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The diagnosis of kidney allograft rejection is based on late histological and clinical markers. Early, specific and minimally-invasive biomarkers may improve rejection diagnosis. Endothelial cells (EC) are one of the earliest targets in kidney transplant rejection. We investigated whether circulating EC (cEC) could serve as an earlier and less invasive biomarker for allograft rejection. Blood was collected from a cohort of 51 kidney transplant recipients before and at multiple timepoints after transplantation, including during a for cause biopsy. The number and phenotype of EC was assessed by flow-cytometric analysis. Unbiased selection of EC was done using principal component (PCA) analysis. Paired analysis revealed a transient cEC increase of 2.1-fold on the third day post-transplant, recovering to preoperative levels at seventh day post-transplant and onwards. Analysis of HLA subtype demonstrated that cEC mainly originate from the recipient. cEC levels were not associated with allograft rejection, allograft function or other allograft pathologies. However, cEC in patients with allograft rejection and increased levels of cEC showed elevated levels of KIM-1 (kidney injury marker-1). These findings indicate that cEC numbers and phenotype are affected after kidney transplantation but may not improve rejection diagnosis.

After transplantation self-management is essential for graft survival and optimal quality of life. To address the need for home-based support in self-management, we implemented the “SelfCare after Renal Transplantation” (SeCReT) box, containing home-monitoring equipment combined with a smartphone application that was linked to the electronic patient records. This study investigated the uptake and continuation, protocol adherence, and subjective evaluation of this home-monitoring program. All “ de novo ” kidney recipients who received the SeCReT-box in the study period (Aug 2021–Dec 2022) were eligible for inclusion. Protocol adherence was defined as ≥75%. Subjective evaluation was assessed with a 5-item questionnaire. Of the 297 recipients transplanted, 178 participants (60%) were included in the analysis. Protocol adherence was 83%, 73%, 66%, and 57% respectively at 5, 10, 20, and 40 weeks of the protocol. With regard to continuation, 135 participants were still in the program at the end of the study period (75% retention rate). Regarding subjective evaluations, 82% evaluated the program positively, and 52% reported lower care needs due to home-monitoring. Results are positive among those who entered and continued the program. Qualitative research is needed on barriers to entering the program and facilitators of use in order to promote optimal implementation.

All transplant recipients receive tacrolimus, mycophenolate and glucocorticoids and these drugs have many side-effects and drug-drug interactions. Common complications include surgical complications, infections, rejection and acute kidney injury. Infections as CMV and PJP can be prevented with prophylactic treatment. Given the complexity of organ transplant recipients a multi-disciplinary team of intensivists, surgeons, pharmacists and transplant specialists is essential. After heart transplantation a temporary pacemaker is required until the conduction system recovers. Stiffening of the heart and increased cardiac markers indicate rejection. An endomyocardial biopsy is performed via the right jugular vein, necessitating its preservation. For lung transplant patients, early intervention for aspiration is warranted to prevent chronic rejection. Risk of any infection is high, requiring active surveillance and intensive treatment, mainly of fungal infections. The liver is immunotolerant requiring lower immunosuppression. Transplantation surgery is often accompanied by massive blood loss and coagulopathy. Other complications include portal vein or hepatic artery thrombosis and biliary leakage or stenosis. Kidney transplant recipients have a high risk of cardiovascular disease and posttransplant anemia should be treated liberally. After postmortal transplantation, delayed graft function is common and dialysis is continued. Ureteral anastomosis complications can be diagnosed with ultrasound. •The complexity of transplant recipients makes a multi-disciplinary team essential.•Immunosuppressive drugs are nephrotoxic and have many drug-drug interactions.•Heart transplant recipients have conduction system ischemia necessitating pacing.•In lung transplant recipients prevention of aspiration reduces chronic rejection.•Liver transplant recipients require less immunosuppression than other organ recipients.•The high cardiovascular risk of renal transplant recipients warrants liberal anemia correction.

Objective To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care.Design Randomised controlled, open label, non-inferiority strategy trial.Setting Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014.Participants 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care.Interventions Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated.Main outcome measures Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events.Results Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval −12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care.Conclusions A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.Trial registration Dutch trial register (www.trialregister.nl), NTR 3216.

BackgroundAutologous haematopoietic stem cell transplantation (HSCT) improves survival in systemic sclerosis (SSc) with poor prognosis, but is hampered by treatment-related mortality (TRM).ObjectiveTo evaluate event-free survival (EFS), TRM, response to treatment, disease progression and patient characteristics associated with events.MethodsAll patients treated with HSCT for SSc in The Netherlands until 2017 (n=92) were included. Data on skin involvement (modified Rodnan skin score (mRSS), pulmonary function (forced vital capacity (FVC) and diffusion capacity of the lungs for carbon monoxide (DLCO)), extent of interstitial lung disease on high-resolution CT using Goh scores and left ventricular ejection fraction (LVEF) were collected at baseline, 1, 2 and 5 years. Occurrence of events, defined as death or major organ failure, were collected until 2019. As control, a comparison between patients treated with cyclophosphamide (CYC) and patients with HSCT who participated in the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial was performed.ResultsMedian follow-up was 4.6 years. EFS estimates at 5, 10 and 15 years were 78%, 76% and 66%, respectively. Twenty deaths occurred. Mean FVC, DLCO, mRSS and Goh scores all improved significantly. Disease progression occurred in 22 patients. Frequency of TRM decreased over time and occurred more often in males. Events were independently associated with male sex, LVEF <50% and older age. In ASTIS, patients treated with HSCT (n=23) 7 events occurred versus 13 in the CYC group (n=22).ConclusionOur data confirm long-term efficacy of HSCT in improving survival, skin and lung involvement in SSc. Male sex, lower LVEF and older age at baseline were identified as risk factors for events.

In this randomized, controlled trial from Europe involving patients with persistent symptoms attributed to Lyme disease, there was no benefit associated with 12 additional weeks of treatment with either doxycycline or clarithromycin–hydroxychloroquine. Patients with Lyme disease, which is caused by the Borrelia burgdorferi sensu lato complex (including B. afzelii and B. garinii in Europe), often report persistent symptoms. 1 These symptoms are also referred to as the post–Lyme disease syndrome or chronic Lyme disease and may occur after resolution of an erythema migrans rash or after other — possibly unnoticed — manifestations of early Lyme disease, regardless of whether a patient received initial appropriate antibiotic treatment. Patients present mainly with pain, fatigue, and neurologic or cognitive disturbances. 2 , 3 Previous randomized, clinical trials have not shown convincingly that prolonged antibiotic treatment has beneficial effects . . .

ObjectiveTumour necrosis factor inhibitors (TNFi) are effective in rheumatoid arthritis (RA), but disadvantages include adverse events (AEs) and high costs. This can be improved by disease activity-guided dose reduction (DR). We aimed to assess long-term outcomes of TNFi DR in RA by using 3-year data from the DRESS study (Dose REduction Strategy of Subcutaneous TNF inhibitors study).MethodsIn the intervention phase (month 0–18) of the DRESS study (Dutch trial register, NTR 3216), patients were randomised to DR or usual care (UC). In the extension phase (month 18–36), treatment strategies in both groups converged to continuation of protocolised tight control and allowed dose optimisation. Intention-to-treat analyses were done on flare, disease activity (28 joint count-based disease activity score with C reactive protein (DAS28-CRP)), functioning (health assessment questionnaire-disability index (HAQ-DI)), quality of life (Euroqol 5 dimensions 5 levels questionnaire (EQ5D–5L)), medication use, radiographic progression (Sharp van der Heijde score (SvdH)) and AE.Results172/180 patients included in the DRESS study were included in the extension phase. Cumulative incidences of major flare were 10% and 12% (−2%, 95% CI −8 to 15) in DR and UC groups in the extension phase, and 17% and 14% (3%, 95% CI −9 to 13) from 0 to 36 months. Cumulative incidences of short-lived flares were 43% (33 to 52%)%) and 35% (23 to 49%)%) in DR and UC groups in the extension phase, and 83% (75 to 90%)%) and 44% (31 to 58%)%) from 0 to 36 months. Mean DAS28-CRP, HAQ-DI, EQ5D-5L and SvdH remained stable and not significantly different between groups. TNFi use remained low in the DR group and decreased in the UC group. Cumulative incidences of AE were not significantly different between groups.ConclusionsSafety and efficacy of disease activity guided TNFi DR in RA are maintained up to 3 years, with a large reduction in TNFi use, but no other benefits. Implementation of DR would vastly improve the cost-effective use of TNFi.

BackgroundThe REDO trial (REtreatment with Rituximab in RhEmatoid arthritis: Disease Outcome after Dose Optimisation) showed similar disease activity for retreatment with ultralow doses (200 mg and 500 mg per 6 months) compared with standard low-dose rituximab (RTX, 1000 mg per 6 months). We performed an observational extension study of the REDO trial to assess long-term effectiveness.MethodsPatients from the REDO trial were followed from start of the trial to censoring in April 2021. RTX use was at the discretion of patient and rheumatologist using treat to target. The primary outcome was disease activity (disease activity score in 28 joints C-reactive protein (DAS28-CRP)), analysed using a longitudinal mixed model by original randomisation and time-varying RTX dose. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used. RTX dose and persistence, safety and radiological outcomes were also assessed.FindingsData from 126 of 142 REDO patients was collected from 15 December 2016, up to 30 April 2021. Drop-outs continued treatment elsewhere (n=3) or did not consent (n=13).Disease activity did not differ by original randomisation group: 1000 mg mean DAS28-CRP (95% CI) of 2.2 (2.0 to 2.5), 500 mg 2.3 (2.1 to 2.4) and 200 mg 2.4 (2.2 to 2.5). Lower time-varying RTX dose was associated with higher DAS28-CRP (0.22 (95% CI 0.05 to 0.40) higher for 200 mg/6 months compared with 1000 mg/6 months), but remained within the NI-margin. RTX persistence was 93%. Median RTX dose was 978 mg (IQR 684–1413) per year, and no association was found between RTX dose and adverse events or radiological damage.InterpretationLong-term use of ultralow doses of RTX is effective in patients with rheumatoid arthritis responding to standard dose RTX.

Nodules harboring nitrogen-fixing rhizobia are a well-known trait of legumes, but nodules also occur in other plant lineages, with rhizobia or the actinomycete Frankia as microsymbiont. It is generally assumed that nodulation evolved independently multiple times. However, molecular-genetic support for this hypothesis is lacking, as the genetic changes underlying nodule evolution remain elusive. We conducted genetic and comparative genomics studies by using Parasponia species (Cannabaceae), the only nonlegumes that can establish nitrogen-fixing nodules with rhizobium. Intergeneric crosses between Parasponia andersonii and its nonnodulating relative Trema tomentosa demonstrated that nodule organogenesis, but not intracellular infection, is a dominant genetic trait. Comparative transcriptomics of P. andersonii and the legume Medicago truncatula revealed utilization of at least 290 orthologous symbiosis genes in nodules. Among these are key genes that, in legumes, are essential for nodulation, including NODULE INCEPTION (NIN) and RHIZOBIUM-DIRECTED POLAR GROWTH (RPG). Comparative analysis of genomes from three Parasponia species and related nonnodulating plant species show evidence of parallel loss in nonnodulating species of putative orthologs of NIN, RPG, and NOD FACTOR PERCEPTION. Parallel loss of these symbiosis genes indicates that these nonnodulating lineages lost the potential to nodulate. Taken together, our results challenge the view that nodulation evolved in parallel and raises the possibility that nodulation originated ∼100 Mya in a common ancestor of all nodulating plant species, but was subsequently lost in many descendant lineages. This will have profound implications for translational approaches aimed at engineering nitrogen-fixing nodules in crop plants.

In the extension phase, both groups were treated according to a treat-to-target protocol: tapering was recommended in case of a stable low disease activity, at the discretion of the rheumatologist in both groups.1 3 Quality-adjusted life years (QALYs) were determined by trapezoid method based on the EuroQol-5D5L measured quality of life. Since medication costs were the main cost drivers in the DRESS study, only medication costs were recorded from 18 to 36 months. Because comparisons within one group are paired observations, we bootstrapped within-patient differences in QALY and costs instead of group-level differences for these comparisons for a more efficient analysis. [...]the cost-effectiveness of protocolised tapering was maintained from 18 to 36 months, although medication costs rose slightly (but non-significantly), possibly because a subset of patients returned to a higher dose during follow-up.