Granzyme K mediates IL-23-dependent inflammation and keratinocyte proliferation in psoriasis.

Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization in vitro revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity.

Hospital Outcomes Among Children With Congenital Heart Disease and Adenovirus Pneumonia.

BACKGROUND: The aim of the study is to evaluate the mortality risk factors and hospitalization outcomes of adenovirus pneumonia in pediatric patients with congenital heart disease. METHODS: In this retrospective multicenter cohort study utilizing the Pediatric Health Information System database, we analyzed congenital heart disease patients with adenovirus pneumonia from January 2004 to September 2018, categorizing them into shunts, obstructive lesions, cyanotic lesions and mixing lesions. Multivariate logistic regression analysis was employed to identify mortality risk factors with 2 distinct models to mitigate collinearity issues and the Mann-Whitney U test was used to compare the hospital length of stay between survivors and nonsurvivors across these variables. RESULTS: Among 381 patients with a mean age of 3.2 years (range: 0-4 years), we observed an overall mortality rate of 12.1%, with the highest mortality of 15.1% noted in patients with shunts. Model 1 identified independent factors associated with increased mortality, including age 0-30 days (OR: 8.13, 95% CI: 2.57-25.67, P < 0.005), sepsis/shock (OR: 3.34, 95% CI: 1.42-7.83, P = 0.006), acute kidney failure (OR: 4.25, 95% CI: 2.05-13.43, P = 0.0005), shunts (OR: 2.95, 95% CI: 1.14-7.67, P = 0.03) and cardiac catheterization (OR: 6.04, 95% CI: 1.46-24.94, P = 0.01), and Model 2, extracorporeal membrane oxygenation (OR: 3.26, 95% CI: 1.35-7.87, P = 0.008). Nonsurvivors had a median hospital stay of 47 days compared to 15 days for survivors. CONCLUSION: The study revealed a 12.1% mortality rate in adenoviral pneumonia among children with congenital heart disease, attributed to risk factors such as neonates, sepsis, acute kidney failure, shunts, cardiac catheterization, extracorporeal membrane oxygenation use and a 3-fold longer hospital stay for nonsurvivors compared to survivors.

Incidence and profile of skin cancers in patients following ultraviolet phototherapy without psoralens: A retrospective cohort study.

BACKGROUND: Psoralen + ultraviolet-A (PUVA) is associated with photocarcinogenesis. However, carcinogenic risk with other ultraviolet phototherapies remains unclear. OBJECTIVE: Evaluate whether phototherapy without psoralens increases skin cancer risk. METHODS: Retrospective cohort study of patients treated at a teaching-hospital phototherapy center (1977-2018). Skin cancer records were validated against pathology reports. Age-standardized incidence rates (ASIRs) of skin cancer were evaluated for gender, skin phototype, diagnosis, ultraviolet modality, anatomical site; and compared to provincial population incidence rates (2003). RESULTS: In total, 3506 patients treated with broadband-ultraviolet-B, narrowband-UVB and/or combined UVAB were assessed with a mean follow-up of 7.3 years. Majority of patients had psoriasis (60.9%) or eczema (26.4%). Median number of treatments was 43 (1-3598). Overall, 170 skin cancers (17 melanoma, 33 squamous cell carcinoma and 120 basal cell carcinoma) occurred in 79 patients. Patient-based and tumor-based ASIR of skin cancer was 149 (95% CI: 112-187)/100,000 and 264 (219-309)/100,000 person-years, respectively. There was no significant difference between tumor-based ASIRs for melanoma, squamous cell carcinoma, and basal cell carcinoma compared to the general population; or in phototherapy patients with-psoriasis or eczema; or immunosuppressants. No cumulative dose-response correlation between UVB and skin cancer was seen. LIMITATIONS: Treatment and follow-up duration. CONCLUSION: No increased risk of melanoma and keratinocyte cancer was found with phototherapy.

PRAME Immunohistochemistry for Distinguishing Vulvar and Vaginal Melanoma From Benign Melanocytic Nevi.

Vulvovaginal melanoma (VVM) is a rare but deadly disease, accounting for 5% of all vulvar malignancies, with a 5-yr survival rate of only 47% for all stages of the disease. VVM is a distinct subset of melanoma, with a unique genomic profile and underlying pathogenesis unassociated with sun exposure. Distinguishing these rare malignancies from very common pigmented lesions of the vulva and vagina is challenging as histologic features often overlap between entities. PReferentially expressed Antigen in MElanoma (PRAME) is a melanoma-associated protein, and immunohistochemistry (IHC) for PRAME distinguishes cutaneous, oral mucosal, and retinal melanoma from atypical nevi. Given the biological differences between VVM and cutaneous melanoma, the utility of PRAME IHC for the diagnosis of VVM is unknown. We accrued a cohort of 20 VVM and 21 benign vulvar melanocytic nevi. We found that nuclear PRAME IHC staining with 4+ intensity was present in 85% of the VVM and 0% of the nevi. With the assistance of PRAME IHC, we found evidence of close or positive margin involvement in 3 of 10 cases where margins were originally diagnosed as negative for melanoma in situ. Our study is the first to assess PRAME IHC in a cohort of VVM cases and provides confidence for using PRAME IHC to assist with diagnosis and margin assessment in this rare disease.

A comparative study of outcomes of burns across multiple levels of care.

BACKGROUND: Burn injuries are a significant contributor to the burden of diseases. The management of burns at specialised burn centres has been shown to improve survival. However, in low- and middle-income countries (LMICs) major burns are managed at non-specialised burn centres due to resource constraints. There is insufficient data on survival from treatment at non-specialised burn centres in LMICs. This study aimed to compare the outcomes of burns treatment between a specialised burn centre and five non-specialised centres. METHODS: A prospective cohort study was conducted on patients aged 18 years or above from January 1, 2021 to September 30, 2021. Participants were selected from the admission register at the emergency department. All burns irrespective of the mechanism of injury or %TBSA were included. Data were entered into REDCap. Statistical analysis of outcomes such as positive blood culture, length of hospital stay (LOHS) and 90-day mortality between specialised burn versus non-specialised centres was performed. Furthermore, an analysis of risk factors for mortality was performed and survival data computed. RESULTS: Of the 488 study participants, 36% were admitted to a specialised burn centre compared to 64% admitted to non-specialised centres. The demographic characteristics were similar between centres. Patients at the specialised burn centre compared to non-specialised centres had a significantly higher inhalation injury of 30.9% vs 7.7% (p < 0.001), > 10%TBSA at 83.4% vs 45.7% (p < 0.001), > 20%TBSA at 46.9% vs 16.6% (p < 0.001), and a median (IQR) ABSI score of 6 (5-7) vs 5 (4-6) (p < 0.0001). Furthermore, patients from specialised burn vs non-specialised centres had a longer median (IQR) time from injury to first burn excision at 7 (4-11) vs 5 (2-10) days, higher rate of burn sepsis 69% vs 35%, increased LOHS 17 (11-27) vs 12 (6-22) days, and 90-day mortality rates at 19.4% vs 6.4%. After adjusting for cofounding variables, survival data showed no difference between specialised burn and non-specialised centres (HR 1.8 95% CI 1.0-3.2, p = 0.05). CONCLUSION: Although it appears that the survival of burn patients managed at non-specialised centres in a middle-income country is comparable to those managed at specialised burn centres, there is uncounted bias in our survival data. Hence, a change in practice is not advocated. However, due to resource constraint specialised burn centres in addition to managing major burns should provide training and support to the non-specialised centres.

CD34 Staining as a Useful Tool in Disorders of Collagen Degeneration.

ABSTRACT: The human progenitor-cell antigen CD34 is expressed in dermal dendritic cells and is lost in several disorders affecting dermal collagen. The loss of CD34 immunohistochemical staining has been demonstrated to be helpful in the histologic diagnosis of morphea, lichen sclerosus, and the classic pattern of granuloma annulare. This study characterized CD34 expression in 2 sclerosing disorders affecting the subcutis: lipodermatosclerosis (LDS) and the sclerodermoid form of chronic graft-versus-host disease (ScGVHD). In addition, we applied CD34 staining to the interstitial pattern of granuloma annulare (IGA), which is a diagnostically challenging entity with subtle amounts of dermal collagen degeneration. Fifteen cases of LDS, 6 cases of ScGVHD, and 4 cases of IGA were identified and stained with CD34. All cases of LDS showed loss of CD34 within subcutaneous septa, and 9 cases (60%) also exhibited full-thickness dermal loss of interstitial staining. All 6 cases of ScGVHD showed varying degrees of CD34 loss within the dermis and/or subcutaneous septa. The normal subcutis showed diffuse septal staining with CD34, with a density equal to that seen in the dermis. CD34 staining was lost in areas of dermal inflammation in half of the IGA cases. We conclude that CD34 staining is a useful ancillary test in disease processes affecting the subcutaneous collagen such as LDS and ScGVHD. Its utility also extends to diagnostically challenging disorders of dermal collagen degeneration such as IGA.

Small plaque psoriasis re-visited: A type of psoriasis mediated by a type-I interferon pathway.

TNFα-inhibitor-induced psoriasis is mediated by the type-I interferon pathway, of which IFNα, LL37 and IL-36γ are major players. A subset of patients treated with TNFα inhibitors develop small plaque psoriatic lesions. Small plaque psoriasis is similarly observed in patients on immune checkpoint inhibitors (ICI), and with concurrent systemic lupus erythematosus (SLE) or positive antinuclear antibody (ANA). Small plaque psoriasis is also the predominant phenotype in Asian populations. The association between small plaque psoriasis morphology in various clinical scenarios and the type-I interferon pathway has not been previously studied. A cross-sectional study was conducted of patients who developed small plaque psoriasis and had a biopsy for diagnostic clarification between 2009 and 2017. We obtained skin specimens from 14 adults with small plaque psoriasis: four patients taking anti-TNFα treatment, four patients with antecedent SLE, three patients with concurrent ANA positivity and three patients taking ICI. Controls included three patients with chronic plaque psoriasis. Histology confirmed psoriasiform epidermal hyperplasia with focal lichenoid and spongiotic features. Immunohistochemical analysis revealed higher expression of IFNα-induced MXA, LL37 and IL-36γ in all clinical scenarios of small plaque psoriasis compared to chronic plaque psoriasis. There was decreased CD8 T-cell migration to the epidermis and variability in the number of LAMP3+ cytoplasmic dendritic cells in the dermis of small plaque psoriasis. The findings suggest that small plaque psoriasis is a unique type of psoriasis with a distinct morphology and immune-phenotype, primarily mediated by the type-I interferon pathway. Associating morphology and disease pathogenesis may help identify therapeutic targets for better disease control.

Shock index as a prognosticator for emergent surgical intervention and mortality in trauma patients in Johannesburg: A retrospective cohort study.

INTRODUCTION: Trauma is the leading cause of morbidity and mortality worldwide with exsanguination being the primary preventable cause through early surgical intervention. We assessed two popular trauma scoring systems, injury severity scores (ISS) and shock index (SI) to determine the optimal cut off values that may predict the need for emergent surgical intervention (ESI) and in-hospital mortality. METHODS: A retrospective analysis of patient records from a tertiary hospital's trauma unit for the year 2019 was done. Descriptive statistics, univariate and multivariate logistic regression analyses were performed. Receiver operator characteristic (ROC) curve analysis was conducted and area under the curve (AUC) reported for predicting the need for ESI in all study participants, as well as in patients with penetrating injuries alone, based on continuous variables of ISS, SI or a combination of ISS and SI. The Youdin Index was applied to determine the optimal ISS and SI cut off values. RESULTS: A total of 1964 patients' records were included, 89.0% were male and the median age (IQR) was 30 (26-37) years. Penetrating injuries accounted for 65.9% of all injuries. ISS and SI were higher in the ESI group with median (IQR) 11 (10-17) and 0.74 (0.60-0.95), respectively. The overall mortality rate was 4.5%. The optimal cut-off values for ESI and mortality by ISS (AUC) were 9 (0.74) and 12 (0.86) (p = 0.0001), with optimal values for SI (AUC) being 0.72 (0.60), and 0.91 (0.68) (p = 0.0001), respectively. CONCLUSION: ISS and SI are significant, independent prognosticators for the need of ESI and in-hospital mortality.

Variable Presentation of COVID-19 in Pediatric Patients.

Infection by SARS-CoV-2 has led to disease referred to as coronavirus disease 2019 which, in children has been described as of multisystem inflammatory syndrome in children. Our experience demonstrates 2 distinct presentations of this syndrome which have different clinical courses and may have differing long-term outcomes.

Granzyme B inhibition reduces disease severity in autoimmune blistering diseases.

Pemphigoid diseases refer to a group of severe autoimmune skin blistering diseases characterized by subepidermal blistering and loss of dermal-epidermal adhesion induced by autoantibody and immune cell infiltrate at the dermal-epidermal junction and upper dermis. Here, we explore the role of the immune cell-secreted serine protease, granzyme B, in pemphigoid disease pathogenesis using three independent murine models. In all models, granzyme B knockout or topical pharmacological inhibition significantly reduces total blistering area compared to controls. In vivo and in vitro studies show that granzyme B contributes to blistering by degrading key anchoring proteins in the dermal-epidermal junction that are necessary for dermal-epidermal adhesion. Further, granzyme B mediates IL-8/macrophage inflammatory protein-2 secretion, lesional neutrophil infiltration, and lesional neutrophil elastase activity. Clinically, granzyme B is elevated and abundant in human pemphigoid disease blister fluids and lesional skin. Collectively, granzyme B is a potential therapeutic target in pemphigoid diseases.

Comparison of p53 immunohistochemical staining in differentiated vulvar intraepithelial neoplasia (dVIN) with that in inflammatory dermatoses and benign squamous lesions in the vulva.

AIMS: Differentiated vulvar intraepithelial neoplasia (dVIN), the precursor lesion to human papillomavirus-independent vulvar squamous cell carcinoma (VSCC), can be difficult to distinguish from vulvar inflammatory dermatoses. Our goal was to determine if p53 could be a useful biomarker for dVIN, by characterizing p53 percentage, intensity and patterns of staining in dVIN and its histological mimics. METHODS AND RESULTS: We studied p53 immunohistochemical staining patterns in 16 dVIN cases and 46 vulvar non-neoplastic squamous lesions [12 lichen sclerosus (LS); seven lichen simplex chronicus; three lichen planus (LP); six psoriasis; 13 spongiotic dermatitis (SPO); and five candidiasis]. dVIN cases were adjacent to a p16-negative invasive VSCC in resection specimens. All dVIN cases showed null-type or moderate to strong uniform p53 staining in >70% of basal cells, with moderate to strong continuous parabasal staining extending to two-thirds of the epidermis. This was in contrast to weak or weak to moderate patchy p53 staining in the majority of other lesions. Moderate to strong and increased basal p53 staining (≥70%) was also observed in a subset of LS cases (5/12, 42%), LP cases (1/3, 33%), and SPO cases (36%, 4/11); however, in all categories, this was limited to the basal layer, and any staining in the parabasal layers was patchy. CONCLUSION: Strong and uniform p53 staining of basal cells, extending into the parabasal layers, and a complete absence of staining (null type) is useful in distinguishing dVIN from other mimics in the vulva. p53 staining of lesser intensity or quantity, particularly basal overexpression only, overlaps with that in vulvar inflammatory lesions.

Symptom Profiles of a Convenience Sample of Patients with COVID-19 - United States, January-April 2020.

Coronavirus disease 2019 (COVID-19) was first detected in the United States in January 2020 (1), and by mid-July, approximately 3.4 million cases had been reported in the United States (2). Information about symptoms among U.S. COVID-19 patients is limited, especially among nonhospitalized patients. To better understand symptom profiles of patients with laboratory-confirmed COVID-19 in the United States, CDC used an optional questionnaire to collect detailed information on a convenience sample of COVID-19 patients from participating states. Symptom data were analyzed by age group, sex, hospitalization status, and symptom onset date relative to expansion of testing guidelines on March 8, 2020 (3). Among 164 symptomatic patients with known onset during January 14-April 4, 2020, a total of 158 (96%) reported fever, cough, or shortness of breath. Among 57 hospitalized adult patients (aged ≥18 years), 39 (68%) reported all three of these symptoms, compared with 25 (31%) of the 81 nonhospitalized adult patients. Gastrointestinal (GI) symptoms and other symptoms, such as chills, myalgia, headache, and fatigue, also were commonly reported, especially after expansion of testing guidelines. To aid prompt recognition of COVID-19, clinicians and public health professionals should be aware that COVID-19 can cause a wide variety of symptoms.

Characteristics of Persons Who Died with COVID-19 - United States, February 12-May 18, 2020.

During January 1, 2020-May 18, 2020, approximately 1.3 million cases of coronavirus disease 2019 (COVID-19) and 83,000 COVID-19-associated deaths were reported in the United States (1). Understanding the demographic and clinical characteristics of decedents could inform medical and public health interventions focused on preventing COVID-19-associated mortality. This report describes decedents with laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19, using data from 1) the standardized CDC case-report form (case-based surveillance) (https://www.cdc.gov/coronavirus/2019-ncov/php/reporting-pui.html) and 2) supplementary data (supplemental surveillance), such as underlying medical conditions and location of death, obtained through collaboration between CDC and 16 public health jurisdictions (15 states and New York City).