Search

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

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.

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

Abstract Background Microalgae are emerging hosts for the sustainable production of lutein, a high-value carotenoid; however, to be commercially competitive with existing systems, their capacity for lutein sequestration must be augmented. Previous attempts to boost microalgal lutein production have focussed on upregulating carotenoid biosynthetic enzymes, in part due to a lack of metabolic engineering targets for expanding lutein storage. Results Here, we isolated a lutein hyper-producing mutant of the model green microalga Chlamydomonas reinhardtii and characterized the metabolic mechanisms driving its enhanced lutein accumulation using label-free quantitative proteomics. Norflurazon- and high light-resistant C. reinhardtii mutants were screened to yield four mutant lines that produced significantly more lutein per cell compared to the CC-125 parental strain. Mutant 5 (Mut-5) exhibited a 5.4-fold increase in lutein content per cell, which to our knowledge is the highest fold increase of lutein in C. reinhardtii resulting from mutagenesis or metabolic engineering so far. Comparative proteomics of Mut-5 against its parental strain CC-125 revealed an increased abundance of light-harvesting complex-like proteins involved in photoprotection, among differences in pigment biosynthesis, central carbon metabolism, and translation. Further characterization of Mut-5 under varying light conditions revealed constitutive overexpression of the photoprotective proteins light-harvesting complex stress-related 1 (LHCSR1) and LHCSR3 and PSII subunit S regardless of light intensity, and increased accrual of total chlorophyll and carotenoids as light intensity increased. Although the photosynthetic efficiency of Mut-5 was comparatively lower than CC-125, the amplitude of non-photochemical quenching responses of Mut-5 was 4.5-fold higher than in CC-125 at low irradiance. Conclusions We used C. reinhardtii as a model green alga and identified light-harvesting complex-like proteins (among others) as potential metabolic engineering targets to enhance lutein accumulation in microalgae. These have the added value of imparting resistance to high light, although partially compromising photosynthetic efficiency. Further genetic characterization and engineering of Mut-5 could lead to the discovery of unknown players in photoprotective mechanisms and the development of a potent microalgal lutein production system.

The evolving landscape of industrial manufacturing is increasingly embracing automation within smart factories. However, the critical role of human operators, particularly in manual assembly and disassembly tasks, remains undiminished. This paper explores the complexities arising from mass customization and remanufacturing, which significantly enhance the intricacy of these manual tasks. Human involvement is essential in these tasks due to their complexity, necessitating a structured learning process to enhance efficiency and mitigate the learning–forgetting cycle. This study focuses on the utilization of virtual reality (VR) as an innovative training tool to address these challenges. By conducting a systematic literature review (SLR) on the impact of VR on training operators for assembly and disassembly tasks, this paper evaluates the current level of VR application, the used technologies, the operator performance, and the VR benefits and limitations. The analysis reveals a limited but promising application of VR in training, highlighting its potential to improve learning outcomes, productivity, and safety while reducing costs. However, the research also identifies gaps in the practical application of VR for training purposes suggesting a future research agenda to explore its full potential.

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.

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.

Combining remote-sensing data with in-situ observations to achieve a comprehensive 3D reconstruction of the ocean state presents significant challenges for traditional interpolation techniques. To address this, we developed the CLuster Optimal Interpolation Neural Network (CLOINet), which combines the robust mathematical framework of the Optimal Interpolation (OI) scheme with a self-supervised clustering approach. CLOINet efficiently segments remote sensing images into clusters to reveal non-local correlations, thereby enhancing fine-scale oceanic reconstructions. We trained our network using outputs from an Ocean General Circulation Model (OGCM), which also facilitated various testing scenarios. Our Observing System Simulation Experiments aimed to reconstruct deep salinity fields using Sea Surface Temperature (SST) or Sea Surface Height (SSH), alongside sparse in-situ salinity observations. The results showcased a significant reduction in reconstruction error up to 40% and the ability to resolve scales 50% smaller compared to baseline OI techniques. Remarkably, even though CLOINet was trained exclusively on simulated data, it accurately reconstructed an unseen SST field using only glider temperature observations and satellite chlorophyll concentration data. This demonstrates how deep learning networks like CLOINet can potentially lead the integration of modeling and observational efforts in developing an ocean digital twin.

The aim of this retrospective cohort study is to understand if and how much the preventive self-isolation approach might have been a valid model to avoid care-related infection, not only from COVID-19 but also from other non-viral infectious diseases. From March to May 2020, the healthcare and management staff of the Villa Santa Maria long-term care facilities, located in the village of Montenero di Bisaccia (Campobasso, Molise, Italy), decided to carry out a preventive self-isolation plan to safeguard the residents from SARS-CoV-2. The impact on other infectious diseases was evaluated by analyzing the antibiotic therapies prescription trend among the inpatients. Our data showed that although self-isolation protected residents and caregivers from SARS-CoV-2, it can also be associated with mobility reduction, leading to an increase in bedridden pathologies, namely, pressure ulcers and pressure sores. The simultaneous isolation of residents and caregivers in the same location significantly reduced any outside influence as a cause of possible infections.

Objectives Glucocorticosteroids (GCs) are the most used anti-inflammatory and immunosuppressive drugs due to their effectiveness in managing pain and disease modification in many immune-inflammatory rheumatic diseases (IRDs). However, their use is limited because of adverse effects (AEs). Material and methods The authors analyzed recent studies, including randomized controlled trials (RCTs), observational, translational studies and systematic reviews, providing an in-depth viewpoint on the benefits and drawbacks of GC use in rheumatology. Results Glucocorticosteroids are essential in managing life-threatening autoimmune diseases and a cornerstone in many IRDs given their swift onset of action, necessary in flares. Several RCTs and meta-analyses have demonstrated that when administered over a long time and on a low-dose basis, GC can slow the radiographic progression in early rheumatoid arthritis (RA) patients by at least 50%, satisfying the conventional definition of a disease-modifying anti-rheumatic drug (DMARD). In the context of RA treatment, the use of modified-release prednisone formulations at night may offer the option of respecting circadian rhythms of both inflammatory response and HPA activation, thereby enabling low-dose GC administration to mitigate nocturnal inflammation and prolonged morning fatigue and joint stiffness. Long-term GC use should be individualized based on patient characteristics and minimized due to their potential AEs. Their chronic use, especially at medium/high dosages, might cause irreversible organ damage due to the burden of metabolic systemic effects and increased risk of infections. Many international guidelines recommend tapering/withdrawal of GCs in sustained remission. Treat-to-target (T2T) strategies are critical in setting targets for disease activity and reducing/discontinuing GCs once control is achieved. Conclusions Glucocorticosteroids’ use in treating IRDs should be judicious, focused on minimizing use, tapering and discontinuing treatment, when possible, to improve long-term safety. Glucocorticosteroids remain part of many therapeutic regimens, particularly at low doses, and elderly RA patients, especially with associated chronic comorbidities, may benefit from long-term low-dose GC treatment. A personalized GC therapy is essential for optimal long-term outcomes.

Abstract Background The light-harvesting antennae of photosystem (PS) I and PSII are pigment-protein complexes responsible of the initial steps of sunlight conversion into chemical energy. In natural environments plants are constantly confronted with the variability of the photosynthetically active light spectrum. PSII and PSI operate in series but have different optimal excitation wavelengths. The prompt adjustment of light absorption by photosystems is thus crucial to ensure efficient electron flow needed to sustain downstream carbon fixing reactions. Fast structural rearrangements equilibrate the partition of excitation pressure between PSII and PSI following the enrichment in the red (PSII-favoring) or far-red (PSI-favoring) spectra. Redox imbalances trigger state transitions (ST), a photoacclimation mechanism which involves the reversible phosphorylation/dephosphorylation of light harvesting complex II (LHCII) proteins by the antagonistic activities of the State Transition 7 (STN7) kinase/TAP38 phosphatase enzyme pair. During ST, a mobile PSII antenna pool associates with PSI increasing its absorption cross section. LHCII consists of assorted trimeric assemblies of Lhcb1, Lhcb2 and Lhcb3 protein isoforms (LHCII), several being substrates of STN7. However, the precise roles of Lhcb phosphorylation during ST remain largely elusive. Results We inactivated the complete Lhcb1 and Lhcb2 gene clades in Arabidopsis thaliana and reintroduced either wild type Lhcb1.3 and Lhcb2.1 isoforms, respectively, or versions lacking N-terminal phosphorylatable residues proposed to mediate state transitions. While the substitution of Lhcb2.1 Thr-40 prevented the formation of the PSI-LHCI-LHCII complex, replacement of Lhcb1.3 Thr-38 did not affect the formation of this supercomplex, nor did influence the amplitude or kinetics of PSII fluorescence quenching upon state 1—state 2 transition. Conclusions Phosphorylation of Lhcb2 Thr-40 by STN7 alone accounts for ≈ 60% of PSII fluorescence quenching during state transitions. Instead, the presence of Thr-38 phosphosite in Lhcb1.3 was not required for the formation of the PSI-LHCI-LHCII supercomplex nor for re-equilibration of the plastoquinone redox state. The Lhcb2 phosphomutant was still capable of ≈ 40% residual fluorescence quenching, implying that a yet uncharacterized, STN7-dependent, component of state transitions, which is unrelated to Lhcb2 Thr-40 phosphorylation and to the formation of the PSI-LHCI-LHCII supercomplex, contributes to the equilibration of the PSI/PSII excitation pressure upon plastoquinone over-reduction.

Background and Objectives: Vitamin D is a secosteroid hormone essential for calcium homeostasis and skeletal health, but established evidence highlights its significant roles also in muscle health and in the modulation of immune response. This review aims to explore the impact of impaired vitamin D status on outcomes of muscle function and involvement in inflammatory and autoimmune rheumatic diseases damaging the skeletal muscle efficiency both with direct immune-mediated mechanisms and indirect processes such as sarcopenia. Methods: A comprehensive literature search was conducted on PubMed and Medline using Medical Subject Headings (MeSH) terms: “vitamin D, muscle, rheumatic diseases.” Additionally, conference abstracts from The European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR) (2020–2023) were reviewed, and reference lists of included papers were scanned. The review emphasizes the evidence published in the last five years, while also incorporating significant studies from earlier years, structured by the extent of evidence linking vitamin D to muscle health in the most commonly inflammatory and autoimmune rheumatic diseases encountered in clinical practice. Results: Observational studies indicate a high prevalence of vitamin D serum deficiency (mean serum concentrations < 10 ng/mL) or insufficiency (Conclusions: Altered serum vitamin D status is commonly observed in inflammatory and autoimmune rheumatic diseases and seems to be associated with adverse muscle health outcomes. While maintaining adequate serum vitamin D concentrations may confer muscle-protective effects, further research is needed to confirm these findings and establish optimal supplementation strategies to obtain a safe and efficient serum threshold.

Systemic sclerosis (SSc), the most lethal of rheumatologic conditions, is the cause of death in >50% of SSc cases, led by pulmonary fibrosis followed by pulmonary hypertension and then scleroderma renal crisis (SRC). Multiple other preventable and treatable SSc-related vascular, cardiac, gastrointestinal, nutritional and musculoskeletal complications can lead to disability and death. Vascular injury with subsequent inflammation transforming to irreversible fibrosis and permanent damage characterizes SSc. Organ involvement is often present early in the disease course of SSc, but requires careful history-taking and vigilance in screening to detect. Inflammation is potentially reversible provided that treatment intensity quells inflammation and other immune mechanisms. In any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition. A single SSc patient visit often requires much more physician and staff time, organization, vigilance, and direct management for multiple organ systems compared to other rheumatic or pulmonary diseases. Efficiency and efficacy of comprehensive SSc care enlists trending of symptoms and bio-data. Financial sustainability of SSc care benefits from understanding insurance reimbursement and health system allocation policies for complex patients. Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists. As scleroderma specialists, we offer a practical framework with tools to facilitate an optimal, comprehensive and sustainable approach to SSc care. Improved health outcomes in SSc relies upon recogntion, management and, to the extent possible, prevention of SSc and treatment-related complications.

Background: Vaccination is one of the most important measures to contain the COVID-19 pandemic, especially for frail patients. VACCINATE is a multicentre prospective observational study promoted by the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET) aimed at assessing the long-term outcomes of COVID-19 vaccination in patients with rare and complex connective tissue diseases (rcCTDs) in terms of efficacy and safety. Methods: Adult rcCTDs patients were eligible for recruitment. Demographic, clinical and vaccination data were collected at enrolment. Follow-up visits were scheduled 4, 12, 24, 36 and 48 weeks after completion of the first vaccination cycle; data on adverse events, disease exacerbations and the occurrence of new SARS-CoV-2 infections were collected at these time-points. Findings: 365 rcCTDs patients (87 % female, mean age 51.8 ± 14.6 years) were recruited. Overall, 200 patients (54.8 %) experienced at least one adverse event, generally mild and in most cases occurring early after the vaccination. During follow-up, 55 disease exacerbations were recorded in 39 patients (10.7 %), distributed over the entire observation period, although most frequently within 4 weeks after completion of the vaccination cycle. The incidence of new SARS-CoV-2 infections was 8.9 per 1000 person-months, with no cases within 12 weeks from vaccine administration and an increasing trend of infections moving away from the primary vaccination cycle. Only one case of severe COVID-19 was reported during the study period. Interpretation: COVID-19 vaccination seems effective and safe in rcCTDs patients. The rate of new infections was rather low and serious infections were uncommon in our cohort. No increased risk of disease flares was observed compared to previous disease history; however, such exacerbations may be potentially severe, emphasising the need for close monitoring of our patients.

ABSTRACTLaser powder bed fusion (L-PBF), an additive manufacturing (AM) technique, often leads to parts with high surface roughness in as-built condition, hence limited fatigue performance. This paper showcases the favourable impact of applying an in-process surface modification, adopting a hybrid laser processing technique (dual-laser PBF (dL-PBF)), on the three-point bending fatigue life of TiB2-reinforced Al-Cu-Mg-Ag composite coupons. The dL-PBF process parameters are optimised for this high-strength aluminium-based metal matrix composite, followed by a comparative study between 3 surface conditions, i.e. as-built, dL-PBF processed, and milled, focusing on surface roughness, concomitant stress concentration factor, surface residual stress, sub-surface hardness, sub-surface microstructure, and fatigue performance. While no significant hardness or microstructural differences are found, surface roughness and stress concentration factor are substantially decreased (> 50%) and identified as the primary factors for the significantly enhanced fatigue performance of dL-PBF processed TiB2-reinforced Al-Cu-Mg-Ag composite parts with up-facing inclined surfaces.

OBJECTIVE: In the SENSCIS trial in subjects with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) over 52 weeks by 44% versus placebo. This study was undertaken to investigate the effects of nintedanib on categorical changes in FVC and other measures of ILD progression. METHODS: In post hoc analyses, we assessed the proportions of subjects with categorical changes in FVC % predicted at week 52 and the time to absolute decline in FVC of ≥5% predicted or death and absolute decline in FVC of ≥10% predicted or death. RESULTS: A total of 288 subjects received nintedanib and 288 subjects received placebo. At week 52, in subjects treated with nintedanib and placebo, respectively, 55.7% and 66.3% had any decline in FVC % predicted, 13.6% and 20.1% had a decline in FVC of >5% to ≤10% predicted, and 3.5% and 5.2% had a decline in FVC of >10% to ≤15% predicted; 34.5% and 43.8% had a decrease in FVC of ≥3.3% predicted (proposed minimal clinically important difference [MCID] for worsening of FVC), while 23.0% and 14.9% had an increase in FVC of ≥3.0% predicted (proposed MCID for improvement in FVC). Over 52 weeks, the hazard ratio (HR) for an absolute decline in FVC of ≥5% predicted or death with nintedanib versus placebo was 0.83 (95% confidence interval [95% CI] 0.66-1.06) (P = 0.14), and the HR for an absolute decline in FVC of ≥10% predicted was 0.64 (95% CI 0.43-0.95) (P = 0.029). CONCLUSION: These results suggest that nintedanib has a clinically relevant benefit on the progression of SSc-ILD.

Rheumatoid arthritis (RA) is an invalidating chronic autoimmune disorder characterized by joint inflammation and progressive bone damage. Dietary intervention is an important component in the treatment of RA to mitigate oxidative stress, a major pathogenic driver of the disease. Alongside traditional sources of antioxidants, microalgae—a diverse group of photosynthetic prokaryotes and eukaryotes—are emerging as anti-inflammatory and immunomodulatory food supplements. Several species accumulate therapeutic metabolites—mainly lipids and pigments—which interfere in the pro-inflammatory pathways involved in RA and other chronic inflammatory conditions. The advancement of the clinical uses of microalgae requires the continuous exploration of phytoplankton biodiversity and chemodiversity, followed by the domestication of wild strains into reliable producers of said metabolites. In addition, the tractability of microalgal genomes offers unprecedented possibilities to establish photosynthetic microbes as light-driven biofactories of heterologous immunotherapeutics. Here, we review the evidence-based anti-inflammatory mechanisms of microalgal metabolites and provide a detailed coverage of the genetic engineering strategies to enhance the yields of endogenous compounds and to develop innovative bioproducts.

Chemokines play critical roles in numerous physiologic and pathologic processes through their action on seven-transmembrane (TM) receptors. The N-terminal domain of chemokines, which is a key determinant of signaling via its binding within a pocket formed by receptors' TM helices, can be the target of proteolytic processing. An illustrative case of this regulatory mechanism is the natural processing of CXCL12 that generates chemokine variants lacking the first two N-terminal residues. Whereas such truncated variants behave as antagonists of CXCR4, the canonical G protein-coupled receptor of CXCL12, they are agonists of the atypical chemokine receptor 3 (ACKR3/CXCR7), suggesting the implication of different structural determinants in the complexes formed between CXCL12 and its two receptors. Recent analyses have suggested that the CXCL12 N-terminus first engages the TM helices of ACKR3 followed by the receptor N-terminus wrapping around the chemokine core. Here we investigated the first stage of ACKR3-CXCL12 interactions by comparing the activity of substituted or N-terminally truncated variants of CXCL12 toward CXCR4 and ACKR3. We showed that modification of the first two N-terminal residues of the chemokine (K1R or P2G) does not alter the ability of CXCL12 to activate ACKR3. Our results also identified the K1R variant as a G protein-biased agonist of CXCR4. Comparative molecular dynamics simulations of the complexes formed by ACKR3 either with CXCL12 or with the P2G variant identified interactions between the N-terminal 2-4 residues of CXCL12 and a pocket formed by receptor's TM helices 2, 6, and 7 as critical determinants for ACKR3 activation.