Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 r4ra randomized trial

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients

Microbial communities and biogeochemistry in an area of <i>Engraulis encrasicolus</i> spawning in the Sicilian Channel

Attempts to merge marine food webs and marine biogeochemical research have recently been developed in response to the need to understand how global change will impact marine ecosystems and resources (Salihoglu et al., 2013; Painting, et al., 2013). Among the multiple drivers that influence ecosystem dynamics, Link et al. (2012) focused on three main processes that affect marine fish productivity: biophysical (environmental), exploitative (fisheries), and trophodynamic (species interactions) factors. Previous paper underlined the relationships among microbial parameters and physical and chemical conditions of waters (Zaccone et al., 2012). With the aim of providing an ecosystem approach to fisheries management, the monitoring of biological and environmental variables was carried out in the frame of the Bansic12 cruise performed in the Sicily Channel (Ibleo-Maltese platform) during July 2012. The Sicily Channel is a spawning area of Engraulis encrasicolus (Linnaeus, 1758), a pelagic species of commercial interest (Basilone et al., 2013). As a consequence, fish eggs and larvae together with microbial assemblages (virio-, autotrophic and heterotrophic pico-, nano- and microplankton) were quantified in terms of abundance and biomass (Andrade et al., 2003; Caroppo et al., 2010; Fonda Umani et al., 2010; La Ferla et al., 2012). To give a more comprehensive picture of microbial role in supporting the flux of biogeochemical elements in the study area, rates of microbial metabolic processes (primary and secondary production, enzymatic hydrolysis of dissolved and particulate matter, and community respiration) were also quantified (La Ferla et al., 2005; La Ferla et al., 2010; Caruso et al., 2014). In addition, the hydrology, the trophic parameters and correlated indices were analyzed to contribute to the understanding of plankton communities dynamism (Leonardi et al., 2009). The euphotic layer was characterized by the presence of the typically oligotrophic MAW (Modified Atlantic Water), flowing eastward along the Sicilian coast. Low nutrient concentrations were recorded, particularly regarding the phosphorus, whose values were close to the detection limit. The diffuse oligotrophy of the area was confirmed by high N/P ratios as well as by low Chl-a values. Particulate Organic Carbon (POC) concentrations were low, as well as those of Particulate Nitrogen (PN). Peaks of POC and PN were recorded at the Deep Chlorophyll Maximum (DCM) or below the thermocline (Leonardi et al., 2014). As regards biological parameters, virus counts were low with a mean value of 1.68E+05 ± 7.0E+04 VPL ml-1 and prokaryotic biomass ranged between 24.9 and 113.0 µg C L-1, mainly composed by curved rods and coccobacilli (range size: 0.160 – 0.459 µm3). Low nucleic acid cells (LNA) prevails over high nucleic acid cells (HNA) with a HNA/LNA mean ratio of 0.56, similar to that occurring in surface layer of several pelagic Mediterranean areas (La Ferla et al., 2012). The picophytoplanktonic biomass (range 0.29–26 µg C L-1), was mostly due to the presence of coccoid cyanobacteria, belonging to the genus Synechococcus. Total nanoplankton biomass (range 0.11-1.71 µg C L-1) showed the highest values at the DCM or below the thermocline. Nanoplankton was represented, among the others, by the dinoflagellates Amphidinium carterae and Heterocapsa niei. The coccolithophorid Emiliania huxleyi and flagellates of uncertain taxonomic identification were also abundant. Microphytoplankton abundance ranged between 6.1 and 40.5 E+03 cells L-1, while biomass between 0.28 and 2.43 µg C L-1. Diatoms and dinoflagellates were the main components of the community, composed by 24 and 30 species, respectively. Concerning microzooplankton, eggs, nauplia and metazoan larval stages prevailed in terms of biomass in almost all samples. Heterotrophic dinoflagellates were the second more relevant group while aloricate Ciliates and Tintinnids did not significantly contribute to the total biomass. Biomass maxima were generally observed at the surface or at the DCM, but never exceeded 16.0 µg C L-1. Finally, anchovy eggs and larvae mainly occurred in the 0-10/0-25 m depth intervals, with highest densities of 4.2 eggs m-3 and 2.6 larvae m-3. The rates of production, hydrolysis and degradation activities were quite low, in agreement with the general oligotrophy of the area and in agreement with this findings, picophytoplankton contribution to total production amounted to over than 65%. In terms of metabolic activities, different spatial distributions were observed between the autotrophic and heterotrophic components. In particular, heterotrophic metabolism showed high values in the layer located below the thermocline and above the DCM. Concerning the enzymatic activities, total leucine aminopeptidase activity showed the highest rates, followed by alkaline phosphatase and beta-Glucosidase (Caruso et al., 2014). Distribution of the dissolved enzymatic activities acting on proteins varied widely along the column, accounting for 5 to 90% of the total enzymatic activity and always prevailed on dissolved b-GLU. Total enzymatic activity rates were comparable to those obtained in the oligotrophic zones of Ionian and Mediterranean Sea (Zaccone et al., 2012), while the analysis of the dissolved fraction was the first report for the Mediterranean. In conclusion, the multidisciplinary scientific approach used in this study depicted a complex picture of the study area evidencing a high heterogeneity and dynamism of plankton communities, probably associated to peculiar hydrology of this ecosystem. On the whole, the study area appeared to be characterized by a relatively efficient microbial food web. However, low trophic conditions were stressed by all the biological and biochemical patterns, suggesting an important role of heterotrophic processes in this area in the examined summer period. Consequently, how and how much the microbial web sustains fish reproduction and larval survival need a more comprehensive analysis and will be focused in further research

Associations of internalized and anticipated HIV stigma with returning to work for persons living with HIV.

IntroductionEmployment is particularly beneficial for persons living with HIV (PLWH). However, PLWH experiencing internalized stigma or anticipating that they may experience stigma may be less likely to seek employment due to additional barriers associated with HIV. The purpose of this study was to understand the associations between internalized and anticipated stigma and employment barriers for PLWH.MethodsParticipants (N = 712) from 12 sites across the United States were recruited and interviewed about barriers to employment, HIV stigma, and several other factors related to health. A series of unadjusted and adjusted linear regression models were conducted using cross-sectional data.ResultsAdjusted models suggest that greater anticipated stigma was related to increased employment barriers (β = 0.12, p = 0.04). Mental and physical health functioning also positively predicted employment barriers (β = -0.18, p DiscussionEmployment among PLWH has beneficial impacts on HIV-related health outcomes. This study suggests that anticipated stigma may limit and individual's willingness to seek out employment, or may cause them to leave employment. Internalized stigma may not play as large of a role in employment as anticipated stigma for PLWH. HIV-related stigma reduction interventions focused on community-level and employers are essential to improve employment opportunities for PLWH

Pathways to housing stability and viral suppression for people living with HIV/AIDS: Findings from the Building a Medical Home for Multiply Diagnosed HIV-positive Homeless Populations initiative.

BackgroundPeople with HIV with co-occurring substance use and mental health diagnoses who are unstably housed have poorer outcomes for retention in care and viral suppression. Navigation models are a potential strategy to help this vulnerable population obtain the necessary medical and non-medical services across multiple service systems. The Health Resources and Services Administration's Special Projects of National Significance: "Building a Medical Home for Multiply-Diagnosed HIV-positive Homeless Populations initiative 2012-2017 found that navigation models may be an effective intervention to support people with HIV with unstable housing improve HIV health outcomes. However, there is limited information about the mechanisms by which this intervention works. In this article, we explore the participant and program factors for achieving stable housing at 6 months and how these factors influence HIV health outcomes.Methods and findingsThis was a prospective study of 471 unstably housed people with HIV enrolled in a navigation intervention across nine sites in the United Stated from 2013-2017. All sites provided HIV primary medical care. Eight sites were located in urban areas and one site served a predominantly rural population. Two sites were federally qualified health centers, three were city or county health departments, one site was a comprehensive HIV/AIDS service organization, and three sites were outpatient or mobile clinics affiliated with a university -based or hospital system. Data were collected via interview and medical chart review at baseline, post 6 and 12 months. Type and dose of navigation activities were collected via a standardized encounter form. We used a path analysis model with housing stability at 6 months as the mediator to examine the direct and indirect effects of participant's socio-demographics and risk factors and navigation on viral suppression and retention in care at 12 months. Housing stability at 6 months was associated with male gender, younger age, viral suppression at baseline, having a lower risk for opiate use, recent homelessness, lower risk of food insecurity, and a longer length of time living with HIV. Participants who increased self-efficacy with obtaining help by 6 months had significantly higher odds of achieving housing stability. Stable housing, fewer unmet needs, moderate to high risk for opiate use, and viral suppression at baseline had a direct effect on viral suppression at 12 months. The intensity of navigation contact had no direct effect on housing stability and a mixed direct effect on viral suppression. Recent diagnosis with HIV, women, greater social support, increased self-efficacy and higher intensity of navigation contact had a direct effect on improved retention in HIV primary care at 12 months.ConclusionsIn this sample of people with HIV who are experiencing homelessness, housing stability had a significant direct path to viral suppression. Navigation activities did not have a direct effect on the path to housing stability but were directly related to retention in care. These results identify key populations and factors to target resources and policies for addressing the health and social unmet needs of people with HIV to achieve housing stability and HIV health outcomes

The Black women first initiative: using implementation science to examine bundled interventions to improve care and treatment coordination for Black women with HIV

Abstract Background Black cisgender and transgender women are disproportionately affected by the HIV epidemic compared to women of other racial and ethnic identities. Twelve demonstration sites across the United States are adapting, implementing and evaluating a comprehensive bundle of two or more evidence informed interventions to improve health and outcomes and quality of life for Black women with HIV. Methods Guided by Greenhalgh’s Conceptual Model of Diffusion of Innovations in Health Service Organizations and Proctor’s model for use of implementation strategies and evaluating implementation, service and client outcomes, this mixed methods study documents outcomes at the client, organization, and system level. Participant eligibility for the bundled interventions includes: individuals who are 18 years or older, identify as Black or African-American, identify as cisgender or transgender female and have a diagnosis of HIV. Qualitative data are collected systematically through a series of annual site visits and a standardized monthly call form to assess the barriers and facilitators to the implementation process and the key determinants impacting the intervention uptake and implementation strategies. Quantitative data collection for the implementation, service and client outcomes is conducted through a pre-post prospective study to examine the impact on Black women’s health and well-being. Implementation outcomes include: the reach to Black women with HIV, adoption of interventions across the sites and their community; the fidelity to the components of the bundled interventions; the costs of the intervention; and the sustainability of the intervention in the organization and community. Primary service and client outcomes are improved linkage to and retention in HIV care and treatment, increased and sustained viral suppression, improved quality of life and resilience, and stigma reduction. Discussion The study protocol presented is specifically designed to advance the evidence for adopting culturally responsive and relevant care into clinic and public health settings to improve the health and well-being for Black women with HIV. In addition the study may advance the implementation science field by furthering what is known about the ways in which bundled interventions can address barriers to care and facilitate the uptake of organizational practices to improve health

Clinical management of fusion in primary mandibular incisors: a systematic literature review

Objective: Dental anomalies occurring in deciduous teeth can affect the eruption of the permanent dentition and the occlusion stability. The occurrence of dental anomalies such as double teeth during the primary dentition in the daily practice might be frequent. The study aimed to qualitatively summarize the therapeutic management of double teeth in primary incisors.Material and Methods: A systematic review regarding the therapy of primary fused incisors in the mandible was performed and the obtained data were assessed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following electronic databases were screened from 1st January, 1996 until 30th July, 2019: PubMed, Scopus, EBSCO and the archives of paediatric dental journals. The search terms were grouped in anatomic entity: (tooth OR teeth OR incisor), pathological condition: (fused OR fusion OR geminated OR double), intervention: (treatment OR intervention OR therapy OR prevention OR control OR management OR restoration), observed parameters: (primary dentition OR primary tooth OR primary teeth).Results: Ten articles met all inclusion criteria. The data disclosed the occurrence of double teeth in mandibular incisors. The main management of this clinical condition is either preventive or surgical involving the extraction of fused teeth, based on the deciduous nature of the teeth, the degree of caries and malocclusion development risk.Conclusion: An early diagnosis of dental anomalies is fundamental for the application of proper preventive strategies to avoid a potential malocclusion in permanent dentition and to maintain these teeth sound and caries-free until the eruption of the permanent dentition