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Objectives: This study, developed within the Innovative Medicines Initiative Joint Undertaking project PRECISESADS framework, aimed at functionally characterize the monocyte subsets in RA patients, and analyze their involvement in the increased CV risk associated with RA.Methods: The frequencies of monocyte subpopulations in the peripheral blood of 140 RA patients and 145 healthy donors (HDs) included in the PRECISESADS study were determined by flow cytometry. A second cohort of 50 RA patients and 30 HDs was included, of which CD14+ and CD16+ monocyte subpopulations were isolated using immuno-magnetic selection. Their transcriptomic profiles (mRNA and microRNA), proinflammatory patterns and activated pathways were evaluated and related to clinical features and CV risk. Mechanistic in vitro analyses were further performed.Results: CD14++CD16+ intermediate monocytes were extended in both cohorts of RA patients. Their increased frequency was associated with the positivity for autoantibodies, disease duration, inflammation, endothelial dysfunction and the presence of atheroma plaques, as well as with the CV risk score. CD14+ and CD16+ monocyte subsets showed distinctive and specific mRNA and microRNA profiles, along with specific intracellular signaling activation, indicating different functionalities. Moreover, that specific molecular profiles were interrelated and associated to atherosclerosis development and increased CV risk in RA patients. In vitro, RA serum promoted differentiation of CD14+CD16− to CD14++CD16+ monocytes. Co-culture with RA-isolated monocyte subsets induced differential activation of endothelial cells.Conclusions: Our overall data suggest that the generation of inflammatory monocytes is associated to the autoimmune/inflammatory response that mediates RA. These monocyte subsets, -which display specific and distinctive molecular signatures- might promote endothelial dysfunction and in turn, the progression of atherosclerosis through a finely regulated process driving CVD development in RA.

Summary: Background: Augmentation mammoplasty with subpectoral prosthesis implantation is a frequent performed procedure in plastic surgery for reconstructive and aesthetic purposes. Although prosthesis implantation in a pocket under the major pectoralis muscle has been related to volumetric and functional alterations, there is not much information about the associated short- and long-term histological changes. Therefore, the aim of our study was to describe the acute and chronic histological muscle alterations associated with subpectoral prosthesis implantation. Materials and Method: We collected samples from patients with breast tissue expander (1 year after implantation) and from patients without implantation as a control group. The samples were processed for assessing their histological, histochemical and immunohistochemical properties. Results: In the control group, no relevant histological findings were identified. Additionally, in the patients with expander, we observed mild augmentation of the internalised nuclei, normal morphology, significant muscle atrophy and fibrosis, whereas in the patients with prosthesis considerable augmentation of internalised nuclei, significant muscle atrophy, fibrosis and alteration of normal muscle morphology were observed. Conclusion: Prosthesis implantation induces histological changes in the periprosthetic striated muscle. Chronic fibrosis and inflammation play key roles in this process, which should be characterised in more detail from the histological and molecular biological perspective.

This study was aimed at investigating alternate methods for serodiagnosis of tuberculosis (TB), which are needed because bacteriologic diagnosis of childhood TB is difficult. A selection of 80 serum and saliva samples were tested from Warao indigenous children under 15 years of age; 34 high TB suspects (28 positive and 6 negative for the tuberculin skin test, TST) and 46 healthy contact children (32 positive and 14 negative for the TST). Several enzyme-linked immunosorbent assay (ELISA) serological tests were developed to test for Mycobacterium tuberculosis-specific antibodies, including serum IgA, IgG, IgE, and secretory IgA (sIgA) in saliva against 3 specific antigens (PPD, HSP60, 38 kDa). Of these, 2 antigens, PPD and 38 kDa, showed significantly higher reactivity. The sensitivity and specificity of these tests for diagnosis remained limited, between 26.5% and 38.2%, and 77.4% and 97%, respectively. Of all the samples studied and combinations realized between all isotypes and antigens combined with 3 isotypes (anti-PPD IgG, IgE, and anti-38kDa sIgA) managed to detect the largest number of patients, showing an improved sensitivity level of 64.7%, although specificity levels dropped to 81.8%. These results were compared with the Omega diagnostics commercial kit results. The commercial kits showed significantly lower reactivity (sensitivity of 20% and 13.33% to Myco G and Complex Plus, respectively) and a specificity of 100%. This study shows that in indigenous populations of Venezuela, where invasive procedures cannot be used to select samples but evaluation with a chest X-ray for radiological studies is available, the combination of 3 specific isotypes may be a useful tool to increase diagnostic accuracy with pulmonary TB in this population, when used together with clinical and epidemiological criteria.

ABSTRACT Chemosensory systems allow bacteria to respond and adapt to environmental conditions. Many bacteria contain more than one chemosensory system, but knowledge of their specific roles in regulating different functions remains scarce. Here, we address this issue by analyzing the function of the F6, F8, and alternative (non-motility) cellular functions (ACF) chemosensory systems of the model plant pathogen Pseudomonas syringae pv. tomato. In this work, we assign PsPto chemoreceptors to each chemosensory system, and we visualize for the first time the F6 and F8 chemosensory systems of PsPto using cryo-electron tomography. We confirm that chemotaxis and swimming motility are controlled by the F6 system, and we demonstrate how different components from the F8 and ACF systems also modulate swimming motility. We also determine how the kinase and response regulators from the F6 and F8 chemosensory systems do not work together in the regulation of biofilm, whereas both components from the ACF system contribute together to regulate these traits. Furthermore, we show how the F6, F8, and ACF kinases interact with the ACF response regulator WspR, supporting crosstalk among chemosensory systems. Finally, we reveal how all chemosensory systems play a role in regulating virulence.IMPORTANCEChemoperception through chemosensory systems is an essential feature for bacterial survival, as it allows bacterial interaction with its surrounding environment. In the case of plant pathogens, it is especially relevant to enter the host and achieve full virulence. Multiple chemosensory systems allow bacteria to display a wider plasticity in their response to external signals. Here, we perform a deep characterization of the F6, F8, and alternative (non-motility) cellular functions chemosensory systems in the model plant pathogen Pseudomonas syringae pv. tomato DC3000. These chemosensory systems regulate key virulence-related traits, like motility and biofilm formation. Furthermore, we unveil an unexpected crosstalk among these chemosensory systems at the level of the interaction between kinases and response regulators. This work shows novel results that contribute to the knowledge of chemosensory systems and their role in functions alternative to chemotaxis.

Abstract Background The increase in the frequency and intensity of droughts is pointed out as one of the main factors altering biogeochemical cycles in the Amazon basin. An eco-nutritional approach using X-ray fluorescence micro-analysis (µXRF) is proposed to verify the long- and short-term effects of droughts on the growth and xylem nutrient concentrations of Cedrela fissilis Vell. Methods Fourteen radii were selected from a tree-ring width chronology and X-rayed by Itrax Multiscanner. Profiles of ring width, wood density, and concentrations of aluminum (Al), phosphorus (P), sulfur (S), calcium (Ca), potassium (K), manganese (Mn), iron (Fe) and strontium (Sr) together with Al/Ca, Ca/Mn, K/Ca, Sr/Ca and Mn/S ratios were constructed and correlated with precipitation, temperature, the difference between precipitation and potential evapotranspiration (P-PET) and standardized precipitation–evapotranspiration index (SPEI). Results During dry years, C. fissilis showed narrower, less dense rings, lower Al, P, S and Ca, and higher K and Fe concentrations (the opposite was found in wet years). Ring width decreased (together with Al, P, S, K, Ca, Mn, Fe, Sr, Al/Ca, K/Ca and Sr/Ca) and wood density increased (together with Ca/Mn and Mn/S), which was associated with an increase in evapotranspiration and temperature over time, mainly since 1990. Cedrela fissilis showed a tendency to increase its capacity for resistance, and a recovery and resilience in growth over time associated with responses in Al, Ca, P and S. However, it showed a risk in the capacity for recovery of the pre-drought density values, associated with unsatisfactory responses in Al, Ca, K, Fe and P. Conclusions This study is the first attempt to analyze tree-ring nutritional evidences of C. fissilis trees to climate sensitivity and resilience to drought, based on long-term data from seasonal moist tropical forests of the Amazon. Our data suggested that C. fissilis is undergoing alterations in the concentration, use and redistribution of nutrients associated with increasing wood density and decreasing growth over time, due to the increase of drought frequency in the southern Amazon.

Introduction Advocacy for the provision of public health resources, including vaccine for the prevention of acute respiratory illnesses (ARIs) among older adults in India, needs evidence on costs and benefits. Using a cohort of community-dwelling adults aged 60 years and older in India, we estimated the cost of ARI episode and its determinants.Methods We enrolled 6016 participants in Ballabgarh, Chennai, Kolkata and Pune from July 2018 to March 2020. They were followed up weekly to identify ARI and classified them as acute upper respiratory illness (AURI) or pneumonia based on clinical features based on British Thoracic Society guidelines. All pneumonia and 20% of AURI cases were asked about the cost incurred on medical consultation, investigation, medications, transportation, food and lodging. The cost of services at public facilities was supplemented by WHO-Choosing Interventions that are Cost-Effective(CHOICE) estimates for 2019. Indirect costs incurred by the affected participant and their caregivers were estimated using human capital approach. We used generalised linear model with log link and gamma family to identify the average marginal effect of key determinants of the total cost of ARI.Results We included 2648 AURI and 1081 pneumonia episodes. Only 47% (range 36%–60%) of the participants with pneumonia sought care. The mean cost of AURI episode was US$13.9, while that of pneumonia episode was US$25.6, with indirect costs comprising three-fourths of the total. The cost was higher among older men by US$3.4 (95% CI: 1.4 to 5.3), those with comorbidities by US$4.3 (95% CI: 2.8 to 5.7) and those who sought care by US$17.2 (95% CI: 15.1 to 19.2) but not by influenza status. The mean per capita annual cost of respiratory illness was US$29.5.Conclusion Given the high community disease and cost burden of ARI, intensifying public health interventions to prevent and mitigate ARI among this fast-growing older adult population in India is warranted.

Introduction The Pipeline Embolization Device (PED) is commonly used for intracranial aneurysm treatment. While its effectiveness for certain types of aneurysms is well‐established, its efficacy for saccular aneurysms remains debatable. This review and meta‐analysis aimed to assess the long‐term outcomes of PED treatment for unruptured intracranial aneurysms (UIA). Methods A systematic review and meta‐analysis were conducted following PRISMA guidelines. Studies with at least one year of follow‐up after PED treatment for saccular aneurysms were included. The primary endpoint was angiographic complete aneurysm occlusion at long‐term (≥ 12 mo.) follow‐up. Secondary outcomes included long‐term complications. We conducted a meta‐regression analysis to explore the potential sources of heterogeneity across studies. Results Eleven studies on 594 patients with 726 aneurysms were included, of which 5% were previously treated. The mean age was 55.7 years, and 78.3% were women. The mean aneurysm size was 7.72 mm, 8.95% were treated with more than one device, and 2.9% had adjunct coiling. The long‐term complete occlusion rate was 81% (CI 95%: 72% to 88%, p

ABSTRACT Pathogenic spirochetes can alter their morphologies and behaviors to infect and survive within their hosts. Previous reports demonstrate that the formation of the so-called “round bodies” and biofilms, and chemotaxis are involved in spirochete pathogenesis. Here, we report a direct link between these cellular states that involve a new class of protein sensor with hitherto unclear function. Using cryo-electron microscopy, genetics, behavioral assays, and molecular modeling, we demonstrate that spirochetes regulate these behaviors in response to the small molecule S-adenosylmethionine (SAM) via a SAM sensor that is anchored to chemotaxis arrays. Furthermore, we establish an improved model for round body formation that now includes characterizations during log phase growth. IMPORTANCE A new class of bacterial protein sensors monitors intracellular levels of S-adenosylmethionine to modulate cell morphology, chemotaxis, and biofilm formation. Simultaneous regulation of these behaviors enables bacterial pathogens to survive within their niche. This sensor, exemplified by Treponema denticola CheWS, is anchored to the chemotaxis array and its sensor domain is located below the chemotaxis rings. This position may allow the sensor to directly interact with the chemotaxis histidine kinase CheA. Collectively, these data establish a critical role of CheWS in pathogenesis and further illustrate the impact of studying non-canonical chemotaxis proteins.