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Eprinomectin and praziquantel, nematodicide and cestodicide compounds, are both combined with the insecticide and acaricide compounds fipronil and (S)-methoprene in Frontline® Protect/Broadline®, or esafoxolaner in NexGard® Combo. These topical feline endectoparasiticide products were tested for efficacy against fleas and intestinal helminths in a field trial in Brazil. Flea- and/or helminth-infested domestic cats were treated twice at a monthly interval following label instructions: 160 cats with Frontline® Protect/Broadline® and 165 cats with NexGard® Combo. The flea and intestinal helminth infestations were evaluated using comb counts and copromicroscopy, respectively before first treatment for baseline value, then 9 and 30 days after each treatment for fleas, and 9 days after each treatment for helminths. Multiparasitism was very frequent at baseline, as amongst the 325 included cats, 295, 280, 86 and 93 cats were at least infested with Ctenocephalides fleas, Ancylostoma, Toxocara and Dipylidium caninum, respectively. Efficacies were calculated by comparing the geometric means at baseline and at post-treatment timepoints for each parasite genus/species. Inclusive of both products and of all evaluation timepoints, the Ctenocephalides, Ancylostoma, Toxocara and D. caninum efficacies were at least 98.3%, 99.8%, 99.8% and 96.3%, respectively. No adverse reactions were observed, except for a few instances of mild, transient, and self-resolving hypersalivation occurring on the day of treatment in both groups. This field trial demonstrated high-level efficacy of Frontline® Protect/Broadline® and NexGard® Combo against major parasites of cats in Brazil.

The cattle tick, Rhipicephalus microplus, causes significant economic losses to the cattle industry. Tick control is predominately achieved via pesticide applications. However, alternative control methods such as vaccines are needed due to the tick's capacity to quickly develop pesticide resistance and to combat tick-borne diseases. We used an in silico reverse vaccinology approach to evaluate and rank open reading frames (ORFs) from the tick's transcriptome for their potential use as anti-R. microplus vaccine antigens. We manually annotated the 200 highest ranked antigens and selected 10 transcript ORFs as vaccine antigen candidates for expression in Pichia pastoris or insect cells. Six of the ten candidate antigens could be successfully expressed and purified in vitro as recombinant proteins with > 1 mg quantity. RT-PCR confirmed the expression of all six transcripts in tick RNA. However, only three of the six transcripts' corresponding ORFs could be confirmed as present in tick tissue protein extracts. Only four of the six vaccine candidate antigens were successfully expressed and purified in sufficient quantity (> 10 mg) for immunogenicity and efficacy trials in cattle. These four were designated BI-TS002, BI-TS004, BI-TS008, and BI-TS009 and sufficient annotation existed that showed sequence similarity to serine‑rich adhesin for platelets, glycine-rich cell wall structural membrane protein, SWM-1 tick serine protease inhibitor, and venom-like dermonecrotic toxins from ticks and spiders, respectively. Cattle immunized with BI-TS004, BI-TS008 and BI-TS009 yielded a statistically significant difference in antibody response post-immunization. This difference was noted on Days 42, 56, 70, and 84 post-immunization for BI-TS008 and BI-TS009, but only on Day 56 for BI-TS004. BI-TS008 and BI-TS009, were formulated with adjuvant and cattle stall tests conducted over a 175 day period to evaluate efficacy against R. microplus infestations. Both an adjuvant only negative control group and a positive control group using the commercially available GAVAC anti-tick vaccine were used. Efficacy was determined by comparing number of engorged adult female ticks, total egg mass weight, and egg hatchability produced from the immunized group to corresponding data from the adjuvant only negative control group. Thus, effects on engorged adult tick number, reproductive capacity, and fertility were measured. Both initial (designated Phase 1 and calculated from tick collections of Days 60–94 days post-first immunization) and long-term (designated Phase 2 and calculated from tick collections of Days 152–175 post-first immunization) efficacies were determined. The overall Phase 1 trial efficacies of BI-TS008, BI-TS009, and GAVAC were 68.3 %, 48.5 %, and 70.7 %, respectively. The overall Phase 2 trial efficacies of BI-TS008, BI-TS009, and GAVAC were 64.4 %, -30.1 %, and 45.1 %, respectively.

Abstract Recent research studies reported that the employment of wearable augmented reality (AR) systems such as head‐mounted displays for the in situ visualisation of ultrasound (US) images can improve the outcomes of US‐guided biopsies through reduced procedure completion times and improved accuracy. Here, the authors continue in the direction of recent developments and present the first AR system for guiding an in‐depth tumour enucleation procedure under US guidance. The system features an innovative visualisation modality with cutting trajectories that ‘sink’ into the tissue according to the depth reached by the electric scalpel, tracked in real‐time, and a virtual‐to‐virtual alignment between the scalpel's tip and the trajectory. The system has high accuracy in estimating the scalpel's tip position (mean depth error of 0.4 mm and mean radial error of 1.34 mm). Furthermore, we demonstrated with a preliminary user study that our system allowed us to successfully guide an in‐depth tumour enucleation procedure (i.e. preserving the safety margin around the lesion).

Abstract Background Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGFβ1). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients. Methods Fourteen SSc patients, fulfilling the 2013 ACR/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients’ informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1µM) for 3, 16, and 24 h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGFβ1 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGFβ1 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test. Results Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (p

Achieving and maintaining proper image registration accuracy is an open challenge of image-guided surgery. This work explores and assesses the efficacy of a registration sanity check method for augmented reality-guided navigation (AR-RSC), based on the visual inspection of virtual 3D models of landmarks. We analyze the AR-RSC sensitivity and specificity by recruiting 36 subjects to assess the registration accuracy of a set of 114 AR images generated from camera images acquired during an AR-guided orthognathic intervention. Translational or rotational errors of known magnitude up to ±1.5 mm/±15.5°, were artificially added to the image set in order to simulate different registration errors. This study analyses the performance of AR-RSC when varying (1) the virtual models selected for misalignment evaluation (e. g., the model of brackets, incisor teeth, and gingival margins in our experiment), (2) the type (translation/rotation) of registration error, and (3) the level of user experience in using AR technologies. Results show that: 1) the sensitivity and specificity of the AR-RSC depends on the virtual models (globally, a median true positive rate of up to 79.2% was reached with brackets, and a median true negative rate of up to 64.3% with incisor teeth), 2) there are error components that are more difficult to identify visually, 3) the level of user experience does not affect the method. In conclusion, the proposed AR-RSC, tested also in the operating room, could represent an efficient method to monitor and optimize the registration accuracy during the intervention, but special attention should be paid to the selection of the AR data chosen for the visual inspection of the registration accuracy.

Abstract Background The sand flea Tunga penetrans is one of the agents of tungiasis, an important parasitic skin disease affecting humans and several mammalian species. Tungiasis is mainly observed in disadvantaged rural and peripheral urban communities in Latin America and sub-Saharan Africa. The dog is a major reservoir of Tunga fleas. Hematophagous adult female Tunga spp. embed and grow in their host’s epidermis and cause cutaneous inflammatory disorders. NexGard Spectra® is an orally administered endectocide for dogs, a co-formulation of the isoxazoline afoxolaner and the macrocyclic lactone milbemycin oxime. The objective of this study was to assess the efficacy of this product against canine tungiasis. Methods A blinded, negative-controlled field trial was conducted in a Brazilian community known to be highly endemic for tungiasis. Sixty-six dogs naturally infected with live T. penetrans were randomly allocated to a treated group (44 dogs) and an untreated control group (22 dogs). In a first phase, dogs from the treated group were treated on days 0, 30, and 60. Efficacy was evaluated on the basis of the macroscopic parasitic skin lesions (Fortaleza classification) on days 7, 14, 21, 30, 45, 60, 75, and 90. In a second phase, to evaluate natural reinfections, all dogs were treated on day 90 and evaluated every 2 weeks thereafter until at least 30% of dogs were infected with live sand fleas. Results During the first phase, efficacy (reduction in live sand fleas) of 92.4% was demonstrated on day 7. From day 14 until day 90, the efficacy of NexGard Spectra® was 100%. In the second phase, all dogs were free of live T. penetrans from 15 until 45 days after the day 90 treatment; 60 days post-treatment, 11% of dogs were reinfected, and 75 days post-treatment, 40% of dogs were reinfected. Conclusions NexGard Spectra® was demonstrated to be highly effective against canine tungiasis. In addition to an obvious beneficial effect on the health and welfare of the treated dog, the use of this product may have a one-health benefit on human cases by controlling the main reservoir of sand fleas. Graphical Abstract

From sea shores to the abysses of the deep ocean, marine ecosystems have provided humanity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharmacopoeias of different times and geographic regions and is still deeply rooted in traditional medicine. Thanks to present-day, large-scale bioprospecting and rigorous screening for bioactive metabolites, the ocean is coming back as an untapped resource of natural compounds with therapeutic potential. This renewed interest in marine drugs is propelled by a burgeoning research field investigating the molecular mechanisms by which newly identified compounds intervene in the pathophysiology of human diseases. Of great clinical relevance are molecules endowed with anti-inflammatory and immunomodulatory properties with emerging applications in the management of chronic inflammatory disorders, autoimmune diseases, and cancer. Here, we review the historical development of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine resources through biotechnology.

Objectives To investigate pregnancy outcomes in women with autoimmune rheumatic diseases (ARD) in the Italian prospective cohort study P-RHEUM.it.Methods Pregnant women with different ARD were enrolled for up to 20 gestational weeks in 29 Rheumatology Centres for 5 years (2018–2023). Maternal and infant information were collected in a web-based database.Results We analysed 866 pregnancies in 851 patients (systemic lupus erythematosus was the most represented disease, 19.6%). Maternal disease flares were observed in 135 (15.6%) pregnancies. 53 (6.1%) pregnancies were induced by assisted reproduction techniques, 61 (7%) ended in miscarriage and 11 (1.3%) underwent elective termination. Obstetrical complications occurred in 261 (30.1%) pregnancies, including 2.3% pre-eclampsia. Two cases of congenital heart block were observed out of 157 pregnancies (1.3%) with anti-Ro/SSA. Regarding treatments, 244 (28.2%) pregnancies were treated with glucocorticoids, 388 (44.8%) with hydroxychloroquine, 85 (9.8%) with conventional synthetic disease-modifying anti-rheumatic drugs and 122 (14.1%) with biological disease-modifying anti-rheumatic drugs. Live births were 794 (91.7%), mostly at term (84.9%); four perinatal deaths (0.5%) occurred. Among 790 newborns, 31 (3.9%) were small-for-gestational-age and 169 (21.4%) had perinatal complications. Exclusive maternal breast feeding was received by 404 (46.7%) neonates. The Edinburgh Postnatal Depression Scale was compiled by 414 women (52.4%); 89 (21.5%) scored positive for emotional distress.Conclusions Multiple factors including preconception counselling and treat-to-target with pregnancy-compatible medications may have contributed to mitigate disease-related risk factors, yielding limited disease flares, good pregnancy outcomes and frequency of complications which were similar to the Italian general obstetric population. Disease-specific issues need to be further addressed to plan preventative measures.

In this paper, the recently proposed structural optimization strategy, the Galilei-Optimization (GO), is adapted for improving the toughness response of a holed two-dimensional lattice system made of a network of micro-beams whose geometrical arrangement was prescribed. By taking advantage of the possibility of minimizing stress gradients and stress peaks around the hole via GO, we redesigned the cross sections of the lattice beam elements, equalizing the stresses over the entire domain. Consequently, the resulting optimized microstructure highlighted a significant enhancement of the overall toughness due to a drastic decrease of the stress concentration factor in the hole proximity, preserving the initial stiffness and lowering the total overall weight. To validate the robustness of the procedure and the numerical Finite Element outcomes, two non-optimized and optimized structures were actually built up through 3D printing and tested in the laboratory under the same boundary conditions used for the simulations. This evidence confirmed the effectiveness of the proposed method in obtaining optimized beam-like plates with high toughness, which could pave the way for designing new light materials with extreme mechanical performance well beyond the sole stiffness and strength.

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumor-specific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient’s clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-γ following onco-virotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to onco-virotherapy at the early stage of the preclinical phases.