Shortcutting the diagnostic odyssey: the multidisciplinary Program for Undiagnosed Rare Diseases in adults (UD-PrOZA).

BACKGROUND: In order to facilitate the diagnostic process for adult patients suffering from a rare disease, the Undiagnosed Disease Program (UD-PrOZA) was founded in 2015 at the Ghent University Hospital in Belgium. In this study we report the five-year results of our multidisciplinary approach in rare disease diagnostics. METHODS: Patients referred by a healthcare provider, in which an underlying rare disease is likely, qualify for a UD-PrOZA evaluation. UD-PrOZA uses a multidisciplinary clinical approach combined with state-of-the-art genomic technologies in close collaboration with research facilities to diagnose patients. RESULTS: Between 2015 and 2020, 692 patients (94% adults) were referred of which 329 (48%) were accepted for evaluation. In 18% (60 of 329) of the cases a definite diagnosis was made. 88% (53 of 60) of the established diagnoses had a genetic origin. 65% (39 of 60) of the genetic diagnoses were made through whole exome sequencing (WES). The mean time interval between symptom-onset and diagnosis was 19 years. Key observations included novel genotype-phenotype correlations, new variants in known disease genes and the identification of three new disease genes. In 13% (7 of 53), identifying the molecular cause was associated with therapeutic recommendations and in 88% (53 of 60), gene specific genetic counseling was made possible. Actionable secondary findings were reported in 7% (12 of 177) of the patients in which WES was performed. CONCLUSION: UD-PrOZA offers an innovative interdisciplinary platform to diagnose rare diseases in adults with previously unexplained medical problems and to facilitate translational research.

Mycoplasma genitalium acquisition and macrolide resistance after initiation of HIV pre-exposure prophylaxis in men who have sex with men.

OBJECTIVES: Recent evidence shows that patients using HIV pre-exposure prophylaxis (PrEP) have an increased rate of bacterial STIs, including syphilis, chlamydia and gonorrhoea. Our study aimed to describe the acquisition and the susceptibility for macrolides of Mycoplasma genitalium in men who have sex with men (MSM) on PrEP. METHODS: We studied all MSM who started PrEP in the AZ Sint-Jan Hospital Bruges from 1 June 2017 to 31 March 2019 with at least one follow-up visit. Patients were screened for M. genitalium and other STIs with pooled rectal swabs, pharyngeal swabs and first-voided urine, and blood samples at baseline and quarterly intervals after initiating PrEP. TaqMan Array Card technology was used to detect M. genitalium and determine macrolide-resistance mediating mutations in region V of the 23S rRNA gene (A2058G, A2059G, A2058C and others). Patients with an STI were treated based on a national guideline. RESULTS: 131 MSM (median age 40 years, range 20-79) were included in the study. The median follow-up time was 12 months (IQR 6.1-17). Baseline prevalence of M. genitalium was 6.9% and incidence rate after PrEP initiation was 28.8 per 100 person-years (95% CI 21.7 to 37.2), without significant differences in proportions between the first four quarterly intervals. All but one acquisitions were asymptomatic. Younger age and positivity for M. genitalium at baseline were significantly associated with incident M. genitalium acquisition. The observed proportion of macrolide resistance increased not significantly from 44% at baseline to 57%-86% after PrEP initiation. None of the 27 macrolide-resistant M. genitalium acquisitions could be linked to azithromycin exposure in the three preceding months. CONCLUSIONS: After initiation of PrEP, we found a stable incidence of almost exclusively asymptomatic M. genitalium. However, a non-significant trend of an increased percentage of macrolide-resistant strains was observed.

Reporting of "dialysis adequacy" as an outcome in randomised trials conducted in adults on haemodialysis.

BACKGROUND: Clinical trials are most informative for evidence-based decision-making when they consistently measure and report outcomes of relevance to stakeholders, especially patients, clinicians, and policy makers. However, sometimes terminology used is interpreted differently by different stakeholders, which might lead to confusion during shared decision making. The construct dialysis adequacy is frequently used, suggesting it is an important outcome both for health care professionals as for patients. OBJECTIVE: To assess the scope and consistency of the construct dialysis adequacy as reported in randomised controlled trials in hemodialysis, and evaluate whether these align to the insights and understanding of this construct by patients. METHODS: To assess scope and consistency of dialysis adequacy by professionals, we performed a systematic review searching the Cochrane Central Register of Controlled Trials (CENTRAL) up to July 2017. We identified all randomised controlled trails (RCT) including patients on hemodialysis and reporting dialysis adequacy, adequacy or adequacy of dialysis and extracted and classified all reported outcomes. To explore interpretation and meaning of the construct of adequacy by patients, we conducted 11 semi-structured interviews with HD patients using thematic analysis. Belgian registration number B670201731001. FINDINGS: From the 31 included trials, we extracted and classified 98 outcome measures defined by the authors as adequacy of dialysis, of which 94 (95%) were biochemical, 3 (3%) non-biochemical surrogate and 2 (2%) patient-relevant. The three most commonly reported measures were all biochemical. None of the studies defined adequacy of dialysis as a patient relevant outcome such as survival or quality of life. Patients had a substantially different understanding of the construct dialysis adequacy than the biochemical interpretation reported in the literature. Being alive, time spent while being on dialysis, fatigue and friendliness of staff were the most prominent themes that patients linked to the construct of dialysis adequacy. CONCLUSION: Adequacy of dialysis as reported in the literature refers to biochemical outcome measures, most of which are not related with patient relevant outcomes. For patients, adequate dialysis is a dialysis that enables them to spend as much quality time in their life as possible.

Intravenous immunoglobulins modify relapsing membranous glomerulonephritis after kidney transplantation: a case report.

OBJECTIVES: Recurrence of membranous glomerulonephritis after transplant is common and is an important cause of loss of renal graft. This case supports the effect of immunoglobulins in the treatment of this disease after transplantation. It is the first report in the literature with a follow-up of more than 10 years and because of the sustained effect of the immunoglobulins, it strengthens the idea that this can alter long-term outcome. METHODS: Single case study and search of the literature. RESULTS: A female transplant recipient, who had an early histologically proven relapse of an idiopathic membranous glomerulonephritis and who was, before transplantation, refractory to various immunosuppressive agents. This relapsing disease has now been stable for over 10 years of intravenous immunoglobulins treatment in conjunction with belatacept and low doses of corticosteroids after gradual withdrawal of mycophenolate mofetil. This report supports the finding that immunoglobulins could influence the course of a relapse of membranous glomerulonephritis after transplantation. CONCLUSION: This case illustrates that immunoglobulins had long-lasting effects on the renal transplant although the glomerulonephritis had been resistant to other lines of therapy before transplant. We advocate that the use of immunoglobulins as a rescue therapy in refractory idiopathic membranous glomerulonephritis should be further investigated. Presently, existing evidence only comes from retrospective data and non-randomized trials.