bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Evidence of the Effects of Sweet Flavors: Sweetness Increases Nicotine Intake and Seeking
Authors: Bagdas Deniz , Addy Nii A 
Published: October 2024

Abstract

Introduction
The influence of early exposure to sweet and fruit flavors on subsequent nicotine use behaviors during adolescence remains poorly understood. To address this gap, we utilized a rodent model to simulate childhood flavor exposure and examine its effects on later nicotine use behaviors.

Aims and Methods
We employed a two-bottle choice paradigm in weanling rats to mimic human childhood flavor exposure. Subsequently, we investigated the impact of early exposure to sweet (saccharin) and cherry fruit (benzaldehyde) flavors on adolescent nicotine use behaviors. This included assessing subsequent nicotine acquisition, maintenance, and seeking behaviors using intraoral flavor and intravenous nicotine self-administration.

Results
Our findings reveal that rats exposed to saccharin during early development exhibited altered patterns of nicotine intake and seeking behaviors during adolescence. Specifically, rats demonstrated increased nicotine intake and seeking of saccharin flavored solutions when paired with nicotine, indicating a potential predisposition towards nicotine use following childhood flavor exposure. Intraoral benzaldehyde did not affect nicotine reinforcement in early sessions of self-administration, but significantly decreased nicotine reinforcement during later sessions. Both saccharin exposure alone or in combination with benzaldehyde promoted nicotine reinforcement. No significant sex differences in nicotine-related behaviors were observed.

Conclusions
This study highlights the significance of early flavor exposure in shaping adolescent nicotine use behaviors. The findings suggest that childhood exposure to sweet flavors may contribute to heightened susceptibility to nicotine use and addiction later in life. Understanding these early influences is crucial for developing targeted interventions to prevent the onset of nicotine addiction during adolescence.

Implications
Our study highlights the importance of how sweetness can contribute to and possibly even alter the effects of the flavor itself. The sweetness of a tobacco product does not solely stem from sweeteners, but it is also influenced by other components such as the propylene glycol (PG) and vegetable glycerin (VG) ratio (eg, higher VG) and the inclusion of flavors associated with sweetness (eg, vanillin and ethyl maltol). Therefore, sweet-associated constituents in tobacco products should be investigated further to inform regulatory policy. We believe that our findings can inform regulatory decisions on controlling sweet-associated constituents in tobacco products.
A Pumpless and Tubeless Microfluidic Device Enables Extended In Vitro Development of Cryptosporidium parvum
Authors: Gunasekera Samantha , Thierry Benjamin , Cheah Edward , King Brendon , Monis Paul , Carr Jillian M , Chopra Abha , Watson Mark , O’Dea Mark , Ryan Una 
Published: October 2024

Abstract

Background
The enteric parasite Cryptosporidium remains a treatment challenge for drinking water utilities globally due to its resistance to chlorine disinfection. However, the lack of an in vitro culture system for Cryptosporidium that is both cost-effective and reliable remains a key bottleneck in Cryptosporidium research.

Methods
Here we report that the microfluidic culture of human ileocecal colorectal adenocarcinoma (HCT-8) cells under fluid shear stress enables the extended development of Cryptosporidium parvum. Specifically, the growth of C. parvum in a user-friendly pumpless microfluidic device was assessed using immunofluorescence assays, scanning electron microscopy, and quantitative polymerase chain reaction, which revealed that development continued for 10 days in total.

Results
Oocysts produced within the microfluidic device were infective to fresh HCT-8 monolayers; however, these oocysts were only present at low levels.

Conclusions
We anticipate that such microfluidic approaches will facilitate a wide range of in vitro studies on Cryptosporidium and may have the potential to be further developed as a routine infectivity assessment tool for the water industry.
Enhancers in Plant Development, Adaptation and Evolution
Authors: Beernink Bliss M , Vogel John P , Lei Li 
Published: October 2024

Abstract
Understanding plant responses to developmental and environmental cues is crucial for studying morphological divergence and local adaptation. Gene expression changes, governed by cis-regulatory modules (CRMs) including enhancers, are a major source of plant phenotypic variation. However, while genome-wide approaches have revealed thousands of putative enhancers in mammals, far fewer have been identified and functionally characterized in plants. This review provides an overview of how enhancers function to control gene regulation, methods to predict DNA sequences that may have enhancer activity, methods utilized to functionally validate enhancers and the current knowledge of enhancers in plants, including how they impact plant development, response to environment and evolutionary adaptation.
Prevalence and associated risk factors of myocardial ischemia in children living with sickle cell anemia in Lagos, Nigeria
Authors: Adeniyi Oluwatoyin , Salako Abideen , Sokunbi Ogochukwu , Odubela Oluwatosin , Aworanti Oladapo , Okoromah Christy , Akinsulie Adebola 
Published: October 2024

Abstract
Myocardial ischemia (MI) in children living with sickle cell anemia (SCA) is rarely reported. MI among children living with this disease could portend untoward outcomes on their quality of life and survival. This study evaluated the prevalence and associated risk factors of MI in children living with SCA during a vaso-occlusive crisis (VOC) compared with those with SCA who had no symptoms nor an MI in the past (those in “steady state”) in Lagos, Nigeria. This comparative cross-sectional study was conducted over 10 months (between March and December 2019) among 250 children living with SCA aged 6 months–18 years (125 in VOC and 125 age and sex-matched controls in steady state). The assessment of MI was determined by measuring cardiac troponin T (cTnT) and electrocardiography (ECG). The prevalence of MI measuring cTnT alone in children with SCA during VOC and steady state was 42.4% and 23.2%, respectively. Comparatively, measuring ECG alone, the prevalence of MI in VOC and steady state was 40.8% and 20.8%, respectively. The prevalence of MI measuring cTnT and ECG in children with SCA in VOC and steady state was 38.4% and 20%, respectively. Older age, severity of pain, longer duration of illness, frequent crises per year, elevated white blood cells, and platelet count were significantly associated with MI in participants with SCA. However, with multivariate analysis, age, severity of pain, and elevated platelet counts remained significantly associated with the occurrence of MI. This study affirms the high prevalence of MI in children with SCA irrespective of the diagnostic criteria. Routine evaluation should be done in this cohort to avert MI-associated sequelae.
Styles, strategies, and challenges of PA leaders nationally
Authors: Grubb Bethany 
Published: October 2024

ABSTRACT

Objectives:
To identify the leadership styles, strengths, strategies, and key factors of PA leaders in healthcare executive, clinical, and academic settings.

Methods:
An exploratory, qualitative study was completed through the American Academy of Physician Associates 2023 Practice Survey to answer seven qualitative questions. Of the 1,423 PAs who responded to the survey invitation, 348 PA leaders in formal and informal roles chose to answer, for a 24.4% response rate.

Results:
For PA leaders' styles and strengths, collaborative and emotional intelligence emerged as themes. For key factors of PA leadership, balancing expectations and giving and receiving critical feedback emerged as themes. For skills or qualities PA leaders wish they had before starting to lead, project management skills and increased confidence emerged as themes.

Conclusions:
Leadership development training needs to be in the didactic and clinical curriculum of PA programs for the future of PA leadership. Leadership pathways for PA leaders in healthcare executive, clinical, and academic settings need to be created and established more widely.
Mismatch Repair Status and Surgical Outcomes in Localized Colorectal Cancer: A Nationwide Cohort Study
Authors: Justesen Tobias Freyberg , Orhan Adile , Rosen Andreas Weinberger , Gögenur Mikail , Gögenur Ismail 
Published: October 2024

Objective:
This study examined the association between deficient mismatch repair (dMMR) versus proficient MMR (pMMR) status and overall survival and disease-free survival in patients with localized colorectal cancer.

Background:
Several distinctions exist between patients with dMMR and pMMR colorectal cancer. However, the impact on prognosis is yet to be investigated in large-scale cohort studies.

Methods:
In this cohort study, we included patients who underwent curative-intent surgery for localized colorectal cancer between 2009 and 2020. Patients were identified in the Danish Colorectal Cancer Group database and patient-level data were extracted from 6 registry databases. After inclusion, patients with dMMR status were matched 1:1 to patients with pMMR status using an estimated propensity score.

Results:
After matching, 5994 patients were included. The patients had a median age of 74 years and a median follow-up of 4.1 years. There was no significant association between mismatch repair (MMR) status and overall survival (hazard ratio, 0.91; 95% confidence interval [CI], 0.81–1.03) or disease-free survival (hazard ratio, 0.89; 95% CI, 0.78–1.01). However, the restricted 5-year mean disease-free survival time, calculated due to violation of the proportional hazards assumption, showed a significant absolute difference of 0.13 years (95% CI, 0.03–0.23; P = 0.01) in favor of the dMMR group.

Conclusions:
No significant association with overall survival was found according to MMR status. dMMR status was, however, found to be associated with marginally improved disease-free survival compared to pMMR status in patients with localized colorectal cancer undergoing curative-intent surgery.
A Variable-Stimulus Distortion Product Otoacoustic Emission Screening Method to Match Cochlear Place-Specific Properties
Authors: Stiepan Samantha , Dhar Sumitrajit 
Published: October 2024

Objectives:
Distortion product otoacoustic emissions (DPOAEs) are a popular screening tool for hearing loss in specific populations (e.g., newborns). Current screening protocols use stimulus conditions that are agnostic to local mechanical properties of the cochlea and are also limited to a narrow frequency range. We have recently reported locally optimized stimulus frequency ratio and level combinations for recording DPOAEs up to stimulus frequencies of 19 kHz. In normally functioning cochlea, optimized stimuli improved the signal to noise ratios and allowed the registration of higher DPOAE levels, especially at higher frequencies. The purpose of this study was to evaluate the clinical performance of these physiologically motivated, locally appropriate, stimulus parameters for a screening application to identify the presence of hearing loss.

Design:
Subjects were 24 adults with sensorineural hearing loss and 31 adults with normal hearing. The cubic DPOAE was measured and analyzed up to frequencies of 16 kHz using a range of stimulus conditions. Receiver operating characteristic curves were used to identify stimulus combinations most sensitive to screening for hearing loss.

Results:
Receiver operating characteristic curves demonstrated improved test efficacy for hearing loss detection when using stimulus frequency ratios and levels that are frequency-dependent and consistent with known mechanical properties of the cochlea.

Conclusions:
We propose a new DPOAE recording paradigm (variable-stimuli DP) using stimuli aligned to local cochlear properties which may improve early and accurate detection of decline in cochlear function.
Hardware Removal After Lisfranc Open Reduction and Internal Fixation Results in Improved Physical Function
Authors: Sroka Oliver , Campbell Megan , Thorne Tyler , Haller Justin , Rothberg David , Higgins Thomas , Marchand Lucas 
Published: October 2024

OBJECTIVES:
The purpose of this study was to investigate whether hardware removal (HWR) after Lisfranc open reduction and internal fixation (ORIF) resulted in significant impact through PROMIS physical function (PF) and pain intensity (PI) scores.

METHODS:

Design:
Retrospective cohort.

Setting:
Level-1 trauma center.

Patient Selection Criteria:
Adult patients with isolated Lisfranc injuries who were treated through ORIF between 2002 and 2023 who had PROMIS PF and PI scores through 6 months follow-up were included. Patients were excluded if they received index treatment other than ORIF or underwent secondary surgical intervention before HWR. A subanalysis was performed at 1-year follow-up.

Outcome Measures and Comparisons:
Primary outcomes were PROMIS PF and PI scores. The Wilcoxon signed-rank test compared differences between PROMIS scores within the HWR group. The Wilcoxon ranked-sum test compared differences between HWR versus no HWR. Distributive MCID was calculated using the 0.5 SD method.

RESULTS:
There were 482 patients (489 feet) identified with isolated Lisfranc injuries. Seventy-seven feet underwent ORIF followed by HWR. Thirty feet underwent ORIF without HWR. The average age of the no HWR group was 45.8 (18.0–81.3) years versus the HWR group that was 38.7 (18.3–74.1) years (P = 0.053). Nineteen (63.3%) were women in the no HWR group compared with 33 (42.9%) in the HWR group (P = 0.084). HWR occurred an average of 4.43 months after ORIF. Patients who underwent HWR had a statistically significant increase in average PF scores (39.7–45.9, P < 0.001) at their standard 6 weeks (1.5 months) postoperative visit. HWR patients had a nonsignificant decrease in average PI scores (56.5–53.9, P = 0.24). Compared with those with retained hardware, the HWR group demonstrated a statistically significant net improvement in PF and PI scores from surgery, with an average improvement of 5.6 and 1.7, respectively (P = 0.002, 0.008).

CONCLUSIONS:
Patients experienced significant improvement in PROMIS PF scores for Lisfranc ORIF at 6 weeks after HWR. Compared with patients with retained hardware, they also experienced significant improvement in PROMIS PF and PI scores.

LEVEL OF EVIDENCE:
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Subcutaneous Sweet Syndrome With Vasculitis Features: Case Report and Review
Authors: Tang Jia , Lv Bing 
Published: October 2024

Abstract:

Background:
Subcutaneous Sweet Syndrome (SSS) is a rare variant of Sweet Syndrome characterized by neutrophilic infiltration of subcutaneous adipose tissue without vasculitis. The presence of vasculitis in SSS is uncommon and poses diagnostic challenges.

Case Presentation:
A 38-year-old female presented with a one-year history of recurrent painful erythematous nodules on her limbs and face. Physical examination revealed asymmetrical erythematous patches and tender subcutaneous nodules with central necrotic eschars on the lower limbs. Laboratory tests were unremarkable except for a mildly elevated erythrocyte sedimentation rate. Histopathological analysis showed significant neutrophilic infiltration within the adipose lobules and vascular walls, along with extravasation of red blood cells, indicating vasculitis. The patient responded promptly to systemic corticosteroids; however, symptoms recurred upon tapering, necessitating ongoing steroid therapy.

Discussion:
This case underscores the rare occurrence of vasculitis in SSS, expanding the histopathological spectrum of the disease. Literature review suggests that vasculitis in SSS may result from neutrophil-mediated vascular damage rather than immune complex deposition. The recurrent symptoms upon steroid tapering highlight the therapeutic challenges in managing SSS with vasculitis.

Conclusion:
Recognition of vasculitis in SSS is crucial for accurate diagnosis and effective management. Further research is warranted to elucidate the pathogenesis and develop targeted treatment strategies for SSS with vasculitis.
Rapidly Progressive Primary Cutaneous Gamma Delta T-Cell Lymphoma With FYN Gene Alteration
Authors: Azimpouran Mahzad , Bui Chau M. , Balzer Bonnie , Kitahara Sumire 
Published: October 2024

Abstract:
Primary cutaneous gamma delta T-cell lymphoma (PCGDTCL) is a rare type of non-Hodgkin lymphoma accounting for <1% of primary cutaneous T-cell lymphomas. The exact cause of PCGDTCL is not known, however, it is thought that chronic antigen exposure in the skin may lead to immune dysregulation at the site, resulting in abnormal proliferation of mature, post-thymic cytotoxic gamma delta T cells. Mutations are the most common genetic alteration seen in PCGDTCL, while structural abnormalities such as gene fusions are not common. We report a case of PCGDTCL with atypical immunophenotypic features, including expression of CD5 with lack of cytotoxic marker expression, and a structural alteration leading to FYN deletion at exon 8. Recently, it was described that a deletion of the area between FYN exon 8 and TRAF3IP2 intron 2 results in a novel FYN::TRAF3IP2 fusion in peripheral T-cell lymphoma, not otherwise specified. We describe our patient's clinical course, differential diagnosis, and potential implications of FYN deletion on disease pathogenesis. To our knowledge, this is the first report of an FYN structural alteration to be described in PCGDTCL.
Evaluating CD1a Immunohistochemistry for Tegumentary Leishmaniasis Diagnosis in the New World: A Focus on Colombia
Authors: Aristizábal-Parra Lucero Katherine , Ospina-Gómez Juan Pablo , Restrepo-Rivera Lina , Ramírez Juan David , Ospina-Varón Carlos Mario , González Juan David , Serrano-Coll Héctor 
Published: October 2024

Introduction:
Leishmaniasis, a chronic vector-borne disease caused by parasites of the genus Leishmania, presents diagnostic challenges. Conventional diagnostic methods struggle with accurate visualization of these parasites. Immunostaining with CD1a has demonstrated effectiveness in visualizing Leishmania parasites, particularly in the Old World. However, the application of CD1a immunostaining in Colombian leishmaniasis remains unexplored.

Objective:
To determine the utility of CD1a as an immunomarker in detecting chronic forms of tegumentary leishmaniasis.

Materials and methods:
This proof-of-concept study involved 48 paraffin-embedded samples categorized into 3 groups: moderate-to-high parasite load (n = 15), low load (n = 15), and chronic granulomatous inflammation (n = 13); 5 samples diagnosed with cutaneous histoplasmosis. These samples were stained with the immunomarker CD1a clone EP3622 for comparative analysis. In addition, CD1a immunohistochemistry was compared with 18S rDNA qPCR and hematoxylin–eosin staining to evaluate its performance in relation to these established methods.

Results:
CD1a immunohistochemistry was positive in 46.51% of the samples evaluated. This immunomarker showed lower sensitivity and negative predictive value than 18S rDNA qPCR and hematoxylin–eosin staining; specificity and negative predictive value were consistent. ROC indicated inferior discrimination for leishmaniasis compared with 18 s rDNA qPCR and hematoxylin–eosin staining.

Conclusions:
Immunohistochemistry for CD1a could be a diagnostic support in the detection of chronic forms of tegumentary leishmaniasis.
Topical Therapies for Periorbital Dyschromia: A 30-Year Review of the Literature
Authors: Woolhiser Emily , Sobotka Michelle , Burnette Colin , Gawey Lauren , Dunnick Cory A. 
Published: October 2024

BACKGROUND
Periorbital dyschromia (POD) is a prevalent dermatologic problem with multifactorial etiology, making treatment outcomes inconsistent and unclear.

OBJECTIVE
To evaluate and compose a comprehensive review of topical ingredients proven to be effective in the treatment of POD.

MATERIALS AND METHODS
Scopus, PubMed, and OVID databases were searched in a span of 30 years through December 31, 2023, to identify articles with original findings of topical therapies for the treatment of POD. Findings of interest were objectively and subjectively measured regarding pigmentation, skin texture, aesthetic improvement, elasticity, hydration, and eye-bag volume.

RESULTS
The database searches yielded 339 unique studies. After screening and review, 22 studies were included totaling 13 nonrandomized control trials, 7 randomized clinical trials, 1 retrospective case series, and 1 prospective single-arm study. Studies included all reported statistically significant results with topical therapies inclusive of acids, bark extract, bicyclic monoterpene diols, caffeine, combo ingredient serums, ethyl ximenynate, gentiopicroside, glycosaminoglycans, growth factors, topical PRP, and vitamins.

CONCLUSION
The findings of this review suggest that topical therapies can be effective in the treatment of POD. Future trials should focus on delineating specific etiology of POD and evaluation of therapies specific to their cause.
Excimer Laser-Assisted Deep Anterior Lamellar Keratoplasty Versus Penetrating Keratoplasty for Patients With Keratoconus: A Retrospective Analysis From the Homburg Keratoconus Center
Authors: Daas Loay , Aljundi Wissam , Abdin Alaa Din , Munteanu Cristian , Seitz Berthold 
Published: October 2024

Purpose:
To evaluate the outcome of excimer laser-assisted deep anterior lamellar keratoplasty (Exc-DALK) and penetrating keratoplasty (Exc-PKP) for keratoconus (KC).

Methods:
We included 123 eyes and compared the outcome of 30 eyes undergoing big-bubble Exc-DALK after stromal debulking (G1) against a matched group of 83 eyes undergoing Exc-PKP (G2) in our department. G2 was created after performing a pseudorandom stratified bootstrapping of our PKP database starting with 2802 surgeries with removal of any bias. Main outcomes included best corrected visual acuity (BCVA), spherical equivalent (SE), tomographic changes, and endothelial cell density (ECD). Data were compared preoperatively, postoperatively with 2 double-running cross-stitch sutures according to Hoffmann [2 and 10 months postoperatively (T1 and T2)], after first suture removal [15 months postoperatively (T3)], and after final suture removal [26 months postoperatively (T4)].

Results:
Preoperatively, all parameters were comparable without significant differences. At T1, G1 showed significantly better BCVA (P = 0.01), lower SE (P = 0.04), lower anterior and posterior topographic astigmatism (ATA and PTA, P < 0.01), lower maximal keratometry (P = 0.02), and lower central corneal thickness (P < 0.01). At T2, G1 showed significantly better BCVA (P = 0.04), lower PTA (P < 0.01), and higher ECD (P < 0.01). At T3, G1 showed significantly lower ATA (P = 0.01) and PTA (P < 0.01) and higher ECD (P = 0.02). At T4, G1 showed significantly lower PTA and higher ECD (P < 0.01) but no significant difference in BCVA (P = 0.07).

Conclusions:
Exc-DALK provided faster visual rehabilitation and represented an endothelial cell-sparing method compared with Exc-PKP. After final suture removal, Exc-DALK showed noninferior outcomes compared with Exc-PKP if the graft was placed on naked Descemet membrane.