bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Wnt5a and its effect on oxLDL uptake in THP‐1 cells (LB534)
Authors: Szymanski Candice , Kantake Noriko , McCall Kelly , Malgor Ramiro 
Published: June 2021

Objective: To study Wnt5a expression and determine its effect on oxLDL uptake and foam cell development.Introduction: Atherosclerosis is a chronic inflammatory disease involving plaque buildup in the arteries. This disease can lead to a heart attack and stroke, which are two of the biggest causes of death in this country. A key step in the pathogenesis of atherosclerosis is oxLDL uptake by macrophages and foam cell formation in the intima of the artery. Our group has been investigating the role of Wnt5a signaling in atherosclerosis. Previous results in the lab have shown that oxLDL up‐regulated Wnt5a mRNA expression in human monocyte‐derived macrophages and THP‐1 cells (an acute monocytic leukemia cell line). It was also found that Frizzled 5 (Fz5), a Wnt5a receptor, is highly expressed in foam cells present in human atherosclerotic plaques. Our hypothesis is that Wnt5a stimulates oxLDL uptake in macrophages.Methods: THP‐1 cells were cultured in RPMI 1640 with 10% FBS. The cells were differentiated with Phorbol‐12‐Myristate‐13‐Acetate (PMA) for 24 hours. Cells were treated with oxLDL, nLDL, and rWnt5a in combinations to determine their effects on oxLDL uptake. Oil Red staining was used to assess lipid uptake in‐vitro. Expression of CD68, CD36, scavenger receptor, ROR2, Fz5, and Wnt5a were evaluated using immunofluorescence and western blot. RT‐PCR was done to evaluate mRNA expression.Results: Oil Red staining showed a significant increase in the lipid uptake in macrophages treated with oxLDL. Immunofluorescence showed that oxLDL increased CD68 and Wnt5a expression in THP‐1 cells. Wnt5a also increased Fz5 and scavenger receptor expression in THP‐1 cells. Western blot showed that oxLDL significantly increased CD36 expression in THP‐1 cells. RT‐PCR showed that oxLDL induced Wnt5a expression in THP‐1cells.Conclusions: The results show that oxLDL increases the expression of Wnt5a in THP‐1cells. Furthermore, Wnt5a increases the expression of receptors involved in the uptake of oxLDL. While the mechanism of this uptake is still unknown, our results suggest that Wnt5a plays a role in atherogenesis.
Renal denervation changes hemodynamic response to losartan in SHR rats (LB651)
Authors: Skrzypecki Janusz , Drapala Adrian , Sikora Mariusz , Ufnal Marcin 
Published: June 2021

Efficacy of renal denervation in the treatment of drug‐resistant hypertension is currently under debate. Recently, SIMPLICITY III study showed that the combined therapy with renal denervation and antihypertensive drugs is not superior to appropriate pharmacotherapy alone. In this study we checked if renal denervation affects hypotensive effect of losartan, an angiotensin II type 1 receptor blocker, in Spontaneuosly Hypertensive Rats (SHR). We exposed renal arteries from extraperitoneal access. In the study group all visible nerves adjacent to renal arteries were dissected and then the arteries were wiped with 5% phenol in absolute ethanol. In controls renal arteries were left intact. In both groups we implanted subcutaneously osmotic minipumps releasing either losartan or 0,9% NaCl. One week later we measured mean arterial blood pressure (MABP) and heart rate (HR) in conscious rats. We found that losartan produced greater decrease in MABP than renal denervation. Rats treated with renal denervation and losartan exhibited similar decrease in MABP to rats treated with losartan alone. Interestingly, treatment with losartan alone significantly increased HR while renal denervation combined with losartan did not affect HR. In conclusion, this study shows that combined renal denervation and pharmacotherapy may produce different hemodynamic effects than pharmacotherapy alone.Grant Funding Source: Supported by the Ministry of Science and Higher Education Republic of Poland, Diamond grant DI2012 008042
Exploring the Association Between USMLE Scores and ACGME Milestone Ratings: A Validity Study Using National Data From Emergency Medicine
Authors: Hamstra Stanley J. , Cuddy Monica M. , Jurich Daniel , Yamazaki Kenji , Burkhardt John , Holmboe Eric S. , Barone Michael A. , Santen Sally A. 
Published: June 2021

Purpose
The United States Medical Licensing Examination (USMLE) sequence and the Accreditation Council for Graduate Medical Education (ACGME) milestones represent 2 major components along the continuum of assessment from undergraduate through graduate medical education. This study examines associations between USMLE Step 1 and Step 2 Clinical Knowledge (CK) scores and ACGME emergency medicine (EM) milestone ratings.

Method
In February 2019, subject matter experts (SMEs) provided judgments of expected associations for each combination of Step examination and EM subcompetency. The resulting sets of subcompetencies with expected strong and weak associations were selected for convergent and discriminant validity analysis, respectively. National-level data for 2013–2018 were provided; the final sample included 6,618 EM residents from 158 training programs. Empirical bivariate correlations between milestone ratings and Step scores were calculated, then those correlations were compared with the SMEs’ judgments. Multilevel regression analyses were conducted on the selected subcompetencies, in which milestone ratings were the dependent variable, and Step 1 score, Step 2 CK score, and cohort year were independent variables.

Results
Regression results showed small but statistically significant positive relationships between Step 2 CK score and the subcompetencies (regression coefficients ranged from 0.02 [95% confidence interval (CI), 0.01–0.03] to 0.12 [95% CI, 0.11–0.13]; all P < .05), with the degree of association matching the SMEs’ judgments for 7 of the 9 selected subcompetencies. For example, a 1 standard deviation increase in Step 2 CK score predicted a 0.12 increase in MK-01 milestone rating, when controlling for Step 1. Step 1 score showed a small statistically significant effect with only the MK-01 subcompetency (regression coefficient = 0.06 [95% CI, 0.05–0.07], P < .05).

Conclusions
These results provide incremental validity evidence in support of Step 1 and Step 2 CK score and EM milestone rating uses.
Farewell to the Step 2 Clinical Skills Exam: New Opportunities, Obligations, and Next Steps
Authors: Yudkowsky Rachel , Szauter Karen 
Published: June 2021

The unexpected discontinuation of the United States Medical Licensing Examination Step 2 Clinical Skills (CS) exam in January 2021 carries both risks and opportunities for medical education in the United States. Step 2 CS had far-reaching effects on medical school curricula and school-based clinical skills assessments. Absent the need to prepare students for this high-stakes exam, will the rigor of foundational clinical skills instruction and assessment remain a priority at medical schools? In this article, the authors consider the potential losses and gains from the elimination of Step 2 CS and explore opportunities to expand local summative assessments beyond the narrow bounds of Step 2 CS.
The responsibility for implementing a rigorous and credible summative assessment of clinical skills that are critical for patient safety as medical students transition to residency now lies squarely with medical schools. Robust human simulation (standardized patient) programs, including regional and virtual simulation consortia, can provide infrastructure and expertise for innovative and creative local assessments to meet this need. Novel applications of human simulation and traditional formative assessment methods, such as workplace-based assessments and virtual patients, can contribute to defensible summative decisions about medical students’ clinical skills. The need to establish validity evidence for decisions based on these novel assessment methods comprises a timely and relevant focus for medical education research.
X-linked Malformation Deafness: Neurodevelopmental Symptoms Are Common in Children With IP3 Malformation and Mutation in POU3F4
Authors: Smeds Henrik , Wales Jeremy , Karltorp Eva , Anderlid Britt-Marie , Henricson Cecilia , Asp Filip , Anmyr Lena , Lagerstedt-Robinson Kristina , Löfkvist Ulrika 
Published: June 2021

Objective:
Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms.

Material and methods:
Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene.

Results:
Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their child’s psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms.

Conclusions:
While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an extensive and consistent multidisciplinary team approach during childhood to support their overall habilitation.
Beyond Audition: Psychosocial Benefits of Music Training for Children With Hearing Loss
Authors: Lo Chi Yhun , Looi Valerie , Thompson William Forde , McMahon Catherine M. 
Published: June 2021

Objectives:
Children with hearing loss tend to have poorer psychosocial and quality of life outcomes than their typical-hearing (TH) peers—particularly in the areas of peer relationships and school functioning. A small number of studies for TH children have suggested that group-based music activities are beneficial for prosocial outcomes and help develop a sense of belonging. While one might question whether perceptual limitations would impede satisfactory participation in musical activities, findings from a few studies have suggested that group music activities may have similar benefits for children with hearing loss as well. It is important to note that the effect of music on psychosocial outcomes has primarily been investigated at an anecdotal level. The objective of this study was to explore the effect of a music training program on psychosocial and quality of life outcomes for children with hearing loss. It was hypothesized that music training would provide benefits for domains centered upon peer relationships and prosocial measures.

Design:
Fourteen children aged 6 to 9 years with prelingual sensorineural hearing loss (SNHL) participated in a 12-week music training program that consisted of group-based face-to-face music therapy supplemented by online music apps. The design was a pseudorandomized, longitudinal study (9 participants were waitlisted, initially serving as a passive control group). Psychosocial wellbeing and quality of life were assessed using a questionnaire battery comprised of the Strengths and Difficulty Questionnaire (SDQ), the Pediatric Quality of Life Inventory, the Hearing Environments and Reflection on Quality of Life (HEAR-QL), and the Glasgow Children’s Benefit Inventory. For comparative purposes, responses were measured from 16 TH children that ranged in age from 6 to 9 years.

Results:
At baseline, children with SNHL had poorer outcomes for internalizing problems, and all measures of the HEAR-QL compared with the TH children. There were no differences for general psychosocial and physical health. After music training, SDQ internalizing problems such as peer relationships and emotional regulation were significantly reduced for the children with SNHL. There were no changes for any outcomes for the passive control group. Additional benefits were noted for emotional and learning factors on the Glasgow Children’s Benefit Inventory. However, there were no significant changes for any psychosocial and quality of life outcomes as measured by the Pediatric Quality of Life Inventory or HEAR-QL instruments.

Conclusions:
The present study provides initial evidence that music training has a positive effect on at least some psychosocial and quality of life outcomes for children with hearing loss. As they are at a greater risk of poorer psychosocial and quality of life outcomes, these findings are cause for cautious optimism. Children with hearing loss should be encouraged to participate in group-based musical activities.
Is Sacral Dysmorphism Protective Against Spinopelvic Dissociation? Multicenter Case Series
Authors: Obey Mitchel R. , Barnwell Jonathan , Routt M. L. Chip , Miller Anna N. 
Published: June 2021

Objectives:
Investigate the incidence of sacral dysmorphism (SD) in patients with spinopelvic dissociation (SPD).

Design:
Retrospective case series.

Setting:
Two academic level 1 trauma centers.

Patients/Participants:
One thousand eight hundred fifty adult patients with sacral and pelvic fractures (OTA/AO 61-A, B, C).

Intervention:
Plain pelvic radiographs and CT scans.

Main Outcome Measurements:
Incidence of SD in patients with SPD. Secondary radiographic evaluation of fracture classification and deformity on sagittal imaging.

Results:
Eighty-two patients with SPD were identified, and 12.2% displayed features of SD, significantly less than reported in the literature. The S2 sacral body was the most common horizontal fracture location in patients with SD and nondysmorphic sacra (ND). Roy-Camille type I patterns were more common in ND (35%), versus type II in SD patients (40%). SD patients had lower body mass indexes (19.7 vs. 25.2, P = 0.001). Segmental kyphosis (22.5 degrees ND vs. 23.8 degrees SD, P = 0.838) and sacral kyphosis (26 degrees ND vs. 31 degrees SD, P = 0.605) were similar between groups. Percutaneous fixation was the most common surgical technique.

Conclusions:
We report a significantly lower prevalence of SD in patients with SPD than previously reported in the literature. This suggests that variations in sacral osseous anatomy alter force transmission across the sacrum during traumatic loading, which may be protective against certain high-energy fracture patterns. Preoperative evaluation of sacral anatomy is critical, not only in determining the size and orientation of sacral segment safe zones for screw placement, but also to better understand the pathomechanics involved in sacral trauma.

Level of Evidence:
Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Evolution of Dupilumab-Associated Cutaneous Atypical Lymphoid Infiltrates
Authors: Sokumbi Olayemi , Shamim Huma , Davis Mark Dennis P. , Wetter David A. , Newman Catherine C. , Comfere Nneka 
Published: June 2021

Background:
Observations highlighting the “unmasking” of cutaneous T-cell lymphoma after treatment with dupilumab for atopic dermatitis (AD) have been recently reported. However, there remains a paucity of literature describing the evolution of clinical and histopathological features that characterizes this phenomenon.

Objective:
To define the clinical and histopathologic evolution of atypical lymphoid infiltrates after the administration of dupilumab for AD.

Methods:
A cross-sectional study of clinical and histopathologic features in 7 consecutive patients with a diagnosis of “atypical lymphoid infiltrate” or mycosis fungoides (MF) on dupilumab for AD was performed.

Results:
Seven patients with atypical lymphoid infiltrates or MF in evolution after dupilumab therapy (age range 27–74 years) were reviewed. Average duration of AD before MF diagnosis was 5.7 years, and the average duration on dupilumab treatment was 9.8 months. Notable histopathologic features across predupilumab and postdupilumab biopsies included progressive increase in the densities of the atypical lymphoid infiltrates (7/7), presence of atypical epidermotropic lymphocytes (6/7), and papillary dermal fibrosis (6/7).

Limitations:
Small retrospective cohort study.

Conclusion:
These cases highlight the transformation of lymphoid infiltrates after dupilumab treatment for AD and emphasize the importance of clinical and histopathologic evaluation before and during treatment with dupilumab for treatment-refractory presumed AD.
Kikuchi–Fujimoto Disease With Unusual Cutaneous Findings
Authors: Gates Gregory A. , Li Yunfeng , Magyar Clara , Sarantopoulos G. Peter 
Published: June 2021

Abstract:
We present a case of the rare Kikuchi–Fujimoto disease (KFD) in a 14-year-old patient admitted to UCLA Medical Center with fever, weight loss, and pancytopenia. Physical examination revealed tender subcutaneous nodules and cervical lymphadenopathy. A lymph node biopsy showed findings consistent with KFD. The skin biopsy showed mild superficial dermal edema with neutrophil-predominant inflammation. In addition, rare atypical monocytoid cells were seen. This histologic finding of a Sweet-like morphology has not been reported previously in the literature in association with KFD. The differential diagnosis included Sweet syndrome arising in association with KFD, underlying connective tissue, and an infectious etiology.
Basaloid Follicular Hamartoma: An Additional Criterion of Nevoid Basal Cell Carcinoma Syndrome
Authors: Chikeka Ijeuru , Chang Li-Wei , Collins Mary-Katherine , Pugliano Melissa , Ho Jonhan , House Nancy , Kazlouskaya Viktoryia 
Published: June 2021

Abstract:
Basaloid follicular hamartoma (BFH) is a rare, benign follicular neoplasm which typically presents as brown to skin-colored papules on the face, scalp, and trunk. Histologically, BFH consists of cords and strands of basaloid cells forming cystic structures with scant stroma and should be distinguished from infundibulocystic basal cell carcinoma to avoid overly aggressive treatment. Although BFH has been found to be associated with distinct syndromes, including alopecia, myasthenia gravis, and cystic fibrosis, there is often clinical, histopathologic, and genetic overlap with nevoid basal cell carcinoma syndrome (NBCCS). In this article, we describe a case of a 13-year-old patient with NBCCS who presented with multiple BFHs and propose that it its inclusion into the diagnostic criteria for NBCCS be considered.
T-Cell–Driven Fibroinflammation Inducing Follicular Dedifferentiation in Alopecia Areata and IgG4-Modified Disease
Authors: Kossard Steven , Sheriff Tabrez , Murrell Dedee 
Published: June 2021

Abstract:
The definition of IgG4-related diseases incorporates a broad range of systemic diseases particularly a subset dominated by fibroinflammation. CD4+cytotoxic T cells have emerged as the major driving force for the fibroinflammation, and the pathogenetic role of IgG4 still remains to be determined. Cutaneous involvement is uncommon and is not well defined as elevated tissue IgG4 plasma cells are not a specific marker and prominent cutaneous fibroinflammation is often absent in cutaneous disease. We report the case of a patient with longstanding alopecia universalis and severe atopic dermatitis who presented with diffuse induration and mottled dyspigmentation of his scalp. Multiple scalp biopsies revealed diffuse interfollicular fibroinflammation and IgG4 plasma cells with induction of distinctive dedifferentiated follicles not seen in alopecia areata. This complex case may provide insight into the role of specific subsets of T cells not only in respect to the fibroinflammation linked to IgG4-related diseases but also the capacity to modify disease, follicular stem cell activation, immune privilege, cytotoxicity in alopecia areata, and the presence of atopy that may have contributed to the pathogenesis of this case.
Atypical Fibroxanthoma Demonstrating HMB45+ Staining
Authors: Sahni Vikram N. , Sahni Dev R. , Cassarino David S. 
Published: June 2021

Abstract:
Immunohistochemistry is useful and often necessary for the diagnosis of many histopathological entities, including atypical fibroxanthoma (AFX), which is typically considered a diagnosis of exclusion after ruling out spindle cell melanoma, sarcomatoid carcinoma, and other spindle cell tumors. AFX is a superficial fibrohistiocytic tumor previously believed to be related to pleomorphic sarcoma (formerly known as malignant fibrous histiocytoma), but is now considered a distinct clinicopathological entity. AFXs commonly express CD68, smooth muscle actin, and lysozyme and are usually negative for melanocytic markers such as HMB45 and S100. However, immunohistochemistry can sometimes be misleading, especially when used without other relevant markers in making a histopathologic diagnosis. HMB45 is a glycoprotein marker of premelanosomes and is often helpful in identifying melanoma because it stains melanosomes in the epidermis, dermis, and nevi glycocomplexes. We report a case of AFX which was strongly positive for HMB45, but negative for all other melanocytic markers. This case emphasizes the potential pitfall of relying on a single immunohistochemical marker to make the diagnosis, especially of melanoma, and also is one of the only rare reported cases of AFXs which are HMB45+.
Safety and Functional Pharmacokinetic Profile of APAC, a Novel Intravascular Antiplatelet and Anticoagulant
Authors: Craige Simon , Jouppila Annukka , Humphries Bob , Lassila Riitta 
Published: June 2021

Abstract:
Vascular intervention–induced platelet and coagulation activation is often managed with a combination of antiplatelets and anticoagulants, with evident benefits, but with a risk of systemic bleeding. Antiplatelet and anticoagulant (APAC) is a dual antiplatelet and anticoagulant heparin bioconjugate, which targets vascular injury sites to act as a local antithrombotic. We assessed the nonclinical safety and exposure of intravenously infused APAC in rats and cynomolgus monkeys by using single-day and 14-day repeat dose toxicology and pharmacodynamic markers. Activated partial thromboplastin time (APTT) was used as a functional surrogate of anticoagulant exposure of APAC. Routine clinical in-life observations were followed by clinical pathology and necropsy. The no-observed-adverse-effect level (NOAEL) in rats for the single APAC dose was 20 mg/kg and for the repeated administration was 10 mg/kg/d. Monkeys tolerated a single APAC dose of 10 mg/kg, although the red blood cell count reduced 16%–19% correlating with tissue hemorrhage at vein puncture and affected muscle sites during handling of the animals. However, after 2-week recovery, all clinical signs were normal. The single dose NOAEL exceeded 3 mg/kg. The repeat administration of 3–6 mg/kg/d of APAC was tolerated, but some clinical signs were observed. The NOAEL for repeated dosing was 0.5 mg/kg/d. APAC prolonged APTT dose-dependently in both species, returning to baseline after 1.5 (<10 mg/kg) or essentially by 6 hours also under repetitive dosing. The toxicology profile supports the safety of an intravenous APAC dose of 0.5 mg/kg/d for possible clinical applications. APTT is an acceptable indicator of the immediate systemic anticoagulation effect of APAC.