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Background: Hereditary alpha tryptasemia (HαT) has significant prevalence and potential morbidity in the general population. However, it remains largely undiagnosed in routine clinical diagnostics due to low availability of efficient assessment methods. To address this issue, we developed a reliable and efficient single-well multiplex digital droplet PCR assay., Methods: The assay was based on the reconstruction of the TPSAB1 gene through quantification of the ratio of α- and β-tryptase copy number variants (CNV) in a single-well measurement. We performed analytical validation by determining CNV measurement clustering around the expected copy numbers in 281 cases and determined the diagnostic accuracy of basal serum tryptase (BST) to predict HαT and HαT subtypes in 141 symptomatic patients., Results: The assay determined α- and β-tryptase CNVs with an overall accuracy, expressed as a 99% prediction interval, of 0.03 ± 0.27 copy numbers. The optimal BST cutoff level to predict HαT in symptomatic patients, who had no other explanation for relatively high tryptase levels (i.e., no diagnosis of systemic mastocytosis, myeloid neoplasm, or end-stage renal failure), was 9.2 ng/mL (sensitivity: 98.1%; specificity: 96.6%). HαT showed a linear gene-dose effect, with an average gene-dose increase of 7.5 ng/mL per extra α-tryptase gene., Conclusion: Our single-well multiplex digital droplet PCR assay accurately determined HαT and could be implemented as a state-of-the-art routine diagnostic test. The assay demonstrated a strong correlation with BST and the optimal threshold for identifying HαT in symptomatic patients with unexplained high tryptase concentrations was at a BST level of 9.2 ng/mL., (© The Author(s) 2023. Published by Oxford University Press on behalf of Association for Diagnostics & Laboratory Medicine.)

Background: Socio-economic disadvantage at both individual and neighbourhood levels has been found to be associated with single lifestyle risk factors. However, it is unknown to what extent their combined effects contribute to a broad lifestyle profile. We aimed to (i) investigate the associations of individual socio-economic disadvantage (ISED) and neighbourhood socio-economic disadvantage (NSED) in relation to an extended score of health-related lifestyle risk factors (lifestyle risk index); and to (ii) investigate whether NSED modified the association between ISED and the lifestyle risk index., Methods: Of 77 244 participants [median age (IQR): 46 (40-53) years] from the Lifelines cohort study in the northern Netherlands, we calculated a lifestyle risk index by scoring the lifestyle risk factors including smoking status, alcohol consumption, diet quality, physical activity, TV-watching time and sleep time. A higher lifestyle risk index was indicative of an unhealthier lifestyle. Composite scores of ISED and NSED based on a variety of socio-economic indicators were calculated separately. Linear mixed-effect models were used to examine the association of ISED and NSED with the lifestyle risk index and to investigate whether NSED modified the association between ISED and the lifestyle risk index by including an interaction term between ISED and NSED., Results: Both ISED and NSED were associated with an unhealthier lifestyle, because ISED and NSED were both positively associated with the lifestyle risk index {highest quartile [Q4] ISED beta-coefficient [95% confidence interval (CI)]: 0.64 [0.62-0.66], P < 0.001; highest quintile [Q5] NSED beta-coefficient [95% CI]: 0.17 [0.14-0.21], P < 0.001} after adjustment for age, sex and body mass index. In addition, a positive interaction was found between NSED and ISED on the lifestyle risk index (beta-coefficient 0.016, 95% CI: 0.011-0.021, Pinteraction < 0.001), which indicated that NSED modified the association between ISED and the lifestyle risk index; i.e. the gradient of the associations across all ISED quartiles (Q4 vs Q1) was steeper among participants residing in the most disadvantaged neighbourhoods compared with those who resided in the less disadvantaged neighbourhoods., Conclusions: Our findings suggest that public health initiatives addressing lifestyle-related socio-economic health differences should not only target individuals, but also consider neighbourhood factors., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Importance: Higher plasma concentrations of vitamin B12 have been associated with mortality in elderly and hospitalized populations, including patients with chronic kidney disease, but the association of plasma concentrations of vitamin B12 with mortality in the general population remains unclear., Objective: To investigate the association of plasma concentrations of vitamin B12 with all-cause mortality., Design, Setting, and Participants: This longitudinal cohort study used post hoc analysis to examine data from participants of the Prevention of Renal and Vascular End-stage Disease Study in Groningen, the Netherlands. Participants included individuals who completed the second screening visit beginning January 1, 2001, excluding those who were missing values of vitamin B12 plasma concentrations or used vitamin B12 supplementation. Follow-up time was defined between the beginning of the second screening round to end of follow-up on January 1, 2011. Data analysis was conducted from October 2, 2018, to February 22, 2019., Exposures: Plasma vitamin B12 concentration level., Main Outcomes and Measures: Death as recorded by the Central Bureau of Statistics of Groningen, the Netherlands., Results: A total of 5571 participants (mean [SD] age, 53.5 [12.0] years; 2830 [50.8%] men) were included in analyses. Median (interquartile range) plasma concentration of vitamin B12 was 394.42 (310.38-497.42) pg/mL. During the median (interquartile range) of 8.2 (7.7-8.9) years of follow-up, 226 participants (4.1%) died. According to quartiles of the distribution of plasma vitamin B12 concentration levels, mortality rates were 33.8 deaths per 10 000 person-years for the quartile with the lowest plasma concentration of vitamin B12 and 65.7 deaths per 10 000 person-years for the quartile with the highest plasma concentration of vitamin B12. After adjustment for multiple clinical and laboratory variables, Cox regression analyses found a significant association between higher vitamin B12 plasma concentration level and increased risk of all-cause mortality (hazard ratio per 1-SD increase, 1.25 [95% CI, 1.06-1.47]; P = .006)., Conclusions and Relevance: These findings suggest that higher levels of plasma concentrations of vitamin B12 were associated with increased risk of all-cause mortality after adjusting for age, sex, renal function, and other clinical and laboratory variables. The mechanisms underlying this association remain to be established.

Epidemiologic studies have linked urinary oxalate excretion to risk of chronic kidney disease (CKD) progression and end-stage renal disease. We aimed to investigate whether urinary oxalate, in stable kidney transplant recipients (KTR), is prospectively associated with risk of graft failure. In secondary analyses we evaluated the association with post-transplantation diabetes mellitus, all-cause mortality and specific causes of death. Oxalate excretion was measured in 24-h urine collection samples in a cohort of 683 KTR with a functioning allograft ≥1 year. Mean eGFR was 52 ± 20 mL/min/1.73 m 2 . Median (interquartile range) urinary oxalate excretion was 505 (347-732) µmol/24-h in women and 519 (396-736) µmol/24-h in men ( p = 0.08), with 302 patients (44% of the study population) above normal limits (hyperoxaluria). A consistent and independent inverse association was found with all-cause mortality (HR 0.77, 95% CI 0.63-0.94, p = 0.01). Cause-specific survival analyses showed that this association was mainly driven by an inverse association with mortality due to infection (HR 0.56, 95% CI 0.38-0.83, p = 0.004), which remained materially unchanged after performing sensitivity analyses. Twenty-four-hour urinary oxalate excretion did not associate with risk of graft failure, post-transplant diabetes mellitus, cardiovascular mortality, mortality due to malignancies or mortality due to miscellaneous causes. In conclusion, in KTR, 24-h urinary oxalate excretion is elevated in 44% of KTR and inversely associated with mortality due to infectious causes.

L-Arginine:glycine amidinotransferase (AGAT) is the main producer of the creatine precursor, guanidinoacetate (GAA), and L-homoarginine (hArg). We and others previously reported lower levels of circulating and urinary hArg in renal transplant recipients (RTR) compared to healthy subjects. In adults, hArg emerged as a novel risk factor for renal and cardiovascular adverse outcome. Urinary GAA was found to be lower in children and adolescents with kidney transplants compared to healthy controls. Whether GAA is also a risk factor in the renal and cardiovascular systems of adults, is not yet known. In the present study, we aimed to investigate the significance of circulating GAA and the GAA-to-hArg molar ratio (GAA/hArg) in adult RTR. We hypothesized that GAA/hArg represents a measure of the balanced state of the AGAT activity in the kidneys, and would prospectively allow assessing a potential association between GAA/hArg and long-term outcome in RTR. The median follow-up period was 5.4 years. Confounders and potential mediators of GAA/hArg associations were evaluated with multivariate linear regression analyses, and the association with all-cause and cardiovascular mortality or death-censored graft loss was studied with Cox regression analyses. The study cohort consisted of 686 stable RTR and 140 healthy kidney donors. Median plasma GAA concentration was significantly lower in the RTR compared to the kidney donors before kidney donation: 2.19 [1.77-2.70] µM vs. 2.78 [2.89-3.35] µM (P < 0.001). In cross-sectional multivariable analyses in RTR, HDL cholesterol showed the strongest association with GAA/hArg. In prospective analyses in RTR, GAA/hArg was associated with a higher risk for all-cause mortality (hazard ratio (HR): 1.35 [95% CI 1.19-1.53]) and cardiovascular mortality (HR: 1.46 [95% CI 1.24-1.73]), independent of potential confounders. GAA but not GAA/hArg was associated with death-censored graft loss in crude survival and Cox regression analyses. The association of GAA and death-censored graft loss was lost after adjustment for eGFR. Our study suggests that in the kidneys of RTR, the AGAT-catalyzed biosynthesis of GAA is decreased. That high GAA/hArg is associated with a higher risk for all-cause and cardiovascular mortality may suggest that low plasma hArg is a stronger contributor to these adverse outcomes in RTR than GAA.

Context: Derangement of 11- β hydroxysteroid dehydrogenase type 1 and type 2 (11 β -HSD1 and 11 β -HSD2), which regulate intracellular cortisol production, has been suggested in both type 2 diabetes (T2D) and chronic kidney disease (CKD). However, activity of 11 β -HSD enzymes in patients with T2D and CKD has never been assessed., Objectives: To compare 11 β -HSD activities between patients with T2D and healthy controls, and assess whether in T2D, renal function is associated with 11 β -HSD activities., Design: Cross-sectional analysis in the Diabetes and Lifestyle Cohort Twente (DIALECT-1)., Setting: Referral center for T2D., Patients: Patient with T2D [n = 373, age 64 ± 9 years, 58% men, 26% of patients estimated glomerular filtration rate (eGFR) <60 mL/min·1.73 m 2 ] and healthy controls (n = 275, age 53 ± 11 years, 48% men)., Mean Outcome Measure: We measured cortisol, cortisone, and metabolites [tetrahydrocortisol (THF), allo-THF (aTHF), and tetrahydrocortisone (THE)] in 24-hour urine samples. Whole body 11 β -HSD and 11 β -HSD2 activities were calculated as the urinary (THF + aTHF)/THE and cortisol/cortisone ratios, respectively., Results: Patients with T2D had a higher (THF + aTHF)/THE ratio [1.02 (0.84 to 1.27) vs 0.94 (0.79 to 1.0), P < 0.001] and cortisol/cortisone ratio [0.70 (0.58 to 0.83) vs 0.63 (0.54 to 0.74), P < 0.001] than healthy controls. In T2D, lower eGFR was associated with a higher (THF + aTHF)/THE ratio ( β = -0.35, P < 0.001), and a higher cortisol/cortisone ratio ( β = -0.16, P = 0.001)., Conclusions: In this real-life secondary care setting of patients with T2D, 11 β -HSD enzymes activities were shifted to higher intracellular cortisol production in T2D, which was further aggravated in patients with CKD. Prospective analyses are warranted to investigate causality of these associations.

Background: Many chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) patients (35-68%) use nutritional supplements, while it is unclear whether deficiencies in vitamins and minerals contribute to symptoms in these patients. Objectives were (1) to determine vitamin and mineral status in CFS and FMS patients as compared to healthy controls; (2) to investigate the association between vitamin and mineral status and clinical parameters, including symptom severity and quality of life; and (3) to determine the effect of supplementation on clinical parameters., Methods: The databases PubMed, EMBASE, Web of Knowledge, and PsycINFO were searched for eligible studies. Articles published from January 1st 1994 for CFS patients and 1990 for FMS patients till March 1st 2017 were included. Articles were included if the status of one or more vitamins or minerals were reported, or an intervention concerning vitamins or minerals was performed. Two reviewers independently extracted data and assessed the risk of bias., Results: A total of 5 RCTs and 40 observational studies were included in the qualitative synthesis, of which 27 studies were included in the meta-analyses. Circulating concentrations of vitamin E were lower in patients compared to controls (pooled standardized mean difference (SMD): -1.57, 95%CI: -3.09, -0.05; p = .042). However, this difference was not present when restricting the analyses to the subgroup of studies with high quality scores. Poor study quality and a substantial heterogeneity in most studies was found. No vitamins or minerals have been repeatedly or consistently linked to clinical parameters. In addition, RCTs testing supplements containing these vitamins and/or minerals did not result in clinical improvements., Discussion: Little evidence was found to support the hypothesis that vitamin and mineral deficiencies play a role in the pathophysiology of CFS and FMS, and that the use of supplements is effective in these patients., Registration: Study methods were documented in an international prospective register of systematic reviews (PROSPERO) protocol, registration number: http://www.crd.york.ac.uk/PROSPERO/display&#95;record.asp?ID=CRD42015032528.

Objectives: To determine the feasibility of preparing a long-term stable ready-to-use parenteral amiodarone formulation using cyclodextrins as dissolution enhancer., Methods: A preformulation study was performed with different molar ratios of hydroxypropyl-beta-cyclodextrin (HP-BCD) or sulfobutylether-beta-cyclodextrin (SBE-BCD) to amiodarone in order to investigate enhancement of amiodarone's water solubility. Further, effects of pH and temperature on the dissolution rate during production were investigated. Shelf-life was determined for a ready-to-use iso-osmotic preparation of 1.8 mg/mL amiodarone with SBE-BCD in a molar ratio of 1:3. Amiodarone content was assessed using a validated high-pressure liquid chromatography ultraviolet method., Results: Amiodarone-SBE-BCD in a molar ratio of 1:3 at pH 4.0-5.0 yielded the best results in terms of increased solubility and dissolution time (90 min). With SBE-BCD, a smaller molar ratio to amiodarone was needed than with HP-BCD. The amiodarone content of the final formulation stored 12 months at 21°C in daylight remained unchanged., Conclusions: A ready-to-use or ready-to-administer amiodarone product, prepared in a hospital pharmacy, for intravenous application in an acute clinical setting is a feasible option from a chemical, physical and microbiological point of view. The availability of such a product will have a significant impact on medication safety, and production should therefore be considered., Competing Interests: Competing interests: None declared.