Efficacy and safety of Dupilumab in Chinese elderly patients with Atopic dermatitis: a Real-World study.

Introduction With the aging of the population in China, the prevalence of atopic dermatitis (AD) is high in the elderly patients. These patients usually have more comorbidities and they need more effective and safer treatments. Dupilumab is an anti-interleukin-4 (IL-4) receptor monoclonal antibody which was approved for the treatment of moderate to severe AD. Objective To investigate the efficacy and safety of dupilumab in elderly patients with moderate to severe AD. Methods A real world retrospective study was conducted. Elderly patients (60 years or older) with moderate-to-severe AD who treated with dupilumab were included. Eczema Area and Severity Index (EASI) score, Peak Pruritus Numerical Rating Scale (PP-NRS), EASI-50, EASI-75 and EASI-50 were evaluated. The efficacy in subgroups was also investigated. Results Fifty-eight patients were enrolled. The EASI score and PP-NRS score were significantly reduced at week 4, 16, 28 and 52 during dupilumab treatments. 91.2% and 79.4% of the patients achieved EASI-50 and EASI-75 at week 16, respectively. This results sustained across 52 weeks. 95.8% and 87.5% patients achieved EASI-50 and EASI-75 at week 52, respectively. Adverse events were reported in 10 (17.2%) patients and no severe adverse event was reported. Male，older age and moderate AD (EASI＜21) was related to better efficacy of dupilumab. Conclusions This study demonstrated that dupilumab is an effective and safe treatment in elderly patients with AD.

Effective Manipulation of a Colossal Second-Order Transverse Response in an Electric-Field-Tunable Graphene Moiré System.

The second-order nonlinear transport illuminates a frequency-doubling response emerging in quantum materials with a broken inversion symmetry. The two principal driving mechanisms, the Berry curvature dipole and the skew scattering, reflect various information including ground-state symmetries, band dispersions, and topology of electronic wave functions. However, effective manipulation of them in a single system has been lacking, hindering the pursuit of strong responses. Here, we report on the effective manipulation of the two mechanisms in a single graphene moiré superlattice, AB-BA stacked twisted double bilayer graphene. Most saliently, by virtue of the high tunability of moiré band structures and scattering rates, a record-high second-order transverse conductivity ∼ 510 µm S V-1 is observed, which is orders of magnitude higher than any reported values in the literature. Our findings establish the potential of electrically tunable graphene moiré systems for nonlinear transport manipulations and applications.

Unbalanced Aryl Hydrocarbon Receptor Expression in Peripheral and Lesional T Cell Subsets of Atopic Dermatitis.

Background and Objective: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which is involved in the pathogenesis of a variety of skin diseases such as atopic dermatitis (AD). In this study, we aimed to study the AhR-expressing cells in T helper 17 (Th17), T helper 22 (Th22), regulatory T cells (Treg) and B cells in peripheral blood and in AD skin lesions. Methods: Twenty AD patients defined according to the Chinese criteria of atopic dermatitis and eighteen healthy subjects were included in our study. The AhR-expressing Th17, Th22, Treg and total B cells in peripheral blood were measured by flow cytometry. The AhR+ Th17 cells and AhR+ Th22 cells in AD skin lesions were measured by immunofluorescence. The mRNA of AhR, interleukin (IL)-22, IL-17A, IL-10, Foxp3, RORγT and TGF-ß in peripheral blood mononuclear cells (PBMCs) was measured by real-time quantitative polymerase chain reaction. Results: The expression of AhR in peripheral CD4+ T cells, Th22 cells, Treg cells and total B cells was significantly increased in AD. AhR+IL-17A+ and AhR+IL-22+ lymphocytes were also increased in AD skin lesions. The mRNA levels of AhR, IL-22 and IL-17A in PBMCs in AD patients were significantly higher. AhR mRNA levels in PBMCs positively correlated with peripheral basophil count, peripheral eosinophil count and mRNA levels of IL-22. Conclusion: AhR was highly expressed in subpopulations of CD4+ T cells in peripheral blood and skin lesions of AD, suggesting that AhR might contribute to the pathogenesis of AD.

Volume overload impedes the maturation of sarcomeres and T-tubules in the right atria: a potential cause of atrial arrhythmia following delayed atrial septal defect closure.

Introduction: Adult patients with atrial septal defects (ASD), the most common form of adult congenital heart disease, often die of arrhythmias, and the immaturity of cardiomyocytes contributes significantly to arrhythmias. ASD typically induces a left-to-right shunt, which then leads to the right atrium (RA) volume overload (VO). Whether or not VO contributes to RA cardiomyocyte immaturity and thereby causes arrhythmias in adult patients with ASD remains unclear. Methods: Here, we developed the first neonatal RA VO mouse model by creating a fistula between the inferior vena cava and abdominal aorta on postnatal day 7. RA VO was confirmed by increases in the mean flow velocity, mean pressure gradient, and velocity time integral across the tricuspid valve, and an increase in the RA diameter and RA area middle section. Results: We found that VO decreased the regularity and length of sarcomeres, and decreased the T-element density, regularity, and index of integrity of T-tubules in RA cardiomyocytes, suggesting that the two most important maturation hallmarks (sarcomere and T-tubules) of RA cardiomyocytes were impaired by VO. Accordingly, the calcium handling capacity of cardiomyocytes from postnatal day 21 (P21) RA was decreased by VO. VO caused a significant elongation of the PR interval. The expression of connexin 43 (Cx43) was decreased in RA VO. Moreover, gene ontology (GO) analysis of the downregulated genes in RA demonstrated that there was an abundance of enriched terms associated with sarcomeres and T-tubules exposed to VO. The results were further verified by qRT-PCR. Conclusions: In conclusion, the first neonatal RA VO mouse model was developed; furthermore, using this neonatal RA VO mouse model, we revealed that VO impeded RA sarcomere and T-tubule maturation, which may be the underlying causes of atrial arrhythmias in adult patients with ASD.

Novel Calculation Method for the Shear Capacity of a UHPC Beam with and without Web Reinforcement.

To accurately predict the shear-bearing capacity of UHPC beams, it is crucial to quantify the shear contribution of the fiber bridging effect and UHPC compression zone. Nevertheless, it should be noted that the shear contribution of UHPC in the compression zone is not fully considered in most existing calculation methods, and the probability distribution of fibers within the matrix is also not taken into full account, which reduces the calculation accuracy of the shear bearing capacity of UHPC beams. In this paper, a UHPC beam shear test database containing 247 samples was created, and the influencing factors on the shear capacity of UHPC beams, such as the shear span ratio, the web reinforcement ratio, and the volume fraction of steel fiber, were analyzed. It was found that the ratio of cracking load to ultimate load ranges from 0.2 to 0.6, and the failure in the compression zone of UHPC beams can be divided into diagonal tension failure and shear compression failure. Based on the failure mechanism of the compression zone, considering the contribution of fiber micro tensile strength, a formula for calculating the shear-bearing capacity of UHPC beams with and without web reinforcement was proposed. Verified by experimental data, the proposed formula accurately predicts the shear-bearing capacity of UHPC beams. In comparison with other shear capacity formulas in current design codes, the proposed formula in this paper provides a higher prediction accuracy.

Hhex and Prox1a synergistically dictate the hepatoblast to hepatocyte differentiation in zebrafish.

The specification of endoderm cells to prospective hepatoblasts is the starting point for hepatogenesis. However, how a prospective hepatoblast gains the hepatic fate remains elusive. Previous studies have shown that loss-of-function of either hhex or prox1a alone causes a small liver phenotype but without abolishing the hepatocyte differentiation, suggesting that absence of either Hhex or Prox1a alone is not sufficient to block the hepatoblast differentiation. Here, via genetic studies of the zebrafish two single (hhex-/- and prox1a-/-) and one double (hhex-/-prox1a-/-) mutants, we show that simultaneous loss-of-function of the hhex and prox1a two genes does not block the endoderm cells to gain the hepatoblast potency but abolishes the hepatic differentiation from the prospective hepatoblast. Consequently, the hhex-/-prox1a-/- double mutant displays a liverless phenotype that cannot be rescued by the injection of bmp2a mRNA. Taken together, we provide strong evidences showing that Hhex teams with Prox1a to act as a master control of the differentiation of the prospective hepatoblasts towards hepatocytes.

Interaction mechanism of carotenoids and polyphenols in mango peels.

In this study, carotenoids and polyphenols were demonstrated to be the major active substances in the crude pigment extracts (CPE) of mango peels, accounting for 0.26 mg/g and 0.15 mg/g, respectively. The interactions between carotenoids and polyphenols in CPE was observed, as evidenced by that polyphenols significantly improved the antioxidant activity and storage stability of carotenoids in the CPE. Meanwhile, scanning electron microscopy showed that polyphenols are tightly bound to carotenoids. To further elucidate the interaction mechanism, the monomers of carotenoids and polyphenols were identified by HPLC and LC-MS analysis. Lutein (203.85 µg/g), ß-carotene (41.40 µg/g), zeaxanthin (4.20 µg/g) and α-carotene (1.50 µg/g) were authenticated as the primary monomers of carotenoids. Polyphenols were mainly consisted of gallic acid (95.10 µg/g), quercetin-3-ß-glucoside (29.10 µg/g), catechin (11.85 µg/g) and quercetin (11.55 µg/g). The interaction indexes between carotenoid and polyphenol monomer of CPE were calculated. The result indicated that lutein and gallic acid showed the greatest synergistic effect on the scavenging of DPPH and ABTS radical, suggesting the interaction between carotenoids and polyphenols in CPE was mainly caused by lutein and gallic acid. Molecular dynamics simulations and thermodynamic parameters analysis demonstrated that hydrogen bonding, electrostatic interactions, and van der Waals forces played dominant roles in the interaction between lutein and gallic acid, which was confirmed by Raman and X-ray diffraction. These results provided a new perspective on the interaction mechanism between carotenoids and polyphenols, which offered a novel strategy for the enhancement of the activities and stability of bioactive substances.

Impact of heat on emergency hospital admission in Texas: geographic and racial/ethnic disparities.

BACKGROUND: Studies exploring the racial/ethnicity disparity of the impact of heat on hospital admission are notably limited, especially in Texas, a state with a diverse population and consistently ranking among the top ten U.S. states for heat-related deaths per capita from 2018 to 2020. OBJECTIVE: Our objective is to determine the correlation between elevated temperatures and emergency hospital admissions for various causes and age groups across 12 Metropolitan Statistical Areas(MSAs) in Texas. Additionally, we aim to investigate health inequalities in the five largest MSAs in Texas between 2004 and 2013. METHODS: We used MSA-level hospital admission and weather data to estimate the relationship between heat and emergency hospital admissions. We applied a Generalized Additive Model and random effects meta-analysis to calculate MSA-specific associations and overall correlation, repeating the analysis for age groups and specific causes of admission. We also investigated health disparities across racial and ethnic groups and performed a sensitivity analysis. RESULTS: The results showed that a 1 °C increase in temperature was associated with a 0.50% (95% CI [0.38%, 0.63%]) increase in all-cause emergency hospital admissions. Heat's impact on hospital admissions varied among age groups and causes, with children under 6 years showing the highest effect estimate (0.64% (95% CI [0.32%,0.96%])). Statistically significant associations were found for Cardiovascular Diseases (0.27% (95% CI [0.07%,0.47%])), Ischemic Heart Diseases (0.53% (95% CI [0.15%,0.92%])), Pneumonia (0.70% (95% CI [0.25%,1.16%])), and Respiratory Diseases (0.67% (95% CI [0.18%,1.17%])). Health disparities were found among racial and ethnic groups in the five largest MSAs. IMPACT STATEMENT: Studies exploring the impact of heat on hospital admission in Texas are notably limited. Our research provided a comprehensive examination of the connection between heat and emergency hospital admissions throughout Texas. Furthermore, we are the first to examine racial/ethnic disparities, identifying African American and Hispanic groups as disproportionately affected. These insights provide valuable insights for policymakers to allocate resources and implement strategies to mitigate the negative consequences of rising temperatures.

Suppression of PGE2/EP2 signaling alleviates Hirschsprung disease by upregulating p38 mitogen-activated protein kinase activity.

Hirschsprung disease (HSCR) is a congenital disorder caused by the failure of enteric neural crest cells (ENCCs) to colonize the distal bowel, resulting in absence of enteric nervous system. While a range of molecules and signaling pathways have been found to contribute to HSCR development, the risk factors and pathogenesis of this disease in many patients remain unknown. We previously demonstrated that increased activity of the prostaglandin E2 (PGE2)/PGE2 receptor subtype EP2 pathway can be a risk factor for HSCR. In this study, an Ednrb-deficient mouse model of HSCR was generated and used to investigate if PGE2/EP2 pathway could be a potential therapeutic target for HSCR. We found that downregulation of PGE2/EP2 signaling by siRNA-mediated ablation of a PGE2 synthase or pharmacologic blockage of EP2 enhanced ENCC colonization in the distal bowel of Ednrb-/- mice and alleviated their HSCR-like symptoms. Furthermore, blockage of EP2 was shown to promote ENCC migration through upregulating p38 mitogen-activated protein kinase activity, which was downregulated in the colon of Ednrb-/- mice and in the distal aganglionic bowel of HSCR patients. These data provide evidence that maternal exposure during embryonic development to an environment with dysregulated activation of the PGE2/EP2 pathway may predispose genetically susceptible offspring to HSCR, and avoidance or early disruption of maternal events (e.g. inflammation) that possibly enhance PGE2/EP2 signaling during pregnancy would reduce the occurrence and severity of this disease. KEY MESSAGES : Knockdown of PTGES alleviates HSCR severity in Ednrb-/- mice. Blockage of EP2-mediated PGE2 signaling alleviates HSCR severity in Ednrb-/- mice. Blockage of EP2-mediated PGE2 signaling promotes ENCC migration via enhancing p38 activity.

De novo transcriptome assembly and metabolomic analysis of three tissue types in Cinnamomum cassia.

Objective: The barks, leaves, and branches of Cinnamomum cassia have been historically used as a traditional Chinese medicine, spice, and food preservative, in which phenylpropanoids are responsible compounds. However phenylpropanoid biosynthesis pathways are not clear in C. cassia. We elucidated the pathways by descriptive analyses of differentially expressed genes related to phenylpropanoid biosynthesis as well as to identify various phenylpropanoid metabolites. Methods: Chemical analysis, metabolome sequencing, and transcriptome sequencing were performed to investigate the molecular mechanisms underlying the difference of active components content in the barks, branches and leaves of C. cassia. Results: Metabolomic analysis revealed that small amounts of flavonoids, coumarine, and cinnamaldehyde accumulated in both leaves and branches. Transcriptome analysis showed that genes associated with phenylpropanoid and flavonoid biosynthesis were downregulated in the leaves and branches relative to the barks. The observed differences in essential oil content among the three tissues may be attributable to the differential expression of genes involved in the phenylpropanoid and flavonoid metabolic pathways. Conclusion: This study identified the key genes in the phenylpropanoid pathway controling the flavonoid, coumarine, and cinnamaldehyde contents in the barks, branches and leaves by comparing the transcriptome and metabolome. These findings may be valuable in assessing phenylpropanoid and flavonoid metabolites and identifying specific candidate genes that are related to the synthesis of phenylpropanoids and flavonoids in C. cassia.

A survey of drug-target interaction and affinity prediction methods via graph neural networks.

The tasks of drug-target interaction (DTI) and drug-target affinity (DTA) prediction play important roles in the field of drug discovery. However, biological experiment-based methods are time-consuming and expensive. Recently, computational-based approaches have accelerated the process of drug-target relationship prediction. Drug and target features are represented in structure-based, sequence-based, and graph-based ways. Although some achievements have been made regarding structure-based representations and sequence-based representations, the acquired feature information is not sufficiently rich. Molecular graph-based representations are some of the more popular approaches, and they have also generated a great deal of interest. In this article, we provide an overview of the DTI prediction and DTA prediction tasks based on graph neural networks (GNNs). We briefly discuss the molecular graphs of drugs, the primary sequences of target proteins, and the graph reSLBpresentations of target proteins. Meanwhile, we conducted experiments on various fundamental datasets to substantiate the plausibility of DTI and DTA utilizing graph neural networks.

Discovery of novel benzimidazole derivatives as potent potassium-competitive acid blockers for the treatment of acid-related diseases.

H+, K+-ATPase, as the most critical enzyme in gastric acid secretion, has long been an attractive target for the treatment of acid-related diseases. In this study, a series of benzimidazole derivatives were designed and synthesized through conformational restriction and skeleton hopping strategies by using vonoprazan as the lead compound. Among them, compounds A12 (IC50 = 9.32 µM) and A18 (IC50 = 5.83 µM) showed better inhibition at the enzyme level. In addition, gastric acid secretion inhibition was assessed in vivo, and the results showed that A12 and A18 significantly inhibited basal gastric acid secretion, 2-deoxy-d-glucose (2DG) stimulated gastric acid secretion and histamine-stimulated gastric acid secretion. In further in vitro metabolic experiments, A12 and A18 demonstrated excellent stability and low toxicity. Pharmacokinetic studies showed that the p.o. and i.v. half-lives of A18 were 3.21 h and 8.67 ± 1.15 h, respectively. In summary, A18 might be a novel and effective potassium-competitive acid blocker, and this study provides strong support for it use in the treatment of acid-related diseases.

Effects of Florfenicol on Intestinal Histology, Apoptosis and Gut Microbiota of Chinese Mitten Crab (Eriocheir sinensis).

Excessive use of antibiotics in aquaculture causes residues in aquatic animal products and harms human health. However, knowledge of florfenicol (FF) toxicology on gut health and microbiota and their resulting relationships in economic freshwater crustaceans is scarce. Here, we first investigated the influence of FF on the intestinal health of Chinese mitten crabs, and then explored the role of bacterial community in FF-induced intestinal antioxidation system and intestinal homeostasis dysbiosis. A total of 120 male crabs (48.5 ± 4.5 g) were experimentally treated in four different concentrations of FF (0, 0.5, 5 and 50 µg/L) for 14 days. Responses of antioxidant defenses and changes of gut microbiota were assessed in the intestine. Results revealed that FF exposure induced significant histological morphology variation. FF exposure also enhanced immune and apoptosis characteristics in the intestine after 7 days. Moreover, antioxidant enzyme catalase activities showed a similar pattern. The intestinal microbiota community was analyzed based on full-length 16S rRNA sequencing. Only the high concentration group showed a marked decrease in microbial diversity and change in its composition after 14 days of exposure. Relative abundance of beneficial genera increased on day 14. These findings illustrate that exposure to FF could cause intestinal dysfunction and gut microbiota dysbiosis in Chinese mitten crabs, which provides new insights into the relationship between gut health and gut microbiota in invertebrates following exposure to persistent antibiotics pollutants.

Impaired cell-cell communication and axon guidance because of pulmonary hypoperfusion during postnatal alveolar development.

BACKGROUND: Pulmonary hypoperfusion is common in children with congenital heart diseases (CHDs) or pulmonary hypertension (PH) and causes adult pulmonary dysplasia. Systematic reviews have shown that some children with CHDs or PH have mitigated clinical outcomes with COVID-19. Understanding the effects of pulmonary hypoperfusion on postnatal alveolar development may aid in the development of methods to improve the pulmonary function of children with CHDs or PH and improve their care during the COVID-19 pandemic, which is characterized by cytokine storm and persistent inflammation. METHODS AND RESULTS: We created a neonatal pulmonary hypoperfusion model through pulmonary artery banding (PAB) surgery at postnatal day 1 (P1). Alveolar dysplasia was confirmed by gross and histological examination at P21. Transcriptomic analysis of pulmonary tissues at P7(alveolar stage 2) and P14(alveolar stage 4) revealed that the postnatal alveolar development track had been changed due to pulmonary hypoperfusion. Under the condition of pulmonary hypoperfusion, the cell-cell communication and axon guidance, which both determine the final number of alveoli, were lost; instead, there was hyperactive cell cycle activity. The transcriptomic results were further confirmed by the examination of axon guidance and cell cycle markers. Because axon guidance controls inflammation and immune cell activation, the loss of axon guidance may explain the lack of severe COVID-19 cases among children with CHDs or PH accompanied by pulmonary hypoperfusion. CONCLUSIONS: This study suggested that promoting cell-cell communication or supplementation with guidance molecules may treat pulmonary hypoperfusion-induced alveolar dysplasia, and that COVID-19 is less likely to cause a cytokine storm in children with CHD or PH accompanied by pulmonary hypoperfusion.

mascRNA alleviates STING-TBK1 signaling-mediated immune response through promoting ubiquitination of STING.

mascRNA (MALAT1-associated small cytoplasmic RNA) is a tRNA-like cytoplasmic small noncoding RNA whose function remains elusive. We previously revealed that this small RNA negatively regulates TLR4/2-triggered proinflammatory response while positively regulates TLR3-induced antiviral response. Here, we investigated whether and how mascRNA influences the stimulator of interferon genes (STING) signaling-triggered immune response. We found that overexpression of mascRNA inhibited the expression of type I interferon (IFN) genes and proinflammatory cytokines in response to cytosolic DNA stimulation; meanwhile, the abundance of STING protein and the level of phosphorylated TBK1 and STAT1 was decreased. By contrast, depletion of mascRNA potentiated the expression of type I IFNs, increased STING protein abundance, and promoted STING-mediated phosphorylation of TBK1 and STAT1 in response to DNA stimulation. In a mouse model of DNA-induced lung injury, exogenous mascRNA mitigated the antiviral response and the severity of lung inflammation. Mechanically, mascRNA was found to promote STING for K48-linked ubiquitination and degradation in macrophages both with and without cytosolic DNA stimulation. Hence, mascRNA suppresses STING-TBK1 signaling-mediated innate immunity through promoting proteasomal degradation of STING, and this tRNA-like small RNA holds promise for the treatment of certain inflammatory diseases such as COVID-19 where aberrant STING signaling drives type I IFN immunopathology.

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.

Ability of the Right Ventricle to Serve as a Systemic Ventricle in Response to the Volume Overload at the Neonatal Stage.

BACKGROUND: In children with hypoplastic left heart syndrome (HLHS), volume overload (VO) is inevitable, and the right ventricle (RV) pumps blood into the systemic circulation. Understanding the molecular differences and their different responses to VO between the RV and left ventricle (LV) at the neonatal and highly plastic stages may improve the long-term management of children with HLHS. METHODS AND RESULTS: A neonatal rat ventricular VO model was established by the creation of a fistula between the inferior vena cava and the abdominal aorta on postnatal day 1 (P1) and confirmed by echocardiographic and histopathological analyses. Transcriptomic analysis demonstrated that some of the major differences between a normal neonatal RV and LV were associated with the thyroid hormone and insulin signaling pathways. Under the influence of VO, the levels of insulin receptors and thyroid hormone receptors were significantly increased in the LV but decreased in the RV. The transcriptomic analysis also demonstrated that under the influence of VO, the top two common enriched pathways between the RV and LV were the insulin and thyroid hormone signaling pathways, whereas the RV-specific enriched pathways were primarily associated with lipid metabolism and arrhythmogenic right ventricular cardiomyopathy (ARVC); further, the LV-specific enriched pathways were primarily associated with nucleic acid metabolism and microRNAs in cancer. CONCLUSIONS: Insulin and thyroid hormones may play critical roles in the differences between a neonatal RV and LV as well as their common responses to VO. Regarding the isolated responses to VO, the RV favors an ARVC change and the LV favors a reduction in microRNAs in cancer. The current study suggests that insulin, thyroid hormone, and cancer-associated microRNAs are potential therapeutic targets that should be explored by basic science studies to improve the function of the RV to match that of the LV.

A Comparison for Type 2 Cytokines and Lesional Inflammatory Infiltrations in Bullous Pemphigoid and Atopic Dermatitis.

Background: Bullous pemphigoid (BP) and atopic dermatitis (AD) are both type 2 inflammatory skin diseases with similar clinical features. Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine which is upregulated in AD. However, the expression of TSLP in BP and the correlation between TSLP and inflammatory infiltrations have not been fully studied. Objective: To characterize the serum Th2 cytokines level and Th2 inflammatory cell infiltrations in BP and AD. To study TSLP levels in serum, blister fluids and expression in lesional skin in patients with BP and AD. Methods: TSLP level in serum and blister fluids was measured by enzyme-linked immunosorbent assay (ELISA). Inflammatory cells (CD4+ T cells, CD8+ T cells, CD1a+ cells, eosinophils and mast cells) were stained immunohistochemically and quantified by image analysis. Results: TSLP level was significantly increased in blister fluids of BP and was highly expressed in lesional skin of BP and AD. Serum levels of IL-6, IL-4, IL-22, IFN-γ and thymic activation regulates chemokines (TARC) were significantly higher in patients with BP and AD than in healthy controls. CD4+ T cells, CD8+ T cells and CD1a+ cells were significantly more in upper dermis of BP and AD lesions. Eosinophils were found more in BP lesions while mast cells were found more in AD lesions than in healthy controls. A distinct correlation was found between TSLP levels and the intensities of CD4+ T cells, CD1a+ cells infiltrations. Conclusion: TSLP was significantly higher in blister fluids and skin lesions of BP, suggesting that it might contribute to the pathogenesis of BP. BP exhibited a similar type 2 immune response and a slight difference in cells infiltrations with AD.

Spatiotemporal Distribution of HIV Self-testing Kits Purchased on the Web and Implications for HIV Prevention in China: Population-Based Study.

BACKGROUND: HIV self-testing (HIVST) holds great promise for expanding HIV testing. Nonetheless, large-scale data on HIVST behavior are scant. Millions of HIVST kits are sold through e-commerce platforms each year. OBJECTIVE: This study aims to analyze the spatiotemporal distribution of the HIVST kit-purchasing population (HIVSTKPP) in China. METHODS: Deidentified transaction data were retrieved from a leading e-commerce platform in China. A joinpoint regression model was used to examine annual trends of the HIVSTKPP rates by calculating average annual percentage change. Bayesian spatiotemporal analysis was performed to locate hot spots with HIVSTKPP rates. Spatial autocorrelation analysis and space-time cluster analysis were conducted to identify clusters of HIVSTKPP. High-high clusters of HIVSTKPP can be identified by spatial autocorrelation analysis, and high-high clusters indicate that a region and its surrounding region jointly had a higher-than-average HIVSTKPP rate. Spatial regression analysis was used to elucidate the association between the number of HIV testing facilities, urbanization ratio (the proportion of urban population in the total population), and gross domestic product per capita and the HIVSTKPP. RESULTS: Between January 1, 2016, and December 31, 2019, a total of 2.18 million anonymous persons in China placed 4.15 million orders and purchased 4.51 million HIVST kits on the web. In each of these 4 years, the observed monthly size of the HIVSTKPP peaked in December, the month of World AIDS Day. HIVSTKPP rates per 100,000 population significantly increased from 20.62 in 2016 to 64.82 in 2019 (average annual percentage change=48.2%; P<.001). Hot spots were mainly located in municipalities, provincial capitals, and large cities, whereas high-high clusters and high-demand clusters were predominantly detected in cities along the southeast coast. We found positive correlations between a region's number of HIV testing facilities, urbanization ratio, and gross domestic product per capita and the HIVSTKPP. CONCLUSIONS: Our study identified key areas with larger demand for HIVST kits for public health policy makers to reallocate resources and optimize the HIV care continuum. Further research combining spatiotemporal patterns of HIVST with HIV surveillance data is urgently needed to identify potential gaps in current HIV-monitoring practices.