Association of human leukocyte antigen (HLA) footprints with the comorbidity of latent autoimmune diabetes in adults (LADA) and hepatitis C virus (HCV) infection: A multicenter cross-sectional study.

AIMS: This study aims to investigate the interplay between hepatitis C virus (HCV) infection and major forms of diabetes: type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA). METHODS: This multicenter study analyzed a cohort of 2699 diabetic and 7344 non-diabetic subjects who visited medical centers in China from 2014 to 2021. T1D, T2D, LADA, and HCV were diagnosed using standard procedures. High-throughput sequencing was conducted to identify genetic footprints of human leukocyte antigen (HLA) alleles and haplotypes at the DRB1, DQA1, and DQB1 loci. RESULTS: HCV infection was detected in 3 % (23/766) of LADA patients, followed by 1.5 % (15/977) of T2D patients, 1.4 % (13/926) of T1D patients, and 0.5 % (38/7344) of non-diabetic individuals. HCV prevalence was significantly higher in people with diabetes than in non-diabetic individuals (p < 0.01). HLA alleles (DQB1*060101, DQB1*040101) and haplotypes (DRB1*080302-DQA1*010301-DQB1*060101) in LADA patients with HCV revealed higher frequencies than in LADA patients without HCV (adjusted p < 0.03). Furthermore, a higher risk of diabetes complications was found among LADA patients with HCV infection (p < 0.001). CONCLUSIONS: LADA patients are susceptible to HCV infection, potentially associated with certain HLA alleles/haplotypes. Early diagnosis and treatment of HCV infection among people with diabetes are important for the management of severe complications.

The Spatial-Temporal Effects of Bacterial Growth Substrates on Antibiotic Resistance Gene Spread in the Biofilm.

Biofilm is considered as the hotspot of antibiotic resistance gene (ARG) dissemination. Bacterial growth substrates are important factors for biofilm formation, but its spatial-temporal effects on ARG spread in biofilm is still unclear. In this study, microfluidics combined with microscopic observation were used to reveal spatial-temporal effects of bacterial growth substrates on ARG transfer at real time. The initial horizontal gene transfer events were found to be independent of substrate levels. However, subsequent transfer processes varied greatly depending on the availability of growth substrates. The proportion of transconjugants was much higher (~12%) when observed in substrate-rich regions (under the channel) at 24 h, followed by an exponential decline, with the distance far from the channel. Furthermore, three-dimensional observation revealed that vertical gene transfer influenced by the concentrations of bacterial growth substrates was important for ARG spread in biofilm. The transfer frequency was 8.2 times higher in the high substrate concentration (50×) compared to low concentration (0.5×) in simulated sewage, underscoring the substantial impact of bacterial growth substrate variability on ARG dissemination. This study is helpful for in-depth understanding of ARG dissemination through biofilms and indicates that reducing pollutant emission is important for ARG control in the environment.

Combination therapy with saxagliptin and vitamin D for the preservation of ß-cell function in adult-onset type 1 diabetes: a multi-center, randomized, controlled trial.

Disease modifying therapies aiming to preserve ß-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre, randomized, controlled trial to assess the ß-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes. In this 3-arm trial, 301 participants were randomly assigned to a 24-month course of the conventional therapy (metformin with or without insulin) or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy. The primary endpoint was the change from baseline to 24 months in the fasting C-peptide. The secondary endpoints included the area under the concentration-time curve (AUC) for C-peptide level in a 2-h mixed-meal tolerance test, glycemic control, total daily insulin use and safety, respectively. The primary endpoint was not achieved in saxagliptin plus vitamin D group (P = 0.18) and saxagliptin group (P = 0.26). However, compared with the conventional therapy, 2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D (-276 pmol/L vs. -419 pmol/L; P = 0.01), and not to the same degree with saxagliptin alone (-314 pmol/L; P = 0.14). Notably, for participants with higher glutamic acid decarboxylase antibody (GADA) levels, the decline of ß-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group (P = 0.001). Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control. In conclusion, the combination of saxagliptin and vitamin D preserves pancreatic ß-cell function in adult-onset autoimmune type 1 diabetes, an effect especially efficacious in individuals with higher GADA levels. Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes. (ClinicalTrials.gov identifier: NCT02407899).

Latent autoimmune diabetes in adults: a focus on ß-cell protection and therapy.

Latent autoimmune diabetes in adults (LADA) is a heterogeneous disease sharing some phenotypic, genetic, and immunological features with both type 1 and 2 diabetes. Patients with LADA have a relatively slow autoimmune process and more residual islet ß-cell function at onset, allowing a time window to protect residual islet ß cells and delay or inhibit disease progression. It is crucial to discover various heterogeneous factors affecting islet ß-cell function for precise LADA therapy. In this review, we first describe the natural history of LADA. Thereafter, we summarize ß-cell function-related heterogeneous factors in LADA, including the age of onset, body mass index, genetic background, and immune, lifestyle, and environmental factors. In parallel, we evaluate the impact of current hypoglycemic agents and immune intervention therapies for islet ß-cell protection. Finally, we discuss the opportunities and challenges of LADA treatment from the perspective of islet ß-cell function protection.

Nursing Research on Benign Prostatic Hyperplasia Based on Continuous Nursing Care.

Purpose: To explore the nursing research of prostatic hyperplasia based on continuous nursing and based on the combination of medical care and nursing. Methods: A prospective study of 96 patients with benign prostatic hyperplasia admitted to our hospital from November 2019 to May 2021 was selected. According to the random number table method, they were divided into an observation group and a control group with 48 cases each. The control group used routine nursing and discharge guidance, and the observation group implemented continuous care based on the combination of medical care and nursing on the basis of the control group. The differences in the scores of quality of life, self-care ability, quality of life score, and sleep quality were compared between the two groups. Results: After 3 months of nursing, the quality of life scores (health status, psychology, social relationship, environment, physiology, and quality of life scores) of the observation group was higher than those of the control group (P < 0.05). After 3 months of nursing, the quality of life scores of disease, physiology, society, psychology, and satisfaction of the observation group was significantly higher than those of the control group, which was statistically significant (P < 0.05). After 3 months of nursing, the observation group's sleep quality scores in all dimensions (time to fall asleep, sleep time, sleep quality, sleep efficiency, hypnotics, sleep disorders, and day disorders) were higher than those of the control group (P < 0.05). After 3 months of nursing, the observation group's self-care skill score, self-responsibility score, health knowledge score, and self-concept score were better than those of the control group (P < 0.05). Conclusion: Continued nursing care based on the combination of medical and health care for prostate hyperplasia is beneficial to improve sleep quality and improve the patient's quality of life score and self-care ability and provide certain references for clinical care of patients with benign prostatic hyperplasia.

Poor guideline adherence in type 1 diabetes education in real-world clinical practice: Evidence from a multicentre, national survey.

OBJECTIVE: To examine how physicians implement guidelines to deliver insulin dosing education for type 1 diabetes patients in real-world settings. METHODS: A nationally representative sample of endocrinologists from top tertiary hospitals in China was obtained by a multistage random sampling method (n = 385). Knowledge, perceptions and practices of insulin dosing were assessed by validated questionnaires. Multivariable logistic regression was used to identify independent determinants of clinical practice and knowledge. RESULTS: Only 20.5% of endocrinologists correctly answered> 75% of the items regarding insulin dosing knowledge. Only 37.7% of endocrinologists reported often teaching insulin-to-carbohydrate ratio and insulin sensitivity factor. Practice behaviours were independently associated with guideline familiarity (OR: 5.92, 95% CI: 3.36-10.41), receiving standardized training (OR: 2.00, 95% CI:1.23-3.25), self-reported lack of time (OR: 0.58, 95% CI:0.34-0.99) and insufficient teaching approaches (OR: 0.57, 95% CI:0.33-0.97) CONCLUSIONS: There was a large gap between guidelines and clinical practice in insulin dosing education. Modifiable factors, including self-reported lack of time, unfamiliarity with guidelines, the shortage of medical training and educational tools hinder insulin dosing education. PRACTICE IMPLICATIONS: Sufficient medical training and educational tools are important to optimize insulin dosing education. The current care paradigm should also be modified to relieve the burden of physicians.

Frequency, clinical features, inflammatory cytokines and genetic background of latent autoimmune diabetes in youth in youth-onset type 2 diabetes: Results from a nationwide, multicentre, clinic-based, cross-sectional study (LADA China).

AIM: To investigate the frequency, clinical phenotype, inflammatory cytokine levels and genetics of glutamic acid decarboxylase autoantibody (GADA)-positive phenotypic youth-onset type 2 diabetes. MATERIALS AND METHODS: This nationwide, multicentre, cross-sectional study included 5324 newly diagnosed subjects with phenotypic type 2 diabetes aged 15 years or older enrolled in the LADA China study. GADA was screened in 248 subjects with youth-onset type 2 diabetes aged 15-29 years. Subjects who presented as GADA-positive were defined as having latent autoimmune diabetes in youth (LADY). We added subjects with LADY, type 1 diabetes, type 2 diabetes and controls from the Diabetes Center of Central South University, and measured serum concentrations of interleukin-6, lipocalin 2, high-sensitivity C-reactive protein, adiponectin and human leukocyte antigen (HLA) genotyping in subjects with LADY, age- and sex-matched GADA-negative type 2 diabetes, type 1 diabetes and controls. RESULTS: Twenty-nine of the 248 subjects (11.7%) were GADA positive. Compared with subjects with type 2 diabetes, subjects with LADY were less probable to have metabolic syndrome (27.6% vs. 59.4%; p = .001). The fasting C-peptide levels tended to be lower in subjects with LADY than in subjects with type 2 diabetes, but the difference was not statistically significant (LADY vs. type 2 diabetes: 0.21 [0.17-0.64] vs. 0.47 [0.29-0.77] nmol/L; p = .11). The cytokine levels of subjects with LADY were indistinguishable from subjects with type 1 diabetes, but subjects with LADY presented increased adiponectin levels compared with subjects with type 2 diabetes after adjusting for age, sex and body mass index (7.19 [4.05-11.66] vs. 3.42 [2.35-5.74] µg/mL; p < .05). The frequency of total susceptible HLA genotypes (DR3/3, -3/9 and -9/9) in subjects with LADY and type 1 diabetes were similarly higher than controls (LADY and type 1 diabetes vs. controls: 21.4% and 30.8% vs. 2.6%, respectively; p < .001). CONCLUSIONS: A high GADA positivity was observed in youth-onset type 2 diabetes subjects in China. As subjects with LADY had an increased susceptible HLA genetic load and different cytokine levels compared with subjects with type 2 diabetes, differentiating LADY from phenotypic type 2 diabetes subjects is important.

Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)?

The emergent outbreak of coronavirus disease 2019 (COVID-19) has caused a global pandemic. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application.

Past, present and future of latent autoimmune diabetes in adults.

Latent autoimmune diabetes in adults (LADA) is the most common form of autoimmune diabetes diagnosed in adults. Similar to type 1 diabetes, the prevalence of LADA is impacted by ethnicity and geography. LADA is characterized by ß cell loss due to autoimmunity and insulin resistance and has highly heterogeneous clinical features, autoimmunity, and genetics in a glutamic acid decarboxylase antibody (GADA) titre-dependent manner, suggesting LADA is part of a continuum spectrum between type 1 and type 2 diabetes. Although LADA is the most frequent form of autoimmune diabetes diagnosed in adults, clinical trials involving LADA are scarce. Here we review the recent advancements in LADA epidemiology, clinical features, pathogenesis, and interventions. We also highlight the environmental factors that are thought to play an important role in addition to genetics in the pathogenesis of LADA. In the future, high-throughput molecular profiles might shed light on the nature of LADA among the wide spectrum of diabetes and offer new opportunities to identify novel LADA-specific biomarkers.

Microfluidic Sensors with Impregnated Fluorophores for Simultaneous Imaging of Spatial Structure and Chemical Oxygen Gradients.

Interior surfaces of polystyrene microfluidic structures were impregnated with the oxygen sensing dye Pt(II) tetra(pentafluorophenyl)porphyrin (PtTFPP) using a solvent-induced fluorophore impregnation (SIFI) method. Using this technique, microfluidic oxygen sensors are obtained that enable simultaneous imaging of both chemical oxygen gradients and the physical structure of the microfluidic interior. A gentle method of fluorophore impregnation using acetonitrile solutions of PtTFPP at 50 °C was developed leading to a 10-µm-deep region containing fluorophore. This region is localized at the surface to sense oxygen in the interior fluid during use. Regions of the device that do not contact the interior fluid pathways lack fluorophores and are dark in fluorescent imaging. The technique was demonstrated on straight microchannel and pore network devices, the latter having pillars of 300 µm diameter spaced center to center at 340 µm providing pore throats of 40 µm. Sensing within channels or pores and imaging across the pore network devices were performed using a Lambert LIFA-P frequency domain fluorescence lifetime imaging system on a Leica microscope platform. Calibrations of different devices prepared by the SIFI method were indistinguishable. Gradient imaging showed fluorescent regions corresponding to the fluid pore network, dark pillars, and fluorescent lifetime varying across the gradient, thus providing both physical and chemical imaging. More generally, the SIFI technique can impregnate the interior surfaces of other polystyrene containers, such as cuvettes or cell and tissue culture containers, to enable sensing of interior conditions.

The Imbalance of B-Lymphocyte Subsets in Subjects with Different Glucose Tolerance: Relationship with Metabolic Parameter and Disease Status.

B lymphocytes are involved in inflammation and are related to insulin resistance in obesity and type 2 diabetes (T2D). This study investigated the phenotype and frequency of B-lymphocyte subsets in subjects recently diagnosed with T2D (n = 60), impaired glucose regulation (IGR, n = 73), and normal glucose tolerance (NGT, n = 169) by flow cytometry. T2D subjects had an increased percentage of CD19+CD23+ (B-2) cells and a decreased percentage of CD19+CD23- (B-1) cells attributing to CD19+CD23-CD5- (B-1b) cells, but not CD19+CD23-CD5+ (B-1a) cells, compared to NGT and IGR subjects. The proportion of CD19+CD5+CD1dhi (B10) cells did not differ between the IGR or T2D group and NGT controls. Of note, HbA1c and triglyceride showed a positive correlation with B-2 cells but an inverse correlation with B-1 and B-1b cells, which were independently associated with the presence of T2D by logistic regression models. In summary, this study shows an unbalanced proinflammatory phenotype of B-cell subsets correlated with glycemia and lipidemia in patients with T2D. Our data provide new insight into chronic activation of the immune system and subclinical inflammation in T2D. Further prospective studies are warranted to confirm our observations.

In Situ Mass Spectrometric Monitoring of the Dynamic Electrochemical Process at the Electrode-Electrolyte Interface: a SIMS Approach.

The in situ molecular characterization of reaction intermediates and products at electrode-electrolyte interfaces is central to mechanistic studies of complex electrochemical processes, yet a great challenge. The coupling of electrochemistry (EC) and mass spectrometry (MS) has seen rapid development and found broad applicability in tackling challenges in analytical and bioanalytical chemistry. However, few truly in situ and real-time EC-MS studies have been reported at electrode-electrolyte interfaces. An innovative EC-MS coupling method named in situ liquid secondary ion mass spectrometry (SIMS) was recently developed by combining SIMS with a vacuum compatible microfluidic electrochemical device. Using this novel capability, we report the first in situ elucidation of the electro-oxidation mechanism of a biologically significant organic compound, ascorbic acid (AA), at the electrode-electrolyte interface. The short-lived radical intermediate was successfully captured, which had not been detected directly before. Moreover, we demonstrated the power of this new technique in real-time monitoring of the formation and dynamic evolution of electrical double layers at the electrode-electrolyte interface. This work suggests further promising applications of in situ liquid SIMS in studying more complex chemical and biological events at the electrode-electrolyte interface.

Compartmentalized microchannel array for high-throughput analysis of single cell polarized growth and dynamics.

Interrogating polarized growth is technologically challenging due to extensive cellular branching and uncontrollable environmental conditions in conventional assays. Here we present a robust and high-performance microfluidic system that enables observations of polarized growth with enhanced temporal and spatial control over prolonged periods. The system has built-in tunability and versatility to accommodate a variety of scientific applications requiring precisely controlled environments. Using the model filamentous fungus, Neurospora crassa, our microfluidic system enabled direct visualization and analysis of cellular heterogeneity in a clonal fungal cell population, nuclear distribution and dynamics at the subhyphal level, and quantitative dynamics of gene expression with single hyphal compartment resolution in response to carbon source starvation and exchange. Although the microfluidic device is demonstrated on filamentous fungi, the technology is immediately extensible to a wide array of other biosystems that exhibit similar polarized cell growth, with applications ranging from bioenergy production to human health.

Argon Cluster Sputtering Source for ToF-SIMS Depth Profiling of Insulating Materials: High Sputter Rate and Accurate Interfacial Information.

The use of an argon cluster ion sputtering source has been demonstrated to perform superiorly relative to traditional oxygen and cesium ion sputtering sources for ToF-SIMS depth profiling of insulating materials. The superior performance has been attributed to effective alleviation of surface charging. A simulated nuclear waste glass (SON68) and layered hole-perovskite oxide thin films were selected as model systems because of their fundamental and practical significance. Our results show that high sputter rates and accurate interfacial information can be achieved simultaneously for argon cluster sputtering, whereas this is not the case for cesium and oxygen sputtering. Therefore, the implementation of an argon cluster sputtering source can significantly improve the analysis efficiency of insulating materials and, thus, can expand its applications to the study of glass corrosion, perovskite oxide thin film characterization, and many other systems of interest.

Counterflow isotachophoresis in a monolithic column.

This study describes stationary counterflow isotachophoresis (ITP) in a poly(acrylamide-co-N,N'-methylenebisacrylamide) monolithic column as a means for improving ITP processing capacity and reducing dispersion. The flow profile in the monolith was predicted using COMSOL's Brinkman Equation application mode, which revealed that the flow profile was mainly determined by monolith permeability. As monolith permeability decreases, the flow profile changes from a parabolic shape to a plug shape. An experimental monolithic column was prepared in a fused-silica capillary using an ultraviolet-initiated polymerization method. A monolithic column made from 8% (wt.) monomer was chosen for the stationary counterflow ITP experiments. Counterflow ITP in the monolithic column showed undistorted analyte zones with significantly reduced dispersion compared to the severe dispersion observed in an open capillary. Particularly, for r-phycoerythrin focused by counterflow ITP, its zone width in the monolithic column was only one-third that observed in an open capillary. These experiments demonstrate that stationary counterflow ITP in monoliths can be a robust and practical electrofocusing method.

In situ molecular imaging of a hydrated biofilm in a microfluidic reactor by ToF-SIMS.

A novel microfluidic reactor for biofilm growth and in situ characterization using time-of-flight secondary ion mass spectrometry (ToF-SIMS) was constructed to enable two-dimensional chemical imaging of hydrated biofilms. We demonstrate the detection of characteristic fatty acid fragments from microfluidic reactor-grown biofilms and illustrate advantages of hydrated-state ToF-SIMS imaging.

ITP of lanthanides in microfluidic PMMA chip.

An ITP separation of eight lanthanides on a serpentine PMMA microchip with a tee junction and a 230-mm-long serpentine channel is described. The cover of the PMMA chip is 175 µm thick so that a C(4) D in microchip mode can be used to detect the lanthanides as they migrate through the microchannel. Acetate and α-hydroxyisobutyric acid are used as complexing agents to increase the electrophoretic mobility difference between the lanthanides. Eight lanthanides are concentrated within ∼ 6 min by ITP in the microchip using 10 mM ammonium acetate at pH 4.5 as the leading electrolyte and 10 mM acetic acid at ∼ pH 3.0 as the terminating electrolyte. In addition, a 2D numerical simulation of the lanthanides undergoing ITP in the microchip is compared with experimental results using COMSOL Multiphysics v4.3a.

In situ chemical probing of the electrode-electrolyte interface by ToF-SIMS.

A portable vacuum interface allowing direct probing of the electrode-electrolyte interface was developed. A classical electrochemical system consisting of a gold working electrode, platinum counter electrode, platinum reference electrode, and potassium iodide electrolyte was used to demonstrate real-time observation of the gold iodide adlayer on the electrode and chemical species as a result of redox reactions using cyclic voltammetry (CV) and time-of-flight secondary ion mass spectrometry (ToF-SIMS, a vacuum-based surface technique) simultaneously. This microfluidic electrochemical probe provides a new way to investigate the surface region with adsorbed molecules and the region of the diffused layer with chemical speciation in liquids in situ by surface sensitive techniques.

Isotachophoresis with counterflow in an open capillary: computer simulation and experimental validation.

The purpose of applying a countercurrent flow to isotachophoretic migration is to increase the effective separation channel length during ITP. However, severe dispersion induced by applying a counterflow can be detrimental to ITP. This paper uses numerical simulations in a 2D axisymmetric domain to investigate the dispersion caused by a parabolic counterflow in open-capillary ITP. Counterflow in these simulations was generated by applying a back pressure to stop the isotachophoretic stack, i.e., forming stationary ITP zones. It is found that dispersion is strongly related to analyte molecular diffusivity: R-phycoerythrin, due to its small diffusivity, showed ~20-fold increase in zone width in stationary counterflow ITP, compared to ITP in the absence of counterflow, while fluorescein only had ~10% increase in zone width under similar operating conditions. Applying the Taylor-Aris dispersion formula in counterflow ITP simulations provided only a rough estimate of the dispersion, e.g., overestimation of analyte zone widths. Experiments on counterflow ITP were conducted in a silica capillary that was covalently and dynamically coated to exclude electroosmosis effect. The counterflow was generated by adjusting the relative height of the fluids in the two reservoirs at the capillary ends. Good qualitative agreement between simulations and experiments was found.