Oral Omilancor Treatment Ameliorates Clostridioides difficile Infection During IBD Through Novel Immunoregulatory Mechanisms Mediated by LANCL2 Activation.

BACKGROUND: Clostridioides difficile infection (CDI) is an opportunistic infection of the gastrointestinal tract, commonly associated with antibiotic administration, that afflicts almost 500 000 people yearly only in the United States. CDI incidence and recurrence is increased in inflammatory bowel disease (IBD) patients. Omilancor is an oral, once daily, first-in-class, gut-restricted, immunoregulatory therapeutic in clinical development for the treatment of IBD. METHODS: Acute and recurrent murine models of CDI and the dextran sulfate sodium-induced concomitant model of IBD and CDI were utilized to determine the therapeutic efficacy of oral omilancor. To evaluate the protective effects against C. difficile toxins, in vitro studies with T84 cells were also conducted. 16S sequencing was employed to characterize microbiome composition. RESULTS: Activation of the LANCL2 pathway by oral omilancor and its downstream host immunoregulatory changes decreased disease severity and inflammation in the acute and recurrence models of CDI and the concomitant model of IBD/CDI. Immunologically, omilancor treatment increased mucosal regulatory T cell and decreased pathogenic T helper 17 cell responses. These immunological changes resulted in increased abundance and diversity of tolerogenic gut commensal bacterial strains in omilancor-treated mice. Oral omilancor also resulted in accelerated C. difficile clearance in an antimicrobial-free manner. Furthermore, omilancor provided protection from toxin damage, while preventing the metabolic burst observed in intoxicated epithelial cells. CONCLUSIONS: These data support the development of omilancor as a novel host-targeted, antimicrobial-free immunoregulatory therapeutic for the treatment of IBD patients with C. difficile-associated disease and pathology with the potential to address the unmet clinical needs of ulcerative colitis and Crohn's disease patients with concomitant CDI.

Omilancor is an oral, gut-restricted first-in-class immunoregulatory therapeutic for the treatment of inflammatory bowel disease (IBD). This study demonstrates for the first time that omilancor provides therapeutic efficacy in models of acute and recurrent Clostridioides difficile infection (CDI), and concomitant CDI and IBD, by increasing regulatory T cell function while suppressing effector responses, plus modulating gut microbiome composition and preserving epithelial barrier function.

Treating Autoimmune Diseases With LANCL2 Therapeutics: A Novel Immunoregulatory Mechanism for Patients With Ulcerative Colitis and Crohn's Disease.

Lanthionine synthetase C-like 2 (LANCL2) therapeutics have gained increasing recognition as a novel treatment modality for a wide range of autoimmune diseases. Genetic ablation of LANCL2 in mice results in severe inflammatory phenotypes in inflammatory bowel disease (IBD) and lupus. Pharmacological activation of LANCL2 provides therapeutic efficacy in mouse models of intestinal inflammation, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. Mechanistically, LANCL2 activation enhances regulatory CD4 + T cell (Treg) responses and downregulates effector responses in the gut. The stability and suppressive capacities of Treg cells are enhanced by LANCL2 activation through engagement of immunoregulatory mechanisms that favor mitochondrial metabolism and amplify IL-2/CD25 signaling. Omilancor, the most advanced LANCL2 immunoregulatory therapeutic in late-stage clinical development, is a phase 3 ready, first-in-class, gut-restricted, oral, once-daily, small-molecule therapeutic in clinical development for the treatment of UC and CD. In this review, we discuss this novel mechanism of mucosal immunoregulation and how LANCL2-targeting therapeutics could help address the unmet clinical needs of patients with autoimmune diseases, starting with IBD.

Oral LANCL2 therapeutics are a safe and effective treatment modality for the long-term management of autoimmune diseases, including UC and CD, without causing systemic immunosuppression. This review discusses in detail the immunoregulatory mechanisms of action of LANCL2 therapeutics. More specifically, the article describes how omilancor, a first-in-class, oral, once daily, gut-restricted LANCL2 therapeutic could help address the unmet clinical needs of patients with IBD and other immune-mediated diseases.

Modulation of colonic immunometabolic responses during Clostridioides difficile infection ameliorates disease severity and inflammation.

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea, and its clinical symptoms can span from asymptomatic colonization to pseudomembranous colitis and even death. The current standard of care for CDI is antibiotic treatment to achieve bacterial clearance; however, 15 to 35% of patients experience recurrence after initial response to antibiotics. We have conducted a comprehensive, global colonic transcriptomics analysis of a 10-day study in mice to provide new insights on the local host response during CDI and identify novel host metabolic mechanisms with therapeutic potential. The analysis indicates major alterations of colonic gene expression kinetics at the acute infection stage, that are restored during the recovery phase. At the metabolic level, we observe a biphasic response pattern characterized by upregulated glycolytic metabolism during the peak of inflammation, while mitochondrial metabolism predominates during the recovery/healing stage. Inhibition of glycolysis via 2-Deoxy-D-glucose (2-DG) administration during CDI decreases disease severity, protects from mortality, and ameliorates colitis in vivo. Additionally, 2-DG also protects intestinal epithelial cells from C. difficile toxin damage, preventing loss of barrier integrity and secretion of proinflammatory mediators. These data postulate the pharmacological targeting of host immunometabolic pathways as novel treatment modalities for CDI.

Neuroendocrine Neoplasms of the Head and Neck: A Case Report on an Oropharyngeal Presentation.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors that can appear in many different locations as neuroendocrine cells are distributed throughout the anatomy during embryonic development. This paper presents a case report of a 77-year-old woman with a rare NEN in the lateral wall of the pharynx. In addition to being very infrequent, it can be considered a second metachronous tumor since it is unrelated to a previous sinonasal NEN that the patient presented with 20 years before. We have reviewed the histological characteristics of NENs and the grading system used to determine their potential for metastasis or local invasion. NENs in the oropharynx are very infrequent and typically do not present systemic symptoms or specific local signs. The article concludes that surgical excision is typically the preferred treatment for localized NENs where complete removal is possible.

Increasing of New CA-MRSA Infections Detected in people living with HIV Who Engage in Chemsex in Barcelona: An Ambispective Study.

INTRODUCTION: There are no data on community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections in the context of the chemsex phenomenon. This study aimed to characterize CA-MRSA-related infections in a cohort of people living with HIV (PLWH) who engage in chemsex. METHODS: At the Hospital Clinic of Barcelona, from February 2018 to January 2022, we analyzed CA-MRSA infections diagnosed in a cohort of PLWH who engage in chemsex. Epidemiological, behavioral and clinical variables were assessed. Mass spectrometry identification and antimicrobial susceptibility testing were performed on MRSA isolates. Pulse field electrophoresis was used to assess the clonality of the MRSA strains. The presence of Panton-Valentine leukocidin was also investigated. RESULTS: Among the cohort of 299 participants who engage in chemsex, 25 (8%) with CA-MRSA infections were identified, 9 at baseline and 16 with incident cases; the cumulative incidence was 5.5% (95% CI: 3.2%, 8.8%). The most common drugs were methamphetamine (96%) and GHB/GBL (92%). Poly-consumption and slamming were reported by 32% and 46%, respectively. CA-MRSA was isolated from the infection sites of 20 participants, and CA-MRSA colonization was confirmed in the remaining 5 persons. Seventy-one percent had used antibiotics in the previous year. All participants presented with skin and soft tissue infections, 28% required hospitalization, and 48% had recurrence. Of the 23 MRSA isolates further studied, 19 (82,6%) belonged to the same clone. Panton-Valentine leukocidin was detected in all isolates. CONCLUSION: PLWH who engage in chemsex may present with CA-MRSA infections. Clinical suspicion and microbiological diagnosis are required to provide adequate therapy, and CA-MRSA prevention interventions should be designed.

Experiencia de un programa de profilaxis preexposición en una unidad de virus de la inmunodeficiencia humana hospitalaria. Descripción del perfil basal del usuario e identificación de oportunidades de mejora / PrEP program experience in a hospital HIV unit. Description of baseline user profile and identification of opportunities for improvement

Introducción: La profilaxis preexposición (PrEP) es una intervención biomédica dirigida a prevenir la infección por el VIH en personas seronegativas con alto riesgo de contraer la infección. Esta estrategia fue aprobada por el Ministerio de Salud de España en octubre de 2019. Objetivo: Presentar la experiencia inicial de la PrEP en la Unidad de VIH del Hospital Clínic de Barcelona, poniendo especial atención en el análisis de los factores de vulnerabilidad de la cohorte. Materiales y métodos: Estudio retrospectivo, descriptivo. Se analizan las características epidemiológicas, sociodemográficas y clínicas basales de los usuarios incluidos en el programa durante el primer año de funcionamiento, prestando particular atención a las infecciones, las prácticas de riesgo y el consumo de sustancias. Resultados: Se incluyeron 190 individuos, 177 hombres y 12 mujeres transexuales con una edad media de 35 años (8DE). El 70% tenía estudios superiores y la mitad nacionalidad española. Informaron de tener 10 parejas de media al trimestre y el 60% de practicar sexo anal desprotegido. El 31% presentó al menos una PCR positiva para ITS, siendo la N. gonorrhoeae el germen más prevalente (51%) y la muestra rectal la más afectada (21%). El 63% reportó el uso de chemsex, el 19% policonsumo y el 8% slamming. La mitad expresó su preocupación por el consumo y/o prácticas sexuales y un 25% la necesidad de ayuda. Conclusiones: El perfil del usuario de PrEP visitado en nuestra unidad hospitalaria justifica la creación de equipos multidisciplinares que permitan prestar una atención holística de la vida sexual de estas personas.(AU)

Introduction: Pre-Exposure Prophylaxis (PrEP) is a biomedical intervention to prevent HIV infection in seronegative people at high risk of becoming infected. This strategy was endorsed in October 2019 by the Spanish Ministry of Health. Objective: To present the PrEP initial experience in the HIV Unit of the Hospital Clínic of Barcelona, paying special attention to the analysis of the vulnerability factors in the cohort. Materials and methods: Retrospective, descriptive study. The epidemiological, sociodemographic, and clinical characteristics of the users included in the program during the first year are analyzed, paying particular attention to Infections, risky practices, and substance use. Results: 190 individuals were included, 177 men and 12 trans women with a mean age of 35 years (8 SD). 70% had higher education, and half had Spanish nationality. An average of 10 couples per trimester and 60% reported unprotected anal sex. 31% had at least one positive PCR for STIs, with N. gonorrhoeae being the most prevalent microorganism (51%) and the rectal sample the most affected (21%). 63% reported chemsex use, 19% polydrug use, and 8% “slamming”. Half expressed concern about consumption and/or sexual practices and 25% the need for help. Conclusions: The PrEP user profile attended in our Hospital Unit justifies the creation of multidisciplinary teams that allow us to provide holistic attention to the sexual life of these people.(AU)

PrEP program experience in a hospital HIV unit. Description of baseline user profile and identification of opportunities for improvement.

INTRODUCTION: Pre-Exposure Prophylaxis (PrEP) is a biomedical intervention to prevent HIV infection in seronegative people at high risk of becoming infected. This strategy was endorsed in October 2019 by the Spanish Ministry of Health. OBJECTIVE: To present the PrEP initial experience in the HIV Unit of the Hospital Clínic of Barcelona, paying special attention to the analysis of the vulnerability factors in the cohort. MATERIALS AND METHODS: Retrospective, descriptive study. The epidemiological, sociodemographic, and clinical characteristics of the users included in the program during the first year are analyzed, paying particular attention to Infections, risky practices, and substance use. RESULTS: 190 individuals were included, 177 men and 12 trans women with a mean age of 35 years (8 SD). 70% had higher education, and half had Spanish nationality. An average of 10 couples per trimester and 60% reported unprotected anal sex. 31% had at least one positive PCR for STIs, with N. gonorrhoeae being the most prevalent microorganism (51%) and the rectal sample the most affected (21%). 63% reported chemsex use, 19% polydrug use, and 8% "slamming". Half expressed concern about consumption and/or sexual practices and 25% the need for help. CONCLUSIONS: The PrEP user profile attended in our Hospital Unit justifies the creation of multidisciplinary teams that allow us to provide holistic attention to the sexual life of these people.

Computational modeling of complex bioenergetic mechanisms that modulate CD4+ T cell effector and regulatory functions.

We built a computational model of complex mechanisms at the intersection of immunity and metabolism that regulate CD4+ T cell effector and regulatory functions by using coupled ordinary differential equations. The model provides an improved understanding of how CD4+ T cells are shaping the immune response during Clostridioides difficile infection (CDI), and how they may be targeted pharmacologically to produce a more robust regulatory (Treg) response, which is associated with improved disease outcomes during CDI and other diseases. LANCL2 activation during CDI decreased the effector response, increased regulatory response, and elicited metabolic changes that favored Treg. Interestingly, LANCL2 activation provided greater immune and metabolic modulation compared to the addition of exogenous IL-2. Additionally, we identified gluconeogenesis via PEPCK-M as potentially responsible for increased immunosuppressive behavior in Treg cells. The model can perturb immune signaling and metabolism within a CD4+ T cell and obtain clinically relevant outcomes that help identify novel drug targets for infectious, autoimmune, metabolic, and neurodegenerative diseases.

Guselkumab effectiveness and survival in patients with psoriasis and psoriatic arthritis: Multicenter analysis in daily clinical practice by the Spanish Psoriasis Group.

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/m2 . 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.

Frequent detection of monkeypox virus DNA in saliva, semen, and other clinical samples from 12 patients, Barcelona, Spain, May to June 2022.

A monkeypox (MPX) outbreak has expanded worldwide since May 2022. We tested 147 clinical samples collected at different time points from 12 patients by real-time PCR. MPX DNA was detected in saliva from all cases, sometimes with high viral loads. Other samples were frequently positive: rectal swab (11/12 cases), nasopharyngeal swab (10/12 cases), semen (7/9 cases), urine (9/12 cases) and faeces (8/12 cases). These results improve knowledge on virus shedding and the possible role of bodily fluids in disease transmission.

Chemsex Practices in PrEP: Beyond Addiction and Risk Toward a Healthy Sex Life-Baseline Experiences from a Hospital-Based PrEP Program in Barcelona, Spain.

Pre-exposure prophylaxis (PrEP) is a biomedical intervention that has demonstrated efficacy in HIV prevention in individuals at high-risk, among them chemsex users. Out of 190 PrEP users followed at Hospital Clinic of Barcelona until October 2020, 89% reported drug use, and 63% disclosed that they had engaged in chemsex practices, initiated in 64% of cases within the past year. Twenty-one percent used 3 or more drugs simultaneously, being GHB/GBL, nitrites, sildenafil, and methamphetamine the most prevalent combination. Eight percent reported slamming. Forty-one percent described having had negative experiences and 8% did not remember the last time they had sober sex. Methamphetamine, mephedrone, GHB/GBL, and having had open relationships, group sex, double penetration, and fisting were significantly more prevalent. Forty-nine percent admitted being worried about chemsex use, and 18% said they needed help. A comprehensive, interdisciplinary approach is mandatory to enable the attainment of a healthy approach to one's sex life.

RESUMEN: La PrEP es una intervención biomédica eficaz en la prevención del VIH en personas con alto riesgo, entre ellas las personas que practican chemsex. De los 190 usuarios de PrEP seguidos en el Hospital Clínic de Barcelona hasta octubre de 2020, el 89% refirió utilizar drogas y el 63% en contexto de chemsex, iniciando el consumo el 64% durante el último año. El 21% refería policonsumo, siendo GHB/GBL, nitritos, sildenafilo y metanfetamina la combinación más prevalente. El 8% reportó slamming. El 41% describió haber tenido experiencias negativas y el 8% no recordaba la última vez que tuvo sexo sobrio. Metanfetamina, mefedrona, GHB/GBL y haber tenido relaciones abiertas, sexo en grupo, doble penetración y fisting fueron significativamente más frecuentes. El 49% refirió estar preocupado por la práctica de chemsex y el 18% necesitar ayuda. Un abordaje integral e interdisciplinar mejoraría el acompañamiento global de la sexualidad en estas personas.

WITHDRAWN: EFFICACY, SAFETY, AND TOLERABILITY OF OMILANCOR IN A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF PATIENTS WITH ULCERATIVE COLITIS.

BACKGROUND: Omilancor is an oral, once-daily, gut-restricted, small molecule, first-in-class therapeutic for Crohn's disease (CD) and ulcerative colitis (UC) that targets the novel LANCL2 pathway. Through LANCL2 activation, omilancor increases the suppressive capacity of regulatory immune cells, including regulatory CD4+ T cells (Tregs), locally within the intestinal mucosa. In a Phase I study in normal healthy volunteers no changes in AEs or trends in safety laboratory trends were observed up to daily oral doses of 7500 mg/day. METHODS: In a Phase 2, proof of concept, double blind, parallel-group study, adult patients with Mayo Clinic scores (MCS) of 4 - 10 and endoscopic subscores of 2 or more were randomly assigned to groups given omilancor 440 mg QD (n=66), omilancor 880 mg QD (n=66) or placebo (n=66) for 12 weeks. The primary endpoint was clinical remission after 12 weeks as defined by rectal bleeding (RB) equal to 0, stool frequency (SF) equal to 0 or 1 and endoscopic appearance (MES) equal to 0 or 1. A modified intent to treat (mITT) population was defined by patients with RB > 0, histological activity and elevated fecal calprotectin (FCP) at baseline. Secondary endpoints included histological remission as defined by a Geboes score < 3.1 with absence of neutrophils in the lamina propria, endoscopic remission as defined by a MES < 2, normalization of FCP and pharmacokinetics (PK) of omilancor in stool, tissue and plasma. RESULTS: Oral omilancor was well tolerated with no trends in AE profile observed and most AEs of mild severity and no dose-limiting toxicities. In the mITT population, clinical remission was induced in 30.4% of omilancor treated patients relative to 3.7% of patients given placebo (Δ = 26.7, p = 0.01), thereby meeting the primary endpoint. Endoscopic remission was induced in 41.7% of patients treated with omilancor relative to 18.6% of patients given placebo (Δ = 23.1, p = 0.07). Histological remission was induced in 41.7% of patients treated with omilancor relative to 22.2% of patients given placebo (Δ = 19.5, p = 0.14). In patients with elevated baseline FCP, normalization occurred in 43.8% of the omilancor 880 mg group and 40.6% of the omilancor 440 mg group relative to 21.4% of the placebo group after 2 weeks (p = 0.048). PK analysis validated a gut-restricted profile with stable drug levels in stool over the 12-week treatment period and penetration into colonic biopsy tissue with limited systemic exposure. Reduction of patient reported outcomes occurred during the OLE with nearly 90% of patients reaching SF ≤ 1 and RB = 0 after 36 weeks of open-label treatment. CONCLUSIONS: Once a day oral dosing with omilancor was well-tolerated and induced clinical remission in a Phase II mild to moderate UC population. A Phase II study in CD and a Phase III program in UC (PACIFY) were initiated in 2021 and are currently recruiting.

Exploratory studies with NX-13: oral toxicity and pharmacokinetics in rodents of an orally active, gut-restricted first-in-class therapeutic for IBD that targets NLRX1.

Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is an emerging therapeutic target for a spectrum of human diseases. NX-13 is a small molecule therapeutic designed to target and activate NLRX1 to induce immunometabolic changes resulting in lower inflammation and therapeutic responses in inflammatory bowel disease (IBD). This study investigates the safety of NX-13 in a seven-day, repeat-dose general toxicity study in male and female Sprague Dawley rats at oral doses of 500 and 1000 mg/kg. Weights, clinical signs, functional observational battery, clinical pathology and histopathology were used for evaluation. Daily oral dosing of NX-13 up to 1000 mg/kg did not result in any changes in weight, abnormal clinical signs or behavior. No significant differences were observed between treated and control rats in hematology or blood biochemistry. Histopathological evaluation of 12 tissues demonstrated no differences between controls and treated rats. There were no changes in weights of brain, heart, kidney, liver or spleen. Pharmacokinetic analysis of a single oral dose of NX-13 at 10 mg/kg in Sprague Dawley rats provided a maximum plasma concentration of 57 ng/mL at 0.5 h post-dose. Analysis of colon tissue after oral dosing with 1 and 10 mg/kg indicated high peak concentrations (10 and 100 µg/g, respectively) that scale in a dose-proportional manner. These experiments suggest that NX-13 is safe and well-tolerated in rats given oral doses as high as 1000 mg/kg with a favorable gastrointestinal localized pharmacokinetic profile, confirming NX-13 as a promising therapeutic for Crohn's disease and ulcerative colitis.

Nlrx1-Regulated Defense and Metabolic Responses to Aspergillus fumigatus Are Morphotype and Cell Type Specific.

The Nlr family member X1 (Nlrx1) is an immuno-metabolic hub involved in mediating effective responses to virus, bacteria, fungi, cancer, and auto-immune diseases. We have previously shown that Nlrx1 is a critical regulator of immune signaling and mortality in several models of pulmonary fungal infection using the clinically relevant fungus Aspergillus fumigatus. In the absence of Nlrx1, hosts produce an enhanced Th2 response primarily by CD103+ dendritic cell populations resulting in enhanced mortality via immunopathogenesis as well as enhanced fungal burden. Here, we present our subsequent efforts showcasing loss of Nlrx1 resulting in a decreased ability of host cells to process A. fumigatus conidia in a cell-type-specific manner by BEAS-2B airway epithelial cells, alveolar macrophages, bone marrow-derived macrophages, but not bone marrow-derived neutrophils. Furthermore, loss of Nlrx1 results in a diminished ability to generate superoxide and/or generic reactive oxygen species during specific responses to fungal PAMPs, conidia, and hyphae. Analysis of glycolysis and mitochondrial function suggests that Nlrx1 is needed to appropriately shut down glycolysis in response to A. fumigatus conidia and increase glycolysis in response to hyphae in BEAS-2B cells. Blocking glycolysis and pentose phosphate pathway (PPP) via 2-DG and NADPH production through glucose-6-phosphate dehydrogenase inhibitor resulted in significantly diminished conidial processing in wild-type BEAS-2B cells to the levels of Nlrx1-deficient BEAS-2B cells. Our findings suggest a need for airway epithelial cells to generate NADPH for reactive oxygen species production in response to conidia via PPP. In context to fungal pulmonary infections, our results show that Nlrx1 plays significant roles in host defense via PPP modulation of several aspects of metabolism, particularly glycolysis, to facilitate conidia processing in addition to its critical role in regulating immune signaling.

Enemy of My Enemy: A Novel Insect-Specific Flavivirus Offers a Promising Platform for a Zika Virus Vaccine.

Vaccination remains critical for viral disease outbreak prevention and control, but conventional vaccine development typically involves trade-offs between safety and immunogenicity. We used a recently discovered insect-specific flavivirus as a vector in order to develop an exceptionally safe, flavivirus vaccine candidate with single-dose efficacy. To evaluate the safety and efficacy of this platform, we created a chimeric Zika virus (ZIKV) vaccine candidate, designated Aripo/Zika virus (ARPV/ZIKV). ZIKV has caused immense economic and public health impacts throughout the Americas and remains a significant public health threat. ARPV/ZIKV vaccination showed exceptional safety due to ARPV/ZIKV's inherent vertebrate host-restriction. ARPV/ZIKV showed no evidence of replication or translation in vitro and showed no hematological, histological or pathogenic effects in vivo. A single-dose immunization with ARPV/ZIKV induced rapid and robust neutralizing antibody and cellular responses, which offered complete protection against ZIKV-induced morbidity, mortality and in utero transmission in immune-competent and -compromised murine models. Splenocytes derived from vaccinated mice demonstrated significant CD4+ and CD8+ responses and significant cytokine production post-antigen exposure. Altogether, our results further support that chimeric insect-specific flaviviruses are a promising strategy to restrict flavivirus emergence via vaccine development.

First-in-class topical therapeutic omilancor ameliorates disease severity and inflammation through activation of LANCL2 pathway in psoriasis.

Psoriasis (PsO) is a complex immune-mediated disease that afflicts 100 million people. Omilancor is a locally-acting, small molecule that selectively activates the Lanthionine Synthetase C-like 2 (LANCL2) pathway, resulting in immunoregulatory effects at the intersection of immunity and metabolism. Topical omilancor treatment in an imiquimod-induced mouse model of PsO ameliorates disease severity, epidermal hyperplasia and acanthosis. Further, pharmacological activation of LANCL2 results in significant downregulation of proinflammatory markers including local reduction of IL17, and infiltration of proinflammatory cell subsets. These therapeutic effects were further validated in an IL-23 PsO model. This model reported increased preservation of homeostatic skin structure, accompanied by a decreased infiltration of proinflammatory T cell subsets. In CD4+ T cells and Th17 cells, the LANCL2 pathway regulates proinflammatory cytokine production, proliferation and glucose metabolism. Metabolically, the loss of Lancl2 resulted in increased glycolytic rates, lactate production and upregulated enzymatic activity of hexokinase and lactate dehydrogenase (LDH). Inhibition of LDH activity abrogated the increased proliferation rate in Lancl2-/- CD4+ T cells. Additionally, topical omilancor treatment decreased the metabolic upregulation in keratinocytes, keratinocyte hyperproliferation and expression of inflammatory markers. Omilancor is a promising topical, LANCL2-targeting therapeutic candidate for the treatment of PsO and other dermatology indications.

PrEP program experience in a hospital HIV unit. Description of baseline user profile and identification of opportunities for improvement. / Experiencia de un programa de profilaxis preexposición en una unidad de virus de la inmunodeficiencia humana hospitalaria. Descripción del perfil basal del usuario e identificación de oportunidades de mejora.

INTRODUCTION: Pre-Exposure Prophylaxis (PrEP) is a biomedical intervention to prevent HIV infection in seronegative people at high risk of becoming infected. This strategy was endorsed in October 2019 by the Spanish Ministry of Health. OBJECTIVE: To present the PrEP initial experience in the HIV Unit of the Hospital Clínic of Barcelona, paying special attention to the analysis of the vulnerability factors in the cohort. MATERIALS AND METHODS: Retrospective, descriptive study. The epidemiological, sociodemographic, and clinical characteristics of the users included in the program during the first year are analyzed, paying particular attention to Infections, risky practices, and substance use. RESULTS: 190 individuals were included, 177 men and 12 trans women with a mean age of 35 years (8 SD). 70% had higher education, and half had Spanish nationality. An average of 10 couples per trimester and 60% reported unprotected anal sex. 31% had at least one positive PCR for STIs, with N. gonorrhoeae being the most prevalent microorganism (51%) and the rectal sample the most affected (21%). 63% reported chemsex use, 19% polydrug use, and 8% "slamming". Half expressed concern about consumption and/or sexual practices and 25% the need for help. CONCLUSIONS: The PrEP user profile attended in our Hospital Unit justifies the creation of multidisciplinary teams that allow us to provide holistic attention to the sexual life of these people.