BACKGROUND: Burn injuries are characterized by extensive and prolonged inflammatory responses that impair wound healing, especially in deep burns. Understanding the post-burn fibroblast dynamics in wound healing is critical to improve recovery and minimize scarring. This study aimed to develop a 3D reconstructed human skin (RhS) burn model to mimic superficial, partial-thickness, and deep burn injuries and assess fibroblast behavior over one week. METHODS: RhS consisted of a reconstructed epidermis on a fibroblast populated collagen hydrogel dermis. Papillary (fibroblast activation protein; FAP ?) and reticular (FAP-) fibroblasts located themselves in the upper and lower regions respectively within the dermal compartment in line with native skin. Burns of increasing temperatures (70 °C, 110 °C, and 140 °C) were introduced and RhS was analyzed up to one-week post-burn. RESULTS: Lactate dehydrogenase (LDH) staining for metabolic active cells in tissue sections enabled distinct histological zones to be observed in RhS with partial (110 °C) and deep burns (140 °C): including a viable fibroblast zone (zone V), a mixed dead and viable fibroblast zone (zone M), and a necrotic zone (zone N). Fibroblast migration from the wound edge (M) into the viable area (V) and changes in fibroblast phenotype, particularly an increase in papillary fibroblast markers (FAP ?), were observed, with a marked increased expression of Ki67 in fibroblasts at the burn wound edge (M).Additionally, burn temperature influenced the protein secretion of inflammatory and tissue remodeling mediators SAA, NGAL, MRP8/13, ICAM-1, CCL20, and MMP-9. CONCLUSION The RhS burn model enables complex fibroblast dynamics post-burn to be investigated in an organotypic model, providing a platform for studying burn pathophysiology which can be used for evaluating potential therapeutic strategies for enhancing burn wound healing and minimizing scarring in the future.

Objective: The optimal treatment of clinically early-stage cervical cancer with suspicious lymph nodes on pretreatment imaging is unclear. Therefore, we aimed to compare surgery (i.e., radical hysterectomy and pelvic lymphadenectomy±adjuvant therapy) with primary chemoradiotherapy as treatment strategies in this patient group regarding recurrence-free, overall survival and toxicity. Methods: Women diagnosed between 2009–2017 with the International Federation of Gynecology and Obstetrics (2009) stage IA–IIA and suspicious nodes based on radiologic assessment of pretreatment imaging were retrospectively selected from the Netherlands Cancer Registry. Cox proportional hazard was used to estimate survival and logistic regression for toxicity. Inverse probability weighting was used to correct for confounding.Grade ≥2 surgery-related (≤30 days) and grade ≥3 chemotherapy or radiotherapy-related (≤6 months) toxicity were collected. Missing data were imputed. Results: Of 330 patients included, 131 (40%) received surgery (followed by adjuvant therapy in 54%) and 199 (60%) chemoradiotherapy. Pathological nodal status was known in 100% of the surgery group and 32% (n=63) of the chemoradiotherapy group, of whom 43% (56/131) and 89% (56/63), respectively, had metastases. After adjustment for confounders, the recurrence-free survival (hazard ratio [HR]=0.67; 95% confidence interval [CI]=0.34–1.31) and overall survival (HR=0.75; 95% CI=0.38–1.47) were not significantly different between both groups, while surgery was associated with more toxicity (odds ratio=2.82; 95% CI=1.42– 5.60), mainly surgery-related. Conclusion In patients with clinically early-stage cervical cancer and suspicious nodes on imaging, surgery and primary chemoradiotherapy yielded comparable results in terms of survival, whereas surgery might be associated with more (surgery-related) short-term toxicity.

Biliary fibrosis (BF) is the result of pathological repair of bile tract injury, characterized by thickening and sclerosis of the bile duct wall and progressive stricture of the lumen, which may ultimately lead to serious adverse outcomes such as biliary obstruction, biliary cirrhosis, liver failure, and hepatobiliary malignancies. Current research describes BF as a pathological feature of certain bile tract diseases, lacking a systematic summary of its etiology, pathophysiology, molecular mechanisms, and treatment. BF is a common but easily neglected disease state in biliary system, which may promote the development and progression of hepatobiliary diseases through abnormal repair mechanism after pathological biliary tract injury. Based on the latest research progress from both domestic and international perspectives, the authors review the concept, clinical manifestation, etiology, pathogenesis, and therapeutic strategies of BF to provide a reference for clinical physicians.

Background: and Purpose The association of dyslipidemia with stroke has been inconsistent, which may be due to differing associations within etiological stroke subtypes. We sought to determine the association of lipoproteins and apolipoproteins within stroke subtypes. Methods: Standardized incident case-control STROKE study in 32 countries. Cases were patients with acute hospitalized first stroke, and matched by age, sex and site to controls. Concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (apoA1), and apoB were measured. Non-HDL-C was calculated. We estimated multivariable odds ratio (OR) and population attributable risk percentage (PAR%). Outcome measures were all stroke, ischemic stroke (and subtypes), and intracerebral hemorrhage (ICH). Results: Our analysis included 11,898 matched case-control pairs; 77.3% with ischemic stroke and 22.7% with ICH. Increasing apoB (OR, 1.10; 95% confidence interval [CI], 1.06 to 1.14 per standard deviation [SD]) and LDL-C (OR, 1.06; 95% CI, 1.02 to 1.10 per SD) were associated with an increase in risk of ischemic stroke, but a reduced risk of ICH. Increased apoB was significantly associated with large vessel stroke (PAR 13.4%; 95% CI, 5.6 to 28.4) and stroke of undetermined cause. Higher HDL-C (OR, 0.75; 95% CI, 0.72 to 0.78 per SD) and apoA1 (OR, 0.63; 95% CI, 0.61 to 0.66 per SD) were associated with ischemic stroke (and subtypes). While increasing HDL-C was associated with an increased risk of ICH (OR, 1.20; 95% CI, 1.14 to 1.27 per SD), apoA1 was associated with a reduced risk (OR, 0.80; 95% CI, 0.75 to 0.85 per SD). ApoB/A1 (OR, 1.38; 95% CI, 1.32 to 1.44 per SD) had a stronger magnitude of association than the ratio of LDL-C/HDL-C (OR, 1.26; 95% CI, 1.21 to 1.31 per SD) with ischemic stroke (P<0.0001). Conclusions The pattern and magnitude of association of lipoproteins and apolipoproteins with stroke varies by etiological stroke subtype. While the directions of association for LDL, HDL, and apoB were opposing for ischemic stroke and ICH, apoA1 was associated with a reduction in both ischemic stroke and ICH. The ratio of apoB/A1 was the best lipid predictor of ischemic stroke risk.

Dengue is a public health issue in tropical south-eastern Asia responsible for significant morbidity and mortality. Information on dengue epidemiology is necessary for developing strategies to control infections effectively. In the Lao People’s Democratic Republic (Lao PDR), Champasak and Savannakhet provinces account for around 30% of the national dengue burden. In this study, the dengue epidemiological profile in these two southern provinces of Lao PDR was described by analysing seasonal and spatial dengue notification data from 2003–2020 using the long-term mean (LTM) method. Savannakhet had a higher LTM (132.0 cases/month, 95% confidence interval [Cl]: 92.2–171.7) than Champasak (113.3 cases/month, 95% CI: 86.0–140.5), with peaks in dengue notifications following the rainy season in both provinces. The highest notification rates were observed in July to September; these months were also when the LTM was most frequently exceeded. Previously, dengue notifications were largely confined to the western districts of Savannakhet and the northern districts of Champasak, but more recently, notifications have increased in the eastern districts of Savannakhet and southern districts of Champasak. While the notification rate remained high in children and young adults (5–30 years), especially among students and farmers, a shift in the age structure of dengue cases was observed, with a greater proportion of notifications now occurring in those aged over 30 years. Community-based vector control and prevention programmes are needed to restrict the spread of dengue into new geographical areas in the southern provinces of Lao PDR.

The optimal management of patients with asymptomatic carotid stenosis (ACS) is the subject of extensive debate. According to the 2017 European Society for Vascular Surgery guidelines, carotid endarterectomy should (Class IIa; Level of Evidence: B) or carotid artery stenting may be considered (Class IIb; Level of Evidence: B) in the presence of one or more clinical/imaging characteristics that may be associated with an increased risk of late ipsilateral stroke (e.g., silent embolic infarcts on brain computed tomography/magnetic resonance imaging, progression in the severity of ACS, a history of contralateral transient ischemic attack/stroke, microemboli detection on transcranial Doppler, etc.), provided documented perioperative stroke/death rates are <3% and the patient’s life expectancy is >5 years. Besides these clinical/imaging characteristics, there are additional individual, ethnic/racial or social factors that should probably be evaluated in the decision process regarding the optimal management of these patients, such as individual patient needs/patient choice, patient compliance with best medical treatment, patient sex, culture, race/ethnicity, age and comorbidities, as well as improvements in imaging/operative techniques/outcomes. The present multispecialty position paper will present the rationale why the management of patients with ACS may need to be individualized.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
Adenocarcinoma of Lung/genetics* ; Carcinoma, Non-Small-Cell Lung/genetics* ; Carcinoma, Squamous Cell/genetics* ; Genetic Heterogeneity ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Lung Neoplasms/genetics* ; Polymorphism, Single Nucleotide

The optimal management of patients with asymptomatic carotid stenosis (ACS) is the subject of extensive debate. According to the 2017 European Society for Vascular Surgery guidelines, carotid endarterectomy should (Class IIa; Level of Evidence: B) or carotid artery stenting may be considered (Class IIb; Level of Evidence: B) in the presence of one or more clinical/imaging characteristics that may be associated with an increased risk of late ipsilateral stroke (e.g., silent embolic infarcts on brain computed tomography/magnetic resonance imaging, progression in the severity of ACS, a history of contralateral transient ischemic attack/stroke, microemboli detection on transcranial Doppler, etc.), provided documented perioperative stroke/death rates are <3% and the patient’s life expectancy is >5 years. Besides these clinical/imaging characteristics, there are additional individual, ethnic/racial or social factors that should probably be evaluated in the decision process regarding the optimal management of these patients, such as individual patient needs/patient choice, patient compliance with best medical treatment, patient sex, culture, race/ethnicity, age and comorbidities, as well as improvements in imaging/operative techniques/outcomes. The present multispecialty position paper will present the rationale why the management of patients with ACS may need to be individualized.

Objective: This study aimed to determine the incidences of dengue-like illness (DLI), dengue virus (DENV) infection, and serotypes and to identify socio-demographical and entomological risk factors of DLI in selected suburban and rural communities in the Lao People’s Democratic Republic and in Thailand. Methods: A two-year longitudinal study was conducted in four villages during the inter-epidemic period between 2011 and 2013. Entomological surveys, semi-structured interviews of household heads and observations were conducted. Occurrences of DLI were recorded weekly using the World Health Organization’s dengue definition along with blood samples; results were compared with national surveillance dengue data. Risk factors of DLI were assessed using logistic regression. Result: Among the 2007 people in the study, 83 DLI cases were reported: 69 in suburban Lao People’s Democratic Republic, 11 in rural Thailand, three in rural Lao People’s Democratic Republic and none in suburban Thailand. Four were confirmed DENV: two from suburban Lao People’s Democratic Republic (both DENV-1) and two from rural Thailand (both DENV-2). Although the number of detected DLIs during the study period was low, DLI incidence was higher in the study compared to the dengue surveillance data in both countries. DLI in suburban Lao People’s Democratic Republic was associated with age and occupation, but not with the number of pupae per person. Discussion This study highlights the importance of continuous clinical and vector surveillance for dengue to improve early detection of dengue and other mosquito-borne diseases in the region.