Therapeutic drug monitoring of thiopurines: Effect of reduced 6-thioguanine nucleotide target levels in inflammatory bowel disease patients.

AIMS: The effect of the Dutch nationwide adjustment of reducing 6-thioguanine nucleotide (6-TGN) target values (from 600-1200 to 320-630 pmol/8 × 108 red blood cells [RBC]) on toxicity and clinical outcome of thiopurine treatment in patients with inflammatory bowel disease has not yet been established. Therefore, the authors determined the incidence of toxicity-induced discontinuations and efficacy at both target concentrations. METHODS: This retrospective study was performed in inflammatory bowel disease patients treated with azathioprine or mercaptopurine. Two groups were defined: the former target (FT) group with target concentrations of 600-1200 pmol/8 × 108 RBC and the adjusted target (AT) group with target concentrations of 320-630 pmol/8 × 108 RBC. Patients were followed for maximum 52 weeks or until discontinuation of thiopurine therapy. Data were collected from the local hospital electronic health software of Rijnstate Hospital. RESULTS: In total, 151 patients were included, 76 in the FT group and 75 in the AT group. At week 52, 100 out of 151 patients (66%) of the total population discontinued thiopurine therapy. Forty-eight of the discontinuations were due toxicity (48%). The incidence of toxicity induced discontinuations was 35% in the AT group vs. 47% in the FT group (P = .25). No loss of efficacy was seen in the AT group. CONCLUSION: After reduction of the target range, there was a trend towards fewer toxicity-induced discontinuations, albeit not statistically significant. In addition, this study did not find any indication that the reduction of the target range diminished efficacy.

Nonoperative management of hip fractures in very frail elderly patients may lead to a predictable short survival as part of advance care planning.

Background and purpose - Surgical treatment is still the mainstay of care even in very frail elderly hip fracture patients. However, one may argue whether surgery is in the best interest of all patients. We elucidated mortality rates of nonoperative management (NOM) of a hip fracture after shared decision-making in a cohort of very frail elderly patients.Patients and methods - Orthogeriatric patients (age > 70 years) admitted with a hip fracture between 2011 and 2019 were included. In the presence of fragility features the motivation for surgery or NOM was supported by advance care planning (ACP) and shared decision-making through geriatric assessment. Mortality rates after NOM were assessed and also presented for the remaining surgical group for reference.Results - In 1,279 out of 3,467 patients, geriatric assessment was indicated and subsequently 1,188 (93%) had surgery versus 91 (7%) NOM. The motivation for NOM was based on patient and family preferences in only 20% of patients, medical grounds in 54%, and a combination of both in 26%. The 30-day and 1-year mortality in the frail NOM group was 87% and 99% respectively, whereas this was 7% and 28% in the surgery group. No statistical comparison between groups was performed due to profound bias by indication.Interpretation - This study provides further insight into the predictable and high short-term mortality after NOM in carefully selected very frail elderly hip fracture patients. This information may help to consider NOM as an alternative treatment option to surgery when no significant gain from surgery is anticipated.

Raising the Cut-Off Level of Anti-Tissue Transglutaminase Antibodies to Detect Celiac Disease Reduces the Number of Small Bowel Biopsies in Children with Type 1 Diabetes: A Retrospective Study.

OBJECTIVE: To study the optimal cut-off value for anti-tissue transglutaminase type 2 IgA antibodies (TG2A) in serum to select for diagnostic small bowel biopsies for celiac disease in children with type 1 diabetes mellitus. STUDY DESIGN: Children with type 1 diabetes mellitus with elevated TG2A titers and duodenal biopsies performed during the course of their diabetes treatment were included. Anti-endomysial antibodies were recorded if present. The optimal TG2A cut-off value, expressed as the ratio between obtained value and upper limit of normal (ULN), was determined using receiver operating characteristic curve analysis and compared with the cut-off value used in the European Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines in terms of sensitivity, specificity, positive and negative predictive value. RESULTS: We included 63 children. The optimal cut-off value for performing biopsies is demonstrated to be 11 times the ULN. Raising the cut-off value from 3 times the ULN to 11 times the ULN changed sensitivity from 96% to 87% and increased specificity from 36% to 73%, increased the positive predictive value from 88% to 94% and lowered negative predictive value from 67% to 53%. The percentage of normal histology was decreased from 12% to 6%. CONCLUSIONS: Increasing the TG2A cut-off value for performing duodenal biopsies in children with type 1 diabetes mellitus and suspected celiac disease leads to a substantial reduction of unnecessary biopsies. We advocate to adapt the European Society for Pediatric Gastroenterology, Hepatology and Nutrition 2012 guidelines for this group of children, including monitoring patients with TG2A levels of less than 11 times the ULN over time.

Towards an individual screening strategy for first-degree relatives of celiac patients.

Celiac disease (CD) is known to be more prevalent in first-degree relatives of patients. In this retrospective cohort study of 609 relatives between 1994 and 2016, we investigated the effect of sex, HLA type, and age at time of index celiac diagnosis. Pearson's chi-square test and Kaplan-Meier survival analysis were used as statistical analyses. CD screening was carried out for 427 relatives (70%), resulting in a prevalence of 15%. HLA typing in 335 relatives showed HLA-DQ2/DQ8 positivity in 87.5%. In 63% of children and all parents, celiac disease was diagnosed at first screening. It was diagnosed significantly more often in females, HLA-DQ2 homozygosity, and children (all p < 0.05). In children aged 0-1 year at time of index diagnosis, celiac disease was diagnosed after consecutive screening in 58%, after 3.9 ± 2.5 (max 10) years (p < 0.001).Conclusion: Future screening policies for relatives of celiac patients should include retesting, especially in HLA-positive relatives younger than 10 years of age. In addition, one-time celiac-specific antibody testing alone could be sufficient to rule out the disease in adolescent siblings and parents of newly diagnosed celiac patients. What is Known: • Celiac disease is more prevalent in first-degree relatives of celiac patients (risk 3-12%). • HLA-DQ2 homozygous sisters/daughters are at highest risk (25%). What is New: • If younger than 10 years of age, repeated testing is necessary in HLA-DQ2/DQ8-positive first-degree relatives when celiac disease is diagnosed in a family. • One-time celiac-specific antibody testing alone could be sufficient to rule out the disease in adolescent siblings and parents of newly diagnosed celiac patients.

Development and validation of an admission prediction tool for emergency departments in the Netherlands.

OBJECTIVE: Early prediction of admission has the potential to reduce length of stay in the ED. The aim of this study is to create a computerised tool to predict admission probability. METHODS: The prediction rule was derived from data on all patients who visited the ED of the Rijnstate Hospital over two random weeks. Performing a multivariate logistic regression analysis factors associated with hospitalisation were explored. Using these data, a model was developed to predict admission probability. Prospective validation was performed at Rijnstate Hospital and in two regional hospitals with different baseline admission rates. The model was converted into a computerised tool that reported the admission probability for any patient at the time of triage. RESULTS: Data from 1261 visits were included in the derivation of the rule. Four contributing factors for admission that could be determined at triage were identified: age, triage category, arrival mode and main symptom. Prospective validation showed that this model reliably predicts hospital admission in two community hospitals (area under the curve (AUC) 0.87, 95% CI 0.85 to 0.89) and in an academic hospital (AUC 0.76, 95% CI 0.72 to 0.80). In the community hospitals, using a cut-off of 80% for admission probability resulted in the highest number of true positives (actual admissions) with the greatest specificity (positive predictive value (PPV): 89.6, 95% CI 84.5 to 93.6; negative predictive value (NPV): 70.3, 95% CI 67.6 to 72.9). For the academic hospital, with a higher admission rate, a 90% probability was a better cut-off (PPV: 83.0, 95% CI 73.8 to 90.0; NPV: 59.3, 95% CI 54.2 to 64.2). CONCLUSION: Admission probability for ED patients can be calculated using a prediction tool. Further research must show whether using this tool can improve patient flow in the ED.

Diagnostic reference range of κ/λ free light chain ratio to screen for Bence Jones proteinuria is not significantly influenced by GFR.

OBJECTIVES: The aim of our study was to analyse whether the κ/λ free light chain ratio reference range for screening for Bence Jones proteinuria should be dependent on the estimated glomerular filtration rate (eGFR). METHODS: The serum κ/λ free light chain ratio, eGFR, serum M-protein and Bence Jones protein were measured in 544 patients for whom Bence Jones protein analysis was ordered. RESULTS: In the population of patients without Bence Jones proteinuria or a M-protein (n = 402), there is no gradual increase in κ/λ free light chain ratio with diminishing eGFR. The κ/λ free light chain ratio in this group was 0.56-1.86 (95% interval). With this diagnostic reference range of the κ/λ ratio, 105 of the 110 patients with Bence Jones protein could be identified correctly. Only five patients with Bence Jones proteinuria (<0.17 g/L) were missed, without diagnostic or therapeutic consequences. In 36 patients (6.6%), an abnormal κ/λ free light chain ratio was measured without the presence of Bence Jones proteinuria. CONCLUSIONS: A κ/λ free light chain ratio in serum can be used safely and efficiently to select urine samples which should be analysed for Bence Jones proteinuria with an electrophoresis/immunofixation technique. Using this diagnostic reference range, the number of urine samples which should be analysed by electrophoresis/immunofixation could be reduced by 74%. The diagnostic reference interval can be determined best in a group of patients for whom Bence Jones analysis is indicated. For calculation of this reference range, the eGFR value does not need to be taken into account.

A Significant Increase in the Incidence of Neonatal Hyperbilirubinemia and Phototherapy Treatment Due to a Routine Change in Laboratory Equipment.

CONTEXT.­: Total serum bilirubin (TSB) analysis is pivotal for diagnosing neonatal hyperbilirubinemia. Because of a routine change in laboratory equipment, our TSB assay changed from a diazo to a vanadate oxidase method. Upon implementation, TSB results were substantially higher in newborns than expected based on the validation. OBJECTIVE.­: To investigate the application of TSB and intermethod differences in neonates and their impact on phototherapy treatment. DESIGN.­: The diazo and vanadate methods were compared directly using neonatal and adult samples. Anonymized external quality control data were analyzed to explore interlaboratory differences among 8 commercial TSB assays. Clinical patient data were extracted from the medical records to investigate the number of newborns receiving phototherapy. RESULTS.­: The mean bias of the vanadate versus the diazo TSB method was +17.4% and +3.7% in neonatal and adult samples, respectively. External quality control data showed that the bias of commercial TSB methods compared with the reference method varied from -3.6% to +20.2%. Within-method variation ranged from 5.2% to 16.0%. After implementation of the vanadate TSB method, the number of neonates treated with phototherapy increased approximately threefold. CONCLUSIONS.­: Currently available TSB assays lack harmonization for the diagnosis of neonatal hyperbilirubinemia. Between-methods differences are substantially higher in neonatal compared with adult samples, highlighting the importance of including neonatal samples during assay validation. Close collaboration between laboratory specialists and clinicians is essential to prevent overtreatment or undertreatment upon the implementation of novel analyzers or assays. Also, harmonization of TSB assays, with an emphasis on neonatal application, is warranted.

Introduction of a Post-Anaesthesia Care Unit in a Teaching Hospital Is Associated with a Reduced Length of Hospital Stay in Noncardiac Surgery: A Single-Centre Interrupted Time Series Analysis.

BACKGROUND: A post-anaesthesia care unit (PACU) may improve postoperative care compared with intermediate care units (IMCU) due to its dedication to operative care and an individualized duration of postoperative stay. The effects of transition from IMCU to PACU for postoperative care following intermediate to high-risk noncardiac surgery on length of hospital stay, intensive care unit (ICU) utilization, and postoperative complications were investigated. METHODS: This single-centre interrupted time series analysis included patients undergoing eleven different noncardiac surgical procedures associated with frequent postoperative admissions to an IMCU or PACU between January 2018 and March 2019 (IMCU episode) and between October 2019 and December 2020 (PACU episode). Primary outcome was hospital length of stay, secondary outcomes included postoperative complications and ICU admissions. RESULTS: In total, 3300 patients were included. The hospital length of stay was lower following PACU admission compared to IMCU admission (IMCU 7.2 days [4.2-12.0] vs. PACU 6.0 days [3.6-9.1]; p < 0.001). Segmented regression analysis demonstrated that the introduction of the PACU was associated with a decrease in hospital length of stay (GMR 0.77 [95% CI 0.66-0.91]; p = 0.002). No differences between episodes were detected in the number of postoperative complications or postoperative ICU admissions. CONCLUSIONS: The introduction of a PACU for postoperative care of patients undergoing intermediate to high-risk noncardiac surgery was associated with a reduction in the length of stay at the hospital, without increasing postoperative complications.

Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients.

PURPOSE: Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown. METHODS: This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels. RESULTS: A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013). CONCLUSION: A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin. CLINICAL TRIALS REGISTRATION: Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

Two-year effects of the community-based overweight and obesity intervention program Gezond Onderweg! (GO!) in children and adolescents living in a low socioeconomic status and multi-ethnic district on Body Mass Index-Standard Deviation Score and quality of life.

BACKGROUND: In most childhood obesity interventions, disadvantaged groups are underrepresented, and results are modest and not maintained. A long-term collaborative community-based approach is necessary to reach out to children from multi-ethnic backgrounds and achieve sustainable behavior change, resulting in sustained Body Mass Index-Standard Deviation Score (BMI-SDS) reductions. The objective is to determine the effects of GO! on BMI-SDS and Health-Related Quality of Life (HRQoL) for children and adolescents having overweight or obesity. METHODS: A prospective, longitudinal cohort study was used to collect two-year follow-up data from November 2014 to July 2019. Children and adolescents (4-19 years old) from the low socioeconomic status and multi-ethnic district of Malburgen in the Dutch city of Arnhem were included. 178 children having overweight or obesity were recruited, with 155 children measured at baseline and after two years as a minimum, while 23 were lost to follow up. Participants attending the program for over six months were defined as completers (n=107) and participants attending the program for less than six months were defined as non-completers (n=48). The child health coach (CHC) acts as a central care provider in the collaborative community with healthcare providers from both medical and social fields. This coach coordinates, monitors and coaches healthy lifestyles, while increasing self-management for both children and parents. This is done in a customized and neighborhood-oriented manner and provided by all the stakeholders involved in GO!. The main outcomes are the change in BMI-SDS scores and HRQoL scores reported by participants. FINDINGS: After 24 months, completers showed a decrease in BMI-SDS of -0·32 [95% CI: -0·42, -0·21], compared with -0·14 [95% CI: -0·29, 0·01] for non-completers (adjusted for gender and ethnicity; P=0.036). While 25% suffered from overweight and 75% from obesity at the start, following the intervention 5% showed normal weight, with 33% overweight and 62% with obesity. HRQoL reported by participants improved over time, showing no differences between completers and non-completers, gender and ethnicity after two years. INTERPRETATION: Our results suggest that the GO! program might be effective in reaching out and reducing BMI-SDS for participants in a low socioeconomic status and multi-ethnic district over a two-year period. We noticed also trends to beneficial shifts in obesity grades. HRQoL improved regardless of the participation rate, gender and ethnic background. In light of the study limitations, further studies are needed to corroborate our observations. FUNDING: Dullerts-foundation, Nicolai Broederschap foundation, Burger en Nieuwe weeshuis foundation, Rijnkind foundation, Arnhems Achterstandswijken foundation, Menzis-foundation, the municipalities of Arnhem, Rheden, Overbetuwe and Lingewaard, the Association of Dutch municipalities, and Province of Gelderland.

Vitamin D supplementation in nursing home patients: randomized controlled trial of standard daily dose versus individualized loading dose regimen.

BACKGROUND: Supplementation of cholecalciferol 800 IU daily appears to be insufficient to raise vitamin D levels to >75 nmol/l in nursing home (NH) patients. OBJECTIVE: Our objective was to compare the efficacy of an individualized cholecalciferol loading dose (LD) regimen and a daily dose (DD) regimen of cholecalciferol 800 IU in reaching 25-OH vitamin D (25OHD) levels >75 nmol/l. METHODS: A total of 30 NH patients with 25OHD levels <50 nmol/l were included. Patients were randomized using the minimization method in the LD or DD group. The cholecalciferol LD, calculated with an algorithm based on serum 25OHD level and body weight, was administered in divided doses of 50,000 IU twice a week, followed by a monthly maintenance dose of either 50,000 or 25,000 IU. The DD regimen consisted of cholecalciferol 800 IU daily for 26 weeks. Serum 25OHD, calcium, creatinine, phosphate, and parathyroid hormone were measured, and 2-minute walking test, handgrip strength, and timed get up and go test were assessed at baseline (T 0), after 5 weeks (T 5), 12 weeks (T 12), and 26 weeks (T 26). The primary endpoint was the percentage of patients with 25OHD levels >75 nmol/l at T 5. Secondary endpoints were the proportion of patients with 25OHD levels >75 nmol/l at T 26, safety of LD regimen, and improvement of performance tests with normalization of vitamin D levels. RESULTS: Median baseline 25OHD levels (interquartile range) were comparable between the 14 DD and 16 LD patients: 20.9 (15.9-29.6) and 21.7 (16.4-32.8) nmol/l, respectively. Levels of 25OHD >75 nmol/l at T 5 were reached in 79 % of the 14 LD patients, but in none of the 13 DD patients (p < 0.001). At T 26, 25OHD levels >75 nmol/l were reached in 83 % of the 12 LD patients and in 30 % of the ten DD patients (p < 0.05). Side effects or hypercalcemia were not observed. No improvement of performance tests was observed. CONCLUSION: In NH patients with severe 25OHD deficiency, an individualized calculated cholecalciferol LD is likely to be superior to a DD of cholecalciferol 800 IU in terms of the ability to rapidly normalize vitamin D levels.

Naive T cells in the gut of newly diagnosed, untreated adult patients with inflammatory bowel disease.

BACKGROUND: The phenotype of the T-cell subpopulations and their related cytokine networks in the gastrointestinal mucosa of patients with inflammatory bowel disease can potentially be used as a predictive value for clinical course and response to therapy. Here, we analyzed T-cell subpopulations in newly diagnosed, untreated adult patients and correlated them with clinical presentation. METHODS: Mucosal biopsies from duodenum, ileum, and colon mucosa of patients with Crohn's disease and ulcerative colitis and controls were obtained. The simple endoscopy score in Crohn's disease and the full Mayo score in ulcerative colitis were used to score disease activity. Mucosa-infiltrating T cells were characterized by flow cytometric immunophenotyping and were stimulated to assess cytokine secretion. RESULTS: Based on the expression of the maturation and activation markers CD45RA and CD27, we identified 4 different profiles. Profile A contained mainly CD45RA+CD27+ naive T cells; profile B contained mainly CD45RA+CD27+ central memory T cells; profile C contained mainly CD45RA-CD27- effector memory T cells; and profile D consisted of similar percentages of these aforementioned subpopulations. Profile A was only observed in the ileum/colon of patients with inflammatory bowel disease, associated with upper gastrointestinal location and perianal disease in Crohn's disease and expressed more tumor necrosis factor α and less interferon γ. In contrast, profile D was restricted to controls. There was no correlation between the different T-cell profiles and endoscopic disease activity. CONCLUSIONS: Newly diagnosed patients with inflammatory bowel disease display different T-cell maturation profiles in the gut mucosa, corresponding to distinct cytokine responses. Follow-up studies are needed to determine whether the profiles associate with clinical course and response to therapy.