Association of pruritus and chronic cough: an all of us database study.

PURPOSE: Based on a potential shared pathophysiology tied to mast cell activity and neurogenic inflammation that may link pruritus and chronic cough (CC), this study, leveraging the All of Us database, examines the association between the two conditions. MATERIALS AND METHODS: A nested case-control comparison was used to examine the association, identifying cases with SNOMED codes 418363000 (pruritus) and 68154008 (CC). Matching was performed on a 1:4 ratio by age, sex, and ethnicity using the MatchIt package in R, followed by maximum likelihood method to estimate odds ratios (ORs) and 95% confidence intervals from 2x2 contingency tables. RESULTS: CC patients (n = 2,388) were more than twice as likely to be diagnosed with pruritus (OR: 2.65) and pruritus patients (n = 22,496) were more than twice as likely to be diagnosed with CC (OR: 2.57), than respective matched controls. CONCLUSIONS: These results highlight the potential bidirectional relationship between CC and pruritus, suggesting possible shared immune and neural pathways. Treatments like difelikefalin and nalbuphine that modulate these pathways, alongside P2X3 targeting agents, are emerging as potential therapeutic approaches for itch and chronic cough given the possible interconnected pathophysiology. This study's insights into the associations between pruritus and CC may pave the way for targeted therapeutic strategies that address their shared mechanisms.

Quantifying how much host, pathogen, and other factors affect human protective adaptive immune responses.

Recognizing the "essential" factors that contribute to a clinical outcome is critical for designing appropriate therapies and prioritizing limited medical resources. Demonstrating a high correlation between a factor and an outcome does not necessarily imply an essential role of the factor to the outcome. Human protective adaptive immune responses to pathogens vary among (and perhaps within) pathogenic strains, human individual hosts, and in response to other factors. Which of these has an "essential" role? We offer three statistical approaches that predict the presence of newly contributing factor(s) and then quantify the influence of host, pathogen, and the new factors on immune responses. We illustrate these approaches using previous data from the protective adaptive immune response (cellular and humoral) by human hosts to various strains of the same pathogenic bacterial species. Taylor's law predicts the existence of other factors potentially contributing to the human protective adaptive immune response in addition to inter-individual host and intra-bacterial species inter-strain variability. A mixed linear model measures the relative contribution of the known variables, individual human hosts and bacterial strains, and estimates the summed contributions of the newly predicted but unknown factors to the combined adaptive immune response. A principal component analysis predicts the presence of sub-variables (currently not defined) within bacterial strains and individuals that may contribute to the combined immune response. These observations have statistical, biological, clinical, and therapeutic implications.

Tape strips detect molecular alterations and cutaneous biomarkers in skin of patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) has a high unmet need for better treatments. Biopsies are considered the gold standard for studying molecular alterations in skin. A reproducible, minimally invasive approach is needed for longitudinal monitoring in trials and in pediatric populations. OBJECTIVE: To determine whether skin tape strips can detect molecular alterations in HS and identify biomarkers of disease activity. METHODS: We performed RNA sequencing on tape strips collected from lesional and healthy-appearing (nonlesional) HS skin (n = 22) and healthy controls (n = 21). We correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. RESULTS: Tape strips detected upregulation of known HS biomarkers (eg, Interleukin[IL]-17A) in nonlesional and/or lesional skin and also identified novel clinically actionable targets, including OX40 and JAK3. The expression of Th17 and tumor necrosis factor-α pathways were highly correlated between tape strips and biopsies. HS clinical severity was significantly associated with expression of biomarkers (eg tumor necrosis factor-α , IL-17 A/F, OX40, JAK1-3, IL-4R) in HS lesional and/or nonlesional skin. LIMITATIONS: Sample size. Tape stripping is limited in depth. CONCLUSION: This study validates tape strips as a minimally-invasive approach to identify cutaneous biomarkers in HS. This provides a novel avenue for monitoring treatment efficacy and a potential step toward individualized therapy in HS.

Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A Phase 1 study.

BACKGROUND: RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD). METHODS: This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. RESULTS: In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures. CONCLUSIONS: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.

Modulation of Inflammatory Proteins in Serum May Reflect Cutaneous Immune Responses in Cancer Immunotherapy.

Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation (P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP.

Assessment of Spatial and Temporal Variation in the Skin Transcriptome of Atopic Dermatitis by Use of 1.5 mm Minipunch Biopsies.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by a heterogeneous and fluctuating disease course. To obtain a detailed molecular understanding of both the temporal and spatial variation in AD, we conducted a longitudinal case-control study, in which we followed a population, the GENAD (Gentofte AD) cohort, of mild-to-moderate patients with AD and matched healthy controls for more than a year. By the use of 1.5 mm minipunch biopsies, we obtained 393 samples from lesional, nonlesional, and healthy skin from multiple anatomical regions at different time points for transcriptomic profiling. We observed that the skin transcriptome was remarkably stable over time, with the largest variation being because of disease, individual, and skin site. Numerous AD-specific, differentially expressed genes were identified and indicated a disrupted skin barrier and activated immune response as the main features of AD. We also identified potentially novel targets in AD, including IL-37, MAML1, and several long noncoding RNAs. We envisage that the application of small biopsies, such as those introduced in this study, combined with omics technologies, will enable future skin research, in which multiple sampling from the same individual will give a more detailed, dynamic picture of how a disease fluctuates in time and space.

Unique protein signatures evolve during the course of a delayed-type hypersensitivity reaction in human skin.

Diphencyprone (DPCP) is a hapten that causes a delayed-type hypersensitivity reaction when applied topically. It has clinical uses in the treatment of various conditions such as melanoma metastases, warts, and alopecia areata, but the mechanisms are currently not well understood in humans. To further characterize the immunologic effects of DPCP, the authors performed a proteomic analysis of normal skin of eight healthy volunteers following a single application of DPCP and compared them with placebo-treated skin from the same volunteers. A total of 96 proteins were examined using the Olink immuno-oncology panel at 3 days (peak response), 14 days (partially resolved response), and 120 days (completely resolved response). Our analysis revealed significant upregulation of markers of immune cell activation (interleukin [IL] 8), vascular and tissue remodeling (matrix metallopeptidase 12 [MMP12], nitric oxide synthase 3 [NOS3]), antineoplastic markers (granzyme B [GZMB]), and the Th1 axis (interferon gamma [IFNG], chemokine (C-X-C motif) ligand [CXCL] 9, CXCL10, CXCL11) at days 3 and 14 compared with placebo (p < 0.05). In addition, several negative regulators of immune function such as programmed cell death 1 (PD1), programmed cell death ligand 1 (PDL1) (p < 0.001), and lymphocyte activation gene 3 (LAG3) (p < 0.05) were significantly upregulated at days 3 and 14. This induction of negative regulators may explain the seemingly paradoxical therapeutic benefits of DPCP in autoimmune conditions such as alopecia areata. The current analysis also indicated IL-4 upregulation only at day 3, followed by IL-12 upregulation only at day 14, suggesting a transient Th2 response followed by Th1 polarization. Overall, these data suggest a complex and evolving immunological delayed-type hypersensitivity response to a single application of DPCP over time. Future proteomic studies of samples from patients with melanoma metastases, warts, and alopecia areata treated long term with DPCP are needed to further evaluate its pharmacologic mechanisms.

Analysis of alopecia areata surveys suggests a threshold for improved patient-reported outcomes.

BACKGROUND: Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA-targeted QoL surveys in clinical trials, hindering sufficient representation of patient-reported outcomes. OBJECTIVES: Better understanding of patient-reported outcomes may guide treatment goals and future clinical trials. METHODS: In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA-QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in-depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient-reported outcomes. RESULTS: While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA-QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post-treatment was associated with improved patient-reported outcomes, including both AA-related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'. CONCLUSIONS: AASIS is better than AA-QLI to assess patient-reported outcomes. SALT ≤ 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic? Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia. Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient-reported outcomes is unknown. What does this study add? This study investigated the utility of two different alopecia areata-targeted questionnaires - Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) - in a clinical trial setting. AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work? Patients with ≤ 20% scalp hair loss after treatment reported improvement in multiple quality-of-life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials.

Comparison of the clinical phenotype and haematological course of siblings with Fanconi anaemia.

Fanconi anaemia (FA) is a genetic disorder due to mutations in any of the 22 FANC genes (FANCA-FANCW) and has high phenotypic variation. Siblings may have similar clinical outcome because they share the same variants; however, such association has not been reported. We present the detailed phenotype and clinical course of 25 sibling sets with FA from two institutions. Haematological progression significantly correlated between siblings, which was confirmed in an additional 55 sibling pairs from the International Fanconi Anemia Registry. Constitutional abnormalities were not concordant, except for a moderate degree of concordance in kidney abnormalities and microcephaly.

Deep learning-level melanoma detection by interpretable machine learning and imaging biomarker cues.

SIGNIFICANCE: Melanoma is a deadly cancer that physicians struggle to diagnose early because they lack the knowledge to differentiate benign from malignant lesions. Deep machine learning approaches to image analysis offer promise but lack the transparency to be widely adopted as stand-alone diagnostics. AIM: We aimed to create a transparent machine learning technology (i.e., not deep learning) to discriminate melanomas from nevi in dermoscopy images and an interface for sensory cue integration. APPROACH: Imaging biomarker cues (IBCs) fed ensemble machine learning classifier (Eclass) training while raw images fed deep learning classifier training. We compared the areas under the diagnostic receiver operator curves. RESULTS: Our interpretable machine learning algorithm outperformed the leading deep-learning approach 75% of the time. The user interface displayed only the diagnostic imaging biomarkers as IBCs. CONCLUSIONS: From a translational perspective, Eclass is better than convolutional machine learning diagnosis in that physicians can embrace it faster than black box outputs. Imaging biomarkers cues may be used during sensory cue integration in clinical screening. Our method may be applied to other image-based diagnostic analyses, including pathology and radiology.

Interrogating an ICD-coded electronic health records database to characterize the epidemiology of prosopagnosia.

INTRODUCTION: Recognition of faces of family members, friends, and colleagues is an important skill essential for everyday life. Individuals affected by prosopagnosia (face blindness) have difficulty recognizing familiar individuals. The prevalence of prosopagnosia has been estimated to be as high as 3%. Prosopagnosia can severely impact the quality of life of those affected, and it has been suggested to co-occur with conditions such as depression and anxiety. METHODS: To determine real-world diagnostic frequency of prosopagnosia and the spectrum of its comorbidities, we utilized a large database of more than 7.5 million de-identified electronic health records (EHRs) from patients who received care at major academic health centers and Federally Qualified Health Centers in New York City. We designed a computable phenotype to search the database for diagnosed cases of prosopagnosia, revealing a total of n = 902 cases. In addition, data from a randomly sampled matched control population (n = 100,973) were drawn from the database for comparative analyses to study the condition's comorbidity landscape. Diagnostic frequency of prosopagnosia, epidemiological characteristics, and comorbidity landscape were assessed. RESULTS: We observed prosopagnosia diagnoses at a rate of 0.012% (12 per 100,000 individuals). We discovered elevated frequency of prosopagnosia diagnosis for individuals who carried certain comorbid conditions, such as personality disorder, depression, epilepsy, and anxiety. Moreover, prosopagnosia diagnoses increased with the number of comorbid conditions. CONCLUSIONS: Results from this study show a wide range of comorbidities and suggest that prosopagnosia is vastly underdiagnosed. Findings imply important clinical consequences for the diagnosis and management of prosopagnosia as well as its comorbid conditions.