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Abstract Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling. Since dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP) is associated with cardiovascular mortality in systemic sclerosis, a disease associated with PAH, and immune-system involvement in PAH is increasingly recognized, we investigated the relationship between dp-ucMGP, vascular remodeling and soluble immune-checkpoint proteins in PAH. This prospective cohort study included patients with idiopathic (I)PAH, connective tissue disease (CTD)-PAH, chronic thrombo-embolic PH (CTEPH) and CTD patients without PAH. Patients with IPAH and CTD-PAH were stratified by clinical signs of immune-mediated inflammatory disease (IMID). We measured dp-ucMGP plasma levels, soluble immune-checkpoint proteins (sICPs), and vascular smooth muscle cell (iVSMC) calcification. We found elevated dp-ucMGP levels in all PAH subtypes and CTD patients compared to healthy controls. PAH patients showed increased iVSMC calcification, but no direct correlation was found with dp-ucMGP. IMID-PAH patients had higher dp-ucMGP levels than non-IMID PAH patients. dp-ucMGP correlated with several sICPs in both IPAH and CTD patients; multiple sICPs were elevated in IMID PAH patients. High dp-ucMGP levels in IPAH patients were associated with worse survival. Our findings suggest dp-ucMGP as a potential biomarker of immune-mediated vascular remodeling in PAH. Hence, dp-ucMGP, could help identify PAH patients who might benefit from immunosuppressive therapies.

Objective: Systemic sclerosis (SSc) related mortality and morbidity remains high. Immunosuppressive therapy is considered most effective when immune activity and inflammation but not fibrosis still dominates the disease process. This study evaluated long-term intensified immunosuppression combined with therapeutic plasma exchange (TPE) in early-onset progressive SSc-related interstitial lung disease (ILD). Methods: The study cohort consisted of 161 SSc patients, with a median follow-up time of 8.9 years. The standardized mortality rate (SMR) and overall survival was calculated in patients with and without cardiopulmonary involvement. We used a standardized, pragmatic, non-randomized approach to treat 24 consecutive early progressive SSc-ILD patients with intensified immunosuppressive therapy, including plasma exchange. Outcome measurements were event-free survival (EFS), pulmonary function and safety profile. The outcome was compared with the analyzed data from the other SSc-ILD patients, who did not fulfill the inclusion criteria, and instead were treated with estimated optimal care (EOc). Results: The age-adjusted SMR of all 161 SSc patients was 3.0 (CI95%; 0.32–5.68). EFS at 10 years was 49.9% in the intensified treatment group and 43.3% in the EOc group (p = 0.106). Improvement of the percentage of predicted forced vital capacity (%pFVC) and percentage of predicted diffusing capacity for carbon monoxide (%pDLco) in the intensified treatment group was +10.1% respectively +3.6%, compared to a decrease of respectively 10.8% and 7% in the EOc (p

Abstract Background Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). Methods Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. Results In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn’s disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8–59.8) of patients after the first vaccination, 61.5% (95% CI 59.2–63.7) after the second vaccination and 58% (95% CI 55.3–60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3–9.1), 7.4% (95% CI 6.2–8.7) and 6.8% (95% CI 5.4–8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (

Pulmonary arterial hypertension (PAH) is a severe disease with high morbidity and mortality. Current therapies are mainly focused on vasodilative agents to improve prognosis. However, recent literature has shown the important interaction between immune cells and stromal vascular cells in the pathogenic modifications of the pulmonary vasculature. The immunological pathogenesis of PAH is known as a complex interplay between immune cells and vascular stromal cells, via direct contacts and/or their production of extra-cellular/diffusible factors such as cytokines, chemokines, and growth factors. These include, the B-cell—mast-cell axis, endothelium mediated fibroblast activation and subsequent M2 macrophage polarization, anti-endothelial cell antibodies and the versatile role of IL-6 on vascular cells. This review aims to outline the major pathophysiological changes in vascular cells caused by immunological mechanisms, leading to vascular remodeling, increased pulmonary vascular resistance and eventually PAH. Considering the underlying immunological mechanisms, these mechanisms may be key to halt progression of disease.

Starting antiretroviral therapy (ART) same-day, or as soon as possible after HIV diagnosis is advised in guidelines worldwide. Especially during acute HIV infection (AHI), rapid ART start may be more urgent because of a higher risk of transmission or symptoms of acute retroviral syndrome. During this phase, rapid ART start may have additional benefits for viral reservoir size and host immunity. We explored perceptions of rapid ART start among participants of The Netherlands Cohort Study on Acute HIV infection (NOVA study), who started ART rapidly after diagnosis of AHI. We conducted 20 in-depth qualitative interviews with NOVA study participants between October and December 2018. Data were analyzed thematically, using inductive and iterative coding techniques. Roughly half of the participants stated they felt well-informed about the importance of (rapid) ART. Starting ART rapidly was perceived positively by almost all participants, mostly because of the expected benefits on their health, and to prevent HIV transmission. Rapid ART start was seen as a way to cope with the diagnosis. However, a more negative perception was that rapid ART start confronted participants with their diagnosis, when they were still adjusting to a new situation. Our results show that among people diagnosed during AHI, rapid ART is well-accepted. These results should be encouraging to HIV care providers who encounter people with AHI in their clinical practice and to researchers who carry out cure-related studies, in which early ART is often included. The Clinical Trial Registration number is NCT05728996. [ABSTRACT FROM AUTHOR]

Abstract Background Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. Methods In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. Results For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). Conclusion Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.

The mechanical properties of calcium carbonate minerals formed by enzyme-induced carbonate precipitation (EICP) were studied using nanoindentation. Two types of precipitates were considered: (i) a “baseline” precipitate, synthesized via urea hydrolysis in an aqueous solution of urease enzyme, urea, and calcium chloride; and (ii) a “modified” precipitate, synthesized from a similar solution, but with the inclusion of nonfat dry milk. While both precipitates predominantly comprised calcite, X-ray diffraction and Raman spectroscopy indicated broader peaks in the modified precipitate, implying differences in the crystal structure of the two precipitates. Both precipitates were polycrystalline and had a higher average indentation hardness (H) and a lower indentation modulus (M) compared with the values for single calcite crystals reported in the literature. The ductility of the precipitates was quantified by the ratio M/H. The modified precipitate had a higher average M/H, implying greater ductility. The increased ductility of the modified precipitate results in higher resistance to crack propagation. In sands biocemented using the modified EICP solution, the increased ductility of the precipitate, in addition to preferential precipitation at interparticle contacts, may contribute to relatively high unconfined compressive strengths at low carbonate contents.

Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV).Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3+CD4−CD8−. To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied.Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3+CD4−CD8−). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC.Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.

The precipitation of calcium carbonate is well studied in many fields of research and industry. Despite the fact that, or perhaps because of the fact that, it is well studied in many fields, different approaches have been used to describe the kinetics of the precipitation process. The aim of this study was to collect and compare the data available in the literature and find a consistent method to describe the kinetics of growth and nucleation of the various polymorphs of calcium carbonate. Inventory of the available data showed that a significant number of the literature sources were incomplete in providing the required information to recalculate the kinetic constants. Using a unified method, we obtained a unique set of parameters to describe the kinetics for growth for calcite, vaterite and amorphous calcium carbonate (ACC) and nucleation for vaterite and ACC. Recalculation of the kinetic constants demonstrated that calcite confirmed there are two growth mechanisms within one polymorph, namely pure spiral growth and spiral growth mixed with surface nucleation. The spiral growth does not show second-order growth, which is typically attributed to it. Re-evaluation of the available nucleation data confirmed the suggested existence of a second pure ACC polymorph with a solubility product between 10−5.87 and 10−5.51 mol2 kgw−2.

An asymptomatic respiratory viral infection during cardiac surgery could lead to pulmonary complications and increased mortality. For elective surgery, testing for respiratory viral infection before surgery or vaccination could reduce the number of these pulmonary complications. The aim of this study was to investigate the association between influenzalike illness (ILI) seasons and prolonged mechanical ventilation and inhospital mortality in a Dutch cohort of adult elective cardiac surgery patients. Cardiac surgery patients who were admitted to the intensive care unit between January 1, 2014, and February 1, 2020, were included. The primary endpoint was the duration of invasive mechanical ventilation in the ILI season compared with baseline season. Secondary endpoints were the median Pa o 2 to fraction of inspired oxygen ratio on days 1, 3, and 7 and postoperative inhospital mortality. A total of 42,277 patients underwent cardiac surgery, 12,994 (30.7%) in the ILI season, 15,843 (37.5%) in the intermediate season, and 13,440 (31.8%) in the baseline season. No hazard rates indicative of a longer duration of invasive mechanical ventilation during the ILI season were found. No differences were found for the median Pa o 2 to fraction of inspired oxygen ratio between seasons. However, inhospital mortality was higher in the ILI season compared with baseline season (odds ratio 1.67; 95% CI, 1.14-2.46). Patients undergoing cardiac surgery during the ILI season were at increased risk of inhospital mortality compared with patients in the baseline season. No evidence was found that this difference is caused by direct postoperative pulmonary complications. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: The objective of our study is to investigate the Fc glycosylation profiles of both antigen-specific IgG targeted against proteinase 3 (PR3-ANCA) and total IgG as prognostic markers of relapse in patients with Granulomatosis with Polyangiitis (GPA). Methods: Seventy-five patients with GPA and a PR3-ANCA rise during follow-up were included, of whom 43 patients relapsed within a median period of 8 (2–16) months. The N-glycan at Asn297 of affinity-purified and denatured total IgG and PR3-ANCA was determined by mass spectrometry of glycopeptides in samples obtained at the time of the PR3-ANCA rise and at the time of the relapse or time-matched during remission. Results: Patients with total IgG1 exhibiting low galactosylation or low sialylation were highly prone to relapse after an ANCA rise (HR 3.46 [95%-CI 1.73–6.96], p

For delivering high quality pharmaceutical care pharmacy students need to develop the competences for patient centered communication. The aim of the article is to describe how a curriculum on patient centered communication can be designed for a pharmacy program. General educational principles for curriculum design are based on the theories of constructive alignment, self-directed learning and the self-determination theory. Other principles are paying systematic and explicit attention to skills development, learning skills in the context of the pharmacy practice and using a well-balanced system for the assessment of students’ performance. Effective educational methods for teaching communication skills are small group training sessions preferably with (simulation) patients, preceded by lectures or e-learning modules. For (formative or summative) assessment different methods can be used. The Objective Structured Clinical Exam (OSCE) is preferred for summative assessment of communication competence. The principles and educational methods are illustrated with examples from the curriculum of the master Pharmacy program of Utrecht University (The Netherlands). The topics ‘pharmaceutical consultations on prescription medicine,’ ‘pharmaceutical consultations on self-care medication’ and ‘clinical medication reviews’ are described in detail. Finally, lessons learned are shared.

The characteristics of clayey suspensions, majorly composed of quartz microparticles, in the presence of anionic and cationic polyelectrolytes were investigated using different techniques. A wide range of clay concentrations was used, i.e., from 0.07 to 1000 g/L for different experimental techniques, based on the fact that the clay concentration possible to analyze with selected experimental methods was significantly different. The optimum flocculant to clay ratio was defined as the ratio that gives the fastest initial floc growth by static light scattering or fastest initial settling velocity by settling column experiments. In case of anionic polyelectrolyte, it was observed that the optimum flocculant dose depends on the amount of cations present in the system. For suspensions made with demi-water, a lower optimum flocculant dose (

Purpose: This article explores the views of Smallholder Marketing Cooperatives' (SMCs) leaders and staff, to gain insight about the particular roles SMCs play in facilitating smallholders' market access. Design/methodology/approach: The authors conceptualized and executed two international workshops in which participants from 42 SMCs from 24 countries deliberated their lessons learned from real-life experiences. Findings: Participants defined three core issues to be tackled by SMCs to play their role related to facilitating their members' market access: good FO governance and management; access to capital and networking. They highlighted that smallholders' market access improves not only as a result of SMCs networking and negotiation with key actors in the public and private sectors, but also due to improved interrelationships among SMCs and other types of Farmers' Organizations (FOs). Peer-to-peer relationships with other SMCs are critical for mutual learning, collaboration and collective action. Practical implications: Peer-to-peer relationships among SMCs are crucial for them to overcome the internal and external social dilemmas SMCs are bound to face while improving smallholders' market access. This goes beyond the three kinds of relationships that scholars have pointed out thus far needed for effective FO development (relationships with members; the public sector and civil society; and with market players). This can be promoted and supported by development programmes. Originality/value: Most SMC studies concentrate primarily on their efficiency in production and marketing activities. This research proposes looking beyond this perspective, using a qualitative approach to explore the real-life experiences and views of actors involved. (Contains 3 tables, 4 figures and 1 note.)

Although stakeholder participation is expected to promote equitable and sustainable natural resource management, lessons from the past tell us that more careful attention needs to be paid to achieving equitable impacts. Now the question is how to address social inequities and power asymmetries. Some authors emphasize the need for more dialogue, while others prefer a critical perspective, arguing that dialogue might not be sufficient to avert the risk of a process deepening existing social inequities. This article aims to enrich this debate and question the practical implications of the critical perspective through an in-depth analysis of power games in a participatory process. A Companion Modelling (ComMod) process was conducted in an Akha community of Northern Thailand with a critical perspective, i.e. with a concern for the less influent stakeholders. Simulation tools such as role-playing games were used to mediate a cross-cultural learning process among researchers, farmers and administrators about a local irrigation water management problem. The detailed analysis of power games in this learning and negotiation process reveals that in spite of initial power asymmetries, the poorest farmers of the community started to voice and assert their interests. This was very much due to the role of a Western researcher who put the equity issue on the public agenda and to the strategic support of a charismatic Christian leader. We identify a set of practical facilitation methods that helped to manage power asymmetries and to level the playing field, but we also discuss the main limits of our cultural-embedded methodological choices. Acknowledging that "the facilitators' neutrality" is an illusion, this study allows us to raise the question of their social legitimacy. We suggest that they should systematically make explicit and reflect on their cultural-ideological background and methodological hypothesis and choices and their effects on the socio-political context. This article is an original attempt to accept this challenge. (Contains 2 tables and 3 figures.)