Assessing the influence of parameters on tissue welding in small bowel end-to-end anastomosis in vitro and in vivo.

BACKGROUND: The use of high-frequency electric welding technology for intestinal end-to-end anastomosis holds significant promise. Past studies have focused on in vitro, and the safety and efficacy of this technology is uncertain, severely limiting the clinical application of this technology. This study investigates the impact of compression pressure, energy dosage, and duration on anastomotic quality using a homemade anastomosis device in both in vitro and in vivo settings. METHODS: Two hundred eighty intestines and 5 experimental pigs were used for in vitro and in vivo experiments, respectively. The in vitro experiments were conducted to study the effects of initial pressure (50-400 kpa), voltage (40-60 V), and time (10-20 s) on burst pressure, breaking strength, thermal damage, and histopathological microstructure of the anastomosis. Optimal parameters were then inlaid into a homemade anastomosis and used for in vivo experiments to study the postoperative porcine survival rate and the pathological structure of the tissues at the anastomosis and the characteristics of the collagen fibers. RESULTS: The anastomotic strength was highest when the compression pressure was 250 kPa, the voltage was 60 V, and the time was 15 s. The degree of thermal damage to the surrounding tissues was the lowest. The experimental pigs had no adverse reactions after the operation, and the survival rate was 100%. 30 days after the operation, the surgical site healed well, and the tissues at the anastomosis changed from immediate adhesions to permanent connections. CONCLUSION: High-frequency electric welding technology has a certain degree of safety and effectiveness. It has the potential to replace the stapler anastomosis in future and become the next generation of new anastomosis device.

Likelihood for transcriptions in a genetic regulatory system under asymmetric stable Lévy noise.

This work is devoted to investigating the evolution of concentration in a genetic regulation system, when the synthesis reaction rate is under additive and multiplicative asymmetric stable Lévy fluctuations. By focusing on the impact of skewness (i.e., non-symmetry) in the probability distributions of noise, we find that via examining the mean first exit time (MFET) and the first escape probability (FEP), the asymmetric fluctuations, interacting with nonlinearity in the system, lead to peculiar likelihood for transcription. This includes, in the additive noise case, realizing higher likelihood of transcription for larger positive skewness (i.e., asymmetry) index ß, causing a stochastic bifurcation at the non-Gaussianity index value α = 1 (i.e., it is a separating point or line for the likelihood for transcription), and achieving a turning point at the threshold value ß≈-0.5 (i.e., beyond which the likelihood for transcription suddenly reversed for α values). The stochastic bifurcation and turning point phenomena do not occur in the symmetric noise case (ß = 0). While in the multiplicative noise case, non-Gaussianity index value α = 1 is a separating point or line for both the MFET and the FEP. We also investigate the noise enhanced stability phenomenon. Additionally, we are able to specify the regions in the whole parameter space for the asymmetric noise, in which we attain desired likelihood for transcription. We have conducted a series of numerical experiments in "regulating" the likelihood of gene transcription by tuning asymmetric stable Lévy noise indexes. This work offers insights for possible ways of achieving gene regulation in experimental research.

High-Frequency Ultrasound in Blistering Skin Diseases: A Useful Method for Differentiating Blister Locations.

Bullous pemphigoid and pemphigus vulgaris, which belong to the group of subepidermal and intraepidermal bullae, respectively, are two potentially devastating blistering skin diseases. We used high-frequency ultrasound (US) in 3 cases of these diseases as prototypes to study the value of high-frequency US in discriminating blister locations. Our findings showed that high-frequency US has a strong correlation with histomorphometric findings because of its high resolution, and we hope that it will be helpful for differentiating blister locations.

Physical modulation of mesenchymal stem cell exosomes: A new perspective for regenerative medicine.

Mesenchymal stem cell-derived exosomes (MSC-Exo) offer promising therapeutic potential for various refractory diseases, presenting a novel therapeutic strategy. However, their clinical application encounters several obstacles, including low natural secretion, uncontrolled biological functions and inherent heterogeneity. On the one hand, physical stimuli can mimic the microenvironment dynamics where MSC-Exo reside. These factors influence not only their secretion but also, significantly, their biological efficacy. Moreover, physical factors can also serve as techniques for engineering exosomes. Therefore, the realm of physical factors assumes a crucial role in modifying MSC-Exo, ultimately facilitating their clinical translation. This review focuses on the research progress in applying physical factors to MSC-Exo, encompassing ultrasound, electrical stimulation, light irradiation, intrinsic physical properties, ionizing radiation, magnetic field, mechanical forces and temperature. We also discuss the current status and potential of physical stimuli-affected MSC-Exo in clinical applications. Furthermore, we address the limitations of recent studies in this field. Based on this, this review provides novel insights to advance the refinement of MSC-Exo as a therapeutic approach in regenerative medicine.

Trends in cutaneous squamous cell carcinoma on the lip incidence and mortality in the United States, 2000-2019.

Objective: This study provided a systematic analysis of the trend in incidence and incidence-based mortality for cutaneous squamous cell carcinoma (cSCC) on the lips in the USA using demographic characteristics from the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients diagnosed with cSCC on the lips between 2000 and 2019 from the 17 registries of the USA were identified. Incidence and incidence-based mortality rates were analyzed using SEER*Stat 8.4.0.1 software. This paper calculated incidence rates and incidence-based mortality rates by 100,000 person-years for sex, age, race, SEER registries, median household income ($/year), rural-urban distribution, and primary site. The annual percent changes (APC) in incidence and incidence-based mortality rates were then calculated using joinpoint regression software. Results: Among 8,625 patients diagnosed with cSCC on the lips from 2000 to 2019, men (74.67%), white (95.21%), and 60-79 years old were the most common population, and 3,869 deaths from cSCC on the lips occurred. The overall incidence of cSCC on the lips was 0.516 per 100,000 person-years. cSCC on the lip incidence rates were highest among men, white, and patients aged 60-79 years old. cSCC on the lip incidence rates decreased by 3.210%/year over the study period. The incidence of cSCC on the lips has been decreasing in all sexes, ages, high- or low-income households, and urban or rural patients. The overall incidence-based mortality rate of cSCC on the lips during 2000-2019 was 0.235 per 100,000 person-years. cSCC on the lip incidence-based mortality rates were highest among men, whites, and people older than 80 years old. cSCC on the lip incidence-based mortality increased by 4.975%/year over the study period. cSCC on the lip incidence-based mortality rates increased for all sexes, races, ages, primary sites, high- or low-income households, and urban or rural patients during the study period. Conclusion: Among patients in the USA diagnosed with cSCC on the lips from 2000 to 2019, the overall incidence decreased by 3.210% annually, and incidence-based mortality increased by 4.975%/year. These findings update and supplement the epidemiological information of cSCC on the lips in the USA.

Development and evaluation of a droplet digital PCR assay for the diagnosis of paucibacillary leprosy in skin biopsy specimens.

BACKGROUND: The reduced amounts of Mycobacterium leprae (M. leprae) among paucibacillary (PB) patients reflect the need to further optimize methods for leprosy diagnosis. An increasing number of reports have shown that droplet digital polymerase chain reaction (ddPCR) is a promising tool for diagnosis of infectious disease among samples with low copy number. To date, no publications have investigated the utility of ddPCR in the detection of M. leprae. The aim of this study was to develop and evaluate a ddPCR assay for the diagnosis of PB leprosy. METHODOLOGY: The two most sensitive DNA targets for detection of M. leprae were selected from electronic databases for assessment of sensitivity and specificity by quantitative polymerase chain reaction (qPCR) and ddPCR. Control patients (n = 59) suffering from other dermatological diseases were used to define the cut-off of the duplex ddPCR assay. For comparative evaluation, qPCR and ddPCR assays were performed in 44 PB patients and 68 multibacillary (MB) patients. PRINCIPAL FINDINGS: M. leprae-specific repetitive element (RLEP) and groEL (encoding the 65 kDa molecular chaperone GroEL) were used to develop the ddPCR assay by systematically analyzing specificity and sensitivity. Based on the defined cut-off value, the ddPCR assay showed greater sensitivity in detecting M. leprae DNA in PB patients compared with qPCR (79.5% vs 36.4%), while both assays have a 100% sensitivity in MB patients. CONCLUSIONS/SIGNIFICANCE: We developed and evaluated a duplex ddPCR assay for leprosy diagnosis in skin biopsy samples from leprosy patients. While still costly, ddPCR might be a promising diagnostic tool for detection of PB leprosy.

Evaluation of Prospective HLA-B*13:01 Screening to Prevent Dapsone Hypersensitivity Syndrome in Patients With Leprosy.

Importance: Dapsone hypersensitivity syndrome (DHS) is the most serious adverse reaction associated with dapsone administration and one of the major causes of death in patients with leprosy, whose standard treatment includes multidrug therapy (MDT) with dapsone, rifampicin, and clofazimine. Although the HLA-B*13:01 polymorphism has been identified as the genetic determinant of DHS in the Chinese population, no studies to date have been done to evaluate whether prospective HLA-B*13:01 screening could prevent DHS by identifying patients who should not receive dapsone. Objective: To evaluate the clinical use of prospective HLA-B*13:01 screening for reduction of the incidence of DHS by excluding dapsone from the treatment for patients with HLA-B*13:01-positive leprosy. Design, Setting, and Participants: A prospective cohort study was conducted from February 15, 2015, to April 30, 2018, in 21 provinces throughout China. A total of 1539 patients with newly diagnosed leprosy were enrolled who had not received dapsone previously. After excluding patients who had a history of allergy to sulfones or glucose-6-phosphate dehydrogenase deficiency, 1512 individuals underwent HLA-B*13:01 genotyping. All of the patients were followed up weekly for the first 8 weeks after treatment to monitor for adverse events. Exposures: Patients who were HLA-B*13:01 carriers were instructed to eliminate dapsone from their treatment regimens, and noncarrier patients received standard MDT. Main Outcomes and Measures: The primary outcome was the incidence of DHS. The historical incidence rate of DHS (1.0%) was used as a control. Results: Among 1512 patients (1026 [67.9%] men, 486 [32.1%] women; mean [SD] age, 43.1 [16.2] years), 261 (17.3%) were identified as carriers of the HLA-B*13:01 allele. A total of 714 adverse events in 384 patients were observed during the follow-up period. Dapsone hypersensitivity syndrome did not develop in any of the 1251 patients who were HLA-B*13:01-negative who received dapsone, while approximately 13 patients would be expected to experience DHS, based on the historical incidence rate of 1.0% per year (P = 2.05 × 10-5). No significant correlation was found between other adverse events, including dermatologic or other events, and HLA-B*13:01 status. Conclusions and Relevance: Prospective HLA-B*13:01 screening and subsequent elimination of dapsone from MDT for patients with HLA-B*13:01-positive leprosy may significantly reduce the incidence of DHS in the Chinese population.

Genome-Wide Analysis of Protein-Coding Variants in Leprosy.

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 × 10-9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 × 10-8, OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 × 10-10, OR = 1.36), rs146466242 in FLG (P = 3.39 × 10-12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 × 10-6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 × 10-9, OR = 1.14) and rs181206 in IL27 (P = 1.08 × 10-7, OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.

A large-scale genome-wide association and meta-analysis identified four novel susceptibility loci for leprosy.

Leprosy, a chronic infectious disease, results from the uncultivable pathogen Mycobacterium leprae (M. leprae), and usually progresses to peripheral neuropathy and permanent progressive deformity if not treated. Previously published genetic studies have identified 18 gene/loci significantly associated with leprosy at the genome-wide significant level. However as a complex disease, only a small proportion of leprosy risk could be explained by those gene/loci. To further identify more susceptibility gene/loci, we hereby performed a three-stage GWAS comprising 8,156 leprosy patients and 15,610 controls of Chinese ancestry. Four novel loci were identified including rs6807915 on 3p25.2 (P=1.94 × 10-8, OR=0.89), rs4720118 on 7p14.3 (P=3.85 × 10-10, OR=1.16), rs55894533 on 8p23.1 (P=5.07 × 10-11, OR=1.15) and rs10100465 on 8q24.11 (P=2.85 × 10-11, OR=0.85). Altogether, these findings have provided new insight and significantly expanded our understanding of the genetic basis of leprosy.