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Anatomical education is pivotal for medical students, and innovative technologies like augmented reality (AR) are transforming the field. This study aimed to enhance the interactive features of the "AEducAR" prototype, an AR tool developed by the University of Bologna, and explore its impact on human anatomy learning process in 130 second-year medical students at the International School of Medicine and Surgery of the University of Bologna. An interdisciplinary team of anatomists, maxillofacial surgeons, biomedical engineers, and educational scientists collaborated to ensure a comprehensive understanding of the study's objectives. Students used the updated version of "AEducAR," named "AEducAR 2.0," to study three anatomical topics, specifically the orbit zone, facial bones, and mimic muscles. "AEducAR 2.0" offered two learning activities: one explorative and one interactive. Following each activity, students took a test to assess learning outcomes. Students also completed an anonymous questionnaire to provide background information and offer their perceptions of the activity. Additionally, 10 students participated in interviews for further insights. The results demonstrated that "AEducAR 2.0" effectively facilitated learning and students' engagement. Students totalized high scores in both quizzes and declared to have appreciated the interactive features that were implemented. Moreover, interviews shed light on the interesting topic of blended learning. In particular, the present study suggests that incorporating AR into medical education alongside traditional methods might prove advantageous for students' academic and future professional endeavors. In this light, this study contributes to the growing research emphasizing the potential role of AR in shaping the future of medical education.

IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator, and siRNA knockdown of TCF4 in human keratinocytes (KCs) increased IL17C. IL-17C stimulation of KCs (along with IL-17A and TNF-α stimulation) decreased TCF4 and increased NFKBIZ and ZC3H12A expression in an IL-17RA/RE-dependent manner, thus creating a feedback loop. ZC3H12A (MCPIP1/Regnase-1), a transcriptional immune-response regulator, also increased following TCF4 siRNA knockdown, and siRNA knockdown of ZC3H12A decreased NFKBIZ, IL1B, IL36G, CCL20, and CXCL1, revealing a proinflammatory role for ZC3H12A. Examination of lesional skin from the KC-Tie2 inflammatory dermatitis mouse model identified decreases in TCF4 protein concomitant with increases in IL-17C and Zc3h12a that reversed following the genetic elimination of Il17c, Il17ra, and Il17re and improvement in the skin phenotype. Conversely, interference with Tcf4 in KC-Tie2 mouse skin increased Il17c and exacerbated the inflammatory skin phenotype. Together, these findings identify a role for TCF4 in the negative regulation of IL-17C, which, alone and with TNF-α and IL-17A, feed back to decrease TCF4 in an IL-17RA/RE-dependent manner. This loop is further amplified by IL-17C-TCF4 autocrine regulation of ZC3H12A and IL-17C regulation of NFKBIZ to promote self-sustaining skin inflammation.

Interferon (IFN) activity exhibits a gender bias in human skin, skewed toward females. We show that HERC6, an IFN-induced E3 ubiquitin ligase, is induced in human keratinocytes through the epidermal type I IFN; IFN-κ. HERC6 knockdown in human keratinocytes results in enhanced induction of interferon-stimulated genes (ISGs) upon treatment with a double-stranded (ds) DNA STING activator cGAMP but not in response to the RNA-sensing TLR3 agonist. Keratinocytes lacking HERC6 exhibit sustained STING-TBK1 signaling following cGAMP stimulation through modulation of LATS2 and TBK1 activity, unmasking more robust ISG responses in female keratinocytes. This enhanced female-biased immune response with loss of HERC6 depends on VGLL3, a regulator of type I IFN signature. These data identify HERC6 as a previously unrecognized negative regulator of ISG expression specific to dsDNA sensing and establish it as a regulator of female-biased immune responses through modulation of STING signaling.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.

In the modern era of agriculture and horticulture, biodiversity conservation requires plant species identification skills, and automatic detection is a challenging and interesting task. However, many factors often make some people mistaken in recognizing plant species that have unique and varied visual characteristics, making manual identification difficult. This problem requires an effective and accurate model for identifying plant species. So this research aims to produce a model to identify plant species that are effective and have a high level of accuracy. This research offers the use of the YOLOv5 algorithm method. The training process with epoch 200 and 53 minutes with a total of 1,220 images. Based on the results of the model performance test, the mAP value was 85.73%, precision 98.27%, and recall 94.36%. During testing, the model can identify plant species accurately on single objects and multiple objects. The results of this research show that the proposed method is successful in identifying plant species accurately.

BACKGROUND: Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions. OBJECTIVES: This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level. METHODS: Single-cell RNA-sequencing of skin from 15 healthy donors and nonlesional and lesional skin from 6 patients each with PN and atopic dermatitis, combined with spatial-sequencing using the 10x Visium platform. Integration with bulk RNA-sequencing data from patients treated with nemolizumab. RESULTS: This study demonstrates that PN is an inflammatory skin disease characterized by both keratinocyte proliferation and activation of profibrotic responses. This study also demonstrates that the COL11A1+ fibroblast subset is a major contributor to fibrosis and is predominantly found in the papillary dermis of PN skin. Activation of fibrotic responses is the main distinguishing feature between PN and atopic dermatitis skin. This study further shows the broad effect of nemolizumab on PN cell types, with a prominent effect driving COL11A1+ fibroblast and keratinocyte responses toward normal. CONCLUSIONS: This study provides a high-resolution characterization of the cell types and cellular processes activated in PN skin, establishing PN as a chronic fibrotic inflammatory skin disease. It further demonstrates the broad effect of nemolizumab on pathological processes in PN skin.

A marketplace is a place in cyberspace where there are commercial activities between buyers and sellers. Products offered from the marketplace have reviews to review. Shopee is the most visited marketplace by people and offers various products. Product reviews can provide benefits for other consumers in assessing the products offered. By utilizing NLP technology in particular, this study can classify positive sentiment and negative sentiment in product review data. The IndoBERT model is a model that can be used in NLP technology by utilizing the relationship between each input and output element as well as the weights to be calculated simultaneously. By utilizing this technology, sentiment analysis on Shopee product reviews provides maximum accuracy until 93% with different training conditions. This provide that IndoBERT model can show that the performance of the indoBERT model in this research is very good.

OBJECTIVE: Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship, and share molecular factors between psoriasis and MS. METHODS: We used logistic regression, trans-disease meta-analysis and Mendelian randomization. Medical claims data were included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used genome-wide association study summary statistics from 11,024 psoriatic, 14,802 MS cases, and 43,039 controls for trans-disease meta-analysis, with additional summary statistics from 5 million individuals for Mendelian randomization. RESULTS: Psoriatic patients have a significantly higher risk of MS (4,637 patients with both diseases; odds ratio [OR] 1.07, p = 1.2 × 10-5 ) after controlling for potential confounders. Using inverse variance and equally weighted trans-disease meta-analysis, we revealed >20 shared and opposing (direction of effect) genetic loci outside the major histocompatibility complex that showed significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters that were enriched among pathways for interleukin-17/tumor necrosis factor-α (OR >39, p

Abstract Aiming at understanding the source of the fluids that mineralizing within seismically active fault zones, we investigate the noble gas isotopes (i.e., helium (He), neon (Ne), and argon (Ar)) in the fluid inclusions (FIs) trapped in the calcite veins sampled along high‐angle fault zones of the Contursi hydrothermal basin, southern Italy. The latter basin lies in close vicinity of the MW = 6.9, 1980 Irpinia earthquake and exposes numerous fault scarps dissecting Mesozoic shallow‐water carbonates. The analyses of noble gases (He, Ne, Ar) are conducted to identify the origin of the volatiles circulating along the faults at the time of calcite precipitation. Then, outcomes of this discussions are compared with currently outgassing of deep‐sourced CO2 coupled to mantle‐derived He in that area, whose output is larger than those from some volcanic areas worldwide. The results indicate that He in FIs is dominated by a crustal radiogenic component (4He), and by an up to 20% of a mantle‐derived component (3He), with a highest isotopic signature of 1.38 Ra. This value is consistent with the highest percentage of mantle‐derived He associated to high‐flux CO2 gas emission in the investigated area (1.41 Ra). We propose that the variability of the He isotopic signature measured in primary FIs can result from early trapping of fluid inclusions or post trapping processes and seismic activity that modify the pristine He isotopic signature (i.e., derived from the crust and/or mantle) in groundwater along the faults during periods of background seismicity. Such investigations are fundamental to understand fluid migration in fault systems and the role of fluids in processes of earthquake nucleation.

The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2+ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2+ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2+ myeloid cells, CCR7+ LAMP3+ dendritic cells, and CXCR4 expressed on both CD8+ Tc17 cells and keratinocytes, respectively. The SFRP2+ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.

Recent research into the pathophysiology and treatment of atopic dermatitis (AD) has shown notable progress. An increasing number of aspects of the immune system are being implicated in AD, including the epithelial barrier, TH2 cytokines, and mast cells. Major advances in therapeutics were made in biologic cytokine and receptor antagonists and among Janus kinase inhibitors. We focus on these areas and address new insights into AD epidemiology, biomarkers, endotypes, prevention, and comorbidities. Going forward, we expect future mechanistic insights and therapeutic advances to broaden physicians ability to diagnose and manage AD patients, and perhaps to find a cure for this chronic condition.

Introduction: There are few studies investigating the clinical profile of older patients with interstitial lung disease (ILD), so this study investigated the characteristics of the older population diagnosed with ILD. Material and methods: Retrospective study in a population of new referrals at an ILD clinic from January 2013 to September 2017. Patients over 64 years were selected. Data collection included diseases variables, diagnostic procedures and comorbidities. Gender-age-physiology (GAP) stage, composite physiologic index (CPI) and Charlson index was calculated. Statistical analysis was performed to investigate risk factors associated with survival. Results: A total of 232 patients were included in this study. Mean age was 76.3 years (SD 6.5). As per protocol, 69.3% completed the initial assessment but this was lower in the elderly group (61.5%). The most frequent diagnosis was unclassifiable ILD (24.1%), followed by ILD associated with connective tissue disease (21.6%), IPF (12.1%) and hypersensitivity pneumonitis (10.3%). During follow-up (36.7 months (SD 28.6)) a significant proportion of patients died (55 cases, 23.7% of the cohort), especially in the late older group (30.4%). Kaplan–Meier curves showed that those over 75 years have a worse survival even when adjusted by covariables (p

SLMAP3 is a constituent of the centrosome and is known to assemble with the striatin-interacting phosphatase and kinase (STRIPAK) complex, where it has been reported to repress Hippo signalling. The global knockout of SLMAP3 in mice results in embryonic/perinatal lethality and stunted growth without changes in the phosphorylation status of YAP. Diverse phenotypes present in the SLMAP3−/− embryos include reduced body axis, small and abnormal organs resembling defects in planar cell polarity (PCP) signalling, while also displaying the notable polycystic kidneys, a known manifestation of ciliopathies. Analysis of cell polarity in primary mouse embryonic fibroblasts (MEFs) including cell migration, orientation and mitotic spindle angle did not reveal any changes due to SLMAP3 loss in these cells, although the expression of DVL3 was significantly reduced. Furthermore, MEFs lacking FGFR1OP2 or STRN3, two other STRIPAK members, did not reveal any significant changes in any of these parameters either. Significant changes in the number of ciliated cells and primary cilium length in SLMAP3 and FGFR1OP2 deficient MEFs were evident, while a reduced primary cilium length was notable in chondrocytes of SLMAP3 deficient embryos. Our findings suggest that SLMAP3 is essential for mouse embryogenesis through novel mechanisms involving the primary cilium/PCP and protein stability independent of Hippo signalling.

IntroductionSome cyanobacteria can use far-red light (FRL) to drive oxygenic photosynthesis, a phenomenon known as Far-Red Light Photoacclimation (FaRLiP). It can expand photosynthetically active radiation beyond the visible light (VL) range. Therefore, it holds promise for biotechnological applications and may prove useful for the future human exploration of outer space. Typically, FaRLiP relies on a cluster of ~20 genes, encoding paralogs of the standard photosynthetic machinery. One of them, a highly divergent D1 gene known as chlF (or psbA4), is the synthase responsible for the formation of the FRL-absorbing chlorophyll f (Chl f) that is essential for FaRLiP. The minimum gene set required for this phenotype is unclear. The desert cyanobacterium Chroococcidiopsis sp. CCMEE 010 is unusual in being capable of FaRLiP with a reduced gene cluster (15 genes), and it lacks most of the genes encoding FR-Photosystem I.MethodsHere we investigated whether the reduced gene cluster of Chroococcidiopsis sp. CCMEE 010 is transcriptionally regulated by FRL and characterized the spectral changes that occur during the FaRLiP response of Chroococcidiopsis sp. CCMEE 010. In addition, the heterologous expression of the Chl f synthase from CCMEE 010 was attempted in three closely related desert strains of Chroococcidiopsis.ResultsAll 15 genes of the FaRLiP cluster were preferentially expressed under FRL, accompanied by a progressive red-shift of the photosynthetic absorption spectrum. The Chl f synthase from CCMEE 010 was successfully expressed in two desert strains of Chroococcidiopsis and transformants could be selected in both VL and FRL.DiscussionIn Chroococcidiopsis sp. CCME 010, all the far-red genes of the unusually reduced FaRLiP cluster, are transcriptionally regulated by FRL and two closely related desert strains heterologously expressing the chlF010 gene could grow in FRL. Since the transformation hosts had been reported to survive outer space conditions, such an achievement lays the foundation toward novel cyanobacteria-based technologies to support human space exploration.

This article explores how a re-interpretation of the socio-technical, socio-ecological and transition design approaches to transition from the point of view of Niklas Luhmann’s general systems theory of society. The need to understand and promote changes that include a technological and ecological dimension has led to different approaches, such as socio-technical or socio-environmental approaches, to incorporate links with society. While these approaches often include sociological insights, they rarely offer a general understanding of how these are embedded into society. We need a new environmental sociology that helps catalyze change processes with a collectively reorganized society, empowering more radically transformative actions to change the current structures and processes that have led us to where we are today. The article offers a cross-sectional look at the socio-ecological and socio-technical systems literature, specifically for what concerns their understanding of the ‘systems’ in transition and how they can be governed, and re-interpret it from the theoretical lens of the deep sociological knowledge, which refers to the profound understanding of social systems and their dynamics, embedded in Luhmann’s theory of social systems. From here, we suggest the second-order coupling for a sociologically grounded understanding of the interactions that comprise socio-ecological and socio-technical systems, heterogeneous and almost self-organizing assemblies of social, technical, and natural elements and processes. At the same time, third-order couplings are analyzed, focused on governance, relationships between operations, and structures mediated by a deliberate attempt to ensure coherence and coordination against the autonomy and heterogeneity of socio-techno-ecological systems. Therefore, this manuscript offers a deeper conceptual and methodological understanding of socio-techno-ecological couplings and systems in the context of sustainability transformation and gives insights into its governance.

Palmoplantar skin is structurally and functionally unique, but the transcriptional programs driving this specialization are unclear. Here, we use bulk and single-cell RNA sequencing of human palm, sole, and hip skin to describe the distinguishing characteristics of palmoplantar and non-palmoplantar skin while also uncovering differences between palmar and plantar sites. Our approach reveals an altered immune environment in palmoplantar skin, with downregulation of diverse immunological processes and decreased immune cell populations. Further, we identify specific fibroblast populations that appear to orchestrate key differences in cell-cell communication in palm, sole, and hip. Dedicated keratinocyte analysis highlights major differences in basal cell fraction among the three sites and demonstrates the existence of two spinous keratinocyte populations constituting parallel, site-selective epidermal differentiation trajectories. In summary, this deep characterization of highly adapted palmoplantar skin contributes key insights into the fundamental biology of human skin and provides a valuable data resource for further investigation.

Background: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non-vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. Methods: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non-vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson’s Chi-square and Mann-Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. Results: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non-vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039–0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582–1.703, p = 0.987). Conclusions: This study provides real-world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first-booster uptake rates.

This research aims to assess the adaptability of Neural Radiance Fields (NeRF) for the digital documentation of cultural heritage objects of varying size and complexity. We discuss the influence of object size, desired scale of representation, and level of detail on the choice to use NeRF for cultural heritage documentation, providing insights for practitioners in the field. Case studies range from historic pavements to architectural elements or buildings, representing diverse and multi-scale scenarios encountered in heritage documentation procedures. The findings suggest that NeRFs perform well in scenarios with homogeneous textures, variable lighting conditions, reflective surfaces, and fine details. However, they exhibit higher noise and lower texture quality compared to other consolidated image-based techniques as photogrammetry, especially in case of small-scale artifacts.

The epidermis is the outermost layer of skin. Here, we used targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and we used single-cell RNA-Seq to compare keratinocyte gene expression at acral and nonacral sites. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes that are consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there was a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a 2-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene coexpression analysis revealed a strong connection between lipid and immune gene expression. This work highlights (a) mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces and (b) how inflammation-associated alterations in gene expression affect the epidermal lipidome.

Forensic mitochondrial DNA analysis is a vital investigative tool for wildlife casework, but numts continue to complicate DNA analysis. A major goal of wildlife forensic DNA analysis is to identify non-human biological evidence to its taxonomic source. Species identification is accomplished by sequencing genetic markers on the mitochondrial genome and comparing evidentiary sequence data to published reference sequences. Due to the high level of sequence similarity between mitochondrial genes and numts, current sequencing methods result in co-amplification of the target gene marker and non-target numt. Co-amplification of target and non-target loci results in ambiguous nucleotide calls in sequence data. Reducing the influence of numts during sequence analysis will provide a technique that will maximize accuracy and minimize error in taxonomic identifications. To overcome the analytical burden of numts, we studied the enzymatic removal of numts using exonuclease V. To evaluate the feasibility of exonuclease V as a numt removal method, total Panthera tigris DNA was extracted from blood and liver and divided into three treatment groups: untreated, 1st digest, and 2nd digest. For the untreated sample, 7.6 % of the 620 bp sequence data was classified as ambiguous. Following treatment, all samples demonstrated a reduction in ambiguous calls: liver-1st digest (48 h): 6.6 %, liver-2nd digest (48 h + 16 h): 1.8 %, and blood-1st digest (48 h): 0 %. Based on this preliminary study, exonuclease V treatment effectively removed numts before sequencing analysis. While exonuclease V treatment has demonstrated potential, additional studies are required to optimize the reaction and fully validate the methodology.

Tape stripping is a minimally invasive, nonscarring method that can be utilized to assess gene expression in the skin but is infrequently used given technical constraints. By comparing different tape stripping technologies and full-thickness skin biopsy results of lesional and nonlesional psoriatic skin from the same patients, we demonstrate that tape stripping with optimized high-resolution transcriptomic profiling can be used to effectively assess and characterize inflammatory responses in the skin. Upon comparison with single-cell RNA-sequencing data from psoriatic full-thickness skin biopsies, we illustrate that tape-stripping efficiently captures the transcriptome of the upper layers of the epidermis with sufficient resolution to assess the molecular components of the feed-forward immune amplification pathway in psoriasis. Notably, nonlesional psoriatic skin sampled by tape stripping demonstrates activated, proinflammatory changes when compared to healthy control skin, suggesting a prepsoriatic state, which is not captured on full-thickness skin biopsy transcriptome profiling. This work illustrates an approach to assess inflammatory response in the epidermis by combining noninvasive sampling with high throughput RNA-sequencing, providing a foundation for biomarker discoveries and mechanism of action studies for inflammatory skin conditions.

Introduction: Patients with hematologic malignancies are more likely to develop severe and prolonged SARS-CoV-2 infection, often showing viral persistence despite the use of authorized antivirals. Herein, we report the cases of four patients who received rituximab for different conditions and developed persistent COVID-19 treated with an extended course of dual antivirals, Nirmatrelvir/Ritonavir and Remdesivir. Moreover, we describe the pharmacokinetics and pharmacogenetics (PK/PG) characteristics of Nirmatrelvir/Ritonavir and Remdesivir treatment in two of these patients. Methods: Plasma specimens for evaluation of trough concentrations (Ctrough) were collected 10 min before the daily dose administration, in addition to 3 h (Cmax), 4 h (C4h), 6 h (C6h) and 1 h (Cmax) after the administration of Nirmatrelvir/Ritonavir and Remdesivir, respectively. The following gene single-nucleotide polymorphisms (SNPs) were investigated: ABCB1 3435 (rs1045642) C > T, ABCB1 1236 (rs1128503) C > T, PXR 63396 (rs2472667) T > C, CYP2D6 (rs1135840) G > C, and CYP3A4*1B (rs2740574) G > A. Results: Double antiviral treatment was successful in terms of symptoms resolution, whereas three out of four patients achieved microbiological eradication. Based on our results, concentrations of Nirmatrelvir ranging from 50 to 5000 ng/mL were effective, whereas a higher concentration (range 1068–3377 ng/mL), compared to that previously reported in patients with similar weight and BMI, was evidenced for Ritonavir. Considering the genetic variant analysis, ABCB1 3435 CT and 1236 CT genotypes were found in patient 1; and ABCB1 3435 CC and 1236 CC in patient 2. In conclusion, this real-life study supports the usefulness of TDM and genetics in immunocompromised patients with persistent SARS-CoV-2 infection, a challenging setting for clinicians in which personalized medicine may improve outcome.