiko , Kambara Norito , Ohta Yasutaka
Published: March 2021

Migrating tumor cells are characterized by a sustained front‐rear asymmetry, with a front enriched in filamentous actin, which is induced by Rho small GTPase Rac. Regulation of Rac activity by its regulators should be required for effective motility. Here, we show that FilGAP, a GTPase‐activating protein (GAP) for Rac, controls front‐rear polarity and contributes to maintain effective tumor cell migration through the extracellular matrix (ECM). Overexpression of FilGAP in breast cancer cells induced polarized morphology and led to increased migration speed in collagen matrices, while depletion of FilGAP impaired the cell polarity and migration. FilGAP localizes to the cell front through its pleckstrin‐homology (PH) domain in a phosphatidylinositol 3,4,5‐trisphosphate (PIP3)‐dependent manner and appears to inactivate Rac at its site. We found that the affinity of PH domain to PIP3 is critically involved in the maintenance of cell polarity. Moreover, small GTPase ADP‐ribosylation factor 6 (Arf6), which binds to the FilGAP PH domain, also regulates FilGAP‐mediated cell polarity and migration of breast cancer cells. We propose that FilGAP regulates front‐rear polarity through its PIP3 and Arf6 binding in tumor cell migration through the ECM.
Adipocyte precursor cells from first degree relatives of type 2 diabetic patients feature changes in hsa‐mir‐23a‐5p, ‐193a‐5p, and ‐193b‐5p and insulin‐like growth factor 2 expression
Authors: Mirra Paola , Desiderio Antonella , Spinelli Rosa , Nigro Cecilia , Longo Michele , Parrillo Luca , D’Esposito Vittoria , Carissimo Annamaria , Hedjazifar Shahram , Smith Ulf , Formisano Pietro , Miele Claudia , Raciti Gregory A. , Beguinot Francesco
Published: March 2021

First‐degree relatives (FDRs) of type 2 diabetics (T2D) feature dysfunction of subcutaneous adipose tissue (SAT) long before T2D onset. miRNAs have a role in adipocyte precursor cells (APC) differentiation and in adipocyte identity. Thus, impaired miRNA expression may contribute to SAT dysfunction in FDRs. In the present work, we have explored changes in miRNA expression associated with T2D family history which may affect gene expression in SAT APCs from FDRs. Small RNA‐seq was performed in APCs from healthy FDRs and matched controls and omics data were validated by qPCR. Integrative analyses of APC miRNome and transcriptome from FDRs revealed down‐regulated hsa‐miR‐23a‐5p, ‐193a‐5p and ‐193b‐5p accompanied by up‐regulated Insulin‐like Growth Factor 2 (IGF2) gene which proved to be their direct target. The expression changes in these marks were associated with SAT adipocyte hypertrophy in FDRs. APCs from FDRs further demonstrated reduced capability to differentiate into adipocytes. Treatment with IGF2 protein decreased APC adipogenesis, while over‐expression of hsa‐miR‐23a‐5p, ‐193a‐5p and ‐193b‐5p enhanced adipogenesis by IGF2 targeting. Indeed, IGF2 increased the Wnt Family Member 10B gene expression in APCs. Down‐regulation of the three miRNAs and IGF2 up‐regulation was also observed in Peripheral Blood Leukocytes (PBLs) from FDRs. In conclusion, APCs from FDRs feature a specific miRNA/gene profile, which associates with SAT adipocyte hypertrophy and appears to contribute to impaired adipogenesis. PBL detection of this profile may help in identifying adipocyte hypertrophy in individuals at high risk of T2D.
The use of fluorescence correlation spectroscopy to monitor cell surface β2‐adrenoceptors at low expression levels in human embryonic stem cell‐derived cardiomyocytes and fibroblasts
Authors: Goulding Joëlle , Kondrashov Alexander , Mistry Sarah J. , Melarangi Tony , Vo Nguyen T.N. , Hoang Duc M. , White Carl W. , Denning Chris , Briddon Stephen J. , Hill Stephen J.
Published: March 2021

The importance of cell phenotype in determining the molecular mechanisms underlying β2‐adrenoceptor (β2AR) function has been noted previously when comparing responses in primary cells and recombinant model cell lines. Here, we have generated haplotype‐specific SNAP‐tagged β2AR human embryonic stem (ES) cell lines and applied fluorescence correlation spectroscopy (FCS) to study cell surface receptors in progenitor cells and in differentiated fibroblasts and cardiomyocytes. FCS was able to quantify SNAP‐tagged β2AR number and diffusion in both ES‐derived cardiomyocytes and CRISPR/Cas9 genome‐edited HEK293T cells, where the expression level was too low to detect using standard confocal microscopy. These studies demonstrate the power of FCS in investigating cell surface β2ARs at the very low expression levels often seen in endogenously expressing cells. Furthermore, the use of ES cell technology in combination with FCS allowed us to demonstrate that cell surface β2ARs internalize in response to formoterol‐stimulation in ES progenitor cells but not following their differentiation into ES‐derived fibroblasts. This indicates that the process of agonist‐induced receptor internalization is strongly influenced by cell phenotype and this may have important implications for drug treatment with long‐acting β2AR agonists.
Investigation of the putative role of antisense transcripts as regulators of sense transcripts by correlation analysis of sense‐antisense pairs in colorectal cancers
Authors: Choi Hye‐Mi , Lee Sang‐Hyeop , Lee Min‐Seok , Park Donghyun , Choi Sun Shim
Published: March 2021

Antisense transcription occurs widely more expected than when it was first identified in bacteria in the 1980s. However, the functional relevance of antisense transcripts in transcription remains controversial. Here, we investigated the putative role of antisense transcripts in regulating their corresponding sense transcripts by analyzing changes in correlative relationships between sense‐antisense pairs under tumor and normal conditions. A total of 3469 sense‐antisense gene pairs (SAGPs) downloaded from BioMart mapped to a list of sense and antisense genes in RNA‐seq data derived from 80 paired colorectal cancer (CRC) samples were analyzed. As a result, cancer‐related genes were significantly enriched in the significantly correlated SAGPs (SCPs). Differentially expressed genes estimated between normal and tumor conditions were also significantly more enriched in SCPs than in non‐SCPs. Interestingly, using differential correlation analysis, we found that tumor samples had a significantly larger density of genes with higher correlation coefficients than normal samples, as verified by various cancer transcriptomes from The Cancer Genome Atlas (TCGA). Moreover, we found that the magnitude of the correlation between SAGPs could distinguish poor prognostic CRCs from good prognostic CRCs, showing that correlation coefficients between the SAGPs of CRCs with a poor prognosis were significantly stronger than CRCs with a good prognosis. Consistent with this finding, the Cox proportion hazards model showed that the survival rates were significantly different between patients with high and low expression of genes in the SCPs. All these results strongly support the idea that antisense transcripts are important regulators of their corresponding sense transcripts.
Cyclophilin A is an endogenous ligand for the triggering receptor expressed on myeloid cells‐2 (TREM2)
Authors: Ji Kon‐Young , Kim Su‐Man , Yee Su‐Min , Kim Min‐Jae , Ban Yu‐Jin , Kim Eun‐Mi , Lee Eun‐Hee , Choi Ha‐Rim , Yun Hyosuk , Lee Chul Won , Yun Chul‐Ho , Lee C. Justin , Lee Hyang Burm , Kang Hyung‐Sik
Published: March 2021

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell surface receptor expressed on macrophages, microglial cells, and pre‐osteoclasts, and that participates in diverse cellular function, including inflammation, bone homeostasis, neurological development, and coagulation. In spite of the indispensable role of the TREM2 protein in the maintenance of immune homeostasis and osteoclast differentiation, the exact ligand for TREM2 has not yet been identified. Here, we report a putative TREM2 ligand which is secreted from MC38 cells and identified as a cyclophilin A (CypA). A specific interaction between CypA and TREM2 was shown at both protein and cellular levels. Exogenous CypA specifically interacted and co‐localized with TREM2 in RAW264.7 cells, and the physical interactions were shown to regulate TREM2 signaling transduction. The Pro144 residue in the extracellular domain of TREM2 was found to be the specific binding site of CypA. When considered together, this provides evidence that CypA interacts specifically with TREM2 as a potent ligand.
Omega‐3 fatty acids protect from colitis via an Alox15‐derived eicosanoid
Authors: Rohwer Nadine , Chiu Cheng‐Ying , Huang Dan , Smyl Christopher , Rothe Michael , Rund Katharina M. , Helge Schebb Nils , Kühn Hartmut , Weylandt Karsten‐Henrich
Published: March 2021

An increased omega‐3 polyunsaturated fatty acid (n‐3 PUFA) tissue status can lead to a significant formation of anti‐inflammatory lipid mediators and effective reduction in inflammation and tissue injury in murine colitis. Arachidonic acid lipoxygenases (ALOX) have been implicated in the pathogenesis of inflammatory bowel disease as well as in the formation of pro‐ and anti‐inflammatory lipid mediators. To explore the role of Alox15 in the protective response found in fat1 transgenic mice with endogenously increased n‐3 PUFA tissue status fat1 transgenic mice were crossed with Alox15‐deficient animals and challenged in the dextran sulfate sodium (DSS)‐ and the 2,4,6‐trinitrobenzene sulphonic acid (TNBS)‐induced colitis model. Transgenic fat1 mice rich in endogenous n‐3 PUFAs were protected from colitis. However, additional systemic inactivation of the Alox15 gene counteracted this protective effect. To explore the molecular basis for this effect Alox15 lipid metabolites derived from n‐3 PUFA were analyzed in the different mice. Alox15 deficiency suppressed the formation of n‐3 PUFA‐derived 15‐hydroxy eicosapentaenoic acid (15‐HEPE). In contrast, treating mice with intraperitoneal injections of 15S‐HEPE protected wild‐type mice from DSS‐ and TNBS‐induced colitis. These data suggest that the anti‐colitis effect of increased n‐3 PUFA in the transgenic fat1 mouse model is mediated in part via Alox15‐derived 15‐HEPE formation.
Neurotensin: A novel mediator of ovulation?
Authors: Campbell Genevieve E. , Bender Hannah R. , Parker Grace A. , Curry Thomas E. , Duffy Diane M.
Published: March 2021

The midcycle luteinizing hormone (LH) surge initiates a cascade of events within the ovarian follicle which culminates in ovulation. Only mural granulosa cells and theca cells express large numbers of LH receptors, and LH‐stimulated paracrine mediators communicate the ovulatory signal within the follicle. Recent reports identified the neuropeptide neurotensin (NTS) as a product of granulosa cells. Here, we demonstrate that granulosa cells were the primary site of NTS expression in macaque ovulatory follicles. Granulosa cell NTS mRNA and protein increased after human chorionic gonadotropin (hCG) administration, which substitutes for the LH surge. To identify ovulatory actions of NTS, a NTS‐neutralizing antibody was injected into preovulatory macaque follicles. hCG administration immediately followed, and ovaries were removed 48 hours later to evaluate ovulatory events. Follicles injected with control IgG ovulated normally. In contrast, 75% of NTS antibody‐injected follicles failed to ovulate, containing oocytes trapped within unruptured, hemorrhagic follicles. Serum progesterone was unchanged. Of the three NTS receptors, SORT1 was highly expressed in follicular granulosa, theca, and endothelial cells; NTSR1 and NTSR2 were expressed at lower levels. Excessive blood cells in NTS antibody‐injected follicles indicated vascular anomalies, so the response of monkey ovarian endothelial cells to NTS was evaluated in vitro. NTS stimulated endothelial cell migration and capillary sprout formation, consistent with a role for NTS in vascular remodeling associated with ovulation. In summary, we identified NTS as a possible paracrine mediator of ovulation. Further investigation of the NTS synthesis/response pathway may lead to improved treatments for infertility and novel targets for contraception.
Gender Differences in Milestone Ratings and Medical Knowledge Examination Scores Among Internal Medicine Residents
Authors: Hauer Karen E. , Jurich Daniel , Vandergrift Jonathan , Lipner Rebecca S. , McDonald Furman S. , Yamazaki Kenji , Chick Davoren , McAllister Kevin , Holmboe Eric S.
Published: March 2021

Purpose

To examine whether there are group differences in milestone ratings submitted by program directors working with clinical competency committees (CCCs) based on gender for internal medicine (IM) residents and whether women and men rated similarly on milestones perform comparably on subsequent in-training and certification examinations.

Method

This national retrospective study examined end-of-year medical knowledge (MK) and patient care (PC) milestone ratings and IM In-Training Examination (IM-ITE) and IM Certification Examination (IM-CE) scores for 2 cohorts (2014–2017, 2015–2018) of U.S. IM residents at ACGME-accredited programs. It included 20,098/21,440 (94%) residents, with 9,424 women (47%) and 10,674 men (53%). Descriptive statistics and differential prediction techniques using hierarchical linear models were performed.

Results

For MK milestone ratings in PGY-1, men and women showed no statistical difference at a significance level of .01 (P = .02). In PGY-2 and PGY-3, men received statistically higher average MK ratings than women (P = .002 and P < .001, respectively). In contrast, men and women received equivalent average PC ratings in each PGY (P = .47, P = .72, and P = .80, for PGY-1, PGY-2, and PGY-3, respectively). Men slightly outperformed women with similar MK or PC ratings in PGY-1 and PGY-2 on the IM-ITE by about 1.7 and 1.5 percentage points, respectively, after adjusting for covariates. For PGY-3 ratings, women and men with similar milestone ratings performed equivalently on the IM-CE.

Conclusions

Milestone ratings were largely similar for women and men. Generally, women and men with similar MK or PC milestone ratings performed similarly on future examinations. Although there were small differences favoring men on earlier examinations, these differences disappeared by the final training year. It is questionable whether these small differences are educationally or clinically meaningful. The findings suggest fair, unbiased milestone ratings generated by program directors and CCCs assessing residents.
Medical School Accreditation Factors Associated With Certification by the Educational Commission for Foreign Medical Graduates (ECFMG): A 10-Year International Study
Authors: Tackett Sean , Boulet John R. , van Zanten Marta
Published: March 2021

Purpose

In 2024, international medical graduates seeking Educational Commission for Foreign Medical Graduates (ECFMG) certification will be required to graduate from an accredited medical school. This study’s goal was to examine relationships between medical school accreditation variables and ECFMG certification for a global sample.

Method

Using ECFMG databases, the authors created a 10-year cohort (January 1, 2007–December 31, 2016) of certification applicants, defined as individuals who had attempted at least 2 examinations required for certification. The authors aggregated applicant data at the school level, excluding schools with < 80 applicants. School accreditation statuses were based on agency websites. School region, age, and time of first accreditation were included. Analyses included descriptive and bivariate statistics and multiple linear regressions adjusting for school start year and year of first accreditation.

Results

The cohort included 128,046 applicants from 1,973 medical schools across 162 countries. After excluding low-volume schools, 318 schools across 81 countries remained. These provided 99,598 applicants and 77,919 certificate holders, three-quarters of whom came from the Caribbean, South-Central Asia, and West Asia regions. Two hundred and fifty (78.6%) schools were accredited; 68 (21.4%) were not. Most ECFMG applicants (n = 84,776, 85.1%) and certificate holders (n = 68,444, 87.8%) attended accredited medical schools. Accredited schools had higher rates of ECFMG certification among graduates than nonaccredited schools in comparisons that included all schools (75.0% [standard deviation (SD) = 10.6%] vs 68.3% (SD = 15.9%), P < .001), and for countries that had both accredited and nonaccredited schools (73.9% [SD = 11.4%] vs 67.3% [SD = 16.8%], P = .023). After adjusting for age of school, longer duration of accreditation was associated with higher certification rates (P < .001).

Conclusions

Accreditation had a positive association with ECFMG certification rates. Future studies should investigate how accreditation processes might account for higher certification rates.
Regenerative Peripheral Nerve Interfaces for Advanced Prosthetic Control and Mitigation of Postamputation Pain
Authors: Ganesh Kumar Nishant , Cederna Paul S. , Kung Theodore A.
Published: March 2021

While recent advances have occurred in the field of prosthetic technology, there is still a need for a neuroprosthetic interface that permits high-fidelity prosthetic control to accurately replicate extremity movements. Peripheral nerve interfaces offer more intuitive prosthetic control by harnessing neural signals at a fascicular level. The direct application of electrodes to peripheral nerves is limited by device encapsulation, micromotion, and inevitable neural damage. To overcome these challenges, the regenerative peripheral nerve interface (RPNI) has been developed as a promising solution to enhance prosthetic control. During RPNI surgery, the end of a transected peripheral nerve is implanted into an autologous free skeletal muscle graft. The RPNI has demonstrated feasibility in transducing peripheral nerve signals from patients with upper limb amputations to control an artificial hand. In addition, by leveraging the physiological processes of nerve regeneration, muscle regeneration, and reinnervation, RPNIs have been shown to reduce postamputation pain, including neuroma pain and phantom limb pain. It can be used as a treatment for symptomatic neuromas or performed prophylactically at the time of limb amputation to reduce or eliminate postamputation pain. RPNI surgery is a safe, reliable, and reproducible technique that can be easily adopted across a variety of surgical specialties. This article describes the development, validation, and clinical application of the RPNI and discusses the surgical technique.
ICU Bed Utilization During the Coronavirus Disease 2019 Pandemic in a Multistate Analysis—March to June 2020
Authors: Douin David J. , Ward Michael J. , Lindsell Christopher J. , Howell Michelle P. , Hough Catherine L. , Exline Matthew C. , Gong Michelle N. , Aboodi Michael S. , Tenforde Mark W. , Feldstein Leora R. , Stubblefield William B. , Steingrub Jay S. , Prekker Matthew E. , Brown Samuel M. , Peltan Ithan D. , Khan Akram , Files D. Clark , Gibbs Kevin W. , Rice Todd W. , Casey Jonathan D. , Hager David N. , Qadir Nida , Henning Daniel J. , Wilson Jennifer G. , Patel Manish M. , Self Wesley H. , Ginde Adit A.
Published: March 2021

Objectives:

Given finite ICU bed capacity, knowledge of ICU bed utilization during the coronavirus disease 2019 pandemic is critical to ensure future strategies for resource allocation and utilization. We sought to examine ICU census trends in relation to ICU bed capacity during the rapid increase in severe coronavirus disease 2019 cases early during the pandemic.

Design:

Observational cohort study.

Setting:

Thirteen geographically dispersed academic medical centers in the United States.

Patients/Subjects:

We obtained daily ICU censuses from March 26 to June 30, 2020, as well as prepandemic ICU bed capacities. The primary outcome was daily census of ICU patients stratified by coronavirus disease 2019 and mechanical ventilation status in relation to ICU capacity.

Interventions:

None.

Measurements and Main Results:

Prepandemic overall ICU capacity ranged from 62 to 225 beds (median 109). During the study period, the median daily coronavirus disease 2019 ICU census per hospital ranged from 1 to 84 patients, and the daily ICU census exceeded overall ICU capacity for at least 1 day at five institutions. The number of critically ill patients exceeded ICU capacity for a median (interquartile range) of 17 (12–50) of 97 days at these five sites. All 13 institutions experienced decreases in their noncoronavirus disease ICU population, whereas local coronavirus disease 2019 cases increased. Coronavirus disease 2019 patients reached their greatest proportion of ICU capacity on April 12, 2020, when they accounted for 44% of ICU patients across all participating hospitals. Maximum ICU census ranged from 52% to 289% of overall ICU capacity, with three sites less than 80%, four sites 80–100%, five sites 100–128%, and one site 289%.

Conclusions:

From March to June 2020, the coronavirus disease 2019 pandemic led to ICU censuses greater than ICU bed capacity at fives of 13 institutions evaluated. These findings demonstrate the short-term adaptability of U.S. healthcare institutions in redirecting limited resources to accommodate a public health emergency.
Comparison of Anticoagulation Strategies in Patients Requiring Venovenous Extracorporeal Membrane Oxygenation: Heparin Versus Bivalirudin*
Authors: Rivosecchi Ryan M. , Arakelians Aris R. , Ryan John , Murray Holt , Ramanan Raj , Gomez Hernando , Phillips Dennis , Sciortino Christopher , Arlia Peter , Freeman Danielle , Sappington Penny L. , Sanchez Pablo G.
Published: March 2021

OBJECTIVES:

Extracorporeal membrane oxygenation is a life-sustaining therapy for severe respiratory failure. Extracorporeal membrane oxygenation circuits require systemic anticoagulation that creates a delicate balance between circuit-related thrombosis and bleeding-related complications. Although unfractionated heparin is most widely used anticoagulant, alternative agents such as bivalirudin have been used. We sought to compare extracorporeal membrane oxygenation circuit thrombosis and bleeding-related outcomes in respiratory failure patients receiving either unfractionated heparin or bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation support.

DESIGN:

Retrospective cohort study.

SETTING:

Single-center, cardiothoracic ICU.

PATIENTS:

Consecutive patients requiring venovenous extracorporeal membrane oxygenation who were maintained on anticoagulation between 2013 and 2020.

INTERNVENTIONS:

IV bivalirudin or IV unfractionated heparin.

MEASUREMENTS AND MAIN RESULTS:

Primary outcomes were the presence of extracorporeal membrane oxygenation in-circuit–related thrombotic complications and volume of blood products administered during extracorporeal membrane oxygenation duration. One hundred sixty-two patients receiving unfractionated heparin were compared with 133 patients receiving bivalirudin for anticoagulation on venovenous extracorporeal membrane oxygenation. In patients receiving bivalirudin, there was an overall decrease in the number of extracorporeal membrane oxygenation circuit thrombotic complications (p < 0.005) and a significant increase in time to circuit thrombosis (p = 0.007). Multivariable Cox regression found that heparin was associated with a significant increase in risk of clots (Exp[B] = 2.31, p = 0.001). Patients who received bivalirudin received significantly less volume of packed RBCs, fresh frozen plasma, and platelet transfusion (p < 0.001 for each). There was a significant decrease in the number major bleeding events in patients receiving bivalirudin, 40.7% versus 11.7%, p < 0.001.

CONCLUSIONS:

Patients receiving bivalirudin for systemic anticoagulation on venovenous extracorporeal membrane oxygenation experienced a decrease in the number of extracorporeal membrane oxygenation circuit-related thrombotic events as well as a significant decrease in volume of blood products administered.
Early Palliative Care Is Associated With Reduced Emergency Department Utilization in Pancreatic Cancer
Authors: Bevins Jack , Bhulani Nizar , Goksu Suleyman Y. , Sanford Nina N. , Gao Ang , Ahn Chul , Paulk Mary E. , Terauchi Stephanie , Pruitt Sandi L. , Tavakkoli Anna , Rhodes Ramona L. , Kazmi Syed M.A. , Beg Muhammad S.
Published: March 2021

Objectives:

Most patients with pancreatic cancer have high symptom burden and poor outcomes. Palliative care (PC) can improve the quality of care through expert symptom management, although the optimal timing of PC referral is still poorly understood. We aimed to assess the association of early PC on health care utilization and charges of care for pancreatic cancer patients.

Materials and Methods:

We selected patients with pancreatic cancer diagnosed between 2000 and 2009 who received at least 1 PC encounter using the Surveillance, Epidemiology, and End Results (SEER)-Medicare. Patients who had unknown follow-up were excluded. We defined “early PC” if the patients received PC within 30 days of diagnosis.

Results:

A total of 3166 patients had a PC encounter; 28% had an early PC. Patients receiving early PC were more likely to be female and have older age compared with patients receiving late PC (P<0.001). Patients receiving early PC had fewer emergency department (ED) visits (2.6 vs. 3.0 visits, P=0.004) and lower total charges of ED care ($3158 vs. $3981, P<0.001) compared with patients receiving late PC. Patients receiving early PC also had lower intensive care unit admissions (0.82 vs. 0.98 visits, P=0.006) and total charges of intensive care unit care ($14,466 vs. $18,687, P=0.01). On multivariable analysis, patients receiving early PC were significantly associated with fewer ED visits (P=0.007) and lower charges of ED care (P=0.018) for all patients.

Conclusions:

Early PC referrals were associated with lower ED visits and ED-related charges. Our findings support oncology society guideline recommendations for early PC in patients with advanced malignancies such as pancreatic cancer.
Prognostic role of the ascending aorta dilatation in patients with arterial hypertension
Authors: Leone Dario , Airale Lorenzo , Bernardi Sara , Mingrone Giulia , Astarita Anna , Cesareo Marco , Sabia Luca , Avenatti Eleonora , Tosello Francesco , Bruno Giulia , Catarinella Cinzia , Venturelli Veronica , Giordana Carlo , Veglio Franco , Vallelonga Fabrizio , Milan Alberto
Published: March 2021

Background:

Ascending aorta (ASC) dilatation (AAD) is a common finding in arterial hypertension, affecting about 15% of hypertensive patients. AAD is associated with an increase in cardiac and vascular hypertension-related organ damage, but its prognostic role is unknown. The aim of the study was to evaluate the prognostic value of AAD as predictor of cardiovascular events in essential hypertensive patients.

Methods:

Recruited patients underwent two-dimensional transthoracic echocardiography from 2007 to 2013 and followed-up for cardiovascular events until November 2018 by phone call and hospital information system check. ASC diameter and AAD were defined using both absolute and scaled definitions. Four hundred and twenty-three hypertensive patients were included in our study.

Results:

During a median follow-up of 7.4 years (interquartile range 5.6–9.1 years), 52 events were observed. After adjusting for age, sex and BSA, both ASC diameter and AAD definition, according to ARGO-SIIA project, resulted associated with a greater risk of cardiovascular event (both P < 0.010), even after adjusting for major confounders (both P < 0.010). Moreover, we observed that the assessment of ASC improves risk stratification compared with pulse wave velocity alone, and that in absence of AAD, sinus of valsalva dilatation lost any prognostic value (P = 0.262).

Conclusions:

ASC diameter and AAD are both associated with a greater risk of cardiovascular events. ASC should be assessed to optimize risk stratification in hypertensive patients and its dilatation may be considered as a surrogate for vascular organ damage.
Aqueous Misdirection After Trabeculectomy in a Down Syndrome Patient With Angle-closure Glaucoma
Authors: Fox Austin R. , Alward Wallace L.M. , Fingert John H.
Published: March 2021

Down syndrome is a genetic disease caused by trisomy of chromosome 21 that is characterized by numerous systemic abnormalities including intellectual disability, stereotypical facies, and congenital heart malformations. Ocular abnormalities are commonly seen with Down syndrome including corneal disease (keratoconus), refractive error, and atypical irides (Brushfield spots). We report the first case of aqueous misdirection in a patient with Down syndrome after trabeculectomy. Patients with Down syndrome often have small, hyperopic eyes with narrow iridocorneal angles and may be at increased risk for aqueous misdirection associated with surgical procedures. Awareness of this risk may aid surgical planning and postoperative management.
The Relationship Between Corneal Biomechanics and Intraocular Pressure Dynamics in Patients Undergoing Intravitreal Injection
Authors: Dackowski Evan K. , Moon Jee-Young , Wang Jessie , Shrivastava Anurag , Schultz Jeffrey S.
Published: March 2021

Precis:

A higher “corneal resistance factor” (CRF) was associated with greater intraocular pressure (IOP) elevation after intravitreal injection of bevacizumab. Both higher “corneal hysteresis” (CH) and CRF were associated with more rapid IOP recovery postinjection.

Purpose:

The purpose of this study was to evaluate the relationship between measurable corneal biomechanical properties and acute IOP elevation after rapid intraocular volume expansion from the routine intravitreal injection.

Materials and Methods:

A total of 100 patients necessitating unilateral intravitreal injection with 0.05 mL of bevacizumab for retinal pathology were analyzed before injection with Goldmann Applanation Tonometry to measure IOP, Ocular Response Analyzer (ORA) to measure corneal biomechanical properties, and optical biometry to calculate globe measurements. IOP and ORA were measured again within 5 minutes of the injection and then IOP measurements were taken every 10 minutes until the IOP was ≤150% of the preinjection IOP. Linear regression and logistic regression were used to test variables associated with acute IOP increase. A Cox proportional hazard model accounting for preinjection IOP and postinjection IOP was used to test the effect of CH or CRF on the time required to return to 150% of baseline IOP.

Results:

Higher CRF was associated with greater immediate postinjection IOP (P=0.026) elevation. A preinjection IOP>15.5 mm Hg moderately predicted postinjection IOP≥35 mm Hg (area under the receiver operating characteristics curve=0.74). A preinjection IOP>18.5 mm Hg combined with CH poorly predicted postinjection IOP>50 mm Hg (area under the receiver operating characteristics curve=0.67). A higher CH [hazard ratio (HR)=1.24; 95% confidence interval (CI)=1.08-1.42; P=0.002] and preinjection IOP (HR=1.16; 95% CI=1.09-1.22; P<0.001), along with a lower immediate postinjection IOP (HR=0.93; 95% CI=0.90-0.95; P<0.001), were each independently associated with quicker IOP recovery postinjection. Similar results were seen in the Cox model examining CRF and IOP recovery.

Conclusions:

Higher CRF and preinjection IOP were independently associated with greater postinjection IOP elevations. ORA metrics did not greatly strengthen the prediction of patients who would have postinjection IOP>50 mm Hg. Higher CH and CRF were associated with faster IOP recovery after intravitreal injection, demonstrating the dynamic relationship between ocular biomechanical properties and aqueous outflow pathways.
Global Divergence of Antifungal Prescribing Patterns
Authors: Ferreras-Antolin Laura , Bielicki Julia , Warris Adilia , Sharland Mike , Hsia Yingfen
Published: March 2021

Background:

Globally, invasive fungal diseases (IFDs) have a significant impact in human health. With an increasing pediatric population at risk of IFD, effective antifungal drugs access and affordability should be ensured universally. The aim of our study was to characterize the global antifungal drug use in neonates and children and its variability between countries in different income groups.

Methods:

Data were extracted from the Global Antimicrobial Resistance, Prescribing and Efficacy in Neonates and Children Point Prevalence Survey project, consisting in 1 pilot and four 1-day Point Prevalence Survey between 2015 and 2017. The data had been entered through a study-specific web-based data collection tool.

Results:

From a total of 13,410 children included, 7.8% (1048/13,410) received at least 1 systemic antifungal drug: 9.5% (95% confidence interval: 8.9%–10.1%) in high income countries (HIC) versus 5.0% (95% confidence interval: 4.4%–5.6%) in low-middle income countries (LMIC) (P < 0.01). A significant proportion of patients on antifungals belonged to high-risk group for IFD (67.4%; 706/1048); most of these were managed in HIC (72.8%, P < 0.01). The likelihood of receiving antifungals being in high-risk group was higher in HIC compared with LMIC (ratio of 5.8 vs. 3.4, P < 0.01). Antifungal prophylaxis was more likely prescribed in HIC (67.2% vs. 30.4%, P < 0.01). Fluconazole was the most frequently prescribed drug. The proportional use of fluconazole was higher in LMIC compared with HIC.

Conclusions:

A significant variability of antifungal prescribing patterns was observed. The proportional use of systemic antifungals was twice as high in HIC compared with LMIC. More detailed data on access and antifungal use in limited-resource settings should be explored.
Nevirapine Pharmacokinetics in Neonates Between 25 and 32 Weeks Gestational Age for the Prevention of Mother-to-Child Transmission of HIV
Authors: Hirt Déborah , Kubota Kilengelela Jean , Jarreau Pierre-Henri , Tréluyer Jean-Marc , Marcou Valérie
Published: March 2021

Eleven newborns from 25 to 32 weeks of gestational age, weighting from 0.66 to 1.60 kg received 2 mg/kg doses of nevirapine syrup. In 15 samples, collected 8.75–89 hours after drug intake, concentrations ranged from 0.65 to 16.68 mg/L. Three nevirapine dose of 2 mg/kg at day 0, 2 and 6 days of life achieved nevirapine concentrations above the proposed nevirapine target for HIV prophylaxis for at least 11 days.
Race to the Top of the Hospital Value-Based Purchasing Program
Authors: Spaulding Aaron , Hamadi Hanadi , Xu Jing , Tafili Aurora , Liu Xinliang
Published: March 2021

EXECUTIVE SUMMARY

Medicare’s Hospital Valued-Based Purchasing (HVBP) program measures hospitals’ total performance score (TPS); its measurement strategies have changed regularly since its rollout in 2013. Because the program influences care delivery, it is important to examine how the policy has changed hospitals’ behavior and how it may inform future policies. The purpose of this study was to assess the relationship between hospitals’ performance on TPS annually from 2013 to 2018 and organizational characteristics. Using the HVBP TPS from 2013 to 2018 and associated hospital characteristics—hospital size, teaching hospital status, system membership, ownership type, urban/rural location, average percentages of patients from Medicare and Medicaid, operating margins, percentages of inpatient revenue as a proportion of total revenue, and case mix index—we conducted a retrospective cohort study of all U.S. hospitals participating in the HVBP program. Regression and panel analyses found that organizations that were expected to have robust and rigid resources were unable to score in the superior category consistently. In addition, organizations were unable to consistently perform positively over time because of changes in the HVBP program measurement and the required organizational responses. Policymakers should consider the ability of organizations to respond to changes to the HVBP program. Likewise, healthcare managers, particularly those in larger organizations, should seek to remove bureaucracy or allow for greater resource slack to meet these changes.
Enhancing Psychological Sustainment & Promoting Resilience in Healthcare Workers During COVID-19 & Beyond
Authors: Morganstein Joshua C. , Flynn Brian W.
Published: March 2021

COVID-19 is a unique disaster, which has placed extreme stress on Healthcare Workers (HCWs) and the systems in which they work. Eradicating the pandemic requires sustainment of the healthcare workforce through actions that mitigate stress, promote resilience, and enhance performance. A major barrier is the lack of organizational practices and procedures designed to sustain HCWs during prolonged crisis events, such as COVID-19. Adapting existing best practices from other high-risk occupations allows for a more rapid, efficient response to optimize workforce well-being and preserve healthcare organizational functioning. This paper discusses current and emerging literature on the unique impacts of COVID-19 on HCWs and provides actionable, evidence-informed recommendations for individuals, teams, and leaders to enhance sustainment of HCWs that is critical to the preservation of national and global health security.
Transtympanic Sodium Thiosulfate for Prevention of Cisplatin-Induced Ototoxicity: A Randomized Clinical Trial
Authors: Duinkerken Charlotte W. , de Weger Vincent A. , Dreschler Wouter A. , van der Molen Lisette , Pluim Dick , Rosing Hilde , Nuijen Bastiaan , Hauptmann Michael , Beijnen Jos H. , Balm Alfons J.M. , de Boer Jan Paul , Burgers Jacobus A. , Marchetti Serena , Schellens Jan H.M. , Zuur Charlotte L.
Published: March 2021

Objectives:

To determine safety, feasibility, and preliminary activity of transtympanic injection of sodium thiosulfate (STS) against cisplatin-induced hearing loss (CIHL).

DESIGN Randomized controlled trial.

SETTING Tertiary cancer hospital.

PATIENTS Adults to be treated with high-dose cisplatin (≥ 75 mg/m2).

INTERVENTION Selected by randomization, 0.1 M STS gel on one side and placebo gel on the other side was transtympanically applied to the middle ear 3 hours before cisplatin administration. After amendment, the placebo ear was left untreated.

Main Outcome Measure:

Primary outcome was safety and feasibility. Secondary outcomes included pharmacokinetic analysis of systemic cisplatin and preliminary activity of STS. Clinically relevant CIHL was defined as a ≥ 10 dB threshold shift at pure-tone average 8-10-12.5 kHz (PTA8-12.5). Response to STS was defined as a threshold shift at PTA8-12.5 in the STS-treated ear of ≥ 10 dB smaller than the untreated ear.

Results:

Twelve patients were treated. Average CIHL at PTA8-12.5 was 12.7 dB in untreated ears and 8.8 dB SPL in STS-treated ears (p = 0.403). Four patients did not develop CIHL. Four out of eight patients with CIHL responded to STS: CIHL at PTA8-12.5 in STS-treated ears was 18.4 dB less compared to untreated ears (p = 0.068). Grade 1 adverse events were reported. Pharmacokinetic results were available for 11 patients.

Conclusion:

Transtympanic application of STS was safe and feasible. Based on our pharmacokinetic analysis, we postulate that transtympanic STS does not interfere with the systemically available cisplatin. Our results provide a preliminary proof of concept for transtympanic application of STS in preventing CIHL and warrants further evaluation on a larger scale.
Reducing Sound Exposure During Ocular Vestibular Evoked Myogenic Potential Testing for Superior Semicircular Canal Dehiscence Syndrome
Authors: Zuniga M. Geraldine , Schell Angela , Engst Benjamin G. , Carey John P.
Published: March 2021

Background:

Ocular vestibular evoked myogenic potentials (oVEMP) testing in response to air-conducted sound (ACS) has excellent sensitivity and specificity for superior semicircular canal dehiscence syndrome (SCDS). However, patients with SCDS may experience vertigo with the test, and recent works recommend minimizing acoustic energy during VEMP testing.

Purpose:

To develop an oVEMP protocol that reduces discomfort and increases safety without compromising reliability.

Methods:

Subjects: Fifteen patients diagnosed with SCDS based on clinical presentation, audiometry, standard VEMP testing, and computed tomography (CT) imaging. There were 17 SCDS-affected ears and 13 unaffected ears. In nine (53%) of the SCDS-affected ears surgical repair was indicated, and SCD was confirmed in each. oVEMPs were recorded in response to ACS using 500 Hz tone bursts or clicks. oVEMP amplitudes evoked by 100 stimuli (standard protocol) were compared with experimental protocols with only 40 or 20 stimuli.

Results:

In all three protocols, oVEMP amplitudes in SCDS-affected ears were significantly higher than in the unaffected ears (p < 0.001). 500 Hz tone bursts evoked oVEMPs with excellent (>90%) sensitivity and specificity in each of the three protocols. However, in the unaffected ears, lowering to 20 stimuli reduced the detection of oVEMP responses in some ears. Following surgical repair, oVEMPs normalized in each of the protocols.

Conclusion:

In oVEMP testing using ACS for SCDS, reducing the number of trials from 100 to 40 stimuli results in a more tolerable and theoretically safer test without compromising its effectiveness for the diagnosis of SCDS. Reducing to 20 stimuli may degrade specificity with clicks.
Predictors of Postoperative Complications in Vestibular Schwannoma Surgery—A Population-Based Study
Authors: Alkins Ryan D. , Newsted Daniel , Nguyen Paul , Campbell Robert J. , Beyea Jason A.
Published: March 2021

Objective:

To investigate preoperative patient demographics and comorbidities in relation with postsurgical complications following vestibular schwannoma surgery.

Study Design:

Retrospective population-based cohort study.

Setting:

All hospitals in the Canadian province of Ontario.

Patients:

This study includes 1,456 patients who underwent vestibular schwannoma surgery from April 1, 2002 to March 31, 2018 in Ontario, Canada.

Intervention/Outcome Measures:

For all surgical patients, the demographic data, preoperative comorbidities, and postoperative complications were evaluated. Postoperative complications were examined immediately following surgery in the hospital as well as 1 year following the hospital discharge.

Results:

The most common comorbidities in this cohort were hypertension (30.22%), diabetes (9.48%), asthma (13.53%), and chronic obstructive pulmonary disease (6.73%). Diabetes was the most impactful comorbidity and was associated with higher risk of myocardial infarction (RR = 4.58, p < 0.01), pneumonia (RR = 1.80, p = 0.02), dysphagia (RR = 1.58, p < 0.01), and meningitis (RR = 3.62, p < 0.01). Analysis of surgical approaches revealed that the translabyrinthine approach, compared with the open craniotomy approach, was negatively associated with postoperative complications including pneumonia (RR = 0.43, p < 0.01), urinary tract infection (RR = 0.55, p = 0.01), dysphagia (RR = 0.66, p < 0.01), and readmission (RR = 0.45, p < 0.01).

Conclusion:

This study examines patient demographics, preoperative comorbidities, and postoperative complications in patients who have undergone vestibular schwannoma surgery. The results highlight associations between patient characteristics and postoperative outcomes that can aid in preoperative decision-making and counselling.
Cochlear Implant Fixation Techniques: A Systematic Review of the Literature
Authors: Markodimitraki Laura M. , Strijbos Ruben M. , Stegeman Inge , Thomeer Hans G. X. M.
Published: March 2021

Objective:

Given the lack of consensus on fixation techniques of the cochlear implant, this review aims to create an up-to-date overview of intra- and postoperative complications, focusing on migration of the internal receiver/stimulator (R/S) device and the electrode array.

Data Sources:

On June 29, 2020 we conducted a search in PubMed, Embase, Cochrane, Web of Science, and CINAHL. Keywords were “Cochlear implant,” “complication,” “migration,” and synonyms.

Study Selection:

Studies were considered if: 1) the adult study population consisted of ≥ 10 patients, 2) the R/S device was fixated using the bony well or tight subperiostal pocket technique without bone-anchoring sutures or screws on the implant, and 3) migration of the R/S device or displacement of the electrode array were described as outcomes.

Data Extraction:

Study characteristics, interventions, follow-up, and outcomes were extracted. For critical appraisal, an adapted version of the Newcastle-Ottawa quality assessment scale for cohort studies was used.

Data Synthesis:

Seven studies were included (n = 430 patients). Migration of the R/S device was reported by three studies. Two studies applying the tight pocket technique reported migration rates ranging from 9.0 to 69.2%. One study using the bony bed technique reported migration of 100%, with an average of 2.5 mm. All studies lacked the required standard for comparability, assessment of outcome, and follow-up.

Conclusions and Relevance:

There is currently no evidence of a difference between the bony bed- and tight pocket fixation technique, regarding migration of the R/S device or the electrode array, in adult patients.