Deterministic reprogramming of neutrophils within tumors.

Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.

Efficacy and safety of narrowband ultraviolet B versus combined ultraviolet A/narrowband ultraviolet B phototherapy in the treatment of chronic atopic dermatitis: A randomised double-blind study.

Phototherapy is a useful treatment modality for atopic dermatitis (AD). This is a prospective randomised double-blind study comparing the clinical efficacy of combined ultraviolet-A (UVA)/narrowband ultraviolet-B (NBUVB) versus NBUVB phototherapy in the treatment of chronic AD. Patients with moderate-to-severe AD were randomised to receive either UVA/NBUVB or NBUVB phototherapy twice weekly over 12 weeks. At baseline, weeks 6 and 12, Eczema Area And Severity Index (EASI), itch score and adverse effects were assessed. At baseline and week 12, disease-related quality of life was evaluated using the Dermatology Life Quality Index (DLQI). Nine patients were randomised to receive UVA/NBUVB and 10 received NBUVB. At week 12, both groups showed significant improvement in EASI and itch scores (p < 0.05). Significant improvement in DLQI was seen in the UVA/NBUVB arm (p = 0.009) with a trend towards improvement in the NBUVB arm (p = 0.11). The efficacy of both modalities were comparable, as were reported adverse effects aside from skin dryness which was higher in the NBUVB arm (40% vs. 0%, p = 0.033). Combined UVA/NBUVB and NBUVB phototherapy have comparable clinical efficacy and safety in the treatment of chronic AD. NBUVB may induce greater skin dryness.

In vivo imaging of patients with chronic pruritus of unknown origin reveals partial sweat duct obstruction with partial itch resolution upon retinoid treatment.

Background: Chronic pruritus of unknown origin (CPUO) is poorly understood and lacks effective treatment options. Objectives: We aimed to elucidate abnormalities in the sweat apparatus of patients with CPUO, and to assess efficacy and safety of treatment with systemic retinoids. Methods: An initial case-control study included 20 affected patients and five healthy controls, for whom heat and sweating were induced, either through a standardized exercise protocol or ingestion of hot water. In vivo high-definition optical coherence tomography, whole-body starch-iodine testing, and skin biopsy for immunofluorescence staining were done to evaluate for sweat duct obstruction. A subsequent retrospective cohort analysis included 56 patients with CPUO, seen at an Itch subspecialty clinic of a single tertiary referral centre, who failed conventional treatments and were treated with isotretinoin and/or acitretin from May 2014 to November 2020. Treatment response to retinoids was defined as a sustained reduction in itch score of ≥2/10. Safety was assessed by proportion stopping treatment due to side effects. Results: In vivo imaging in 19 (95%) patients revealed features of partial keratinaceous sweat duct obstruction with statistically significant luminal dilatation compared to controls. Immunofluorescence studies of three patients' paired lesional/non-lesional biopsies revealed dermcidin accumulation within sweat glands coupled with dermcidin leakage in itchy skin. Fifty-six patients (mean [SD] age 55.2 [17.5] years, 69.6% male) were treated with systemic retinoids. Mean (SD) duration of itch was 116.3 (140.4) months and mean (SD) itch score was 8.2 (1.8). Forty-one (73.2%) initially received isotretinoin, and 15 (26.8%) acitretin. At three months, mean itch score reduced by 2.38 (95% CI -3.2 to -1.6, p < 0.0001). Thirty-eight (67.9%) had a sustained response. Eight (14.81%) achieved an itch score of 0 or 1, with four stopping treatment for a mean (SD) of 318.5 (291.2) days without relapse. Eight (14.3%) stopped or switched retinoid due to adverse effects, with similar incidences between both retinoids, the commonest being dryness. Conclusion: Based on novel findings from physiological imaging studies identifying partial keratinaceous sweat duct obstruction in CPUO, we instituted systemic retinoid treatment to address the underlying pathology. In patients who failed conventional therapies, the treatment appears effective and safe.

Clinical efficacy of a gentle anti-dandruff itch-relieving shampoo formulation.

Dandruff is a common scalp condition affecting almost half of the world's population. Despite its high prevalence, the exact pathophysiology is not well established and is understood to be multifactorial, with factors such as fungal colonization, sebaceous gland activity and individual factors being implicated. There is a need for an effective and safe shampoo that can target the above factors. Hence, we have developed a shampoo formulation with properties of oil control, moisturizing, non-irritative, anti-fungal, anti-microbial and itch-relieving. In this interventional, open-label study, we evaluated the efficacy and safety of this shampoo in reducing the clinical signs of dandruff and pruritus in patients with pre-existing mild-to-moderate dandruff over a course of 21-day treatment duration through self-assessment and objective clinical evaluations. After continued use of the shampoo, there was a significant decrease in the adherent and loose scalp flaking scores. Mean pruritus scores also decreased significantly across the 21-day time points. There were also no adverse events or skin intolerances reported. This study showed that our shampoo formulation has led to a significant reduction in both adherent and loose scalp flaking and pruritus when used in individuals suffering from mild to moderate dandruff. As such, it is an ideal shampoo, which can be used to effectively control dandruff.

Les pellicules sont une affection courante du cuir chevelu qui touche près de la moitié de la population mondiale. Malgré sa prévalence élevée, la physiopathologie exacte n'est pas bien établie et est comprise comme étant multifactorielle, avec des facteurs impliqués tels que la colonisation fongique, l'activité des glandes sébacées et des facteurs individuels. Un shampooing sûr et efficace pouvant cibler les facteurs évoqués ci-dessus est nécessaire. Par conséquent, nous avons développé une formulation de shampooing présentant des propriétés de contrôle du sébum, d'hydratation, non irritante, antifongique, antimicrobienne et de soulagement des démangeaisons. Dans cette essaie interventionnelle ouvert, nous avons évalué l'efficacité et la sécurité d'emploi de ce shampooing dans la réduction des signes cliniques de pellicules et de prurit chez des patients présentant des pellicules préexistantes légères à modérées sur une durée de traitement de 21 jours par le biais d'auto-évaluations et d'évaluations cliniques objectives. Après une utilisation continue du shampooing, une diminution significative des scores de squames adhérents et d'excoriation du cuir chevelu a été observée. Les scores de prurit moyens ont également significativement diminué tout au long de la période de 21 jours. De même, aucun événement indésirable ou intolérance cutanée n'a été rapporté. Cette étude a montré que notre formulation de shampooing a entraîné une réduction significative des squames adhérents, de l'excoriation du cuir chevelu et du prurit lorsqu'elle est utilisée chez des personnes souffrant de pellicules légères ou modérées. Il s'agit donc d'un shampooing idéal qui peut être utilisé pour contrôler efficacement les pellicules.

Are There Ethnic Differences in Hand Eczema? A Review.

Hand eczema is a common disease with economic and social ramifications. This study undertakes a review of certain existing literature to provide insight into contributory factors which may result in the varying prevalence and severity of hand eczema among different ethnic groups, particularly to identify modifiable risk factors, as well as to ascertain knowledge gaps for future research direction. The existing literature suggests that factors including (a) genes, (b) differing skin physiology, (c) cultural practices, (d) dietary habits and associated food preparation, (e) climate, (f) predominant occupations, (g) socioeconomic factors, and (h) dissimilar laws and regulations may account for the disparity in the risk of hand eczema among different ethnicities. Given that endogenous factors cannot be avoided, but certain exogenous aspects can be modified, especially as the environment plays an important role in hand eczema flares, it is helpful from a practical perspective to focus on addressing the modifiable risk factors. These factors pertain to unique cultural practices, customs, and food preparation methods. Healthcare professionals should be well-acquainted with such factors to tailor the treatment approach for patients of different ethnicities accordingly because, with globalization, physicians face increasingly diverse patient populations such that cultural customs no longer remain limited to particular geographic regions.

Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology.

Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.

A 3D-printed transepidermal microprojection array for human skin microbiome sampling.

Skin microbiome sampling is currently performed with tools such as swabs and tape strips to collect microbes from the skin surface. However, these conventional approaches may be unable to detect microbes deeper in the epidermis or in epidermal invaginations. We describe a sampling tool with a depth component, a transepidermal microprojection array (MPA), which captures microbial biomass from both the epidermal surface and deeper skin layers. We leveraged the rapid customizability of 3D printing to enable systematic optimization of MPA for human skin sampling. Evaluation of sampling efficacy on human scalp revealed the optimized MPA was comparable in sensitivity to swab and superior to tape strip, especially for nonstandard skin surfaces. We observed differences in species diversity, with the MPA detecting clinically relevant fungi more often than other approaches. This work delivers a tool in the complex field of skin microbiome sampling to potentially address gaps in our understanding of its role in health and disease.

Scar prevention through topical delivery of gelatin-tyramine-siSPARC nanoplex loaded in dissolvable hyaluronic acid microneedle patch across skin barrier.

Currently, there is no effective method to prevent the formation of hypertrophic scars and keloids, which can cause severe physical and psychological burdens to patients. Secreted protein acidic and cysteine-rich (SPARC) is involved in wound fibrosis by modulating fibroblast functions, causing excessive collagen deposition during wound healing. Thus, the reduction in SPARC gene expression after wounding can contribute to the downstream reduction in collagen production at the wound site and prevent scar formation. In this study, a dissolvable and biocompatible hyaluronic acid (HA) microneedle patch loaded with nanoplexes containing tyramine-modified gelatin and siRNA for SPARC (siSPARC/Gtn-Tyr) was investigated for topical scar prevention. Tyramine-modified gelatin (Gtn-Tyr) provides electrostatic protection and enhances cell internalization for siSPARC. In vitro studies using human dermal fibroblasts showed that both siSPARC/Gtn-Tyr nanoplexes and siSPARC/Gtn-Tyr-loaded microneedle patches can significantly reduce SPARC gene expression (P < 0.05) and do not cause discernable cytotoxic effects. Further studies using a mouse wound model demonstrate that the siSPARC/Gtn-Tyr-loaded microneedle patch can reduce collagen production during wound healing without triggering an immune response. When Gtn-Tyr-siSPARC is administered transdermally at the wound site, effective collagen reduction is achieved through silencing of the matricellular SPARC protein, thus promising the reduction of scar formation. Overall, the siSPARC/Gtn-Tyr loaded microneedle patch can potentially provide an effective transdermal anti-fibrotic treatment.

Transitional premonocytes emerge in the periphery for host defense against bacterial infections.

Circulating Ly6Chi monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-resident macrophage niche effectively during bacterial invasion to avert infection morbidity. Here, we show that proliferating transitional premonocytes (TpMos), an immediate precursor of mature Ly6Chi monocytes (MatMos), were mobilized into the periphery in response to acute bacterial infection and sepsis. TpMos were less susceptible to apoptosis and served as the main source of macrophage replenishment when MatMos were vulnerable toward bacteria-induced cellular death. Furthermore, TpMo and its derived macrophages contributed to host defense by balancing the proinflammatory cytokine response of MatMos. Consequently, adoptive transfer of TpMos improved the survival outcome of lethal sepsis. Our findings hence highlight a protective role for TpMos during bacterial infections and their contribution toward monocyte-derived macrophage heterogeneity in distinct disease outcomes.

Novel transdermal device for delivery of triamcinolone for nail psoriasis treatment.

INTRODUCTION: Nail psoriasis treatment is challenging due to difficult drug delivery and systemic therapy toxicities. Self-dissolvable microneedle patches embedded with corticosteroids offers a potentially rapid, minimally invasive drug delivery platform with good efficacy and minimal adverse side effects. METHODS: We conducted a 4-month prospective randomised controlled trial. Subjects with psoriatic nails were randomised to receive microneedle device delivered topical steroids on one hand and control treatment (topical Daivobet gel) on the other. Two independent dermatologists blinded to the treatment assignment scored their Nail Psoriasis Severity Index (NAPSI) during visits at baseline, 2 and 4 months. All treatment was discontinued after 2 months. Average NAPSI score on each hand was analysed. RESULTS: A total of 25 participants were recruited, aged 22 to 73 years. Majority were Chinese (72%), followed by Indian and Malay. There was equal randomisation of treatment to the left and right nail. While there was a rapid significant improvement in average NAPSI score for the control arm at 2 months, the treatment arm had a greater, more sustained improvement of the NAPSI score at 4 months. The average NAPSI score improved for both treatment and control group at 4 months compared to baseline. However, only the NAPSI value improvement in the controls at 2 months compared to baseline was statistically significant (P=0.0039). No severe adverse effects were reported. CONCLUSION: To the best of our knowledge, this is the first prospective randomised control trial comparing microneedle technology against conventional topical steroids in nail psoriasis treatment. Our findings demonstrate microneedle technology is as efficacious as topical therapy.

Skinny deeping: Uncovering immune cell behavior and function through imaging techniques.

As the largest organ of the body, the skin is a key barrier tissue with specialized structures where ongoing immune surveillance is critical for protecting the body from external insults. The innate immune system acts as first-responders in a coordinated manner to react to injury or infections, and recent developments in intravital imaging techniques have made it possible to delineate dynamic immune cell responses in a spatiotemporal manner. We review here key studies involved in understanding neutrophil, dendritic cell and macrophage behavior in skin and further discuss how this knowledge collectively highlights the importance of interactions and cellular functions in a systems biology manner. Furthermore, we will review emerging imaging technologies such as high-content proteomic screening, spatial transcriptomics and three-dimensional volumetric imaging and how these techniques can be integrated to provide a systems overview of the immune system that will further our current knowledge and lead to potential exciting discoveries in the upcoming decades.

Intranasal octenidine for methicillin-resistant Staphylococcus aureus (MRSA) carriers and universal octenidine bathing reduced MRSA acquisition in an acute-care general ward.

In this quasi-experimental before-and-after study in a methicillin-resistant staphylococcus aureus (MRSA) high-prevalence acute-care dermatology ward from August 2016 to November 2018, patients admitted during intervention period who received additional topical intranasal octenidine were 63% less likely to acquire MRSA than those receiving universal daily octenidine bathing alone during baseline period (aOR, 0.37; 95% CI, 0.14-0.98).

Quantitative Comparison of Color Asymmetry Features for Automatic Melanoma Detection.

Asymmetry assessment is an important step towards melanoma detection. This paper compares some of the color asymmetry features proposed in the literature which have been used to automatically detect melanoma from color images. A total of nine features were evaluated based on their accuracy in predicting lesion asymmetry on a dataset of 277 images. In addition, the accuracies of these features in differentiating melanoma from benign lesions were compared. Results show that simple features based on the brightness difference between the two halves of the lesion performed the best in predicting asymmetry and subsequently melanoma.Clinical relevance- The proposed work will assist researchers in choosing better performing color asymmetry features thereby improving the accuracy of automatic melanoma detection. The resulting system will reduce the workload of clinicians by screening out obviously benign cases and referring only the suspicious cases to them.

Factors affecting duration of SARS-Cov-2 viral shedding in mildly symptomatic patients isolated in a community facility.

INTRODUCTION: Mildly symptomatic cases of Covid-19 in previously-well individuals form the majority of infections and also serve as potent vectors of transmission. The factors affecting the duration of SARS-CoV-2 RNA viral shedding (DVS) in these patients remain largely unknown. OBJECTIVES: To perform a systematic analysis of the clinical, radiologic, laboratory investigations in patients with few comorbidities infected with mild Covid-19 to identify factors associated with the DVS. METHODS: In this retrospective cohort study, patients with mild or asymptomatic Covid-19 were included. Baseline characteristics including age, nationality, comorbidities, concomitant medications, and type of isolation arrangement in the facility (single or in pairs) were collected. Clinical features and radiologic/haematologic findings were also collected. Taking day 28 as the cut-off, 187 patients who had a negative swab result up to day 28 (no prolonged DVS) were compared to 126 patients with a persistently positive result on or after day 28 (prolonged DVS). RESULTS: Of 964 consecutive patients included, 851 (88.3%) patients were symptomatic. 266 patients had a documented negative RT-PCR assay with a median DVS of 25 days (range: 13 to 96 days; interquartile range (IQR): 22 to 33 days). Patients isolated in pairs were associated with prolonged DVS (OR: 2.7; 95% CI: 1.7 to 4.5; p<0.0001) compared to those isolated individually. Among vital signs, only tachycardia was associated with prolonged DVS (OR: 2.6; 95% CI: 1.0 to 7.1; p = 0.03). Amongst investigations, only a raised CRP was associated with prolonged DVS (OR: 2.7; 95% CI: 1.1 to 6.8; p = 0.02). CONCLUSIONS: In young, mildly symptomatic Covid-19 patients, prolonged DVS was associated with being isolated in pairs compared to individually. In situations where a negative RT-PCR test result is required, retesting in patients who were not isolated individually, or who had baseline tachycardia or a raised CRP, may be delayed to increase the yield of a negative result.