Soluble Factors and Receptors Involved in Skin Innate Immunity—What Do We Know So Far?

The pattern recognition receptors, complement system, inflammasomes, antimicrobial peptides, and cytokines are innate immunity soluble factors. They sense, either directly or indirectly, the potential threats and produce inflammation and cellular death. High interest in their modulation has emerged lately, acknowledging they are involved in many cutaneous inflammatory, infectious, and neoplastic disorders. We extensively reviewed the implication of soluble factors in skin innate immunity. Furthermore, we showed which molecules target these factors, how these molecules work, and how they have been used in dermatological practice. Cytokine inhibitors have paved the way to a new era in treating moderate to severe psoriasis and atopic dermatitis

Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex)

The incidence of syphilis, gonorrhea, chlamydia, and herpes simplex has increased over the last decade, despite the numerous prevention strategies. Worldwide scientists report a surge in drug-resistant infections, particularly in immunocompromised patients. Antigenic variations in syphilis enable long-term infection, but benzathine penicillin G maintains its efficiency, whereas macrolides should be recommended with caution. Mupirocin and zoliflodacin were recently introduced as therapies against ceftriaxone-resistant gonococcus, which poses a larger global threat. The gastrointestinal and prostatic potential reservoirs of Chlamydia trachomatis may represent the key towards complete eradication. Similar to syphilis, macrolides resistance has to be considered in genital chlamydiosis. Acyclovir-resistant HSV may respond to the novel helicase-primase inhibitors and topical imiquimod, particularly in HIV-positive patients. Novel drugs can overcome these challenges while nanocarriers enhance their potency, particularly in mucosal areas. This review summarizes the most recent and valuable discoveries regarding the immunopathogenic mechanisms of these sexually transmitted infections and discusses the challenges and opportunities of the novel molecules and nanomaterials

PRENATAL DIAGNOSIS OF DEVELOPMENTAL ABNORMALITIES IN FETUSES

Universitatea de Stat de Medicină şi Farmacie „Nicolae Testemiţanu”, Chişinău, Republica MoldovaIntroducere. Rolul diagnosticului prenatal (DP) în sistemul de prevenire al anomaliilor de dezvoltare (AD) este subliniat în studiu. Diagnosticul prenatal genetic pentru anomaliile de dezvoltare se realizează la nivel populațional prin intermediul testelor de screening biochimic și ecografic, precum și utilizând tehnologii de DP citogenetic și molecular-genetic. Scopul lucrării. Evidențierea rolului DP în sistemul de preîntâmpinare al AD și identificarea principalelor măsuri de profilaxie în grupa de risc. Material și metode. Studiul retro- și prospectiv de investigație a inclus 256 de gravide care au solicitat consiliere medico-genetică în CSRGM în perioada 2018-2023. Grupa I: 124 gravide din grupa cu risc mediu și înalt, grupa II: 132 gravide din grupa cu risc scăzut. Diagnosticul genetic a fost efectuat prin metoda citogenetică. Prelucrarea statistică a datelor obținute în studiu s-a realizat prin programul Quanto. Rezultate. Cele două grupe au fost comparabile după vârstă, perioada de gestație, gradul de risc genetic. S-a constatat că vârsta femeilor din grupa de risc obstetrical a fost de la 16 ani până la 45 de ani (vârsta medie 26,7±5,3 ani). DP a contribuit la identificarea patologiilor fetale severe la 29 de gravide, care au constituit 11,3% din numărul total de cazuri feminine investigate. Amniocenteza cu studiul cariotipului fetal a permis identificarea anomaliilor cromozomiale numerice și structurale la 22 (8,6%) de pacienți. Primul loc în structura patologiilor fetale grave este ocupat de anomalii ale sistemului cardio-vascular (6,9% cazuri), locul doi – anomalii ale sistemului nervos central (3,1%), urmate de anomalii ale sistemului osteomuscular (2,6%), ale sistemului renal (2,6%) și digestiv (1,08%). Concluzie. Metodele de examinare prin DP (ecografia fetală, screening biochimic, amniocenteza prin studiul cariotipului fetal) ajută la reducerea frecvenței AD la fetuși, contribuind la scăderea morbidității printre nou-născuți.Background. The role of prenatal diagnosis (PD) in the prevention of developmental abnormalities (DA) is emphasized in this study. Prenatal genetic diagnosis for developmental abnormalities is performed at the population level through biochemical and ultrasound screening tests, as well as by using cytogenetic and molecular genetic PD technologies. Objective of the study. To highlight the role of PD in the prevention system of DA and to identify the main prophylactic measures in the at-risk group. Material and methods. The retrospective and prospective investigation study included 256 pregnant women who sought medical-genetic counselling at the NCRHMG during 2018-2023. Group I: 124 pregnant women from the medium and high-risk group, Group II: 132 pregnant women from the low-risk group. Genetic diagnosis was performed by cytogenetic methods. Statistical processing of the data obtained in the study was carried out using the Quanto program. Results. The two groups were comparable in terms of age, gestational period, and degree of genetic risk. It was ascertained that the age of women in the obstetrical risk group ranged from 16 to 45 years (average age 26.7±5.3 years). PD contributed to the identification of severe fetal pathologies in 29 pregnant women, which constituted 11.3% of the total number of investigated female cases. Amniocentesis with fetal karyotype study allowed the identification of numerical and structural chromosomal abnormalities in 22 (8.6%) patients. The first place in the structure of severe fetal pathologies is occupied by abnormalities of the cardiovascular system (6.9%) cases, followed by abnormalities of the central nervous system (3.1%), musculoskeletal system (2.6%), renal system (2.6%), and digestive system (1.08%) cases. Conclusion. Examination methods through PD (fetal ultrasound, biochemical screening, amniocentesis by fetal karyotype study) help to reduce the frequency of DA in fetuses, contributing to the decrease of morbidity among newborns

A Conservative Combined Laser Cryoimmunotherapy Treatment vs. Surgical Excision for Basal Cell Carcinoma

Surgical excision is the standard treatment for basal cell carcinoma (BCC), but it can be challenging in elderly patients and patients with comorbidities. The non-surgical guidelines procedures are usually regarded as monotherapy options. This quasi-experimental, non-randomized, comparative effectiveness study aims to evaluate the efficacy of a combined, conservative, non-surgical BCC treatment, and compare it to standard surgical excision. Patients with primary, non-ulcerated, histopathologically confirmed BCCs were divided into a conservative treatment (129 patients) and a standard surgery subgroup (50 patients). The conservative treatment consisted of ablative CO2 laser, cryosurgery, topical occlusive 5-fluorouracil, and imiquimod. The follow-up examinations were performed 3 months after remission, then every 3 to 6 months, and were extended with telephone follow-ups. Cosmetic-self assessment was recorded during a telephone follow-up. Subjects from the conservative subgroup presented a clearance rate of 99.11%, and a recurrence rate of 0.98%. No recurrences were recorded in the surgical group, nor during the telephone follow-up. There were no differences regarding adverse events (p > 0.05). A superior self-assessment cosmetic outcome was obtained using the conservative method (p < 0.001). This conservative treatment is suitable for elders and patients with comorbidities, is not inferior to surgery in terms of clearance, relapses, or local adverse events, and displays superior cosmetic outcomes

Monitoring C5AR2 expression using a floxed tdtomato-C5AR2 knock-in mouse

The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1- mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed picture of C5aR2 expression in murine cells and tissues is still lacking. To close this gap, we generated a floxed tandem dye (td)Tomato-C5aR2 knock-in mouse that we used to track C5aR2 expression in tissue-residing and circulating immune cells. We found the strongest C5aR2 expression in the brain, bone marrow, and airways. All myeloid-derived cells expressed C5aR2, although with different intensities. C5aR2 expression in blood and tissue neutrophils was strong and homogeneous. Specific ligation of C5aR2 in neutrophils from tdTomato-C5aR2 mice blocked C5a-driven ERK1/2 phosphorylation, demonstrating functionality of C5aR2 in the reporter mice. In contrast to neutrophils, we found tissue-specific differences in C5aR2 expression in eosinophils, macrophages, and dendritic cell subsets. Naive and activated T cells stained negative for C5aR2, whereas B cells from different tissues homogeneously expressed C5aR2. Also, NK cell subsets in blood and spleen strongly expressed C5aR2. Activation of C5aR2 in NK cells suppressed IL-12/IL-18-induced IFN-g production. Intratracheal IL-33 challenge resulted in decreased C5aR2 expression in pulmonary eosinophils and monocytederived dendritic cells. In summary, we provide a detailed map of murine C5aR2 immune cell expression in different tissues under steady-state conditions and upon pulmonary inflammation. The C5aR2 knock-in mouse will help to reliably track and conditionally delete C5aR2 expression in experimental models of inflammation

SARS-CoV-2 vaccination modelling for safe surgery to save lives: data from an international prospective cohort study

Background Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and mortality in an international cohort study (surgical patients), and community SARS-CoV-2 incidence and case fatality data (general population). NNV estimates were stratified by age (18-49, 50-69, 70 or more years) and type of surgery. Best- and worst-case scenarios were used to describe uncertainty. Results NNVs were more favourable in surgical patients than the general population. The most favourable NNVs were in patients aged 70 years or more needing cancer surgery (351; best case 196, worst case 816) or non-cancer surgery (733; best case 407, worst case 1664). Both exceeded the NNV in the general population (1840; best case 1196, worst case 3066). NNVs for surgical patients remained favourable at a range of SARS-CoV-2 incidence rates in sensitivity analysis modelling. Globally, prioritizing preoperative vaccination of patients needing elective surgery ahead of the general population could prevent an additional 58 687 (best case 115 007, worst case 20 177) COVID-19-related deaths in 1 year. Conclusion As global roll out of SARS-CoV-2 vaccination proceeds, patients needing elective surgery should be prioritized ahead of the general population.The aim of this study was to inform vaccination prioritization by modelling the impact of vaccination on elective inpatient surgery. The study found that patients aged at least 70 years needing elective surgery should be prioritized alongside other high-risk groups during early vaccination programmes. Once vaccines are rolled out to younger populations, prioritizing surgical patients is advantageous

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)