Disease heterogeneity and molecular classification of inflammatory palmoplantar diseases.

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). OBJECTIVE: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. METHODS: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples. RESULTS: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. CONCLUSION: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.

Mastering Sedation and Associated Respiratory Events through Simulation-Based Training: A Randomised Controlled Trial Involving Non-Anaesthesiology Residents.

Non-anaesthetists commonly administer procedural sedation worldwide, posing the risk of respiratory events that can lead to severe complications. This study aimed to evaluate whether simulation-based learning could lead to enhancements in the clinical proficiency of non-anaesthesiology residents in managing sedation and related respiratory complications. Following the evaluation of baseline clinical performance through a pre-test simulation, 34 residents were randomly allocated to either participate in an innovative simulation-based learning module (intervention group) or view a brief self-learning video (control group). After a one-month period, their clinical performance was assessed again in a post-test simulation involving respiratory arrest during procedural sedation. Two independent assessors rated each resident's performance using video recordings and a scoring tool with scores ranging from 0 to 19/19. The two assessments were averaged for each performance, and the pre- to post-test change was calculated for each resident. While baseline clinical performance was similar, mean (SD) increase in clinical performance was significantly greater in the intervention group than in the control group (+2.4 (1.6) points versus +0.8 (1.3) points, respectively; p = 0.002). Our simulation-based learning sedation module resulted in the enhanced management of sedation-related complications compared to baseline and minimal self-learning. Simulation-based medical education may offer an effective approach for equipping non-anaesthesiology residents with essential skills to mitigate risks associated with sedation. (ClinicalTrials.gov identifier: NCT02722226).

Oral Baricitinib in the Treatment of Cutaneous Lichen Planus.

Background: Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon (IFN)-γ, a cytokine implicated in the pathogenesis of LP. Methods: In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre-and post-treatment samples. Results: An early and sustained clinical response was seen with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrate a rapid decrease in interferon signature within 2 weeks of treatment, most prominent in the basal layer of the epidermis. Conclusion: This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP. Trial Registration Number : NCT05188521.

Genetic and Functional Analyses of Cutibacterium Acnes Isolates Reveal the Association of a Linear Plasmid with Skin Inflammation.

Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease.

Development of mobile phone-based dietary data collection applications in pregnant women and infants for the M-SAKHI trial.

In nutritional epidemiological studies, it is imperative to collect high-quality data to ensure accurate dietary assessment. However, dietary data collection using traditional paper forms has several limitations that may compromise data quality. The aim of this study was to propose novel methods to design and develop software applications (Apps) for dietary data collection to assess the nutritional status of pregnant women and infants. This study is part of the M-SAKHI (Mobile-Solutions for Aiding Knowledge for Health Improvement) cluster randomised controlled trial (cRCT) implemented in central India. Three tablet-based software Apps were developed in this study: the ACEC (Automated Coding and Energy Calculation) App to establish a generic cooked food recipe database, the FFQ (Food Frequency Questionnaire), and the IDR (24 h Infant Dietary Recall) Apps to collect dietary data from pregnant women and their infants from rural area of Bhandara and Nagpur districts. Regional food lists, recipes, and portion resource kits were developed to support the data collection using the Apps. In conclusion, the Apps were user-friendly, required minimal prior training, had built-in validation checks for erroneous data entry and provided automated calculations. The Apps were successfully deployed in low-resource rural settings to accurately collect high-quality regional cooked food data and individual-level dietary data of pregnant women and their infants.

Evidence of residual micellar structures in a lipid nanocapsule dispersion. A multi-technique approach.

Nanoemulsions are metastable emulsions in the nanometric range which can be obtained using low-energy processes. A decade ago, it was demonstrated that a non-negligible amount of residual surfactant micelles may coexist with the oil nanodroplets in a model oil/surfactant system. Those micelles were called "wasted" micelles as they did not participate in the formation of the nanodroplets. Little attention has been focused on the potential presence or effect of such secondary structures in nanoemulsions used as drug delivery systems. Here, we present an extensive characterization of lipid nanocapsules, a nanoemulsion obtained from a medium-chain triglyceride mixed with a pegylated surfactant by a process comprising a temperature-dependent phase inversion followed by a cold-water quench. Lipid nanocapsules demonstrate a very good shelf stability. First, for clarity and academic purposes, we briefly present the pros and the cons of the various diffusion-based characterization techniques used i.e., multi-angle and single-angle dynamic light scattering, nanoparticle tracking analysis, fluorescence recovery after photobleaching, and diffusometry nuclear magnetic resonance. Then, combining all these techniques, we show that up to 40 wt% of the surfactant is not involved in the lipid nanocapsule construction but forms residual micellar structures. Those micelles also contain a small quantity of medium-chain triglyceride (2 wt% of the initial amount) and encapsulate around 40 wt% of a fluorescent dye originally dispersed in the oily phase.

Facial Hypertrophy as a Complication of Weight Gain in Autologous Fat Graft Patients: Considerations and Recommendations.

Fat grafting can restore facial volume for reconstructive and cosmetic indications. Common practice often involves extracting lipoaspirate from the most abundant anatomic location. However, grafted fat retains the phenotypic characteristics of its original location and can undergo exaggerated hypertrophy with patient weight fluctuations. The aim of this study was to systematically assess the literature to summarize the reported effects of postoperative weight gain on facial hypertrophy in patients after facial fat grafting and to determine potentially avoidable factors. A search through PubMed/MEDLINE was conducted on October 4, 2022, to identify relevant articles with appropriate search terms. No lower date limit was applied and all eligible nonanimal clinical articles in English were included for review. Reports were summarized and presented as descriptive statistics. The search generated 714 articles. After abstract and full-text review of the initial set of articles, 6 were included in our analysis. All articles described poor cosmetic outcomes resulting from nonanatomic hypertrophy of the grafted fat. None of the articles reported a thorough methodology for selecting the donor site to minimize fat hypertrophy with potential future weight fluctuations. Grafted facial fat is susceptible to exaggerated hypertrophy as a result of changes in patient weight. Specifically, harvesting lipoaspirate from maximally abundant areas of the body may increase this risk. Individualizing the area of fat donation may attenuate unwanted fat growth and further contribute to increased patient quality of life.

Socio-economic and agricultural factors associated with stunting of under 5-year children: findings from surveys in mountains, dry zone and delta regions of rural Myanmar (2016-2017).

OBJECTIVE: The study's objective was to investigate multiple underlying social, economic and agricultural determinants of stunting among under-five children in three distinct ecological areas in rural Myanmar. DESIGN: Repeated cross-sectional surveys in three states of Myanmar. SETTING: Rural households in Chin (mountainous), Magway (plains) and Ayeyarwady (delta). PARTICIPANTS: From two purposively selected adjacent townships in each state, we randomly selected twenty villages and, in each village, thirty households with under-five children. Households in the first survey in 2016 were revisited in late 2017 to capture seasonal variations. RESULTS: Stunting increased from 40·4 % to 42·0 %, with the highest stunting prevalence in Chin state (62·4%). Univariate Poisson regression showed factors contributing to child stunting varied across the regions. Adjusted Poisson regression models showed that child's age and short maternal stature (aRR = 1·14 for Chin, aRR = 1·89 for Magway and aRR = 1·86 for Ayeyarwady) were consistently associated with child stunting across three areas. For Chin, village-level indicators such as crop consumption (aRR = 1·18), crop diversity (aRR = 0·82) and land ownership (aRR = 0·89) were significantly associated with stunting. In Magway, the number of household members (aRR = 1·92), wealth status (aRR = 0·46), food security status (aRR = 1·14), land ownership (aRR = 0·85) and in Ayeyarwady, women's decision-making (aRR = 0·67) and indicators related to hygiene (aRR = 1·13) and sanitation (aRR = 1·45) were associated with stunting. CONCLUSIONS: Area-specific factors were associated with stunting. Maternal short stature and child age were consistent determinants of stunting. A multi-sectoral local approach, including improvements in transport, is needed to address the intergenerational malnutrition problem.

Severe COVID-19 pneumonia in pregnant woman treated with pulse corticosteroids therapy and third-trimester caesarean section: A case report.

A 44-year-old woman at 30 weeks of pregnancy was admitted to the Intensive Care Unit with a diagnosis of severe COVID-19 pneumonia. Her condition worsened quickly, defined by prolonged hypoxia even with intensive therapy and oxygen supplementation. This led to the decision to perform a caesarean delivery and continue pulse corticosteroids therapy after delivery. Soon after she recovered from COVID-19 pneumonia, her life was threatened again by septic shock from hospital-acquired pneumonia. After nearly 1 month of hospitalization, she was discharged and fully recovered on the re-examination day 10 months later.

The Effects of One-Point Mutation on the New Delhi Metallo Beta-Lactamase-1 Resistance toward Carbapenem Antibiotics and ß-Lactamase Inhibitors: An In Silico Systematic Approach.

Antibiotic resistance has been becoming more and more critical due to bacteria's evolving hydrolysis enzymes. The NDM-1 enzyme could hydrolyze not only carbapenems but also most of ß-lactam's antibiotics and inhibitors. In fact, variant strains could impose a high impact on the resistance of bacteria producing NDM-1. Although previous studies showed the effect of some variants toward antibiotics and inhibitors binding, there has been no research systematically evaluating the effects of alternative one-point mutations on the hydrolysis capacity of NDM-1. This study aims to identify which mutants could increase or decrease the effectiveness of antibiotics and ß-lactamase inhibitors toward bacteria. Firstly, 35 different variants with a high probability of emergence based on the PAM-1 matrix were constructed and then docked with 5 ligands, namely d-captopril, l-captopril, thiorphan, imipenem, and meropenem. The selected complexes underwent molecular dynamics simulation and free energy binding estimation, with the results showing that the substitutions at residues 122 and 124 most influenced the binding ability of NDM-1 toward inhibitors and antibiotics. The H122R mutant decreases the binding ability between d-captopril and NDM-1 and diminishes the effectiveness of this antibiotic toward Enterobacteriaceae. However, the H122R mutant has a contrary impact on thiorphan, which should be tested in vitro and in vivo in further experiments.

Virtual Interviews Improve Equity and Wellbeing: Results of a Survey of Applicants to Obstetrics and Gynecology Subspecialty Fellowships.

BACKGROUND: Nationwide restrictions and recommendations from the Association of American Medical Colleges mandated program directors to conduct all graduate medical education interviews virtually in the Spring of 2020 in response to the COVID-19 pandemic. This study was conducted to assess the impact of virtual interviews on a candidates' ability to effectively create a rank list. OBJECTIVE: The primary objective of this study was to evaluate Obstetrics and Gynecology (ObGyn) subspecialty fellowship applicants' perspectives regarding the effectiveness of virtual interviews for creating a rank list. Secondary outcomes included perceived advantages and disadvantages of the process and costs of the process. METHODS: This was a cross-sectional IRB-exempt study, using an electronic survey administered to a convenience sample of applicants to ObGyn subspecialty fellowship programs. The survey was administered via RedCap between the rank list submission deadline and the Match. Descriptive statistics were used. RESULTS: Response rate was 158/330 (48%). Overall, 129/158 (82%) percent of respondents felt confident in making their rank list based on the virtual interviews, and 146/158 (92%) were "very satisfied" or "somewhat satisfied" with the process. Of those who expressed an interview style preference, 65/149(44%) of respondents preferred virtual interviews; 49/149(33%) had no preference or were not sure. Nearly all 146/148(99%) applicants cited cost-savings as a distinct advantage of virtual interviews. CONCLUSION: Applicants to ObGyn subspecialty fellowships felt comfortable to create a rank list based on the virtual interview. This study indicates that the virtual format is effective, less stressful and less costly for ObGyn subspecialty interviews and should be considered beyond the pandemic to remove barriers and burdens for applicants.

TREM2 macrophages induced by human lipids drive inflammation in acne lesions.

Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of Cutibacterium acnes, and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill C. acnes. The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.

Assessment of Knowledge, Attitude, and Practice in Adverse Drug Reaction Reporting of Healthcare Professionals in Vietnam: A Cross-Sectional Study.

Background: Under-reporting is a major issue of ADR spontaneous reporting system. This study assesses the knowledge, attitude, and practice of healthcare professionals in Children's Hospital in Vietnam and suggests solutions to enhance ADR reporting rate based on findings. Methods: A cross-sectional study was conducted and 397 self-administered structured questionnaires were distributed to all potential HCPs working in surveyed hospital within 2 weeks from June 03 to June 20, 2020. Results: Overall response rate was 97% with 384 responses. A majority answered correctly ADRs' knowledge apart from form supplier (1.6%) and possible causes (2.6%). The need to focus on patient care (33.3%) and the trivia of reaction (31.5%) reduced HCPs' attention. About 61.7% reported once in their career, 49.7% had training. Having trained group had numbers of practice significantly higher than their counterparts. Major reason for not reporting was lack of information and instruction. Preferred solutions were regularly training, updating, and collaboration of HCPs in reporting ADR. Conclusion: Healthcare professionals had adequate knowledge, positive attitude, and moderate practice. Training significantly raised the number of practices in reporting ADR. Preferred solutions were regular training, updating, and collaboration of healthcare professionals in ADR reporting.

The impact of a package of behaviour change interventions on breastfeeding practices in East Java Province, Indonesia.

Suboptimal infant young child feeding practices are frequently reported globally, including in Indonesia. This analysis examined the impact of a package of behaviour change interventions on breastfeeding practices in Malang and Sidoarjo Districts, East Java Province, Indonesia. The BADUTA study (which in the Indonesian Language is an acronym for BAwah DUa TAhun, or children aged less than 2 years) was an impact evaluation using a cluster-randomized controlled trial with two parallel treatment arms. We conducted household surveys in 12 subdistricts from Malang and Sidoarjo. We collected information from 5175 mothers of children aged 0-23 months: 2435 mothers at baseline (February 2015) and 2740 mothers at endline (January to February 2017). This analysis used two indicators for fever and diarrhoea and seven breastfeeding indicators (early initiation of breastfeeding, prelacteal feeding, exclusive breastfeeding under 6 months, predominant breastfeeding, continued breastfeeding, age-appropriate breastfeeding and bottle-feeding). We used multilevel logistic regression analysis to assess the effect of the intervention. After 2 years of implementation of interventions, we observed an increased odds of exclusive breastfeeding under 6 months (adjusted odds ratio [aOR] = 1.85; 95% confidence interval [CI]: 1.35-2.53) and age-appropriate breastfeeding (aOR = 1.39; 95% CI: 1.07-1.79) in the intervention group than in the comparison group, at the endline survey. We found significantly lower odds for prelacteal feeding (aOR = 0.52; 95% CI: 0.41-0.65) in the intervention than in the comparison group. Our findings confirmed the benefits of integrated, multilayer behaviour change interventions to promote breastfeeding practices. Further research is required to develop effective interventions to reduce bottle use and improve other breastfeeding indicators that did not change with the BADUTA intervention.

Chalcone Derivatives as Potential Inhibitors of P-Glycoprotein and NorA: An In Silico and In Vitro Study.

The human P-glycoprotein (P-gp) and the NorA transporter are the major culprits of multidrug resistance observed in various bacterial strains and cancer cell lines, by extruding drug molecules out of the targeted cells, leading to treatment failures in clinical settings. Inhibiting the activity of these efflux pumps has been a well-known strategy of drug design studies in this regard. In this manuscript, our earlier published machine learning models and homology structures of P-gp and NorA were utilized to screen a chemolibrary of 95 in-house chalcone derivatives, identifying two hit compounds, namely, F88 and F90, as potential modulators of both transporters, whose activity on Staphylococcus aureus strains overexpressing NorA and resistant to ciprofloxacin was subsequently confirmed. The findings of this study are expected to guide future research towards developing novel potent chalconic inhibitors of P-gp and/or NorA.

Histidine-Mediated Ion Specific Effects Enable Salt Tolerance of a Pore-Forming Marine Antimicrobial Peptide.

Antimicrobial peptides (AMPs) preferentially permeate prokaryotic membranes via electrostatic binding and membrane remodeling. Such action is drastically suppressed by high salt due to increased electrostatic screening, thus it is puzzling how marine AMPs can possibly work. We examine as a model system, piscidin-1, a histidine-rich marine AMP, and show that ion-histidine interactions play unanticipated roles in membrane remodeling at high salt: Histidines can simultaneously hydrogen-bond to a phosphate and coordinate with an alkali metal ion to neutralize phosphate charge, thereby facilitating multidentate bonds to lipid headgroups in order to generate saddle-splay curvature, a prerequisite to pore formation. A comparison among Na+ , K+ , and Cs+ indicates that histidine-mediated salt tolerance is ion specific. We conclude that histidine plays a unique role in enabling protein/peptide-membrane interactions that occur in marine or other high-salt environment.

Antimicrobial production by perifollicular dermal preadipocytes is essential to the pathophysiology of acne.

Innate immune defense against deep tissue infection by Staphylococcus aureus is orchestrated by fibroblasts that become antimicrobial when triggered to differentiate into adipocytes. However, the role of this process in noninfectious human diseases is unknown. To investigate the potential role of adipogenesis by dermal fibroblasts in acne, a disorder triggered by Cutibacterium acnes, single-cell RNA sequencing was performed on human acne lesions and mouse skin challenged by C. acnes. A transcriptome consistent with adipogenesis was observed within specific fibroblast subsets from human acne and mouse skin lesions infected with C. acnes. Perifollicular dermal preadipocytes in human acne and mouse skin lesions showed colocalization of PREF1, an early marker of adipogenesis, and cathelicidin (Camp), an antimicrobial peptide. This capacity of C. acnes to specifically trigger production of cathelicidin in preadipocytes was dependent on TLR2. Treatment of wild-type mice with retinoic acid (RA) suppressed the capacity of C. acnes to form acne-like lesions, inhibited adipogenesis, and enhanced cathelicidin expression in preadipocytes, but lesions were unresponsive in Camp-/- mice, despite the anti-adipogenic action of RA. Analysis of inflamed skin of acne patients after retinoid treatment also showed enhanced induction of cathelicidin, a previously unknown beneficial effect of retinoids in difficult-to-treat acne. Overall, these data provide evidence that adipogenic fibroblasts are a critical component of the pathogenesis of acne and represent a potential target for therapy.