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African swine fever virus (ASFV) infection causes a frequently fatal disease in domestic swine that has affected more than 50 countries worldwide since 2021, with a major impact on animal welfare and economy. The development of effective vaccines or antivirals against this disease are urgently required for its effective control. Live detection of viral replication has been used as a tool for the screening and characterization of antiviral compounds in other dsDNA genome containing viruses. Here, we have adapted the ANCHOR fluorescent DNA labelling system to ASFV by constructing and characterizing a novel recombinant virus. We show that this virus is viable and effectively tags viral DNA replication sites, which can be detected and quantified in real time. Further, we have used high content cell microscopy to test the antiviral activity of bisbenzimide compounds and show that Hoechst 33342 has specific anti-ASFV activity. We expect this novel tool to be useful both in the further study of ASFV replication as in the screening of new specific antiviral compounds., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier B.V.)

The authors report their experience with twenty-one consecutive patients who presented with symptoms and imaging characteristics of a herniated lumbar disc; of whom, at the time of surgery had a vascular loop instead. The procedure was performed on 14 women and seven men with a mean age of 39 years. Clinical complaints included lumbar aching with one limb overt radiculopathy in all patients; with additional sphincter dysfunction in two cases. Symptoms had developed within a mean period of three months. In all patients, the disc was exposed through an L5-S1 (n = 10); L4-L5 (n = 5) and L3-L4 (n = 6) open minimal laminotomy. In 16 patients, rather than a herniated disc they had a lumbar epidural varix, while an arterio-venous fistula was found in the remaining five cases. In all cases, the vascular disorder was resected and its subjacent disc was left intact. One patient had a postoperative blood transfusion. While the radiculopathy dysfunction improved in all patients, four patients reported lasting lumbar pain following surgery. The postoperative imaging confirmed the resolution of the vascular anomaly and an intact disc. The mean length of the follow-up period was 47 months. Either epidural varix or arterio-venous fistula in the lumbar area may mimic a herniated disc on imaging studies. With the usual technique they can be operated safely. Resection of the anomaly can be sufficient for alleviating radiculopathy symptoms., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aimed to explore and identify motivational factors and barriers for pharmacy personnel participation in specific opioid mitigation programs, using the Theory of Planned Behavior (TPB) as an investigational framework., Methods: A naturalistic inquiry method was employed involving semi-structured interviews with pharmacy personnel to assess their intentions, attitudes, normative beliefs, and behaviors towards participating in naloxone dispensing and provision of at-home drug disposal solutions. Purposive sampling was utilized to recruit participants, with saturation achieved after 12 interviews. Interviews were transcribed and coded to identify recurring themes., Results: Four primary themes emerged: 1) the value and benefits of helping others, emphasizing societal, patient, and environmental benefits; 2) limits and barriers to participation, including financial concerns, management support, and time constraints; 3) pharmacists' intrinsic motivators, highlighting personal motivations and differentiation between programs for specific patient types; and 4) program implementation challenges and strategies., Conclusion: The findings underscore the applicability of the TPB in understanding pharmacy engagement in opioid abatement programs. Despite facing barriers such as financial considerations and time constraints, the overall positive attitudes towards the programs indicate a strong motivation to contribute to public health efforts. Addressing identified barriers and leveraging motivators could enhance participation, potentially mitigating the opioid crisis. Future research should incorporate patient perspectives to fully understand the impact and effectiveness of pharmacy-led interventions, such as naloxone dispensing and disposal solutions, in opioid misuse prevention., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Psoriasis is a chronic skin disease that negatively impacts on patient's life. A holistic approach integrating well-being assessment could improve disease management. Since a consensus definition of well-being in psoriasis is not available, we aim to achieve a multidisciplinary consensus on well-being definition and its components. A literature review and consultation with psoriasis patients facilitated the design of a two-round Delphi questionnaire targeting healthcare professionals and psoriasis patients. A total of 261 panellists (65.1% patients with psoriasis, 34.9% healthcare professionals) agreed on the dimensions and components that should integrate the concept of well-being: emotional dimension (78.9%) [stress (83.9%), mood disturbance (85.1%), body image (83.9%), stigma/shame (75.1%), self-esteem (77.4%) and coping/resilience (81.2%)], physical dimension (82.0%) [sleep quality (81.6%), pain/discomfort (80.8%), itching (83.5%), extracutaneous manifestations (82.8%), lesions in visible areas (84.3%), lesions in functional areas (85.8%), and sex life (78.2%)], social dimension (79.5%) [social relationships (80.8%), leisure/recreational activities (80.3%), support from family/friends (76.6%) and work/academic life (76.5%)], and satisfaction with disease management (78.5%) [treatment (78.2%), information received (75.6%) and medical care provided by the dermatologist (80.1%)]. This well-being definition reflects patients' needs and concerns. Therefore, addressing them in psoriasis will optimise management, contributing to better outcomes and restoring normalcy to the patient's life., (© 2024. The Author(s).)

Background: Certolizumab is an Fc-free PEGylated tumor necrosis factor-alpha (TNFα) inhibitor recently approved for the treatment of moderate-to-severe plaque psoriasis, although there is limited real-world evidence on the effectiveness and safety in patients with plaque psoriasis treated with certolizumab. The objective of this article is to determine the effectiveness, drug survival, and safety, including pregnancy, childbirth, and lactation, of certolizumab in moderate-to-severe plaque psoriasis under real-world conditions., Methods: This is a retrospective, multicenter, observational study performed in 15 hospitals in Spain. It evaluates the effectiveness and safety of certolizumab in plaque psoriasis in the clinical practice setting., Results: A total of 67 patients (73% female) were evaluated with a mean baseline Psoriasis Area Severity Index (PASI) of 8.9. At Week 12, the mean PASI was 2.3 (n = 67), 1.3 (n = 57) at Week 24 and 1.3 at Week 52 (n = 34). Absolute PASI < 3 was achieved in 69, 86, and 92% of patients at Weeks 12, 24, and 52, respectively, as observed. For its part, using the under-response imputation analysis, PASI < 3 at Weeks 12, 24, and 52 were achieved by 69, 73, and 49% of the patients, respectively. A total of 35 patients (52%) had concomitant psoriatic arthritis, and, in 24 of them, Disease Activity in Psoriatic Arthritis Score (DAPSA) was recorded at baseline, with a mean value of 17.9 which decreased to 8.2 at Week 12 (n = 22) and to 3.6 at Week 24 (n = 18). Certolizumab treatment was discontinued in 14 out of 67 patients (21%), due to lack/loss of cutaneous or articular effectiveness (n = 11) or patient decision (n = 2) or adverse event in only one patient who developed active tuberculosis. A lower baseline PASI [hazard ratio (HR): 1.12 (1.02-1.23); P = 0.023] and a more significant reduction in PASI at Week 12 [HR: 1.16 (1.07-1.27); P < 0.001] and Week 52 [HR: 1.47 (1.11-1.96); P = 0.007] was shown to be significantly related with better survival for the entire follow-up period. Fourteen patients were treated during pregnancy and/or lactation without reporting adverse events in either the patient or the newborn., Conclusions: Certolizumab consistently showed high effectiveness and drug survival rates in this real-life cohort. The safety demonstrated in clinical trials during pregnancy and lactation seems to be confirmed in clinical practice., (© 2024 the International Society of Dermatology.)

New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC 50 0.0035 μM, SI 740) and for thymidine kinase VZV deficient strains (EC 50 0.018 μM, SI 145), with a low morphological toxicity in cell culture at 100 μM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited antiviral activity against HCMV (EC 50 0.021 μM) and VV (EC 50 0.050 μM), as well as against HSV-1 (TK-) (EC 50 0.0085 μM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: The present study aimed to identify, through a critical review of the literature, the success factors associated with the splinting of fixed prostheses on adjacent implants of the posterior sectors in partially edentulous patients compared with those not splinted., Study Selection: A MEDLINE strategy was implemented based on a research question to systematically search and extract information from databases (PubMed and Scopus) using MeSH terms/keywords identified for each domain. Systematic reviews, clinical and in vitro studies were selected and classified according to eligibility criteria based on the research question and level of evidence using the PRISMA flowchart., Results: A total of 32 studies were selected for data extraction and analysis according to study design (three systematic reviews, 14 clinical studies, and 15 in vitro studies). Overall, the studies found no significant difference in the association between the survival rate and prosthesis type. In clinical studies, there have been no differences in marginal bone loss between splinted and non-splinted prostheses, and the influence of peri-implant status and restorative materials has been poorly evaluated. The distribution of stress and loads determined in the in vitro studies showed results that could favor splinted prostheses; however, are generally associated with implant design., Conclusions: The need for splinted or non-splinted adjacent implant-supported prostheses remains controversial. The reviewed evidence indicates that factors such as implant size and its relationship with coronal height could be important in decision-making.

Background: GWAS have identified several non-functional tagSNPs associated with severe malaria. We hypothesized that causal SNPs could play a significant role in severe malaria by altering promoter or enhancer activity. Here, we sought to identify such regulatory SNPs., Methods: SNPs in linkage disequilibrium with tagSNPs associated with severe malaria were identified and were further annotated using FUMA. Then, SNPs were prioritized using IW-scoring method to identify regulatory ones. Gene reporter assays were performed to assess the regulatory effect of a region containing candidates. The association between SNPs and severe malaria was assessed using logistic regression models in a Senegalese cohort., Results: Among 418 SNPs, the best candidates were rs116525449 and rs79644959, which were in full disequilibrium between them, and located within the ARL14 promoter. Our gene reporter assay results revealed that the region containing the SNPs exhibited cell-specific promoter or enhancer activity, while the SNPs influenced promoter activity. We detected an association between severe malaria and those two SNPs using the overdominance model and we replicated the association of severe malaria with the tagSNP rs116423146., Conclusions: We suggest that these SNPs regulate ARL14 expression in immune cells and the presentation of antigens to T lymphocytes, thus influencing severe malaria development., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Mogamulizumab (MOG) is an antibody targeting the CCR4 receptor, authorized for relapsed or refractory peripheral T-cell (PTCL) and cutaneous T-cell lymphomas (CTCL). Its adoption in guidelines and endorsement by FDA and EMA established it as a systemic treatment, especially for advanced disease stages due to its comparatively lower toxicity. Clinical trials and real-world evidence have underscored its efficacy in advanced CTCLs, including mycosis fungoides and Sézary syndrome; PTCLs; and adult T-cell leukemia/lymphoma (ATLL), showcasing positive outcomes. Notably, the drug has demonstrated significant response rates, disease stability, and extended periods of progression-free survival, suggesting its applicability in cases with multiple treatment lines. Its safety profile is generally manageable, with adverse events (AEs) primarily related to the skin, infusion-related reactions, drug eruptions, autoimmune diseases, and skin disorders. The latter seem to appear as CCR4 can promote the skin-specific homing of lymphocytes, and MOG is directed against this receptor. While combination with immunostimulatory agents like interferon alpha and interleukin 12 has shown promising results, caution is urged when combining with PD1 inhibitors due to the heightened risk of immune-mediated AEs. The introduction of MOG as a systemic treatment implies a significant advancement in managing these diseases, supported by its favorable safety profile and complementary mechanisms.

Introduction and Objectives: Catheter-directed therapy (CDT) for acute pulmonary embolism (PE) is an emerging therapy that combines heterogeneous techniques. The aim of the study was to provide a nationwide contemporary snapshot of clinical practice and CDT-related outcomes., Methods: This Investigator-initiated multicenter registry aimed to include consecutive patients with intermediate-high risk (IHR) or high-risk (HR), acute PE eligible for CDT. The primary outcome of the study was in-hospital all-cause death., Results: A total of 253 patients were included, of whom 93 (36.8%) had HR-PE, and 160 (63.2%) had IHR-PE with a mean age of 62.3±15.1 years. Local thrombolysis was performed in 70.8% and aspiration thrombectomy in 51.8%, with 23.3% of patients receiving both. However, aspiration thrombectomy was favored in the HR-PE cohort (80.6% vs 35%; P<.001). Only 51 patients (20.2%) underwent CDT with specific PE devices. The success rate for CDT was 90.9% (98.1% of IHR-PE patients vs 78.5% of HR-PE patients, P<.001). In-hospital mortality was 15.5%, and was highly concentrated in the HR-PE patients (37.6%) and significantly lower in IHR-PE patients (2.5%), P<.001. Long-term (24-month) mortality was 40.2% in HR-PE patients vs 8.2% in IHR-PE patients (P<.001)., Conclusions: Despite the high success rate for CDT, in-hospital mortality in HR-PE is still high (37.6%) compared with very low IHR-PE mortality (2.5%)., (Copyright © 2023 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

A redescription of the genus Aldrichiopa Aldrich, 1934 (Diptera: Tachinidae) is provided and a new species, Aldrichiopa serrata Torres-Domnguez & Mulieri sp. nov. is described from specimens collected in Argentina and Chile. A detailed morphological description of the egg, first instar larva, and adult male and female including terminalia are presented for the first time. Exhaustive photographic records, scanning electron microscopy images, morphological detail of antennal ultrastructure, and updated geographic distributions are provided for the two species of the genus, Aldrichiopa coracella (Aldrich) and A. serrata sp. nov. An identification key based on males is provided. The taxonomic placement of Aldrichiopa to subfamily and tribe is discussed and information on the hosts of this genus of small tachinid flies is compiled.

Psoriasis and hidradenitis suppurativa are often associated with obesity. Because chronic low-grade inflammation underlies these 2 diseases, they can progress to more severe forms in patients with obesity if weight-reduction measures are not taken. This review covers pharmacologic alternatives for treating obesity, with emphasis on the benefits associated with the novel use of glucagon-like peptide-1 (GLP-1) agonists that act on satiety receptors. These drugs have led to greater weight loss in clinical trials and real-world settings than orlistat, which until recently was the only drug approved for treating obesity in the European Union. Although experience with GLP-1 agonists in patients with obesity and inflammatory skin diseases is currently scarce, the promising results reported suggest they may offer a useful tool for managing obesity., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Human respiratory syncytial virus (hRSV) is the most common cause of bronchiolitis and pneumonia in newborns, with all children being infected before the age of two. Reinfections are very common throughout life and can cause severe respiratory infections in the elderly and immunocompromised adults. Although vaccines and preventive antibodies have recently been licensed for use in specific subpopulations of patients, there is still no therapeutic treatment commonly available for these infections. Here, we investigated the potential antiviral activity of Retro-2.2, a derivative of the cellular retrograde transport inhibitor Retro-2, against hRSV. We show that Retro-2.2 inhibits hRSV replication in cell culture and impairs the ability of hRSV to form syncytia. Our results suggest that Retro-2.2 treatment affects virus spread by disrupting the trafficking of the viral de novo synthetized F and G glycoproteins to the plasma membrane, leading to a defect in virion morphogenesis. Taken together, our data show that targeting intracellular transport may be an effective strategy against hRSV infection.

Background: Previous investigations pointed out a role for antigen stimulation in Sezary syndrome (SS). High-throughput sequencing of the T cell receptor (TR) offers several applications beyond diagnostic purposes, including the study of T cell pathogenesis., Methods: We performed high-throughput RNA sequencing of the TR alpha (TRA) and beta (TRB) genes focusing on the complementarity-determining region 3 (CDR3) in 11 SS and one erythrodermic mycosis fungoides (MF) patients. Five psoriasis patients were employed as controls. Peripheral blood CD4 + cells were isolated and RNA sequenced (HiSeq2500). High-resolution HLA typing was performed in neoplastic patients., Results: Highly expanded predominant TRA and TRB CDR3 were only found in SS patients (median frequency: 94.4% and 93.7%). No remarkable CDR3 expansions were observed in psoriasis patients (median frequency of predominant TRA and TRB CDR3: 0.87% and 0.69%, p < 0.001 compared to SS). CDR3 almost identical to the predominant were identified within each SS patient and were exponentially correlated with frequencies of the predominant CDR3 (R 2  = 0.918, p < 0.001). Forty-six different CDR3 were shared between SS patients displaying HLA similarities, including predominant TRA and TRB CDR3 in one patient that were found in other three patients. Additionally, 351 antigen matches were detected (Cytomegalovirus, Epstein-Barr, Influenza virus, and self-antigens), and the predominant CDR3 of two different SS patients matched CDR3 with specificity for Influenza and Epstein-Barr viruses., Conclusions: Besides detecting clonality, these findings shed light on the nature of SS-related antigens, pointing to RNA sequencing as a useful tool for simultaneous clonality and biological analysis in SS., (© 2023 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Antibodies play a crucial role in activating protective immunity against malaria by interacting with Fc-gamma receptors (FcγRs). Genetic variations in genes encoding FcγRs can affect immune cell responses to the parasite. In this study, our aim was to investigate whether non-coding variants that regulate FcγR expression could influence the prevalence of Plasmodium falciparum infection. Through bioinformatics approaches, we selected expression quantitative trait loci (eQTL) for FCGR2A, FCGR2B, FCGR2C, FCGR3A , and FCGR3B genes encoding FcγRs ( FCGR ), in whole blood. We prioritized two regulatory variants, rs2099684 and rs1771575, located in open genomic regions. These variants were identified using RegVar, ImmuNexUT, and transcription factor annotations specific to immune cells. In addition to these, we genotyped the coding variants FCGR2A /rs1801274 and FCGR2B /rs1050501 in 234 individuals from a malaria-endemic area in Burkina Faso. We conducted age and family-based analyses to evaluate associations with the prevalence of malarial infection in both children and adults. The analysis revealed that the regulatory rs1771575-CC genotype was predicted to influence FCGR2B/FCGR2C/FCGR3A transcripts in immune cells and was the sole variant associated with a higher prevalence of malarial infection in children. In conclusion, this study identifies the rs1771575 cis-regulatory variant affecting several FcγRs in myeloid and neutrophil cells and associates it with the inter-individual capacity of children living in Burkina Faso to control malarial infection.

The action of cis-regulatory elements with either activation or repression functions underpins the precise regulation of gene expression during normal development and cell differentiation. Gene activation by the combined activities of promoters and distal enhancers has been extensively studied in normal and pathological contexts. In sharp contrast, gene repression by cis-acting silencers, defined as genetic elements that negatively regulate gene transcription in a position-independent fashion, is less well understood. Here, we repurpose the STARR-seq approach as a novel high-throughput reporter strategy to quantitatively assess silencer activity in mammals. We assessed silencer activity from DNase hypersensitive I sites in a mouse T cell line. Identified silencers were associated with either repressive or active chromatin marks and enriched for binding motifs of known transcriptional repressors. CRISPR-mediated genomic deletions validated the repressive function of distinct silencers involved in the repression of non-T cell genes and genes regulated during T cell differentiation. Finally, we unravel an association of silencer activity with short tandem repeats, highlighting the role of repetitive elements in silencer activity. Our results provide a general strategy for genome-wide identification and characterization of silencer elements., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Genome-wide association studies have identified ATP2B4 as a severe malaria resistance gene. Recently, 8 potential causal regulatory variants have been shown to be associated with severe malaria., Methods: Genotyping of rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452 was performed in 154 unrelated individuals (79 controls and 75 mild malaria patients). rs10751450, rs10751451 and rs10751452 were genotyped by Taqman assays, whereas the fragment of the ATP2B4 gene containing the remaining SNPs was sequenced. Logistic regression analysis was used to assess the association between the SNPs and mild malaria., Results: The results showed that mild malaria was associated with rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452. The homozygous genotypes for the major alleles were associated with an increased risk of mild malaria. Furthermore, the haplotype containing the major alleles and that containing the minor alleles were the most frequent haplotypes. Individuals with the major haplotypes had a significantly higher risk of mild malaria compared to the carriers of the minor allele haplotype., Conclusions: ATP2B4 polymorphisms that have been associated with severe malaria are also associated with mild malaria., (© 2023. The Author(s).)

Abstract: An 84-year-old woman presented with a 3-month history of a papular rash on the trunk, abdomen, and back. Histopathological examination revealed atypical lymphoid deep and band-like dermal infiltrates with marked epidermotropism. Neoplastic cells expressed B-cell markers (CD20), and clonal immunoglobulin gene rearrangement was observed. A complete peripheral blood study revealed aberrant circulating villous lymphocytes with the expression of B-cell markers (CD20, CD22, and CD79a) and aberrant expression of CD5. A staging workup revealed discrete splenic enlargement and bone marrow and gastrointestinal tract involvement. Skin lesions regressed spontaneously several weeks after diagnosis. Throughout evolution, the patient developed scattered cutaneous nodules and generalized papulo-nodules showing either epidermotropic or nonepidermotropic atypical dermal lymphoid infiltrates. This case illustrates the observation of autoinvolutive and recurrent epidermotropic B-cell atypical cutaneous infiltrates as a characteristic feature of secondary cutaneous involvement in splenic marginal B-cell lymphoma. Previously reported cases of epidermotropic B-cell lymphoma have been reviewed. Concurrent and simultaneous observation of epidermotropic and nonepidermotropic lesions seems to indicate that epidermotropism is an important but nonconstant diagnostic feature of splenic marginal B-cell lymphoma., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Brentuximab vedotin (BV) has been approved for CD30-expressing cutaneous T-cell lymphoma (CTCL) after at least one previous systemic treatment. However, real clinical practice is still limited., Objectives: To evaluate the response and tolerance of BV in a cohort of patients with CTCL., Methods: We analysed CTCL patients treated with BV from the Spanish Primary Cutaneous Lymphoma Registry (RELCP)., Results: Sixty-seven patients were included. There were 26 females and the mean age at diagnosis was 59 years. Forty-eight were mycosis fungoides (MF), 7 Sézary syndrome (SS) and 12 CD30+ lymphoproliferative disorders (CD30 LPD). Mean follow-up was 18 months. Thirty patients (45%) showed at least 10% of CD30+ cells among the total lymphocytic infiltrate. The median number of BV infusions received was 7. The overall response rate (ORR) was 67% (63% in MF, 71% in SS and 84% in CD30 LPD). Ten of 14 patients with folliculotropic MF (FMF) achieved complete or partial response (ORR 71%). The median time to response was 2.8 months. During follow-up, 36 cases (54%) experienced cutaneous relapse or progression. The median progression free survival (PFS) was 10.3 months. The most frequent adverse event was peripheral neuropathy (PN) (57%), in most patients (85%), grades 1 or 2., Conclusions: These results confirm the efficacy and safety of BV in patients with advanced-stage MF, and CD30 LPD. In addition, patients with FMF and SS also showed a favourable response. Our data suggest that BV retreatment is effective in a proportion of cases., (© 2022 European Academy of Dermatology and Venereology.)

The ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. We isolated and sequenced a virus from the first clinical MPXV case diagnosed in France (May 2022). We report that tecovirimat (ST-246), a US Food and Drug Administration approved drug, is efficacious against this isolate in vitro at nanomolar concentrations, whereas cidofovir is only effective at micromolar concentrations. Our results support the use of tecovirimat in ongoing human clinical trials., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Deregulation of JAK-STAT pathway seems to be relevant in mycosis fungoides (MFs). We report the case of a 23-year-old woman diagnosed of atypical MF carrying isolated PCM1::JAK2 fusion and eosinophilia. The disease was refractory to common treatments and progressed increasing the number of large CD30 positive T-cells. After progression, treatment with brentuximab vedotin was decided and decreased the proportion of large cells, but the low-grade component persisted, and the skin lesions worsened. Immunohistochemical expression of p-STAT3 detected in most tumor cells demonstrated the abnormal activation of JAK-STAT pathway. Very few cases of mature T-cell lymphomas carrying PCM1::JAK2 gene fusion have been reported to date, and we review previous cases described with this alteration. Described cases shared similar clinicopathological features and low genetic complexity, and the presence of PCM1::JAK2 fusion associates with a distinctive form of the disease., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Guselkumab is a monoclonal antibody that selectively blocks the p19 subunit of interleukin 23 and has been approved for the treatment of moderate to severe psoriasis and active psoriatic arthritis in adult patients due to its efficacy in different clinical trials. Therefore, itis important to know the performance of guselkumab in this setting of patients in clinical practice given that a high percentage of them are not represented in these clinical trials. Our objective was to evaluate the effectiveness and tolerability of guselkumab in clinical practice in the first patients with psoriasis and psoriatic arthritis treated since the date of its approval for psoriasis in Spain, in joint dermatology-rheumatology clinics. A multicenter retrospective data collection was carried out, in which 14 hospitals participated, including a total of 90 patients with psoriatic arthritis confirmed by a rheumatologist. Data collection was recorded at baseline and at weeks 12, 24, and 52 for both the articular and cutaneous domains. Ninety PsA patients started treatment with guselkumab and therefore were included in this study. The vast majority had already failed to at least to one biologic therapyprior guselkumab prescription. The median age was 55 years, 61% were female and 46% had a BMI ≥ 30 kg/m 2 . Sixty-nine percent suffered from peripheral arthritis, and in 34% an axial involvement was also detected; dactylitis or enthesitis was present in 24% and 29% of patients, respectively. Guselkumab was effective in controlling both articular and skin manifestations of PsA patients. Absolute PASI significantly decreased from 10.5 to 4.8, 1.9 and 1.3 at weeks 12, 24, and 52, respectively. In 29 out of 61 (48%) of cases, DAPSA was moderate or high, and patients showed a significant reduction in DAPSA at 12, 24, and 52 weeks of treatment (mean DAPSA values at baseline and follow up were 29, 20, 16, and 14, respectively). Patients with DAPSA in low activity or in remission at the time of initiation of guselkumab maintained response at the end of the study period. No new safety concerns were detected. Seventy-eight out of 90 patients (84.4%) persisted on treatment after 2 years follow-up. Our experience suggests that guselkumab isan effective drug for PsA and PsO patients in clinical practice with good tolerability and no additional safety signals, making it a new therapeutic alternative for the treatment of PsA and PsO patients., (© 2022 Wiley Periodicals LLC.)

Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25-30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-κB elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous γδ T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms.

Current therapeutic approaches for Sézary syndrome (SS) do not achieve a significant improvement in long-term survival of patients, and they are mainly focused on reducing blood tumor burden to improve quality of life. Eradication of SS is hindered by its genetic and molecular heterogeneity. Determining effective and personalized treatments for SS is urgently needed. The present work compiles the current methods for SS patient-derived xenograft (PDX) generation and management to provide new perspectives on treatment for patients with SS. Mononuclear cells were recovered by Ficoll gradient separation from fresh peripheral blood of patients with SS (N = 11). A selected panel of 26 compounds that are inhibitors of the main signaling pathways driving SS pathogenesis, including NF-kB, MAPK, histone deacetylase, mammalian target of rapamycin, or JAK/STAT, was used for in vitro drug sensitivity testing. SS cell viability was evaluated by using the CellTiter-Glo&#95;3D Cell Viability Assay and flow cytometry analysis. We validated one positive hit using SS patient-derived Sézary cells xenotransplanted (PDX) into NOD-SCID-γ mice. In vitro data indicated that primary malignant SS cells all display different sensitivities against specific pathway inhibitors. In vivo validation using SS PDX mostly reproduced the responses to the histone deacetylase inhibitor panobinostat that were observed in vitro. Our investigations revealed the possibility of using high-throughput in vitro testing followed by PDX in vivo validation for selective targeting of SS tumor cells in a patient-specific manner., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The calcineurin pathway is often activated in mycosis fungoides. We aimed to assess the activity and safety of topical pimecrolimus, a calcineurin inhibitor, in patients with early mycosis fungoides., Methods: PimTo-MF was a single-arm, multicentre, phase 2 trial done at six medical centres in Spain. Patients (aged ≥18 years) had histologically confirmed early mycosis fungoides (stages IA-IIA) and an Eastern Cooperative Oncology Group performance status of 0-1. Key exclusion criteria included the use of concurrent treatments for mycosis fungoides, including sunbathing, topical or systemic corticosteroids, and other calcineurin inhibitors. Patients applied topical pimecrolimus 1% cream on their skin lesions twice daily for 16 weeks (1 g per 2% of body surface), with subsequent follow-up of 12 months. Dosage modifications were not allowed. To evaluate adherence to the treatment, patients were instructed to return all empty tubes to the hospital (as per drug accountability protocols). The primary endpoint was the overall response ratein the intention-to-treat population. PimTo-MF is registered with EudraCT, 2014-001377-14, and is complete., Findings: Between March 1, 2015, and Sept 30, 2016, 39 patients were enrolled. All patients were assessable, with a median age of 51·5 years (IQR 45-62), and the population was predominantly male (24 male [62%], 15 female [38%]). Median follow-up after baseline was 5·7 years (IQR 5·7-6·2). 22 (56%) of 39 patients had an overall response (one complete response, 21 partial responses). Responses were observed across IA (14 [54%] of 26 patients) and IB (eight [73%] of 11 patients) clinical stages, but not IIA. Topical pimecrolimus was well tolerated and no patient required a dose reduction or discontinued treatment because of unacceptable drug-related toxicity. No patients were lost to follow-up or discontinued treatment. 13 (33%) of 39 patients reported adverse events; transitory mild burning or pruritus (grade 1) was the most common, seen in eight (21%) patients. In three (8%) of these patients, the burning or pruritus was considered related to treatment. No grade 4 or 5 adverse events were observed., Interpretation: Pimecrolimus 1% cream seems active and safe in patients with early stage mycosis fungoides. Our findings should be taken with caution until long-term follow-up data are obtained that confirm the safety of this treatment. Further controlled clinical trials are warranted to confirm these results., Funding: Instituto de Salud Carlos III and the European Regional Development Fund., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests PLO-R reports advisory board honoraria from Takeda, Kyowa, 4SC, MIRAGEN, Helsinn, Recordati Rare Diseases, and Innate Pharma. CM reports advisory board honoraria from Kyowa and Takeda. TE reports advisory board honoraria from Takeda. OS reports advisory board honoraria from Takeda, Eisai, Kyowa-Kirim, and Ferrer Pharma. FG reports speaker fees from Takeda. OS reports consulting, advisory, and advisory board honoraria from Roche, ISDIN, and Sanofi. MAPP reports advisory board honoraria, lecture fees, and research funding from Millenium Pharmaceuticals (now Takeda Oncology); advisory board honoraria and research funding from Gilead; advisory board honoraria and lecture fees from Jansen; advisory board honoraria from Celgene, Nanostring, and Kyowa Kirin; and research funding from Kura. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five ATP2B4 SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca 2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental pathologies characterized by social and communication deficits, for which treatments are limited. Cell therapies, including intrathecal (IT) administration of bone marrow (BM) mononuclear cells (BM-MNC), improves symptoms in patients with ASD. Twenty-four patients diagnosed with ASD, according to the Diagnostic and Statistical Manual of Mental Disorders Text Revision Fourth Edition (DSM-IV-TR) criteria, were autologously treated with IT BM-MNC, and the clinical effect was evaluated using the Childhood Autism Rating Scale (CARS) on Days 30 (n=24) and 180 (n=14) post-treatment. IT BM-MNC improved clinical outcomes by Day 30 ( p =0.0039), and those benefits remained and were further accentuated by Day 180 post-treatment (n=14; p =<0.0001). Clinical benefit at Days 30 ( p =0.001; r= -0.51) and 180 ( p =0.01; r= -0.60) posttreatment positively correlated with the enrichment of a putative BM stem cell population expressing the cluster of differentiation 133+ (CD133+) surface marker., Competing Interests: DISCLOSURES: All authors are employees of Hospital Universitario “Dr. José Eleuterio González.”, (Copyright © 2022. Matrix Medical Communications. All rights reserved.)

Abstract: A 59-year-old woman presented with a persistent eruption manifested as multiple agminated miliary facial papules. Histopathological examination showed prominent nodular dermal lymphoid infiltrates with hyperplastic follicles that were initially interpreted as B-cell reactive lymphoid hyperplasia. Several years later, an additional biopsy showed a dense perifollicular infiltrate with reactive primary and secondary follicles. Accompanying T cells corresponded to CD3/CD4/PD1/CXCL13-positive cells and scattered Epstein-Barr virus-positive B cells were identified by in situ hybridization. A monoclonal T-cell population was demonstrated by TCRγ and TCRβ Polymerase Chain Reaction amplification, as well as a minor abnormal circulating T-cell population by flow cytometry (0.62% of the white blood cells, CD4+CD3s-CD7-). A biopsy specimen from an enlarged right supraclavicular lymph node disclosed nodal involvement by angioimmunoblastic T-cell lymphoma. The observation of B-cell dermal nodular infiltrates with well-demarcated lymphoid aggregates forming primary lymphoid follicles may lead to overlook the T-cell component in some cases of angioimmunoblastic T-cell lymphoma. In such cases, a careful assessment of the apparently minor T-cell component is important to establish a correct diagnosis., Competing Interests: B. Sánchez-González is a consultant and/or speaker bureau for Novartis, Amgen, Alexion, Gilead, Takeda, and Shire. The other authors have no conflicts of interest to declare., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Although epidemiologic research has demonstrated significant differences in incidence and outcomes of sepsis according to sex, their underlying biological mechanisms are poorly understood. Here, we studied the influence of hormonal status by comparing in vivo cardiac performances measured by MRI in non-ovariectomized and ovariectomized septic female rats. Control and ovariectomized rats were randomly allocated to the following groups: sham, sepsis and sepsis plus landiolol. Sepsis was induced by caecum ligation and punction (CLP). Landiolol, a short-acting selective β1-adrenergic blocker improving the in vivo cardiac performance of septic male rats was perfused continuously after sepsis induction. Cardiac MRI was carried out 18 h after induction of sepsis to assess in vivo cardiac function. Capillary permeability was evaluated by Evans Blue administration and measurement of its tissue extravasation. Variation in myocardial gene and protein expression was also assessed by qPCR and western-blot in the left ventricular tissue. Sepsis reduced indexed stroke volume, cardiac index and indexed end-diastolic volume compared to sham group in ovariectomized females whereas it had no effect in control females. This was associated with an overexpression of JAK2 expression and STAT3 phosphorylation on Ser727 site, and an inhibition of the adrenergic pathways in OVR females. Landiolol increased the indexed stroke volume by reversing the indexed end-diastolic volume reduction after sepsis in ovariectomized females, while it decreased indexed stroke volume and cardiac index in control. This was supported by an overexpression of genes involved in calcium influx in OVR females while an inactivation of the β-adrenergic and a calcium efflux pathway was observed in control females. Sepsis decreased in vivo cardiac performances in ovariectomized females but not in control females, presumably associated with a more pronounced inflammation, inhibition of the adrenergic pathway and calcium efflux defects. Administration of landiolol prevents this cardiac dysfunction in ovariectomized females with a probable activation of calcium influx, while it has deleterious effects in control females in which calcium efflux pathways were down-regulated., (© 2022. The Author(s).)

T Cells comprise many subtypes of specified lymphocytes, and their differentiation and function take place in different tissues. This cellular diversity is also observed in the multiple ways T-cell transformation gives rise to a variety of T-cell neoplasms. This review covers the main types of T-cell malignancies and their specific characteristics, emphasizing recent advances at the cellular and molecular levels as well as differences and commonalities among them., Competing Interests: Conflict of interest disclosure The authors have no conflicts of interest to declare., (Copyright © 2021 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Introduction: Venous leg ulcers (VLU) embody the most severe stage of the broad spectrum of chronic venous disease. Approximately 40% of patients with VLU present with the underlying deep venous disease (DVD). Although the data are scarce, these deep venous disease-related VLU (DRV) are thought to have higher recurrence rates and a substantial economic burden. The objective of this study was to assess the economic burden of DRV across Australia, France, Germany, Italy, Spain, the UK, and the USA., Methods: A comprehensive literature review was undertaken to identify publications documenting the incidence and prevalence of VLU and DRV, medical resource utilization, and associated costs of DRV. Findings from this literature review were used to estimate the economic burden of illness, including direct medical costs over a 12-month interval following initial presentation of a newly formed DRV., Results: Total annual incidence of new or recurrent DRV in Australia, France, Germany, Italy, Spain, UK, and the US are estimated at 122,000, 263,000, 345,000, 253,000, 85,000, 230,000, and 643,000 events, respectively, in 2019. Incidence ranges from 0.73 to 3.12 per 1000 persons per year. The estimated annual direct medical costs for patients managed conservatively in these geographies total ~ $10.73 billion (USD) or $5527 per person per year., Conclusion: The availability of published data on the costs of VLU care varies widely across countries considered in this analysis. Although country-specific VLU practice patterns vary, there is a uniform pattern of high-cost care.

A first clue to gene function can be obtained by examining whether a gene is required for life in certain standard conditions, that is, whether a gene is essential. In bacteria, essential genes are usually identified by high-density transposon mutagenesis followed by sequencing of insertion sites (Tn-seq). These studies assign the term "essential" to whole genes rather than the protein domain sequences that encode the essential functions. However, genes can code for multiple protein domains that evolve their functions independently. Therefore, when essential genes code for more than one protein domain, only one of them could be essential. In this study, we defined this subset of genes as "essential domain-containing" (EDC) genes. Using a Tn-seq data set built-in Burkholderia cenocepacia K56-2, we developed an in silico pipeline to identify EDC genes and the essential protein domains they encode. We found forty candidate EDC genes and demonstrated growth defect phenotypes using CRISPR interference (CRISPRi). This analysis included two knockdowns of genes encoding the protein domains of unknown function DUF2213 and DUF4148. These putative essential domains are conserved in more than two hundred bacterial species, including human and plant pathogens. Together, our study suggests that essentiality should be assigned to individual protein domains rather than genes, contributing to a first functional characterization of protein domains of unknown function., (© 2022. The Author(s).)