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RDW is an erythrocyte index that increase in multiple myeloma, in which it appears to have an important role in predicting outcome. For this reason, we performed a retrospective analysis to evaluate the relationships of RDW with some important prognostic predictors. Specifically, in a cohort of 190 newly diagnosed multiple myeloma patients, we have examined the behaviour of RDW and its trend in relation to the ISS stage and other prognostic factors, such as albumin, beta-2 microglobulin, LDH and bone marrow plasma cell infiltration. We performed the analysis in the entire cohort of patients and in the three different disease isotypes (Light chain, IgA, and IgG multiple myeloma). The evaluation of RDW in the different isotypes was made with the Kruskal–Wallis test, integrated by the Dunn test. The comparison between the subgroups allocated above and below the median value of each prognostic factor, was made with the Mann–Whitney test. From our analysis, we observed that RDW is higher in the IgA multiple myeloma, and it increases significantly from ISS I to III. Moreover, RDW increases in the presence of lower albumin values, higher levels of beta2-microglobulin and LDH and in the presence of a greater bone marrow plasma cell infiltrate.

We argue that theories and methods drawn from complexity science are urgently needed to guide the development and use of digital twins for cities. The theoretical framework from complexity science takes into account both the short-term and the long-term dynamics of cities and their interactions. This is the foundation for a new approach that treats cities not as large machines or logistic systems but as mutually interwoven self-organizing phenomena, which evolve, to an extent, like living systems.

Background Despite recent improvements in survival due to advances in treatment, the quality of life of patients with lymphoma may be compromised by the long-term complications of chemotherapy and steroid therapy. Among these, a potentially relevant problem is bone loss and the development of fragility fractures. Aim To provide further evidence of clinical or subclinical skeletal complications in correlation with biological variables and markers of bone disease in patients with complete response to therapy. Method A cross-sectional observational study was conducted on subjects diagnosed with lymphoma with subsequent antineoplastic treatment, disease status after therapy defined as complete response disease for at least a year now. We performed: blood chemistry tests, imaging techniques and screening tools for the assessment of functional status and quality of life (SARC-F and mini-Osteoporosis Quality of Life). Results Approximately 50% of patients had osteoporosis, with a prevalence of vertebral fractures of 65.5%. In most patients, we found hypovitaminosis D and high levels of parathyroid hormone (PTH). Furthermore, a statistically significant association was observed between high PTH levels and previous lymphoma treatment. Finally, the Mini-Osteoporosis Quality of life (mini-OQLQ) questionnaire demonstrated a loss of quality of life as a consequence of the change in bone status. Conclusions Patient treatment design for personalized chemotherapy would be desirable to reduce late effects on bone. Also, early prevention programs need to be applied before starting treatment. The most benefited subpopulations could be not only elderly but also young patients.

Abstract Background and Aims Anaesthesia for medical purposes was introduced in the 19th century. However, the physiological mode of anaesthetic drug actions on the nervous system remains unclear. One of the remaining questions is how these different compounds, with no structural similarities and even chemically inert elements such as the noble gas xenon, act as anaesthetic agents inducing loss of consciousness. The main goal here was to determine if anaesthetics affect the same or similar processes in plants as in animals and humans. Methods A single-lens reflex camera was used to follow organ movements in plants before, during and after recovery from exposure to diverse anaesthetics. Confocal microscopy was used to analyse endocytic vesicle trafficking. Electrical signals were recorded using a surface AgCl electrode. Key Results Mimosa leaves, pea tendrils, Venus flytraps and sundew traps all lost both their autonomous and touch-induced movements after exposure to anaesthetics. In Venus flytrap, this was shown to be due to the loss of action potentials under diethyl ether anaesthesia. The same concentration of diethyl ether immobilized pea tendrils. Anaesthetics also impeded seed germination and chlorophyll accumulation in cress seedlings. Endocytic vesicle recycling and reactive oxygen species (ROS) balance, as observed in intact Arabidopsis root apex cells, were also affected by all anaesthetics tested. Conclusions Plants are sensitive to several anaesthetics that have no structural similarities. As in animals and humans, anaesthetics used at appropriate concentrations block action potentials and immobilize organs via effects on action potentials, endocytic vesicle recycling and ROS homeostasis. Plants emerge as ideal model objects to study general questions related to anaesthesia, as well as to serve as a suitable test system for human anaesthesia.

Background:The new classification criteria for antiphospholipid antibody syndrome (APS) have introduced many novelties, such as the presence of an entry criterion, the use of a scoring system, the introduction of previously “extra-criteria” manifestations, the weighting of thrombotic events according to thromboembolic and cardiovascular risk factors and the redefinition of obstetric APS (OAPS).Objectives:The aim of this study is to apply the latest classification criteria to a monocentric cohort of patients with diagnosis of APS and to compare it with the previous criteria.Methods:We retrospectively collected data from patients with clinical diagnosis of APS from the Lupus Clinic of Sapienza University of Rome and applied the new classification criteria and the previous 2006 “Sapporo” criteria.Results:In our cohort of 165 APS patients, 139 could be classified according to Sapporo criteria, while 106 patients fulfilled the new classification criteria. Among the 33 patients that could not be reclassified by the new criteria, 21 patients did not meet clinical domains (8 thrombotic APS patients did not reach enough points due to a high thromboembolic/cardiovascular risk and 13 OAPS patients due to the presence of poliabortivity or fetal death alone), while 18 lacked laboratory domains due to only IgM aPL positivity (Graph 1).Conclusion:In our cohort, the application of the new APS classification criteria identifies a smaller number of patients compared to the previous ones, confirming the reduced sensitivity of the former. The new criteria may lead to the exclusion of patients with specific clinical and laboratory characteristics, that require larger studies to be assessed.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:It is reported that up to 90.4% of individuals diagnosed with Rheumatoid Arthritis (RA) seek medical assistance due to severe pain. The underlying causes of this pain are multifaceted, involving factors such as inflammation, secondary osteoarthritis, as well as central and peripheral sensitization. CGRP (calcitonin gene-related peptide) is a peptide exerting nociceptive and vasodilatory effects and a debated immunomodulatory effect; inflammatory arthropathies have been associated a local increase of CGRP release and CGRP seems to increase IL6 and IL8 secretion from fibroblast-like synoviocytes isolated from RA patients.Objectives:The aim of this prospective pilot study was to determine whether patients with RA have detectable levels of circulating CGRP, to investigate the correlation between CGRP and with pain levels reported by the patients and to assess the effect of baricitinib on pain and CGRP levels.Methods:We enrolled RA patients starting treatment with baricitinib for high-to-moderate active RA. At baseline and after 4 and 12 weeks of treatment we collected clinical data (number of tender and swollen joints), Erytrhosedimentation Rate (ESR), C Reactive Protein (CRP) levels, and patients reported outcomes [Patients Global Assessment (PGA) and pain on a 0-10 cm Visual Analogic Scale (VAS)]. CGRP serum levels were assessed in serum from RA patients at baseline and after 4 and 12 weeks of treatment with baricitinib using an ELISA kit. Data were expressed as mean ± standard deviation or median (IQR) according to distribution. Mann-Whitney and Spearman tests were performed for comparisons and p values < 0.05 were considered statistically significant.Results:We enrolled 43 patients (F:M =36:7, median age=58, IQR 11 years, median disease duration =144, IQR 150) starting baricitinib. We defined responders (R) patients those who achieved at least a EULAR moderate response (1.2 point reduction) of DAS28_CRP from baseline value and not-responders (NR) those who did not. At baseline pain VAS score did not differ significantly between R and NR. Already after 4 weeks of treatment all patients showed a significant reduction of pain (median pain score was 8(2) at baseline, 4(5) and 2(5) after 4 and 12 weeks, respectively; p=0.0014 and p<0.0001 vs baseline, respectively). R patients had lower pain VAS scores after 4 and 12 weeks of follow-up (p=0.0038 and p=0.0026) compared to NR. CGRP was significantly reduced in the whole cohort at 4 (p=0.0016) and 12 weeks (p=0.018) (Figure 1a). NR patients showed higher CGRP serum levels compared to R, after one month of baricitinib. Levels of CGRP significantly correlated with pain VAS (p=0.0152, r=0.22) (Figure 1b) and PGA (p=0.02, r=0.21), but not with ESR, CRP or disease activity (DAS28_CRP).Conclusion:With the same disease activity, we found higher levels of CGRP in active RA patients with higher levels of pain. Interestingly, CGRP was reduced to a greater extent in patients who responded to the JAK inhibitor. This preliminary result sheds light on a possible additional mechanism of baricitinib efficacy, linked to modulation of neurotransmission other than to control of inflammation. On the other hand, in NR patients, other mechanisms underlying pain may contribute to non-response to therapy.REFERENCES:[1] Walsh DA, et al. Nat Rev Rheumatol. Oct 2014;10(10):581-92.[2] Russell FA, et al. Physiol Rev. Oct 2014;94(4):1099-142.[3] Raap T, et al. J Rheumatol. Nov 2000;27(11):2558-65.Figure 1.a. Reduction of serum CGRP in patients treated with baricitinib, from baseline (T0) and after 1 and 3 months of treatment (T1, T3). b. correlation between levels of pain and serum CGRP.Acknowledgements:NIL.Disclosure of Interests:Cristina Garufi: None declared, Silvia Mancuso: None declared, Letizia Caruso: None declared, Fulvia Ceccarelli: None declared, Simona Truglia: None declared, Fabrizio Conti Eli Lilly, Abbvie, UCB, Pfizer, Galapagos, Francesca Romana Spinelli Eli Lilly, Abbvie, UCB, Galapagos

Mechanical stimulation of trigger hairs on the adaxial surface of the trap of Dionaea muscipula leads to the generation of action potentials and to rapid leaf movement. After rapid closure secures the prey, the struggle against the trigger hairs results in generation of further action potentials which inhibit photosynthesis. A detailed analysis of chlorophyll a fluorescence kinetics and gas exchange measurements in response to generation of action potentials in irritated D. muscipula traps was used to determine the 'site effect' of the electrical signal-induced inhibition of photosynthesis. Irritation of trigger hairs and subsequent generation of action potentials resulted in a decrease in the effective photochemical quantum yield of photosystem II (Φ PSII ) and the rate of net photosynthesis (A N ). During the first seconds of irritation, increased excitation pressure in photosystem II (PSII) was the major contributor to the decreased Φ PSII . Within ∼1 min, non-photochemical quenching (NPQ) released the excitation pressure at PSII. Measurements of the fast chlorophyll a fluorescence transient (O-J-I-P) revealed a direct impact of action potentials on the charge separation–recombination reactions in PSII, although the effect seems to be small rather than substantial. All the data presented here indicate that the main primary target of the electrical signal-induced inhibition of photosynthesis is the dark reaction, whereas the inhibition of electron transport is only a consequence of reduced carboxylation efficiency. In addition, the study also provides valuable data confirming the hypothesis that chlorophyll a fluorescence is under electrochemical control.

BackgroundNETosis has been described to play a role in the pathogenesis of APS. IgG and sera of APS patients are known to induce NETosis [1], however the direct role of aβ2GPI on NETosis is not fully known.ObjectivesThe aim of this study is to evaluate the interplay between NETosis and aβ2GPI antibodies.MethodsHD neutrophils were stimulated either with polyclonal aβ2GPI isolated from a serum pool of primary APS, with immunoglobulin isolated from HD (IgHD) or PMA. NETs were stained with anti-neutrophils elastase, SYBR green and DAPI. NET quantification was performed with NETQUANT, an automated approach. To evaluate the ability of aβ2GPI to bind to NET, HD neutrophils were stimulated with PMA and stained with anti-neutrophil elastase, SYBR green and with aβ2GPI and, as a control, with IgHD instead of aβ2GPI. Colocalization of aβ2GPI and NET signal was performed with Just Another Co-localization Plugin (JACoP). In order to evaluate the ability of aβ2GPI to bind to NETs and prevent DNA degradation, incubation with DNase I was also performed.ResultsStimulation of HD neutrophils with aβ2GPI was able to induce a significantly higher number of NETs compared to stimulation with IgHD (77.6% vs 20%, p<0.0001). The prevalence of NETs in stimulated IgHD and unstimulated neutrophils was similar (20% vs 16%, p=ns). Two different shapes of NET were identified in neutrophils stimulated with aβ2GPI: “cloudy-like” and “spiky-like”. Unlike IgHD, aβ2GPI binds to NETs (Figure 1), and the aβ2GPI signal colocalized with the anti-neutrophil elastase signal at 93.6%.In addition, we showed that aβ2GPI binding to NETs did not prevent NETs degradation by DNase.ConclusionAβ2GPI antibodies are able to induce NETosis and to bind to NETs.Reference[1]Knight JS, Kanthi Y. Mechanisms of immunothrombosis and vasculopathy in antiphospholipid syndrome. Semin Immunopathol. 2022;44:347-62.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background:The achievement of remission represents a relevant goal in the management of Systemic Lupus Erythematosus (SLE). The beneficial effect of this condition on the prevention of chronic damage has been clearly demonstrated. However, the damage is a multifactorial phenomenon: indeed, besides disease activity, other factors could contribute to its development, including treatment (in particular glucocorticoids - GCs). This evidence suggests the possible progression of damage despite the control of disease activity. Into this scenario fits the concept of Comprehensive Disease Control in SLE (LupusCDC), which underlines as the achievement of remission must go along with the damage control. Indeed, the definition of remission in SLE substantially changed in the last years, emphasizing the need for a broader definition including not only disease activity, but also treatments considered acceptable in a remission status. Hence the definition proposed by the DORIS group, according to which a patient is defined as being in remission in the presence of (i) clinical SLEDAI-2k=0, (ii) PGA<0.5, (iii) PDN≤5mg/daily, (iv) stable immunosuppressant treatment.Objectives:In the present cross-sectional study we analysed a monocentric SLE cohort to assess the prevalence of LupusCDC, defined for the presence of remission according to DORIS definition and the lack of progression in damage, as assessed by SLICC Damage Index (SDI).Methods:We evaluated consecutive SLE patients (2019 ACR/EULAR classification criteria). Clinical and laboratory data were collected in a standardized computerized electronically filled form including demographics, past medical history, comorbidities, treatments. Indeed, we evaluated the presence of remission according to DORIS definition; furthermore, SDI was calculated at the time of the enrolment and in the visit performed 12 months before to assess the damage progression. Finally, we evaluated the prevalence of LupusCDC condition, defined for the achievement of remission plus the absence of damage progression.Results:We evaluated 273 patients [M/F 18/255; median age 49 years (IQR 17); median disease duration 14 years (IQR 14.5).A status of DORIS remission was found in 178 patients (65.2%). Patients achieving remission showed a longer disease duration (p=0.005), and a significantly lower prevalence of acute skin manifestations (p=0.02), proteinuria >0.5g/24h (p=0.03) and lower C3/C4 levels (p=0.003), the latter confirmed at logistic regression (p=0.01; OR=1.9; 95%CI 1.1-3.2). Interestingly, 41 patients (15.0%) did not achieve remission due to the lack of one criterion, represented in most cases by the PGA<0.5 (39.0%), followed by clinical SLEDAI=0 (34.1%).Moving on damage, SDI>0 was found in 147 patients (53.8%; mean土SD 1.03土1.34); the presence of damage was significantly associated with age (p<0.001), disease duration (p<0.001), GCs treatment (p=0.009), hypertension (p<0.0001), hyperuricemia (p<0.0001), concomitant antiphospholipid syndrome (p=0.04). The comparison with the assessment performed 12 months before demonstrated the increase of SDI values in 27 subjects (9.9%). This progression was significantly associated with age (p=0.01). A condition of LupusCDC was found in 164 patients (60.1%, Figure 1). The lack of achieving LupusCDC was significantly associated with low levels of C3/C4 (p=0.03), proteinuria >0.5g/24h (p=0.006), oral ulcers (p=0.009), acute skin lupus (p=0.01), serositis (p=0.03). Logistic regression confirmed the association between serositis and lack of LupusCDC achievement (p=0.02, OR=0.36, CI95% 0.14-0.883).Conclusion:The results of the present study demonstrated that a condition of comprehensive disease control is an achievable goal even in a heterogeneous disease such as SLE. By including DORIS definition, the outcome proposed in this study encompasses disease activity, acceptable treatment, and chronic damage, providing an all-around evaluation of SLE patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background:Undifferentiated connective tissue disease (UCTD) is a condition characterized by serological evidence of autoimmunity and occurrence of clinical symptoms suggestive of systemic autoimmune diseases, yet not fulfilling specific classification/diagnostic criteria. From an evolutionary point of view, three possible situations can be observed: (1) the so-called UCTD could represent an early stage of a specific autoimmune disease, such as Systemic Lupus Erythematosus (SLE); (2) UCTD could remain stable without progressing to another disease; (3) UCTD could resolve over time, with the disappearance of clinical and serological symptoms. The early identification of patients at risk to develop a defined disease could help to introduce an appropriate treatment and to prevent chronic damage. Finally, the update of different classification criteria could modify the UCTD epidemiology due to the possibility to capture more patients affected by specific autoimmune diseases.Objectives:In the present longitudinal, observational, retrospective study we aimed to analyze the evolution of UCTD course, focusing on the impact of 2019 EULAR/ACR classification criteria for SLE.Methods:Since 2008 we have consecutively collected data about patients diagnosed with UCTD. All subjects were evaluated every six months or in accordance with the patient’s clinical course, to record the development of clinical and laboratory features suggestive for specific autoimmune diseases. The present analysis was restricted to UCTD patients with a follow-up in our clinic of at least 6 months. Indeed, we retrospectively applied the 2019 EULAR/ACR SLE classification criteria at the first and last visit in our out-patient clinic.Results:We included 201 UCTD patients [F/M 191/10, median age at first visit 50 years (IQR 19.5), median disease duration at first visit 6 years (IQR 7.5)]. At the first visit, 27 patients (13.4%) already met the 2019 SLE EULAR/ACR classification criteria. In these patients, the most frequent clinical manifestation was joint involvement (70.4%), followed by thrombocytopenia (29.6%) and positivity for antiphospholipid antibodies (29.6%) (Figure 1). We found a significant association between SLE classification and thrombocytopenia (p=0.0001), serositis (p= 0.02), joint involvement (p=0.03), low levels of C3 and C4 (p=0.03, p=0.0001 respectively), positivity for anti-dsDNA/antiSm (p=<0.0001). Logistic regression analysis confirmed the association with thrombocytopenia (OR 25.4, p<0.0001), anti-dsDNA/anti-Sm positivity (OR 18.6, p=0.001), low C4 levels (OR 12.7, p=0.02), joint involvement (OR 4.9, p=0.01). At the first visit, 16 patients (59.2%) were taking a treatment (12 patients hydroxychloroquine, 4 glucocorticoids). At the last visit, 5 patients were lost to follow-up; the proportion of treated patients increased to 95.4%, with the introduction of immunosuppressive agents in 4 patients. According to the SLICC Damage Index (SDI), at the first visit 2 patients (7.4%) showed damage in at least one organ/system; this proportion increased to 18.2% at the last assessment. We longitudinally followed the remaining 174 UCTD patients (Figure 2). During a mean observation period of 45.9 ± 35.6 months, 33 patients (18.9%) were lost to follow-up, while 141 patients were followed. At the last visit, additional 11 patients (7.8%) could be classified as having SLE, three Sjögren Syndrome, 1 psoriatic arthritis, and 1 rheumatoid arthritis (according to specific classification criteria). Indeed, 125 patients (88.6%) remained UCTD and 3 patients (2.1%) experienced a resolution of clinical and serological manifestations.Conclusion:The results of our analysis confirmed that a relevant proportion of UCTD patients could be re-classified as having SLE according to the most recent classification criteria. Thrombocytopenia, antiDNA/antiSm positivity and low C4 levels represent the most associated factors. However, it should be considered the possible evolution to other autoimmune conditions and serological/clinical remission in a small proportion of patients.REFERENCES: NIL.Acknowledgements:NIL.Disclosure of Interests:None declared.