Detecting T-cell receptor clonality in patients with severe atopic dermatitis refractory to dupilumab.

BACKGROUND: Trials and real-life studies demonstrated clinically meaningful improvements of disease activity in the majority of patients with moderate to severe atopic dermatitis (AD) treated with the anti-IL-4RA-antibody dupilumab. However, misdiagnosis or confounding skin diseases in particular cutaneous T-cell lymphoma (CTCL) may lead to inadequate response. OBJECTIVE: To investigate the clinical and pathological features of patients with AD who showed insufficient response to dupilumab. METHODS: We reviewed the medical records of 371 patients treated with dupilumab for severe AD. Insufficient response was defined as failure to achieve an improvement of the eczema area severity index (EASI) of at least 50% (EASI-50) at Week 16 and of 75% (EASI-75) at Week 52. Among 46 patients with insufficient response, 35 patients consented to a re-evaluation including a full physical exam, biopsies and laboratory assessments including immunohistochemistry and T-cell receptor gene rearrangement analysis to differentiate CTCL. RESULTS: Of the 371 patients treated with dupilumab, 46 (12.3%) patients showed insufficient response to dupilumab. Of these, 35 underwent further evaluation, and 19 (54.2% of inadequate responders) were finally diagnosed with mycosis fungoides (MF). In these patients, transition to or addition of conventional MF treatment led to clinical improvements. CONCLUSION: Insufficient response to dupilumab treatment may help uncover early MF on an existing AD background.

Gut microbiome is associated with recurrence-free survival in patients with resected Stage IIIB-D or Stage IV melanoma treated with immune checkpoint inhibitors.

The gut microbiome (GMB) has been associated with outcomes of immune checkpoint blockade therapy in melanoma, but there is limited consensus on the specific taxa involved, particularly across different geographic regions. We analyzed pre-treatment stool samples from 674 melanoma patients participating in a phase-III trial of adjuvant nivolumab plus ipilimumab versus nivolumab, across three continents and five regions. Longitudinal analysis revealed that GMB was largely unchanged following treatment, offering promise for lasting GMB-based interventions. In region-specific and cross-region meta-analyses, we identified pre-treatment taxonomic markers associated with recurrence, including Eubacterium, Ruminococcus, Firmicutes, and Clostridium. Recurrence prediction by these markers was best achieved across regions by matching participants on GMB compositional similarity between the intra-regional discovery and external validation sets. AUCs for prediction ranged from 0.83-0.94 (depending on the initial discovery region) for patients closely matched on GMB composition (e.g., JSD ≤0.11). This evidence indicates that taxonomic markers for prediction of recurrence are generalizable across regions, for individuals of similar GMB composition.

In vitro and in vivo validation of the antiviral effect of hCypA against SARS-CoV-2 via binding to the RBD of spike protein.

The novel coronavirus disease 2019 has stimulated the rapid development of new biological therapeutics to inhibit SARS-CoV-2 infection; however, this remains a challenging task. In a previous study using structural analysis, we revealed that human cyclophilin A inhibits the entry of SARS-CoV-2 into host cells by interfering with the interaction of the receptor-binding domain of the spike protein with angiotensin-converting enzyme 2 on the host cell surface, highlighting its potential for antiviral therapy. For a comprehensive experimental validation, in this study, we verified the antiviral effects of human cyclophilin A against SARS-CoV-2, including its variants, using in vitro assays and experiments on an in vivo mouse model. Human cyclophilin A demonstrated a highly effective antiviral effect, with an 85% survival rate upon SARS-CoV-2 infection. It also reduced viral titers, inflammation in the lungs and brain, and cytokine release in the serum, suggesting a controlled immune response and potentially faster recovery. Overall, our study provides insights into the potential of human cyclophilin A as a therapeutic agent against SARS-CoV-2, which should guide future clinical trials that might provide an additional therapeutic option for patients.

Sociobiome - Individual and neighborhood socioeconomic status influence the gut microbiome in a multi-ethnic population in the US.

Lower socioeconomic status (SES) is related to increased incidence and mortality due to chronic diseases in adults. Association between SES variables and gut microbiome variation has been observed in adults at the population level, suggesting that biological mechanisms may underlie the SES associations; however, there is a need for larger studies that consider individual- and neighborhood-level measures of SES in racially diverse populations. In 825 participants from a multi-ethnic cohort, we investigated how SES shapes the gut microbiome. We determined the relationship of a range of individual- and neighborhood-level SES indicators with the gut microbiome. Individual education level and occupation were self-reported by questionnaire. Geocoding was applied to link participants' addresses with neighborhood census tract socioeconomic indicators, including average income and social deprivation in the census tract. Gut microbiome was measured using 16SV4 region rRNA gene sequencing of stool samples. We compared α-diversity, ß-diversity, and taxonomic and functional pathway abundance by SES. Lower SES was significantly associated with greater α-diversity and compositional differences among groups, as measured by ß-diversity. Several taxa related to low SES were identified, especially an increasing abundance of Prevotella copri and Catenibacterium sp000437715, and decreasing abundance of Dysosmobacter welbionis in terms of their high log-fold change differences. In addition, nativity and race/ethnicity have emerged as ecosocial factors that also influence the gut microbiota. Together, these results showed that lower SES was strongly associated with compositional and taxonomic measures of the gut microbiome, and may contribute to shaping the gut microbiota.

Correction: The emerging role of medical foods and therapeutic potential of medical food-derived exosomes.

[This corrects the article DOI: 10.1039/D3NA00649B.].

Synergistic vesicle-vector systems for targeted delivery.

With the immense progress in drug delivery systems (DDS) and the rise of nanotechnology, challenges such as target specificity remain. The vesicle-vector system (VVS) is a delivery system that uses lipid-based vesicles as vectors for a targeted drug delivery. When modified with target-probing materials, these vesicles become powerful vectors for drug delivery with high target specificity. In this review, we discuss three general types of VVS based on different modification strategies: (1) vesicle-probes; (2) vesicle-vesicles; and (3) genetically engineered vesicles. The synthesis of each VVS type and their corresponding properties that are advantageous for targeted drug delivery, are also highlighted. The applications, challenges, and limitations of VVS are briefly examined. Finally, we share a number of insights and perspectives regarding the future of VVS as a targeted drug delivery system at the nanoscale.

Tuberculous Lymphadenitis in a Patient Treated with Dupilumab: A Case Report.

Tuberculous lymphadenitis is among the most frequent presentations of extrapulmonary tuberculosis; the most common presentation is isolated chronic non-tender lymphadenopathy in young adults without systemic symptoms. Dupilumab is a fully human monoclonal antibody directed against interleukin-4 receptor-α that blocks the synergistic effects of interleukin-4 and interleukin-13 on allergic inflammation. Its well-known adverse events are allergic conjunctivitis, injection site reaction, and dupilumab facial redness. A 32-year-old female with severe atopic dermatitis was treated with dupilumab for 2 months at our clinic. She complained of multiple enlarged palpable lymph nodes on the right side of the neck and inguinal area for 2 months. Laboratory tests showed an increased total eosinophil count and immunoglobulin E level, as well as positive interferon-γ release assays. Radiological examination showed multiple low echoic and heterogeneous well-enhancing lymph nodes in level II, III, IV, and V of the neck. Histological examination revealed caseous necrosis and tuberculoid granuloma. The lymph node enlargements were completely relieved after antituberculosis treatment. The mechanism for the development of tuberculous lymphadenitis in a patient receiving dupilumab is not fully understood yet. In some previous studies, treatment with dupilumab suppressed the expression of genes related not only to T helper 2 and eosinophil response but also to proinflammatory responses. It could not inhibit the intracellular growth of Mycobacterium tuberculosis in macrophages, predisposing them to the development of tuberculous infection. To the best of our knowledge, this is the first report on the development of tuberculosis lymphadenitis in a patient treated with dupilumab.

Very Early Patch Stage of AIDS-related Kaposi Sarcoma: A Case Report.

Kaposi sarcoma (KS) is a vascular and lymphatic neoplasm caused by human herpesvirus 8 (HHV-8). AIDS-related KS has variable clinical courses ranging from mild disease presenting as an incidental finding to severe disease presenting as an aggressively progressing neoplasm that can lead to poor prognosis or even death. Typical clinical manifestation of KS is known as multiple cutaneous lesions on the extremities, trunk, and face with mucosal involvement. A 46-year-old male with AIDS complained of an erythematous patch on the right forearm which appeared 5 months ago. For a year, he was treated with antiretroviral drugs for AIDS. Physical examination revealed a 2.5-cm solitary erythematous patch only on the right forearm. Laboratory data revealed human immunodeficiency virus (HIV)-1 RNA of less than 40 copies/ml and a CD4 cell count of 264 cells/mm3. Histological examination revealed numerous slit-like spaces and vascular proliferation with primitive blood vessels dissecting between the collagen bundles and the dermis. Immunohistochemical staining showed positive HHV-8 nuclear staining of spindle cells. The histological features and positive HHV-8 immunohistochemical stain were consistent with the diagnosis of early patch stage of AIDS-related KS. KS can readily be misdiagnosed in early patch stage even by experienced clinicians, which leads to requirement of pathologic determination. On close inspection, it can be distinguished from other mimickers by its distinctive histologic features and immunohistochemical staining for HHV-8. Therefore, in cases of HIV-positive patients with clinically or histologically vascular-appearing mucocutaneous lesions, KS should be considered as a possible differential diagnosis.

Pathogenic Factors and Recent Study on the Rapid Detection of Shiga Toxin-Producing Escherichia coli (STEC).

This comprehensive review delves into the pathogenicity and detection of Shiga Toxin-Producing Escherichia coli (STEC), shedding light on its various genetic and clinical manifestations. STEC originating from E. coli acquires pathogenicity through mobility and genetic elements. The pathogenicity of STEC is explored in terms of clinical progression, complications, and key toxins such as Shiga toxin (Stx). Stx1 and Stx2 are two distinct Stx types exhibiting different toxicities, with Stx2 often associated with severe diseases. This review also delves into Subtilase cytotoxin, an additional cytotoxin produced by some STEC strains. Pathogenic mechanisms of STEC, such as attaching and effacing intestinal lesions, are discussed, with a focus on roles of genetic factors. Plasmids in STEC can confer unique pathogenicity. Hybridization with other pathogenic E. coli can create more lethal pathogens. This review covers a range of detection methods, ranging from DNA amplification to antigen detection techniques, emphasizing the need for innovative approaches to improve the sensitivity and speed of STEC diagnosis. In conclusion, understanding diverse aspects of STEC pathogenicity and exploring enhanced diagnostic methods are critical to addressing this foodborne pathogen effectively. Pathology of Shiga toxin toxicity. STEC-derived Shiga toxin consists of one A subunit and five B subunits. Pathological symptoms of the disease can progress to HUS within two weeks after the onset of diarrhea. Shiga toxin intoxication is also associated with many complications, such as neurological and cardiac complications. This figure was reconstructed based on data from Bruyand et al.

The emerging role of medical foods and therapeutic potential of medical food-derived exosomes.

Medical food is consumed for the purpose of improving specific nutritional requirements or disease conditions, such as inflammation, diabetes, and cancer. It involves partial or exclusive feeding for fulfilling unique nutritional requirements of patients and is different from medicine, consisting of basic nutrients, such as polyphenols, vitamins, sugars, proteins, lipids, and other functional ingredients to nourish the patients. Recently, studies on extracellular vesicles (exosomes) with therapeutic and drug carrier potential have been actively conducted. In addition, there have been attempts to utilize exosomes as medical food components. Consequently, the application of exosomes is expanding in different fields with increasing research being conducted on their stability and safety. Herein, we introduced the current trends of medical food and the potential utilization of exosomes in them. Moreover, we proposed Medi-Exo, a exosome-based medical food. Furthermore, we comprehensively elucidate various disease aspects between medical food-derived exosomes (Medi-Exo) and therapeutic natural bionanocomposites. This review highlights the therapeutic challenges regarding Medi-Exo and its potential health benefits.

Synergistic outcomes of Chlorella-bacterial cellulose based hydrogel as an ethylene scavenger.

Increasing the freshness of vegetables requires the elimination of ethylene, which can be done through chemical methods. However, the development of eco-friendly approaches is required for environmental reasons. Chlorella vulgaris (C. vulgaris) was selected as a new biological material for demonstrating an excellent performance in ethylene removal. To support C. vulgaris, bacterial cellulose (BC) produced by Gluconacetobacter hansenii (G. hansenii) was chosen due to its high water content and biodegradability. To increase BC productivity, UV-induced mutant G. hansenii was isolated, and they produced high yields of BC (9.80 ±â€¯0.52 g/L). Furthermore, comparative transcriptome analysis revealed metabolic flux changes toward UDP-glucose accumulation and enhanced BC production. BC-based hydrogels (BC hydrogels) were successfully prepared using a 2.4 % carboxymethyl cellulose (CMC) and 1 % agar mixture. We used Chlorella-BC hydrogels as an ethylene scavenger, which reduced 90 % of ethylene even when the immobilized C. vulgaris was preserved for 14 days at room temperature without media supplementation. We demonstrated for the first time the potential of BC hydrogels to integrate C. vulgaris as a sustainable ethylene absorber for green food packaging and biomass technology.

Pneumatically Driven Microfluidic Platform and Fully Automated Particle Concentration System for the Capture and Enrichment of Pathogens.

In this study, we developed a pneumatically driven microfluidic platform (PDMFP) operated by a fully automated particle concentration system (FAPCS) for the pretreatment of micro- and nano-sized materials. The proposed PDMFP comprises a 3D network with a curved fluidic chamber and channel, five on/off pneumatic valves for blocking fluid flow, and a sieve valve for sequential trapping of microbeads and target particles. Using this setup, concentrated targets are automatically released into an outlet port. The FAPCS mainly comprises solenoid valves, glass reservoirs, a regulator, pressure sensor, main printed circuit board, and liquid crystal display touch panel. All pneumatic valves in the microfluidic platform as well as the working fluids in the glass reservoirs are controlled using FAPCS. The flow rate of the working fluids is measured to demonstrate the sequential programed operation of the proposed pretreatment process using FAPCS. In our study, we successfully achieved rapid and efficient enrichment using PDMFP-FAPCS with fluorescence-labeled Escherichia coli. With pretreatment-10 min for the microbead concentration and 25 min for target binding-almost all the target bacteria could be captured. A total of 526 Gram-negative bacteria were attached to 82 beads, whereas Gram-positive bacteria were attached to only 2 of the 100 beads. Finally, we evaluated the PDMFP-FAPCS for SARS-CoV-2 receptor-binding domain (RBD)-based outer membrane vesicles (OMVs) (RBD-OMVs). Specific probes involved in PDMFP-FAPCS successfully isolated RBD-OMVs. Thus, PDMFP-FAPCS exhibits excellent enrichment of particles, including microbes and nanovesicles, and is an effective pretreatment platform for disease diagnosis and investigation.

A microbial causal mediation analytic tool for health disparity and applications in body mass index.

BACKGROUND: Emerging evidence suggests the potential mediating role of microbiome in health disparities. However, no analytic framework can be directly used to analyze microbiome as a mediator between health disparity and clinical outcome, due to the non-manipulable nature of the exposure and the unique structure of microbiome data, including high dimensionality, sparsity, and compositionality. METHODS: Considering the modifiable and quantitative features of the microbiome, we propose a microbial causal mediation model framework, SparseMCMM_HD, to uncover the mediating role of microbiome in health disparities, by depicting a plausible path from a non-manipulable exposure (e.g., ethnicity or region) to the outcome through the microbiome. The proposed SparseMCMM_HD rigorously defines and quantifies the manipulable disparity measure that would be eliminated by equalizing microbiome profiles between comparison and reference groups and innovatively and successfully extends the existing microbial mediation methods, which are originally proposed under potential outcome or counterfactual outcome study design, to address health disparities. RESULTS: Through three body mass index (BMI) studies selected from the curatedMetagenomicData 3.4.2 package and the American gut project: China vs. USA, China vs. UK, and Asian or Pacific Islander (API) vs. Caucasian, we exhibit the utility of the proposed SparseMCMM_HD framework for investigating the microbiome's contributions in health disparities. Specifically, BMI exhibits disparities and microbial community diversities are significantly distinctive between reference and comparison groups in all three applications. By employing SparseMCMM_HD, we illustrate that microbiome plays a crucial role in explaining the disparities in BMI between ethnicities or regions. 20.63%, 33.09%, and 25.71% of the overall disparity in BMI in China-USA, China-UK, and API-Caucasian comparisons, respectively, would be eliminated if the between-group microbiome profiles were equalized; and 15, 18, and 16 species are identified to play the mediating role respectively. CONCLUSIONS: The proposed SparseMCMM_HD is an effective and validated tool to elucidate the mediating role of microbiome in health disparity. Three BMI applications shed light on the utility of microbiome in reducing BMI disparity by manipulating microbial profiles. Video Abstract.

Sociobiome - Individual and neighborhood socioeconomic status influence the gut microbiome in a multi-ethnic population in the US.

Lower socioeconomic status (SES) is related to increased incidence and mortality due to chronic diseases in adults. Association between SES variables and gut microbiome variation has been observed in adults at the population level, suggesting that biological mechanisms may underlie the SES associations; however, there is a need for larger U.S. studies that consider individual- and neighborhood-level measures of SES in racially diverse populations. In 825 participants from a multi-ethnic cohort, we investigated how SES shapes the gut microbiome. We determined the relationship of a range of several individual- and neighborhood-level SES indicators with the gut microbiome. Individual education level and occupation were self-reported by questionnaire. Geocoding was applied to link participants' addresses with neighborhood census tract socioeconomic indicators, including average income and social deprivation in the census tract. Gut microbiome was measured using 16SV4 region rRNA gene sequencing of stool samples. We compared α-diversity, ß-diversity, and taxonomic and functional pathway abundance by socioeconomic status. Lower SES was significantly associated with greater α-diversity and compositional differences among groups, as measured by ß-diversity. Several taxa related to low SES were identified, especially an increasing abundance of Genus Catenibacterium and Prevotella copri. The significant association between SES and gut microbiota remained even after considering the race/ethnicity in this racially diverse cohort. Together, these results showed that lower socioeconomic status was strongly associated with compositional and taxonomic measures of the gut microbiome, suggesting that SES may shape the gut microbiota.

The Frequency and Utility of Drug Cessation Trials in Older Adults With Chronic Eczematous Dermatitis of Unknown Etiology: A Retrospective Cohort Study.

Background: Eczematous dermatitis is a major cause of recalcitrant pruritic eruptions in older adults. Although some medications have been implicated, there are limited data demonstrating the utility of medication changes. Objective: To investigate the utility and possible harms of drug cessation trials (DCTs) in chronic eczematous eruptions in the aging (CEEA). Methods: This is a retrospective cohort study utilizing electronic health records of DCTs in adults older than 65 years with CEEA. Results: We identified 646 patients >65 years with new onset eczematous eruptions, 89 (14%) of whom had no identifiable etiology. In this cohort, 35 patients underwent a total of 40 DCTs. Although there was mention of improvement in 17.5% (7/40), all patients sought tertiary care for their persistent rash. Negative outcomes occurred in 45% (18/40), all of which were due to exacerbation of a comorbidity that the medication was prescribed to treat. Conclusion: Our experience suggests that patients with CEEA undergo DCTs that do not improve their dermatitis and can lead to dangerous worsening of underlying conditions. Further study of the etiology of CEEA is needed.

Real-World Outcomes of Adalimumab Treatment for Moderate and Severe Psoriasis in Korean Patients (RAPSODI Study).

BACKGROUND: Psoriasis imposes a significant treatment burden on patients, particularly impacting well-being and quality of life (QoL). The psychosocial impact of psoriasis treatments remains unexplored in most patient populations. OBJECTIVE: To assess the impact of adalimumab on health-related QoL (HRQoL) in Korean patients with psoriasis. METHODS: This 24-week, multicenter, observational study, assessed HRQoL in Korean patients treated with adalimumab in a real-world setting. Patient-reported outcomes (PROs) including European Quality of Life-5 Dimension scale (EQ-5D), EQ-5D VAS, SF-36, and DLQI were evaluated at week 16 and 24, versus baseline. Patient satisfaction was assessed using TSQM. RESULTS: Among 97 enrolled patients, 77 were assessed for treatment effectiveness. Most patients were male (52, 67.5%) and mean age was 45.4 years. Median baseline body surface area and Psoriasis Area and Severity Index (PASI) scores were 15.00 (range 4.00~80.00) and 12.40 (range 2.70~39.40), respectively. Statistically significant improvements in all PROs were observed between baseline and week 24. Mean EQ-5D score improved from 0.88 (standard deviation [SD], 0.14) at baseline to 0.91 (SD, 0.17) at week 24 (p=0.0067). The number of patients with changes in PASI 75, 90, or 100 from baseline to week 16 and 24 were 65 (84.4%), 17 (22.1%), and 1 (1.3%); and 64 (83.1%), 21 (27.3%), and 2 (2.6%), respectively. Overall treatment satisfaction was reported, including effectiveness and convenience. No unexpected safety findings were noted. CONCLUSION: Adalimumab improved QoL and was well-tolerated in Korean patients with moderate to severe psoriasis, as demonstrated in a real-world setting. Clinical trial registration number (clinicaltrials.gov: NCT03099083).

Grain, Gluten, and Dietary Fiber Intake Influence Gut Microbial Diversity: Data from the Food and Microbiome Longitudinal Investigation.

Although short-term feeding studies demonstrated effects of grains, fiber, and gluten on gut microbiome composition, the impact of habitual intake of these dietary factors is poorly understood. We examined whether habitual intakes of whole and refined grains, fiber, and gluten are associated with gut microbiota in a cross-sectional study. This study included 779 participants from the multi-ethnic Food and Microbiome Longitudinal Investigation study. Bacterial 16SV4 rRNA gene from baseline stool was amplified and sequenced using Illumina MiSeq. Read clustering and taxonomic assignment was performed using QIIME2. Usual dietary intake was assessed by a 137-item food frequency questionnaire. Association of diet with gut microbiota was assessed with respect to overall composition and specific taxon abundances. Whole grain intake was associated with overall composition, as measured by the Jensen-Shannon divergence (multivariable-adjusted P trend for quartiles = 0.03). The highest intake quartile was associated with higher abundance of Bacteroides plebeius, Faecalibacterium prausnitzii, Blautia producta, and Erysipelotrichaceae and lower abundance of Bacteroides uniformis. These bacteria also varied by dietary fiber intake. Higher refined grain and gluten intake was associated with lower Shannon diversity (P trend < 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity. Significance: Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.