tbuckley/cabot-search huggingface dataset:
P125 Improving bench-to-clinic transition with novel psoriasis-on-a-chip fluidics
Journal: British Journal of Dermatology (2024)

Abstract Topical drug development bears a 50× higher cost of failure compared with oral therapies. Adverse skin reactions account for 2% of drug attrition. Current pre-clinical skin models do not fully replicate in vivo skin physiology which impacts bench-to-clinic translation. In psoriasis, no new topical therapeutics has been introduced into the NHS for over 10 years. Thus, there is an urgent need to revolutionise and improve pre-clinical testing to ensure new, effective and safe therapies can reach patients. We present new fluidic skin-on-chip technology that maintains healthy human skin tissue in culture with full barrier function, resident immune cells and viability. By reconsidering environmental control and cell culture media chemistry, full skin barrier function was maintained for 5 days. This enabled novel extended 5-day repeat-dose permeation studies with simultaneous functional and toxicology analysis. The skin-on-chip technology was found to improve the accuracy of skin irritation assessment, due to the ability to include analysis of skin barrier disruption as well as impact on viability, superseding 3D skin models which can only assess skin irritation by loss of viability. This new technology was assessed with topical application of Tapinarof (formulated as VTAMA, an FDA approved therapeutic for psoriasis). We demonstrated a reduction of CD4+ and CD8+ immune cells by FACS analysis in cultured ex vivo skin. VTAMA-treated psoriasis biopsies displayed remarkably improved histology with reduced acanthosis of rete ridges. Recovery of skin barrier function, measured by trans-epidermal water loss, was confirmed after 3 days of culture. Further analysis of the skin-on-chip technology using cultured ex vivo psoriasis biopsies showed the system was able to retain histological features of psoriasis in untreated samples. Overall, our data indicates the skin-on-chip technology provides superior preclinical analysis which better replicates clinical responses compared with current methods. This has the potential to drastically reduce failure rates at clinical testing phases and ensure effective and safe therapies can reach patients faster.
Adverse Events Following Vaccines: From Detection to Research Translation
Authors: Edward Fernandez, Jordon Jaggers, Allison E. Norton, Cosby Stone, Elizabeth Phillips
Journal: Annual Review of Public Health (2024)

Vaccines are lifesaving interventions that reduce the morbidity and mortality of disease. Fortunately, serious adverse events with vaccination are uncommon, but they must promptly be recognized and evaluated to assess and clarify the safety of future administration, a process that the public must understand in order to feel safe in receiving vaccines. In this article, we provide a review of vaccine development, discuss the process by which safety is ensured, and describe key adverse events associated with their administration. We review in detail existing mechanisms for reporting these events and assessing them following recovery, as well as communication related to vaccine safety. We also describe barriers to vaccination, such as nocebo effects and antivaccination groups, and use lessons learned from the successful development of COVID-19 vaccines during the recent pandemic to define future opportunities and directions for vaccine safety.
P101 Are we ready to use the WHO-5 questionnaire in Psoriasis?
Journal: British Journal of Dermatology (2024)

Abstract Since its first publication in 1998, the 5-item World Health Organization Wellbeing index ‘WHO-5’ has become one of the most widely used questionnaires to assess psychological wellbeing. In this systematic review, we provide an overview of its use in psoriasis compared with other disease areas. Studies reporting the use of WHO-5 were searched on the MEDLINE database and classified using the 11th version of the International Classification of Diseases (ICD). The WHO-5 items recall the previous 2-week period and include the following domains: (i) ‘cheerful and in good spirits’; (ii) ‘calm and relaxed’; (iii) ‘active and vigorous’; (iv) ‘I woke up fresh and rested’; and (v) ‘daily life filled with things that interest me’. The answers range from 5 (all the time) to 0 (never), and the resulting score (multiplied by 4) ranges from 0 (wellbeing absence) to 100 (maximal wellbeing). A total of 493 studies belonging to 11 ICD groups were included (Table 1). Only six studies reported the use of WHO-5 in diseases of the skin: three in psoriasis, two in lichen sclerosus, and one in general skin conditions. The first psoriasis study to use WHO-5 in moderate-to-severe patients reported an overall WHO-5 score of 53.8 ± 27.0. A second study found significant differences in wellbeing depending upon the severity of the disease: 58.2 ± 10.7 in patients with mild (PASI&amp;lt;7) vs. 47.8 ± 12.0 in severe disease (PASI &amp;gt; 12). In a third study including patients with controlled psoriasis (PASI 2.4 ± 4.2), WHO-5 at baseline and 12 weeks later were 62.4 ± 11.2 and 65.6 ± 10.8, respectively. The impact of moderate-to-severe psoriasis on psychological wellbeing is of a similar level to other diseases with distress, such as breast cancer (52.0), uncontrolled diabetes (51.4) and idiopathic pulmonary fibrosis (52.4). In conclusion, WHO-5 is a short questionnaire widely used in several disease areas to detect when a disease impairs psychological wellbeing. Despite very few number of studies, data suggest that moderate-to-severe psoriasis has a profound impact on the psychological wellbeing of patients and warrants further research. Table 1WHO-5 use across disease areasDisease-related areaNo. of studiesCOVID-19 pandemic147Endocrinology109Mental, behavioural or neurodevelopmental disorders (excluding clinical depression)89Clinical depression33Diseases of the circulatory system25Diseases of the genitourinary system15Neoplasms17Diseases of the musculoskeletal system or connective tissue15Diseases of the nervous system12Diseases of the respiratory system (excluding COVID-19)7Diseases of the skin6Diseases of the visual system4Others14Total493
New Approaches to Respiratory Syncytial Virus Prevention and Treatment
Authors: Emmanuel B. Walter, Flor M. Munoz
Journal: Annual Review of Medicine (2024)

There have been several recent advances in the prevention of lower respiratory tract disease (LRTD) due to respiratory syncytial virus (RSV) infection in older adults and young children. Three different vaccines are now approved for use in older adults; one of these vaccines is also approved for use in pregnant individuals for the prevention of LRTD due to RSV in their infants. In addition, a new monoclonal antibody is available to prevent RSV LRTD in infants born during or entering their first RSV season and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Despite these advances in prevention efforts, specific antiviral treatment options for RSV infection remain limited. Several promising compounds remain in development.
Human-Centered Design to Enhance Implementation and Impact in Health
Authors: Aaron R. Lyon, Tricia Aung, Kathryn E. Bruzios, Sean Munson
Journal: Annual Review of Public Health (2024)

Human-centered design (HCD) is an approach that aligns innovation development with the needs of the people and the settings where those innovations will be used. HCD is increasingly being applied across a variety of health domains, most often with the goals of translating research into real-world settings and expanding innovation adoption. This review introduces key HCD concepts, reviews the growth of HCD in public health and its alignment with the complementary field of implementation science, and details four prominent proximal outcomes of design processes: ( a ) usability, ( b ) user burden, ( c ) contextual appropriateness, and ( d ) engagement. For each outcome, we provide a definition and background, measurement options, and critiques and future directions. We conclude with a series of opportunities and challenges, including an inclusive big tent spanning different design traditions, pathways for enhancing HCD's scientific legitimacy, and explicit promotion of equitable design processes to improve individual, community, and population health.
FC24 Zasocitinib (TAK-279), an oral, allosteric, highly selective TYK2 inhibitor, modulates disease-central cytokine pathways that define clinical response in patients with moderate-to-severe plaque psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Zasocitinib (TAK-279) demonstrated promising efficacy and was generally well tolerated in a completed Phase 2b study (NCT04999839) in patients with moderate-to-severe plaque psoriasis, with the primary endpoint [75% improvement in psoriasis area and severity (PASI75)] achieved at doses ≥5 mg vs. placebo at Week 12. In an exploratory analysis of this study, associations between zasocitinib treatment, psoriasis/tyrosine kinase 2 (TYK2) biomarkers, and clinical/histological response were investigated. Lesional/non-lesional serum samples and skin biopsies were obtained with consent at Day 1 (pre-dose) and Weeks 4 and 12 from patients receiving zasocitinib (2, 5, 15, and 30 mg) or placebo orally once daily. RT-qPCR, RNA-seq and immunohistochemistry were used to assess changes in lesion keratinocyte proliferation (KRT16 expression), psoriasis/TYK2 biomarkers and lesion gene signatures, and their associations with clinical (PASI75) and histological (plaque resolution) response. Serum samples from 252 patients and biopsy samples from 63 patients were analysed. At Week 12, most clinical responders (n = 21/24, 88%) experienced reductions in KRT16 expression of &amp;gt;87% vs. baseline lesion levels. Pooled analysis showed that, in most histological responders (n = 18/25, 72%), interleukin (IL)17A and IL17F expression reduced by &amp;gt;80% vs. baseline lesion levels. Reductions in lesional type I interferon, IL-12 and IL-23 pathway gene expression were observed at zasocitinib 15 and 30 mg doses compared with baseline levels (P &amp;lt; 0.05). Dose- and time-dependent reductions in serum IL-17A, IL-17C and IL-17F were observed in all zasocitinib groups vs. placebo. In the 15 and 30 mg groups (n = 23), expression of key psoriasis/TYK2 biomarkers (e.g. DEFB4A, IL36G, IL23A) reverted to non-lesional levels at Week 12. Among evaluable PASI90 responders at Week 12 (n = 12), 48/50 of the top upregulated genes in lesions reverted to non-lesional expression levels. In all dose groups, patients had reduced lesional epidermal thickness, CD3+ T-cell counts and CD11c+ myeloid dendritic cell counts with zasocitinib vs. baseline. Zasocitinib treatment did not result in clinically meaningful longitudinal changes in laboratory parameters associated with Janus kinase inhibition. Zasocitinib modulated psoriasis/TYK2 biomarkers were associated with clinical and histological response in patients with moderate-to-severe plaque psoriasis.
P113 Real-world experience of bimekizumab for plaque psoriasis in adult patients with prior exposure to interleukin-23 inhibitors: a 16-week multicentre retrospective cohort study
Journal: British Journal of Dermatology (2024)

Abstract For adult patients with plaque psoriasis, limited information exists on switching between classes from an IL-23 inhibitor (IL-23i) to bimekizumab. We conducted a real-world, multicentre, retrospective study of bimekizumab use in the setting of prior IL-23i exposure. A total of 26 patients with prior IL-23i exposure were identified. Effectiveness outcomes included Investigator Global Assessment (IGA), psoriasis area and severity index (PASI), body surface area (BSA), and IGA × BSA scores. Safety was assessed via treatment-related adverse events (AEs). Mean age was 44.0 (range: 18–76) years, with 57.7% (15/26) being female. Prior IL-23i exposures included guselkumab only (46.2%, 12/26), risankizumab only (34.6%, 9/26), and both guselkumab and risankizumab (19.2%, 5/26). All 26 patients discontinued the IL-23i agent due to inefficacy. Primary non-response to IL-23i was defined as lack of IGA 0/1 and/or 75% improvement in PASI (PASI75) at Week 16, whereas secondary non-response to prior IL-17i was defined as loss of IGA 0/1 and/or PASI75 at any point afterwards. At Weeks 16 ± 6: IGA 0/1 was achieved by 82.6% (19/23); mean PASI, BSA, and IGA × BSA improvements from baseline were 77.5% (7.2–0.9), 81.8% (6.8–0.9%), and 86.9% (19.4–1.3), respectively; 73.1% (19/26), 53.9% (14/26), and 30.8% (8/26) achieved PASI75, 90% improvement in PASI (PASI90), and 100% improvement in PASI (PASI100), respectively; 96.2% (25/26), 92.3% (24/26), and 69.2% (18/26) achieved absolute PASI scores &amp;lt;3, &amp;lt;2, and &amp;lt;1; and 73.1% (19/26) achieved BSA &amp;lt;1%. In prior IL-23i primary non-responders (n = 4), 100% (4/4) achieved IGA 0/1 and/or PASI90; however, none achieved PASI100, with bimekizumab at Week 16 ± 6. In prior IL-23i secondary non-responders (n = 16), 75% (12/16) achieved IGA 0/1 and/or PASI90 and 43.8% (7/16) achieved PASI100 with bimekizumab at Week 16 ± 6. Three treatment-related AEs occurred (11.5%, 3/26), including oral candidiasis (7.7%, 2/26) and folliculitis (3.8%, 1/26); none led to discontinuation. In comparison to clinical trials and an Italian real-world study of biologic-experienced patients (n = 103), our study of bimekizumab in IL-23i-exposed patients demonstrated lower response for PASI90 [85–91% (trials) vs. 87.9% (Italian study) vs. 53.9% (our study)] and PASI100 [59–83% (trials) vs. 74.1% (Italian study) vs. 30.8% (our study)]. This discrepancy may be explained by a more difficult-to-treat population with multiple biologic failures [42.3% utilized &amp;gt;3 biologics (our study) vs. 18.6% with &amp;gt;2 biologics (Italian study)] and IL-23i secondary failures [61.5% (our study)]. Our study included patients with &amp;gt;1 biologic failure, while Phase III clinical trials excluded this population. We highlight the utility of bimekizumab despite IL-23i exposure. Study limitations include its small sample and retrospective nature.
Maintaining Immunizations for Vaccine-Preventable Diseases in a Changing World
Authors: Anurima Baidya, Victoria Willens, Chizoba Wonodi, William J. Moss
Journal: Annual Review of Public Health (2024)

Immunization has saved an estimated 154 million lives over the past 50 years since the launch of the Essential (formerly Expanded) Program on Immunization in 1974, representing 6 lives saved every minute, every year, for 50 years. But achieving and maintaining high immunization coverage have required sustained political and public commitment, financial resources, strong partnerships, research and innovation, and communication and advocacy. New and evolving challenges to maintaining high immunization coverage have emerged alongside long-standing stubborn obstacles. We review some of these key challenges to immunization in this dynamic, changing world and summarize some promising solutions. Success in some regions of the world in eliminating polio, measles, and rubella, and reducing morbidity and mortality from other vaccine-preventable diseases (VPDs), should provide hope that progress can be made in achieving and maintaining high immunization coverage. We cannot afford to do otherwise.
FC04 Dynamic KC-neutrophil-fibroblast communication network centred on IL-36/TNFSF15 responses characterizes inflammatory responses in generalized pustular psoriasis
Journal: British Journal of Dermatology (2024)

Abstract Generalized pustular psoriasis (GPP) is a severe psoriatic subtype characterized by epidermal neutrophil infiltration, often occurring in acute, potentially life-threatening episodes. However, the characterization of the immune microenvironment in GPP lesions compared with plaque psoriasis remains largely unknown. Here, we used single-cell RNA profiling to interrogate the transcriptomes of ∼60 000 single cells from GPP lesional skin (n = 13) and healthy adult skin (n = 4), combined with spatial RNA sequencing. GPP was associated with major shifts in multiple cell populations, including, in particular, increased frequency of myeloid immune cells and supraspinous keratinocytes. We identified a unique myeloid-derived neutrophil subset characterized by the absence of CASP8. CASP8− neutrophils were accompanied by high expression of inflammatory pathway genes, including RIPK1, NF-KB1, IL1B, CXCL1, and CXCL8 in a stable disease state and were found at low levels in an inactive state in healthy skin. Spatial mapping of these genes illustrated the neutrophil transition from pre-inflammation to a pro-inflammation state through casting off CASP8. In silico and in vitro co-culture studies demonstrated that the communication network between IL36G+ spinous KCs and neutrophils is enlarged in the GPP lesions, with TNFSF15 (TL1A) released from neutrophils exaggerating the inflammatory crosstalk. While there was a slight increase in Th17 cells, there was greater prominence of CD8+ cytotoxic T cells highlighted by upregulated GZMB, CCL5, NKG7, and PRF1 expression, hinting at a cytotoxicity tendency rather than inflammation response in GPP lesions. Notably, a subset of S100A9+ fibroblasts in GPP was observed to contribute to the amplification of the GPP immune network through the transition to a pro-inflammatory state, connected by ligand–receptor interactions with other spatially proximate immune cells, including Th17 cells, CD8+ Tc cells, neutrophils, and IL1B+ macrophages. In sum, these data provide an in-depth view of immune cell participation and highlight the role of neutrophil–KC–fibroblast crosstalk in GPP pathogenesis.
P76 Nine years of Project ECHOⓇ Psoriasis Argentina: all teach, all learn
Journal: British Journal of Dermatology (2024)

Abstract Project ECHO® (Extension for Community Healthcare Outcomes) is a virtual community initiative developed at the University of New Mexico, USA, to treat chronic, frequent, and complex diseases safely and effectively in rural or underserved, underprivileged areas or in places where the number of specialists available is not enough to meet patient demands. ECHO® Psoriasis Argentina, the first adaptation of the initiative in dermatological diseases, began in 2015 as a web-based clinical case distance medical education tool for dermatologists across different regions of the country to share the best medical practices for psoriasis. This was in response to the uneven distribution of healthcare professionals. Its main goals include bridging knowledge gaps between general dermatologists and specialists in psoriasis management, extending the best clinical practices to more patients, and reducing the need for referrals to more complex centres. Teleclinics are held every 3 weeks using Zoom® software. Over 350 dermatologists from all provinces of Argentina participate in this project. Each session involves presenting psoriasis cases to a panel of experts and attending dermatologists, followed by discussions and recommendations. Periodic academic updates on the topic are also conducted. Furthermore, ECHO® Psoriasis Argentina fosters a sense of community through a discussion group on WhatsApp® Messenger. Here, participants engage in lively discussions, raising issues and questions from their daily practice. Both the panel of experts and participating dermatologists contribute answers creating a collaborative environment. In commemorating the 130 teleclinics held, we wish to share our experience with ECHO® Psoriasis Argentina. Active participation and interest among attendees have led to the presentation of various studies at conferences, publications, and investigations into reasons dermatologists seek remote assistance. They evaluated modifications suggested by experts and barriers to implementing these suggestions. Studies also assessed the impact of participating in the WhatsApp® discussion group, including topics like immunosuppressant use during the COVID-19 pandemic, methotrexate use across different regions of Argentina, and exceptional patient situations such as pregnancy and paradoxical psoriasis. ECHO® Psoriasis Argentina is more than just a platform for sharing experiences and spreading knowledge, it is a transformative initiative that enhances healthcare professionals' skills and creates a network of professionals across the country. Its success has paved the way for the launch of ECHO® initiatives for hidradenitis suppurativa and atopic dermatitis in Argentina in 2019, further expanding its impact on the healthcare system.
P124 Severe psoriasiform phenotype in CARMIL2 deficiency and successful therapy with dupilumab
Journal: British Journal of Dermatology (2024)

Abstract A 22-year-patient with consanguineous parents presented with a diagnosis of severe psoriasis with erythroderma and recurrent episodes of fever that had been present since childhood. Neither systemic treatment with methotrexate, ciclosporin A, acitretin, apremilast nor tildrakizumab had led to a significant improvement. Clinically, there was persistent erythroderma with coarse lamellar scaling on the entire integument and pronounced lichenification. Histopathologically, the skin biopsy revealed regular acanthosis, raised papillary tips with inflammatory infiltrate, slight para- and hyperkeratosis, hypogranulosis and a strong expression of NOS2 and CCL27. Immunophenotypically, a reduced number of CD4+ and CD8+ memory cells in line with increased numbers of naïve T cells was found. The proportion of FOXP3+ Treg cells was also reduced and there was an increased number of naive B cells and insufficient conversion into memory B cells. Whole exome sequencing identified a novel homozygous frameshift mutation (c.1894del) in the CARMIL2 gene. CARMIL2 deficiency is a recently described autosomal recessive inherited combined immunodeficiency that impairs T- and B-cell activation and maturation through dysfunctional CD28-mediated costimulation and cell motility through impaired cytoskeletal functions. In addition to various skin manifestations, ranging from seborrheic, atopic or psoriasiform dermatitis and an increased susceptibility to bacterial, mycotic and viral skin infections, the majority of affected individuals present with gastrointestinal symptoms, respiratory infections and the occurrence of EBV+-smooth muscle tumours (SMTs). In our patient, the start of treatment with the monoclonal antibody dupilumab, which binds IL-4Rα and inhibits the signalling of IL-4 and IL-13, led to an impressive long-term improvement in the skin condition. Haematopoietic stem cell transplantation could be a therapeutic option for the long-term control of extracutaneous manifestations but requires control of skin inflammation. In refractory psoriasiform manifestations in combination with susceptibility to infection, gastrointestinal inflammation or EBV+-SMTs, CARMIL2 deficiency should be considered in the differential diagnosis. Our case expands the phenotypic spectrum of a newly discovered primary immunodeficiency and proves for the first time that dupilumab may be an effective treatment option for severe psoriasiform cutaneous manifestations in CARMIL2 deficiency.