bluuebunny/crossref_metadata_2025_split huggingface dataset:
Higher‐temperature‐adapted dengue virus serotype 2 strain exhibits enhanced virulence in AG129 mouse model
Authors: Modak Ayan , Mishra Srishti Rajkumar , Awasthi Mansi , Sreedevi Sreeja , Sobha Archana , Aravind Arya , Kuppusamy Krithiga , Sreekumar Easwaran 
Published: June 2023

AbstractThe factors that drive dengue virus (DENV) evolution, and selection of virulent variants are yet not clear. Higher environmental temperature shortens DENV extrinsic incubation period in mosquitoes, increases human transmission, and plays a critical role in outbreak dynamics. In the present study, we looked at the effect of temperature in altering the virus virulence. We found that DENV cultured at a higher temperature in C6/36 mosquito cells was significantly more virulent than the virus grown at a lower temperature. In a mouse model, the virulent strain induced enhanced viremia and aggressive disease with a short course, hemorrhage, severe vascular permeability, and death. Higher inflammatory cytokine response, thrombocytopenia, and severe histopathological changes in vital organs such as heart, liver, and kidney were hallmarks of the disease. Importantly, it required only a few passages for the virus to acquire a quasi‐species population harboring virulence‐imparting mutations. Whole genome comparison with a lower temperature passaged strain identified key genomic changes in the structural protein‐coding regions as well as in the 3′UTR of the viral genome. Our results point out that virulence‐enhancing genetic changes could occur in the dengue virus genome under enhanced growth temperature conditions in mosquito cells.
Epithelial multicellular clustering enabled by polarized macrophages on soft matrices
Authors: Zmuda Hannah , Pathak Amit 
Published: June 2023

AbstractFormation of epithelial structures of variegated geometries and sizes is essential for organogenesis, tumor growth, and wound repair. Although epithelial cells are predisposed with potential for multicellular clustering, it remains unclear whether immune cells and mechanical cues from their microenvironment influence this process. To explore this possibility, we cocultured human mammary epithelial cells with prepolarized macrophages on soft or stiff hydrogels. In the presence of M1 (proinflammatory) macrophages on soft matrices, epithelial cells migrated faster and subsequently formed larger multicellular clusters compared to cocultures with M0 (unpolarized) or M2 (anti‐inflammatory) macrophages. By contrast, stiff matrices disabled active clustering of epithelial cells due to their enhanced migration and cell–ECM adhesion, regardless of macrophage polarization. We found that the copresence of soft matrices and M1 macrophages reduced focal adhesions, but enhanced fibronectin deposition and nonmuscle myosin‐IIA expression, which altogether optimize conditions for epithelial clustering. Upon ROCK inhibition, epithelial clustering was abrogated, indicating a requirement for optimized cellular forces. In these cocultures, TNF‐α secretion was the highest with M1 macrophages and TGF‐β secretion was exclusively detectable in case of M2 macrophages on soft gels, which indicated potential role of macrophage secreted factors in the observed epithelial clustering. Indeed, exogenous addition of TGF‐β promoted epithelial clustering with M1 coculture on soft gels. According to our findings, optimization of both mechanical and immune factors can tune epithelial clustering responses, which could have implications in tumor growth, fibrosis, and would healing.
Hepatic Krüppel‐like factor 14 regulates lipid metabolism in nonalcoholic steatohepatitis mice
Authors: Chen Xiaoyan , Shi Wenjie , Xie Yong , Wang Yunwu , Yao Qian , Ke Huajing , Xu Xuan , Liu Hui , Liu Pi , Zhou Xiaojiang 
Published: June 2023

AbstractExcessive lipid accumulation is a critical characteristic in the development of nonalcoholic steatohepatitis (NASH). The underlying molecular mechanism, however, is unclear. In this study, we explored whether and how Krüppel‐like factor 14 (KLF14) affects hepatic lipid metabolism in NASH. KLF14 expression was detected in NASH patients and mice fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD). Adeno‐associated viruses and adenoviruses were used to alter hepatic KLF14 expression in vivo or in vitro to investigate how KLF14 functions in lipid regulation. The molecular mechanisms were explored using RNA‐seq, luciferase reporter, and ChIP assays. The fatty liver phenotype was analyzed histopathologically, and serum and hepatocyte biochemical parameters were measured. The NASH mouse model developed quickly in C57BL/6J mice fed a CDAHFD for 8 weeks. We found that KLF14 expression was decreased in NASH patients and CDAHFD mice. Oleic acid and palmitic acid treatment also reduced KLF14 levels in hepatocytes. KLF14 knockdown downregulated the genes involved in fatty acid oxidation, promoting the progression of hepatic steatosis. In contrast, hepatic KLF14 overexpression alleviated lipid accumulation and oxidative stress in CDAHFD mice. These effects resulted from direct activation of the PPARα signaling pathway. PPARα inhibition diminished the KLF14 overexpression‐reduced protective effects against steatosis in OA&PA‐treated MPHs and AAV‐KLF14‐infected CDAHFD mice. These data reveal that hepatic KLF14 regulates lipid accumulation and oxidative stress through the KLF14‐PPARα pathway as NASH progresses. KLF14 may be a novel therapeutic target for hepatic steatosis.
Pediatric Fractures: Does Vitamin D Play a Role?
Authors: Karkenny Alexa J. , Avarello Jahn , Hanstein Regina , Lo Yungtai , Burlage Ashley , Crabb Rocio , McNally Kelly , Merwin Sara , Schulz Jacob F. , Poon Selina 
Published: June 2023

Background:
Vitamin D (25-OHD) deficiency and insufficiency are reported in about half of all children. The literature on low 25-OHD and pediatric fracture risk presents inconsistent results. This study evaluates the association between pediatric fractures and 25-OHD, parathyroid hormone (PTH), and calcium.

Methods:
This is a prospective case-control study in 2 urban pediatric emergency departments (2014-2017). Patients aged 1 to 17 requiring intravenous access were enrolled. Demographics, nutrition, and activity information were recorded and levels of 25-OHD, calcium, and PTH were measured.

Results:
Two hundred forty-five subjects were enrolled: 123 fractures and 122 controls. Overall, the mean 25-OHD level was 23 ng/mL±8.5: 52 (21%) of patients were 25-OHD sufficient; 193 (79%) were not. Ninety-six percent of patients with lower extremity fractures had low 25-OHD versus 77% of patients with upper extremity fractures (P=0.024). The fracture cohort was younger (P=0.002), included more males (P=0.020), and spent more time playing outdoor sports (P=0.011) than the control cohort. The 25-OHD level (fracture 22.8 ng/mL±7.6 vs. nonfracture 23.5 ng/mL±9.3, P=0.494) and median calcium level (fracture 9.8 mg/dL vs. nonfracture 10.0 mg/dL, P=0.054) were similar between cohorts. The median PTH level was higher in the fracture than the control cohort (33 vs. 24.5 pg/mL; P<0.0005); PTH was elevated to hyperparathyroidism (>65 pg/mL) in 13% of fractures and 2% of controls (P=0.006). Matched subgroup analysis of 81 fracture patients and 81 controls by age, gender, and race showed that PTH was the only variable independently associated with increased odds of fracture (odds ratio=1.10, 95% CI, 1.01-1.19, P=0.021) in a model adjusted for vitamin D sufficiency and time spent playing outdoor sports.

Conclusions:
Low 25-OHD is common in children with fractures but we found no difference in 25-OHD levels between fracture and nonfracture cohorts. This research can impact evidence-based guidelines on vitamin D level screening and/or supplementation after fracture.

Level of Evidence:
Diagnostic level IV—case-control study.
Epic Sepsis Model Inpatient Predictive Analytic Tool: A Validation Study
Authors: Cull John , Brevetta Robert , Gerac Jeff , Kothari Shanu , Blackhurst Dawn 
Published: June 2023

OBJECTIVES:
Earlier treatment of sepsis leads to decreased mortality. Epic is an electronic medical record providing a predictive alert system for sepsis, the Epic Sepsis Model (ESM) Inpatient Predictive Analytic Tool. External validation of this system is lacking. This study aims to evaluate the ESM as a sepsis screening tool and determine whether an association exists between ESM alert system implementation and subsequent sepsis-related mortality.

DESIGN:
Before-and-after study comparing baseline and intervention period.

SETTING:
Urban 746-bed academic level 1 trauma center.

PATIENTS:
Adult acute care inpatients discharged between January 12, 2018, and July 31, 2019.

INTERVENTIONS:
During the before period, ESM was turned on in the background, but nurses and providers were not alerted of results. The system was then activated to alert providers of scores greater than or equal to 5, a set point determined using receiver operating characteristic curve analysis (area under the curve, 0.834; p < 0.001).

MEASUREMENTS AND MAIN RESULTS:
Primary outcome was mortality during hospitalization; secondary outcomes were sepsis order set utilization, length of stay, and timing of administration of sepsis-appropriate antibiotics. Of the 11,512 inpatient encounters assessed by ESM, 10.2% (1,171) had sepsis based on diagnosis codes. As a screening test, the ESM had sensitivity, specificity, positive predictive value, and negative predictive value rates of 86.0%, 80.8%, 33.8%, and 98.11%, respectively. After ESM implementation, unadjusted mortality rates in patients with ESM score greater than or equal to 5 and who had not yet received sepsis-appropriate antibiotics declined from 24.3% to 15.9%; multivariable analysis yielded an odds ratio of sepsis-related mortality (95% CI) of 0.56 (0.39–0.80).

CONCLUSIONS:
In this single-center before-and-after study, utilization of the ESM score as a screening test was associated with a 44% reduction in the odds of sepsis-related mortality. Due to wide utilization of Epic, this is a potentially promising tool to improve sepsis mortality in the United States. This study is hypothesis generating, and further work with more rigorous study design is needed.
Prognostic Value of Pretreatment Serum Carcinoembryonic Antigen Level in 1130 Patients With Non-small Cell Lung Cancer
Authors: Li Fengzhou , Lv Qing , Wang Yufei , Zhao Shilei , Guo Tao , Wang Gang , Gu Chundong 
Published: June 2023

Objectives:
Carcinoembryonic antigen (CEA) is the most frequently used tumor marker for non-small cell lung cancer (NSCLC). The current study aimed to provide the highest-level evidence of the prognostic value of pretreatment serum CEA level for NSCLC through the appropriate statistical methodology and large-sample cohorts.

Methods:
The current retrospective cohort study with 1130 patients with NSCLC treated by thoracic surgery with pretreatment serum CEA concentrations above/below 5 ng/mL. Propensity score matching, Kaplan-Miere survival analysis, and Cox proportional hazard regression models were used to study the intergroup variance. The overall/disease-free hazard ratios (HRs) of the current study were combined with the previously published studies using cumulative meta-analysis to provide the highest-level evidence.

Results:
Intergroup confounding variables were well controlled by propensity score matching, and the survival differences were statistically significant. The Cox univariate analysis showed that the overall and disease-free HRs of the high CEA towards patients with low CEA were 1.595 (95% CI: 1.329-1.863, P = 0.004) and 1.498 (95% CI: 1.271-1.881, P = 0.004). The HRs of multivariate analysis were adjusted to 1.586 (95% CI: 1.398-1.812, P = 0.016) and 1.413 (95% CI: 1.22-1.734, P = 0.022) respectively. The cumulative meta-analysis showed that the cumulative overall HR was in accord with previous studies, and the cumulative disease-free HR turn to be statistically significant.

Conclusions:
Pretreatment serum CEA level was an independent influence factor of overall/disease-free survival of patients with NSCLC, and even for patients with the same pTNM stages or pathologic stages, it is used for prognosis.
Current Practice in Keloid Treatment: a Survey of Dutch Dermatologists and Plastic Surgeons
Authors: Yin Qi , Wolkerstorfer Albert , Niessen Frank B. , Gibbs Susan , Louter Juliette M.I. , van Zuijlen Paul P.M. , Lapid Oren 
Published: June 2023

BACKGROUND
Several therapeutic options are available for the treatment of keloids, but it remains unclear which treatment options are most commonly used by practitioners.

OBJECTIVE
To explore the prevailing treatment for different keloid phenotypes among dermatologists and plastic surgeons in the Netherlands.

METHODS
Members of the Dutch society for Plastic surgery and the Dutch society for Dermatology and Venereology were asked to participate. Questions elaborated on the treatment for a small and a large keloid on the mandibula and multiple keloids on the chest.

RESULTS
One hundred forty-three responses were obtained. Heterogeneity in treatment was extremely high for the small, large, and multiple keloids with 27, 35, and 33 various first choices, respectively. Intralesional corticosteroids were most often chosen for all 3 different keloid phenotypes. These were mostly (61%) administered as monotherapy for the small keloid and mostly combined with other treatments for the large keloid (19%) and multiple keloids (43%). Surgery was chosen regularly (22%) for the large keloid, mostly combined with intralesional corticosteroids (10%) or brachytherapy (8.4%).

CONCLUSION
Keloid treatment is very heterogeneous among dermatologists and plastic surgeons, even in a relatively small country as the Netherlands. Moreover, the treatment choice depends on the keloid phenotype.
Bilateral Keloid Formation after Otoplasty in the Presence of Prolonged Mask Wearing
Authors: Hoch Cosima C. , Funk Paul F. , Storck Katharina , San Nicoló Marion , Jacobi Christian 
Published: June 2023

Summary:
Prominent ears are the most frequently observed congenital deformity of the head and neck. Various techniques have been proposed for their aesthetic correction. Typically, surgical treatment for protruding ears involves a combination of suture, cutting, and scoring techniques. Herein, we present the clinical case of an 11-year-old child who developed bilateral keloid formations 12 months after otoplasty. Keloids and hypertrophic scars can result from extensive retroauricular skin excisions that do not allow for tension-free wound closure. In addition, skin tension and friction on immature surgical scars are common risk factors for keloid formation. To comply with school guidelines aimed at reducing the transmission of SARS-CoV-2, the patient has consistently worn FFP2 masks with ear loops positioned behind the concha. Although masks play a critical role in preventing the spread of infectious diseases, they can lead to friction in the postauricular area. In light of the presented case, it is important to examine potential cofactors that may contribute to keloid formation after otoplasty, as well as suggest a strategy to safeguard the retroauricular scar.
The prevalence of persistent post-traumatic headache in adult civilian traumatic brain injury: a systematic review and meta-analysis on the past 14 years
Authors: Herrero Babiloni Alberto , Bouferguene Yasmine , Exposto Fernando G. , Beauregard Roxanne , Lavigne Gilles J. , Moana-Filho Estephan J. , Arbour Caroline 
Published: June 2023

Abstract
The most recent prevalence estimate of post-traumatic headache (PTH) after traumatic brain injury (TBI) in veterans and civilians dates back to 2008. The prevalence was found to be 57.8%, with surprising higher rates (75.3%) in mild TBI when compared with those with moderate/severe TBI (32.1%). However, the revision of mild TBI diagnostic criteria and an historic peak of TBI in the elderly individuals attributed to the ageing population may lead to different results. Thus, we conducted a systematic review and meta-analysis to assess the updated prevalence of PTH during the past 14 years only in civilians. A literature search was conducted following PRISMA guidelines guided by a librarian. Screening, full-text assessment, data extraction, and risk of bias assessment were performed blindly by 2 raters. Meta-analysis of proportions using the Freeman and Tukey double arcsine method of transformation was conducted. Heterogeneity, sensitivity analysis, and meta-regressions were performed with the predictors: year of publication, mean age, sex, TBI severity, and study design. Sixteen studies were selected for the qualitative analysis and 10 for the meta-analysis. The overall prevalence estimate of PTH was 47.1%, (confidence interval = 34.6, 59.8, prediction intervals = 10.8, 85.4), being similar at different time points (3, 6, 12, and 36+ months). Heterogeneity was high, and none of the meta-regressions were significant. The overall prevalence of PTH after TBI over the past 14 years remains high even if assessed only in civilians. However, the prevalence rates attributed to mild and moderate/severe TBI were similar, differing significantly from previous reports. Efforts are needed to improve TBI outcomes.
Tip-in Versus Conventional Endoscopic Mucosal Resection for Colorectal Neoplasia
Authors: Niu Chengu , Bapaye Jay , Zhang Jing , Zhu Kaiwen , Liu Hongli , Farooq Umer , Zahid Salman , Elkhapery Ahmed , Okolo Patrick I. 
Published: June 2023

Background:
Early-stage gastrointestinal neoplasms are frequently treated with conventional endoscopic mucosal resection (C-EMR). However, C-EMR frequently leads to incomplete resection of large colorectal lesions. Tip-in endoscopic mucosal resection (EMR), which was recently introduced for en bloc resection of colorectal neoplasms, minimizes slippage during the procedure.

Methods:
We conducted a systematic review and meta-analysis of published studies that compared Tip-in EMR with conventional EMR. We searched several electronic databases and included studies that reported on the primary outcomes of en bloc resection rate and complete resection rate, as well as secondary outcomes such as procedure time and procedure-related complications (including perforation and delayed bleeding rate). We used a random effects model to calculate odds ratios (ORs) with 95% CIs for dichotomous data and weighted mean differences with 95% CIs for continuous data. We also conducted several sensitivity analyses to assess the robustness of our findings.

Results:
A total of 11 studies involving 1244 lesions (684 in the Tip-in EMR group and 560 in C-EMR group) were included in the meta-analysis. Our meta-analysis showed that compared with conventional EMR, Tip-in EMR significantly increased the en bloc resection rate in patients with colorectal neoplasia (OR=3.61; 95% CI, 2.09-6.23; P<0.00001; I
2=0%) and had a higher complete resection rate (OR=2.49; 95% CI, 1.65-3.76; P<0.0001; I
2=0%). However, the procedure time and rates of procedure-related complications did not differ significantly between the 2 groups.

Conclusions:
Tip-in EMR outperformed C-EMR for both the en bloc and complete resection of colorectal lesions with similar rates of procedural complications.
The Effect of Renin-Angiotensin-Aldosterone System Blocking Agents on the Long-term Disease Course of Patients With Crohn’s Disease
Authors: Karime Christian , Hashash Jana G. , Picco Michael F. , Craver Emily C. , Murray Joseph A. , Farraye Francis A. 
Published: June 2023

Background:
The renin-angiotensin-aldosterone system (RAAS) has been associated with gastrointestinal inflammation and fibrosis, suggesting that RAAS blockade may be beneficial in patients with inflammatory bowel disease. Using retrospective analysis, we aimed to compare the disease course of patients with Crohn’s disease (CD) taking two commonly prescribed classes of RAAS-blocking agents.

Study:
Patients with CD initiated on an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) between 2000 and 2016 were enrolled. Data on clinical, radiologic, and procedural surrogate markers of inflammatory bowel disease were collected in the subsequent 3, 5, and 10 years and compared with matched controls using univariate and multivariate analyses.

Results:
Compared with controls, patients taking ARBs had fewer instances of corticosteroid use (1.06 vs 2.88, P < 0.01) at 10 years. Patients taking ACEIs had an overall worse disease course, with more imaging studies (3.00 vs 1.75, P = 0.03) and endoscopic procedures (2.70 vs 1.78, P = 0.01) at 5 years, and more imaging studies (6.19 vs 3.50, P < 0.01), endoscopic procedures (5.91 vs 3.78, P < 0.01), and gastrointestinal operations (0.59 vs 0.18, P < 0.02) at 10 years. Results remained significant on multivariate analysis, adjusting for CD characteristics and the use of other antihypertensive medications.

Conclusions:
Our study provides insight into the long-term use of RAAS-blocking agents in patients with CD, suggesting that differences exist among commonly prescribed medication classes. While ACEIs were associated with an overall worse disease course at 5 and 10 years, patients taking ARBs were noted to have fewer instances of corticosteroid use at 10 years. Future large-scale studies are needed to further explore this association.
Pigmentary retinopathy and nodular granuloma associated with acute retinal necrosis from varicella zoster virus and human herpes virus type 6: Case report
Authors: Keorochana Narumon , Suleesathira Budsarat , Vongkulsiri Sritatath 
Published: June 2023

Rationale:
Acute retinal necrosis (ARN) caused by human herpes virus type 6 (HHV-6) is uncommon. We described a case of consecutive bilateral ARN, which was found to be a coinfection of varicella zoster virus (VZV) and HHV-6 in a 50-year-old woman, not well responded with systemic acyclovir. We showed the atypical findings with corresponding fundus and optical coherence tomography imaging.

Patient concerns:
She presented with anterior segment inflammation with peripheral retinitis and vasculitis in the left eye with disease progression despite of initial antiviral treatment, end up with retinal detachment. The right eye, subsequently, developed focal retinitis.

Diagnosis:
ARN was diagnosed by clinical fundus picture, confirmed by polymerase chain reaction (PCR).

Interventions:
Initially, she was treated with intravenous acyclovir and intravitreal ganciclovir for left eye. Retinal necrosis progressed, followed by retinal detachment. Pars plana vitrectomy with silicone oil was performed. The right eye, subsequently, developed focal retinitis. Medication was switched to intravenous ganciclovir and then oral valganciclovir.

Outcomes:
Retinitis was resolved, generalized hyperpigmentation appeared as a salt-and-pepper appearance in the right eye. The left eye presented preretinal deposits on silicone-retina interphase along retinal vessels. Spectral-domain optical coherence tomography (SD-OCT) showed multiple hyperreflective nodules on retinal surface.

Lessons:
ARN from coinfection of VZV and HHV-6 is rare. Preretinal granulomas and generalized hyperpigmentation could be one of the HHV-6 features. HHV-6 should be in the differential diagnosis for ARN. It responds well to systemic ganciclovir.