The NLRP3 inflammasome and bruton's tyrosine kinase in platelets co-regulate platelet activation, aggregation, and in vitro thrombus formation.

Cleavage of interleukin-1ß (IL-1ß) is a key inflammatory event in immune cells and platelets, which is mediated by nucleotide-binding domain leucine rich repeat containing protein (NLRP3)-dependent activation of caspase-1. In immune cells, NLRP3 and caspase-1 form inflammasome complexes with the adaptor proteins apoptosis-associated speck-like protein containing a CARD (ASC) and bruton's tyrosine kinase (BTK). In platelets, however, the regulatory triggers and the functional effects of the NLRP3 inflammasome are unknown. Here, we show in vitro that the platelet NLRP3 inflammasome contributes to platelet activation, aggregation, and thrombus formation. NLRP3 activity, as monitored by caspase-1 activation and cleavage and secretion of IL-1ß, was upregulated in activated platelets, which was dependent on platelet BTK. Pharmacological inhibition or genetic ablation of BTK in platelets led to decreased platelet activation, aggregation, and in vitro thrombus formation. We identify a functionally relevant link between BTK and NLRP3 in platelets, with potential implications in disease states associated with abnormal coagulation and inflammation.

IL-33 mediates Pseudomonas induced airway fibrogenesis and is associated with CLAD.

BACKGROUND: Long term outcomes of lung transplantation are impacted by the occurrence of chronic lung allograft dysfunction (CLAD). Recent evidence suggests a role for the lung microbiome in the occurrence of CLAD, but the exact mechanisms are not well defined. We hypothesize that the lung microbiome inhibits epithelial autophagic clearance of pro-fibrotic proteins in an IL-33 dependent manner, thereby augmenting fibrogenesis and risk for CLAD. METHODS: Autopsy derived CLAD and non-CLAD lungs were collected. IL-33, P62 and LC3 immunofluorescence was performed and assessed using confocal microscopy. Pseudomonas aeruginosa (PsA), Streptococcus Pneumoniae (SP), Prevotella Melaninogenica (PM), recombinant IL-33 or PsA-lipopolysaccharide was co-cultured with primary human bronchial epithelial cells (PBEC) and lung fibroblasts in the presence or absence of IL-33 blockade. Western blot analysis and quantitative reverse transcription (qRT) PCR was performed to evaluate IL-33 expression, autophagy, cytokines and fibroblast differentiation markers. These experiments were repeated after siRNA silencing and upregulation (plasmid vector) of Beclin-1. RESULTS: Human CLAD lungs demonstrated markedly increased expression of IL-33 and reduced basal autophagy compared to non-CLAD lungs. Exposure of co-cultured PBECs to PsA, SP induced IL-33, and inhibited PBEC autophagy, while PM elicited no significant response. Further, PsA exposure increased myofibroblast differentiation and collagen formation. IL-33 blockade in these co-cultures recovered Beclin-1, cellular autophagy and attenuated myofibroblast activation in a Beclin-1 dependent manner. CONCLUSION: CLAD is associated with increased airway IL-33 expression and reduced basal autophagy. PsA induces a fibrogenic response by inhibiting airway epithelial autophagy in an IL-33 dependent manner.

Factors associated with health-related quality of life of south indian population with chronic venous leg ulcers - A hospital based pilot study.

OBJECTIVE: Venous leg ulcers (VLU) are chronic, recurrent and have a significant impact on the patients' health- related quality of life (HRQoL). This study assessed the association of patient-specific factors on the HRQoL of patients with chronic venous leg ulcers. MATERIALS AND METHODS: The study included 21 males and 21 females aged 18 years and above, with chronic VLU. Data on demographics, education, occupation, per capita income, duration of ulcer were subjectively recorded. The socio-economic status was scored based on the Modified Kuppuswamy scale 2019, ulcer severity was assessed using M.A.I.D. Scale and the HRQoL of the patients were assessed using the 36-Item Short-Form Health Survey Version 1.0. The differences in the mean HRQoL scores between patients based on their gender and socio-economic class were assessed using an unpaired sample t-test. The association of age, severity, duration of the ulcer with the HRQoL were assessed using Pearson's correlation. A probability value of < 0.05 was considered statistically significant. RESULTS: There were 21 (50%) males and 21 (50%) females with a mean age of 55.45 ± 7.73 years. The mean duration of ulcers was 7.26 ± 3.34 months and the mean ulcer severity score was 2.16 ± 0.96. Role limitations due to the physical health were found to be most impacted due to the disease condition with the least mean score of 26.78 ± 31.90 %. There were no significant differences in the mean scores of the physical and the mental components of HRQoL based on gender but there were significant differences based on socio-economic status. The lower the socio-economic status, the poorer the HRQoL. Age, severity of ulcers and ulcer duration had a significant negative correlation with HRQoL. CONCLUSION: The study observed a low HRQoL of patients in physical aspects reflecting on the extensive limitation on the performance of daily physical activities. Patient-specific factors such as age, socio-economic status, severity, and chronicity of ulcers were found to influence HRQoL.

Diversifying the dermatology workforce: Physician characteristics vary by race/ethnicity.

BACKGROUND: In the United States (US), dermatology remains one of the least diverse specialties in medicine. Increasing the diversity of the dermatology workforce is essential for reducing health disparities. OBJECTIVE: To describe the experiences of racially and ethnically diverse physicians in the US who successfully matched into dermatology. METHODS: Board-certified dermatologists and dermatology residents were recruited to participate in an anonymous, online survey in which self-reported demographic, socioeconomic, pre-residency, and post-residency career data were obtained. RESULTS: Of the 100 participants included in the study, 30% were dermatology residents and 25% belonged to a group underrepresented in medicine (UIM). Black physicians were 3.69 times more likely to select dermatology prior to medical school (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.04 - 13.0) compared to non-Black physicians. UIM dermatologists and trainees were more likely to receive a need-based scholarship in medical school (OR, 4.37; 95% CI, 1.30 - 14.7), graduate from a private medical institution (OR, 6.49; 95% CI, 1.95 - 21.6), and have at least one UIM dermatology mentor during medical school (adjusted OR, 13.1; 95% CI, 2.77 - 61.5) compared to non-UIM physicians. CONCLUSIONS: A holistic review of dermatology applicants by residency programs may reduce racial/ethnic disparities in the admission process. Our data provide further evidence in support of pre-medical outreach programs, mentorship, and institutional funding to promote diversity in dermatology.

Behind the Scenes of Extracellular Vesicle Therapy for Skin Injuries and Disorders.

Significance: Skin wounds and disorders compromise the protective functions of skin and patient quality of life. Although accessible on the surface, they are challenging to address due to paucity of effective therapies. Exogenous extracellular vesicles (EVs) and cell-free derivatives of adult multipotent stromal cells (MSCs) are developing as a treatment modality. Knowledge of origin MSCs, EV processing, and mode of action is necessary for directed use of EVs in preclinical studies and methodical translation. Recent Advances: Nanoscale to microscale EVs, although from nonskin cells, induce functional responses in cutaneous wound cellular milieu. EVs allow a shift from cell-based to cell-free/derived modalities by carrying the MSC beneficial factors but eliminating risks associated with MSC transplantation. EVs have demonstrated striking efficacy in resolution of preclinical wound models, specifically within the complexity of skin structure and wound pathology. Critical Issues: To facilitate comparison across studies, tissue sources and processing of MSCs, culture conditions, isolation and preparations of EVs, and vesicle sizes require standardization as these criteria influence EV types and contents, and potentially determine the induced biological responses. Procedural parameters for all steps preceding the actual therapeutic administration may be the key to generating EVs that demonstrate consistent efficacy through known mechanisms. We provide a comprehensive review of such parameters and the subsequent tissue, cellular and molecular impact of the derived EVs in different skin wounds/disorders. Future Directions: We will gain more complete knowledge of EV-induced effects in skin, and specificity for different wounds/conditions. The safety and efficacy of current preclinical xenogenic applications will favor translation into allogenic clinical applications of EVs as a biologic.

Addressing Depression Symptoms among University Students under COVID-19 Restrictions-The Mediating Role of Stress and the Moderating Role of Resilience.

BACKGROUND: The COVID-19 pandemic has contributed to a decline in mental health globally. Compared to the general population, university students have been identified as a group vulnerable to developing depression symptoms during the pandemic. Social isolation, a signature mental health consequence under physical-distancing regulations, is a known predictor of depression symptoms during the pandemic. Yet, more research is required to understand the mechanism that underpins the isolation-depression association and identify psychological factors that may attenuate the association. The current study aimed to understand the role of stress and resilience in the isolation-depression association among university students. METHODS: Data were collected from 1718 university students between 28 and 31 May 2020. Partial least squares structural equation modelling (PLS-SEM) was used to examine the mediating role of perceived stress and the moderating role of resilience in the isolation-depression association. RESULTS: We found that perceived stress partially mediated the association between social isolation and depression symptoms. Both the direct and indirect effects were moderated by participants' resilience levels. CONCLUSIONS: Social isolation during the pandemic may contribute to depression symptoms both directly and through elevated stress levels. As an internal strength, resilience may buffer the adverse effects of isolation and stress on depression symptoms. Targeted interventions including mindfulness and physical exercise training may provide promising results in reducing depression symptoms among university students and should be considered by university administrators particularly during times of imposed physical-distancing measures.

Identifying Predictors of University Students' Wellbeing during the COVID-19 Pandemic-A Data-Driven Approach.

BACKGROUND: The COVID-19 pandemic has posed risks to public mental health worldwide. University students, who are already recognised as a vulnerable population, are at elevated risk of mental health issues given COVID-19-related disruptions to higher education. To assist universities in effectively allocating resources to the launch of targeted, population-level interventions, the current study aimed to uncover predictors of university students' psychological wellbeing during the pandemic via a data-driven approach. METHODS: Data were collected from 3973 Australian university students ((median age = 22, aged from 18 to 79); 70.6% female)) at five time points during 2020. Feature selection was conducted via least absolute shrinkage and selection operator (LASSO) to identify predictors from a comprehensive set of variables. Selected variables were then entered into an ordinary least squares (OLS) model to compare coefficients and assess statistical significance. RESULTS: Six negative predictors of university students' psychological wellbeing emerged: White/European ethnicity, restriction stress, perceived worry on mental health, dietary changes, perceived sufficiency of distancing communication, and social isolation. Physical health status, emotional support, and resilience were positively associated with students' psychological wellbeing. Social isolation has the largest effect on students' psychological wellbeing. Notably, age, gender, international status, and educational level did not emerge as predictors of wellbeing. CONCLUSION: To cost-effectively support student wellbeing through 2021 and beyond, universities should consider investing in internet- and tele- based interventions explicitly targeting perceived social isolation among students. Course-based online forums as well as internet- and tele-based logotherapy may be promising candidates for improving students' psychological wellbeing.