Performance of an automated total body mapping algorithm to detect melanocytic lesions of clinical relevance.

IMPORTANCE: Total body photography for skin cancer screening is a well-established tool allowing documentation and follow-up of the entire skin surface. Artificial intelligence-based systems are increasingly applied for automated lesion detection and diagnosis. DESIGN AND PATIENTS: In this prospective observational international multicentre study experienced dermatologists performed skin cancer screenings and identified clinically relevant melanocytic lesions (CRML, requiring biopsy or observation). Additionally, patients received 2D automated total body mapping (ATBM) with automated lesion detection (ATBM master, Fotofinder Systems GmbH). Primary endpoint was the percentage of CRML detected by the bodyscan software. Secondary endpoints included the percentage of correctly identified "new" and "changed" lesions during follow-up examinations. RESULTS: At baseline, dermatologists identified 1075 CRML in 236 patients and 999 CRML (92.9%) were also detected by the automated software. During follow-up examinations dermatologists identified 334 CRMLs in 55 patients, with 323 (96.7%) also being detected by ATBM with automated lesions detection. Moreover, all new (n = 13) or changed CRML (n = 24) during follow-up were detected by the software. Average time requirements per baseline examination was 14.1 min (95% CI [12.8-15.5]). Subgroup analysis of undetected lesions revealed either technical (e.g. covering by clothing, hair) or lesion-specific reasons (e.g. hypopigmentation, palmoplantar sites). CONCLUSIONS: ATBM with lesion detection software correctly detected the vast majority of CRML and new or changed CRML during follow-up examinations in a favourable amount of time. Our prospective international study underlines that automated lesion detection in TBP images is feasible, which is of relevance for developing AI-based skin cancer screenings.

Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency.

Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.

Health Economic Consequences Associated With COVID-19-Related Delay in Melanoma Diagnosis in Europe.

Importance: The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet. Objective: To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe. Design, Setting, and Participants: This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous melanomas stages I to IV according to the American Joint Committee on Cancer (AJCC) seventh and eighth editions, including melanomas of unknown primary (T0). Data were collected from January 2017 to December 2021 in Switzerland and from January 2019 to December 2021 in Hungary. Data were used to develop an estimation of melanoma upstaging rates in AJCC stages, which was verified with peripandemic data. Years of life lost (YLL) were calculated and were, together with cost data, used for financial estimations. The total financial burden was assessed through direct and indirect treatment costs. Models were building using data from 50 072 patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV according to the AJCC seventh and eighth edition, including melanomas of unknown primary (T0) from 2 European tertiary centers. Data from European cancer registries included patient-based direct and indirect cost data, country-level economic indicators, melanoma incidence, and population rates per country. Data were analyzed from July 2021 to September 2022. Exposure: COVID-19 lockdown-related delay of melanoma detection and consecutive public health and economic burden. As lockdown restrictions varied by country, lockdown scenario was defined as elimination of routine medical examinations and severely restricted access to follow-up examinations for at least 4 weeks. Main Outcomes and Measures: Primary outcomes were the total burden of a delay in melanoma diagnosis during COVID-19 lockdown periods, measured using the direct (in US$) and indirect (calculated as YLL plus years lost due to disability [YLD] and disability-adjusted life-years [DALYs]) costs for Europe. Secondary outcomes included estimation of upstaging rate, estimated YLD, YLL, and DALY for each European country, absolute direct and indirect treatment costs per European country, proportion of the relative direct and indirect treatment costs for the countries, and European health expenditure. Results: There were an estimated 111 464 (range, 52 454-295 051) YLL due to pandemic-associated delay in melanoma diagnosis in Europe, and estimated total additional costs were $7.65 (range, $3.60 to $20.25) billion. Indirect treatment costs were the main cost driver, accounting for 94.5% of total costs. Estimates for YLD in Europe resulted in 15 360 years for the 17% upstaging model, ranging from 7228 years (8% upstaging model) to 40 660 years (45% upstaging model). Together, YLL and YLD constitute the overall disease burden, ranging from 59 682 DALYs (8% upstaging model) to 335 711 DALYs (45% upstaging model), with 126 824 DALYs for the real-world 17% scenario. Conclusions and Relevance: This economic analysis emphasizes the importance of continuing secondary skin cancer prevention measures during pandemics. Beyond the personal outcomes of a delayed melanoma diagnosis, the additional economic and public health consequences are underscored, emphasizing the need to include indirect economic costs in future decision-making processes. These estimates on DALYs and the associated financial losses complement previous studies highlighting the cost-effectiveness of screening for melanoma.

Position statement of the EADV Artificial Intelligence (AI) Task Force on AI-assisted smartphone apps and web-based services for skin disease.

BACKGROUND: As the use of smartphones continues to surge globally, mobile applications (apps) have become a powerful tool for healthcare engagement. Prominent among these are dermatology apps powered by Artificial Intelligence (AI), which provide immediate diagnostic guidance and educational resources for skin diseases, including skin cancer. OBJECTIVE: This article, authored by the EADV AI Task Force, seeks to offer insights and recommendations for the present and future deployment of AI-assisted smartphone applications (apps) and web-based services for skin diseases with emphasis on skin cancer detection. METHODS: An initial position statement was drafted on a comprehensive literature review, which was subsequently refined through two rounds of digital discussions and meticulous feedback by the EADV AI Task Force, ensuring its accuracy, clarity and relevance. RESULTS: Eight key considerations were identified, including risks associated with inaccuracy and improper user education, a decline in professional skills, the influence of non-medical commercial interests, data security, direct and indirect costs, regulatory approval and the necessity of multidisciplinary implementation. Following these considerations, three main recommendations were formulated: (1) to ensure user trust, app developers should prioritize transparency in data quality, accuracy, intended use, privacy and costs; (2) Apps and web-based services should ensure a uniform user experience for diverse groups of patients; (3) European authorities should adopt a rigorous and consistent regulatory framework for dermatology apps to ensure their safety and accuracy for users. CONCLUSIONS: The utilisation of AI-assisted smartphone apps and web-based services in diagnosing and treating skin diseases has the potential to greatly benefit patients in their dermatology journeys. By prioritising innovation, fostering collaboration and implementing effective regulations, we can ensure the successful integration of these apps into clinical practice.

The effects of procedural and conceptual knowledge on visual learning.

Even though past research suggests that visual learning may benefit from conceptual knowledge, current interventions for medical image evaluation often focus on procedural knowledge, mainly by teaching classification algorithms. We compared the efficacy of pure procedural knowledge (three-point checklist for evaluating skin lesions) versus combined procedural plus conceptual knowledge (histological explanations for each of the three points). All students then trained their classification skills with a visual learning resource that included images of two types of pigmented skin lesions: benign nevi and malignant melanomas. Both treatments produced significant and long-lasting effects on diagnostic accuracy in transfer tasks. However, only students in the combined procedural plus conceptual knowledge condition significantly improved their diagnostic performance in classifying lesions they had seen before in the pre- and post-tests. Findings suggest that the provision of additional conceptual knowledge supported error correction mechanisms.

Factors related to the performance of laypersons diagnosing pigmented skin cancer: an explorative study.

It is important but challenging for prospective health professionals to learn the visual distinction between potentially harmful and harmless skin lesions, such as malignant melanomas and benign nevi. Knowledge about factors related to diagnostic performance is sparse but a prerequisite for designing and evaluating evidence-based educational interventions. Hence, this study explored how the characteristics of 240 skin lesions, the number of classified lesions and the response times of 137 laypeople were related to performance in diagnosing pigmented skin cancer. Our results showed large differences between the lesions, as some were classified correctly by more than 90% and others by less than 10% of the participants. A t-test showed that for melanomas, the correct diagnosis was provided significantly more often than for nevi. Furthermore, we found a significant Pearson correlation between the number of solved tasks and performance in the first 50 diagnostic tasks. Finally, t-tests for investigating the response times revealed that compared to true decisions, participants spent longer on false-negative but not on false-positive decisions. These results provide novel knowledge about performance-related factors that can be useful when designing diagnostic tests and learning interventions for melanoma detection.

Multimodal feedback systems for smart laser osteotomy: Depth control and tissue differentiation.

OBJECTIVES: The study aimed to improve the safety and accuracy of laser osteotomy (bone surgery) by integrating optical feedback systems with an Er:YAG laser. Optical feedback consists of a real-time visual feedback system that monitors and controls the depth of laser-induced cuts and a tissue sensor differentiating tissue types based on their chemical composition. The developed multimodal feedback systems demonstrated the potential to enhance the safety and accuracy of laser surgery. MATERIALS AND METHODS: The proposed method utilizes a laser-induced breakdown spectroscopy (LIBS) system and long-range Bessel-like beam optical coherence tomography (OCT) for tissue-specific laser surgery. The LIBS system detects tissue types by analyzing the plasma generated on the tissue by a nanosecond Nd:YAG laser, while OCT provides real-time monitoring and control of the laser-induced cut depth. The OCT system operates at a wavelength of 1288 ± 30 nm and has an A-scan rate of 104.17 kHz, enabling accurate depth control. Optical shutters are used to facilitate the integration of these multimodal feedback systems. RESULTS: The proposed system was tested on five specimens of pig femur bone to evaluate its functionality. Tissue differentiation and visual depth feedback were used to achieve high precision both on the surface and in-depth. The results showed successful real-time tissue differentiation and visualization without any visible thermal damage or carbonization. The accuracy of the tissue differentiation was evaluated, with a mean absolute error of 330.4 µm and a standard deviation of ±248.9 µm, indicating that bone ablation was typically stopped before reaching the bone marrow. The depth control of the laser cut had a mean accuracy of 65.9 µm with a standard deviation of ±45 µm, demonstrating the system's ability to achieve the pre-planned cutting depth. CONCLUSION: The integrated approach of combining an ablative laser, visual feedback (OCT), and tissue sensor (LIBS) has significant potential for enhancing minimally invasive surgery and warrants further investigation and development.

Towards phase-sensitive optical coherence tomography in smart laser osteotomy: temperature feedback.

Thermal effects during bone surgery pose a common challenge, whether using mechanical tools or lasers. An irrigation system is a standard solution to cool the tissue and reduce collateral thermal damage. In bone surgery using Er:YAG laser, insufficient irrigation raises the risk of thermal damage, while excessive water lowers ablation efficiency. This study investigated the potential of optical coherence tomography to provide feedback by relating the temperature rise with the photo-thermal expansion of the tissue. A phase-sensitive optical coherence tomography system (central wavelength of λ=1.288 µm, a bandwidth of 60.9 nm and a sweep rate of 104.17 kHz) was integrated with an Er:YAG laser using a custom-made dichromatic mirror. Phase calibration was performed by monitoring the temperature changes (thermal camera) and corresponding cumulative phase changes using the phase-sensitive optical coherence tomography system during laser ablation. In this experiment, we used an Er:YAG laser with 230 mJ per pulse at 10 Hz for ablation. Calibration coefficients were determined by fitting the temperature values to phase later and used to predict the temperature rise for subsequent laser ablations. Following the phase calibration step, we used the acquired values to predict the temperature rise of three different laser-induced cuts with the same parameters of the ablative laser. The average root-mean-square error for the three experiments was measured to be around 4 °C. In addition to single-point prediction, we evaluated this method's performance to predict the tissue's two-dimensional temperature rise during laser osteotomy. The findings suggest that the proposed principle could be used in the future to provide temperature feedback for minimally invasive laser osteotomy.

Diagnostic performance of augmented intelligence with 2D and 3D total body photography and convolutional neural networks in a high-risk population for melanoma under real-world conditions: A new era of skin cancer screening?

BACKGROUND: Convolutional neural networks (CNNs) have outperformed dermatologists in classifying pigmented skin lesions under artificial conditions. We investigated, for the first time, the performance of three-dimensional (3D) and two-dimensional (2D) CNNs and dermatologists in the early detection of melanoma in a real-world setting. METHODS: In this prospective study, 1690 melanocytic lesions in 143 patients with high-risk criteria for melanoma were evaluated by dermatologists, 2D-FotoFinder-ATBM and 3D-Vectra WB360 total body photography (TBP). Excision was based on the dermatologists' dichotomous decision, an elevated CNN risk score (study-specific malignancy cut-off: FotoFinder >0.5, Vectra >5.0) and/or the second dermatologist's assessment with CNN support. The diagnostic accuracy of the 2D and 3D CNN classification was compared with that of the dermatologists and the augmented intelligence based on histopathology and dermatologists' assessment. Secondary end-points included reproducibility of risk scores and naevus counts per patient by medical staff (gold standard) compared to automated 3D and 2D TBP CNN counts. RESULTS: The sensitivity, specificity, and receiver operating characteristics area under the curve (ROC-AUC) for risk-score-assessments compared to histopathology of 3D-CNN with 95% confidence intervals (CI) were 90.0%, 64.6% and 0.92 (CI 0.85-1.00), respectively. While dermatologists and augmented intelligence achieved the same sensitivity (90%) and comparable classification ROC-AUC (0.91 [CI 0.80-1.00], 0.88 [CI 0.77-1.00]) with 3D-CNN, their specificity was superior (92.3% and 86.2%, respectively). The 2D-CNN (sensitivity: 70%, specificity: 40%, ROC-AUC: 0.68 [CI 0.46-0.90]) was outperformed by 3D CNN and dermatologists. The 3D-CNN showed a higher correlation coefficient for repeated measurements of 246 lesions (R = 0.89) than the 2D-CNN (R = 0.79). The mean naevus count per patient varied significantly (gold standard: 210 lesions; 3D-CNN: 469; 2D-CNN: 1324; p < 0.0001). CONCLUSIONS: Our study emphasises the importance of validating the classification of CNNs in real life. The novel 3D-CNN device outperformed the 2D-CNN and achieved comparable sensitivity with dermatologists. The low specificity of CNNs and the lack of automated counting of TBP nevi currently limit the use of augmented intelligence in clinical practice.

Autoimmunity and immunodeficiency associated with monoallelic LIG4 mutations via haploinsufficiency.

BACKGROUND: Biallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step. OBJECTIVES: This study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance. METHODS: Extensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed. RESULTS: A novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4+ T cells and low TCR-Vα7.2+ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient. CONCLUSIONS: This study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

Pruritus in cutaneous graft-versus-host disease: A systematic review.

Pruritus is a common symptom of cutaneous graft-versus-host disease (GVHD) following haematopoietic stem cell transplantation (HSCT). However, little is known about its prevalence, pathophysiology, perceptual characteristics, impact on quality of life and response to antipruritic therapies. The aim of this review was to determine the current knowledge on pruritus in cutaneous GVHD. The review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Of the 338 studies screened, 13 were included. The prevalence of pruritus in cutaneous GVHD was reported in three studies, ranging from 37.0% to 63.8%. Only four trials used pruritus assessment tools. There was little or no information on the intensity of pruritus, its qualitative perception, the location of pruritus and the impact of pruritus on quality of life. Antipruritic treatments for GVHD-associated pruritus were mentioned in five studies (38.5%), including topical ointments (steroids, tacrolimus and calcipotriene), broadband UVB, systemic antihistamines and oral ursodeoxycholic acid. In conclusion, pruritus in cutaneous GVHD appears to be common, but very little is known about the pathophysiology, impact on quality of life and effective treatment options. Basic research and controlled clinical trials are warranted to improve knowledge and management of this important issue.

Doppler Ultrasound-Guided Filler Injections: Useful Tips to Integrate Ultrasound in Daily Practice.

The development of high-frequency devices and transducers in recent years has enabled the growth of the use of dermatologic ultrasound. Real-time monitoring of the anatomy of the face during the application of aesthetic injectables potentially prevents complications such as vascular occlusions. Injecting physicians starting out in the practice of ultrasound-guided injections are commonly faced with practical questions about its use. In this article, based on the experience with ultrasound-guided filler injections of 2 large clinical centers in 2 countries, the authors summarize the steps involved when setting out to use ultrasound to guide injectable aesthetic procedures, such as fillers and biostimulators. First, the authors discuss factors that guide the choice of equipment and ultrasound transducers to perform the procedures. Next, a detailed discussion on practical issues related to the procedure is provided. The authors then consider the positioning of operators and equipment in the treatment field. The authors conclude by suggesting 2 possible techniques to guide injectable procedures: (1) scan before injecting or (2) scan while injecting.

Swiss Recommendations for Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer in Switzerland and worldwide. Most BCCs can be treated in a curative setting. However, patients can develop locally destructive and, rarely, metastatic tumors that require a different treatment approach. The clinical subtype of individual lesions provides prognostic information and influences management decisions. Surgical excision, topical therapies, and radiotherapy are highly effective in the majority of subtypes as well as in low- and high-risk diseases. For patients with low-risk diseases and superficial tumors not amenable to surgery, several nonsurgical alternatives are available. Systemic therapy is indicated for high-risk BCCs, which are not amenable to either surgery or radiotherapy. Hedgehog pathway inhibitors (HHI) are currently approved. Other therapeutic options such as immune checkpoint inhibitors show promising results in clinical trials. This first version of Swiss recommendations for diagnosis and management of BCC was prepared through extensive literature review and an advisory board consensus of expert dermatologists and oncologists in Switzerland. The present guidelines recommend therapies based on a multidisciplinary team approach and rate of recurrence for individual lesions. Based on the risk of recurrence, two distinct groups have been identified: low-risk (easy-to-treat) and high-risk (difficult-to-treat) tumors. Based on these classifications, evidence-based recommendations of available therapies are presented herein.

Radiotherapy as a Treatment Option for Local Disease Control in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type.

BACKGROUND: Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is an aggressive lymphoma variant. Anthracycline-based chemotherapy with rituximab is recommended as first-line treatment. Radiotherapy (RT) has been considered as a therapeutic option for local disease control in patients with solitary or localized lesions. METHODS: We report the results of a retrospective analysis of PCDLBC, LT patients treated either with RT alone or with physician's decision as first-line treatment, aiming to assess disease progression and/or first recurrence in these treatment groups. RESULTS: We retrospectively analyzed 20 patients treated either with RT alone (n = 8) or with investigator's choice treatment (n = 12), which included chemotherapy alone or combined with local therapy (RT and wide local excision). Complete response (CR) was achieved in 8 patients from the first group and 9 patients from the second group, with 1 treatment failure. Six patients treated with RT alone progressed with a median time to progression (TTP) of 12.5 months. In the second group, 5 patients progressed with a median TTP of 5.2 months. RT showed good local disease control in both groups without any skin relapses during the follow-up period. CONCLUSION: RT as first-line monotherapy followed by watchful waiting did not significantly improve the overall risk of disease progression but resulted in good local disease control. After progression, RT could still easily be combined with systemic treatment. The strength of this analysis needs to be evaluated in a larger patient cohort.

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

BACKGROUND: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice. OBJECTIVE: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians. METHODS: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included. RESULTS: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images. CONCLUSIONS: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.

NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism.

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

Association of Clinical and Demographic Factors With the Severity of Palmoplantar Pustulosis.

Importance: Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied. Objective: To examine the factors associated with PPP severity. Design, Setting, and Participants: An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020. Main Outcomes and Measures: Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). Results: Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = -0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) vs men (4.0 [IQR, 1.0-11.7]) (P = .01). Likewise, moderate to severe PPP was more prevalent among Northern European women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03). In the UK cohort, the median PPPASI score was increased in current smokers (10.7 [IQR, 4.2-17.5]) compared with former smokers (7 [IQR, 2.0-14.4]) and nonsmokers (2.2 [IQR, 1-6]) (P = .003). Comparable differences were observed in the Northern European data set, as the prevalence of moderate to severe PPP was higher in former and current smokers (51 of 130 [39%]) compared with nonsmokers (6 of 24 [25%]) (P = .14). Conclusions and Relevance: The findings of this study suggest that PPP severity is associated with early-onset disease, female sex, and smoking status. Thus, smoking cessation intervention might be beneficial.

National Publication Productivity during the COVID-19 Pandemic-A Preliminary Exploratory Analysis of the 30 Countries Most Affected.

BACKGROUND: The COVID 19 pandemic increased publication productivity enormously with numerous new COVID-19-related articles appearing daily, despite the fact that many health care workers in the partially overburdened national health care systems were faced with major challenges. METHODS: In a cross-sectional, observational, retrospective study we compared and correlated 17 epidemiologic, health care system-related and health-economic factors from medical databases and intergovernmental organisations potentially influencing the COVID-19 and non-COVID-19 publication productivity between 1 January and 30 April 2020 amongst the 30 countries most severely affected by the pandemic. These factors were additionally correlated with the national pre-COVID-19 publication rate for the same pre-year period to identify potential changes in the general publication behaviour. FINDINGS: COVID-19 and non-COVID-19 publication rates correlated strongest with access to and quality of health care (ρ = 0.80 and 0.87, p < 0.0001), COVID-19 cases per capita (ρ = 0.78 and 0.72, p < 0.0001), GDP per capita (ρ = 0.69 and 0.76, p < 0.0001), health spending per capita (ρ = 0.61 and 0.73, p < 0.0001) and the pre-COVID-19 Hirsch-Index (ρ = 0.61 and 0.62, p = 0.002 and <0.0001). Ratios of publication rates for "Cancer", "Diabetes" and "Stroke" in 2020 versus the pre-year period were 0.88 ± 0.06, 1.02 ± 0.18 and 0.9 ± 0.20, resulting in a pooled ratio of 0.93 ± 0.06 for non-COVID-19 publications. INTERPRETATION: There are marked geographic and national differences in publication productivity during the COVID-19 pandemic. Both COVID-19- and non-COVID-19 publication productivity correlates with epidemiologic, health care system-related and healtheconomic factors, and pre-COVID publication expertise. Countries with a stable scientific infrastructure appear to maintain non-COVID-19 publication productivity nearly at the pre-year level and at the same time use their resilience to produce COVID-19 publications at high rates.