Publications by authors named "D P Witte"

669 Publications

[Thrombotic Microangiopathy (TMA) after Gene Replacemant Therapy (GRT) due to Spinal Muscular Atrophy: Case Summary and Recommendations for Treatment].

Klin Padiatr 2021 Aug 13. Epub 2021 Aug 13.

Clinic for Pediatric Kidney-, Liver-, and Metabolic Diseases, Hannover Medical School Centre for Paediatrics and Adolescent Medicine, Hannover, Deutschland.

Introduction: 5q-associated spinal muscular atrophy is one of the most severe and common genetic diseases. In the last few years, innovative methods of therapy have been developed based on SMN2 gene modification, such as splicing, or replacement of the damaged SMN1 gene (gene replacement therapy, GRT). GRT is known to be accompanied by off target effects like temporary elevation of liver and cardiac enzymes usually without serious clinical relevance. We report a 4-year-old girl suffering from thrombotic microangiopathy (TMA) after GRT due to 5q- SMA.

Case Summary: A 4-year-old girl developed TMA indicated by haemolytic anemia and thrombocytopenia in conjunction with renal failure 7 days after GRT with onasemnogene abeparvovec. The latter was characterized by a rise in serum creatinine, oliguria, hypertension, protein- and haematuria, and oedema. The patient was started on eculizumab and antihypertensives resulting in normalization of haemolytic activity, platelet count, kidney function and blood pressure within one week.

Recommendation And Conclusion: SMA patients receiving GRT should undergo close monitoring for early detection of TMA. Adequate measures for TMA including eculizumab or plasmapheresis as well as renal replacement therapy should be available without delay in order to avoid progressive kidney disease or other severe complications in these patients. Careful follow-up including assessment of proteinuria and blood pressure is recommended since patients may require antihypertensive/nephroprotective treatment to avoid chronic kidney disease in later life. Therefore, GRT in SMA patients should only be performed at centers with neuropediatric and paediatric nephrology expertise.
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August 2021

Potentially inappropriate medications (PIMs): frequency and extent of GP-related variation in PIMs: a register-based cohort study.

BMJ Open 2021 07 14;11(7):e046756. Epub 2021 Jul 14.

Research Unit for General Practice, Aarhus, Midtjylland, Denmark.

Objectives: Potentially inappropriate medications (PIMs) pose an increasing challenge in the ageing population. We aimed to assess the extent of PIMs and the prescriber-related variation in PIM prevalence.

Design: Nationwide register-based cohort study.

Setting: General practice.

Participants: The 4.2 million adults listed with general practitioner (GP) clinics in Denmark (n=1906) in 2016.

Main Outcome Measures: We estimated the patients' time with PIMs by using 29 register-operationalised STOPP criteria linking GP clinics and redeemed prescriptions. For each criterion and each GP clinic, we calculated ratios between the observed PIM time and that predicted by multivariate Poisson regressions on the patients. The observed variation was measured as the 90th/10th percentile ratios of these ratios. The extent of expectable random variation was assessed as the 90th/10th percentile ratios in randomly sampled GP populations (ie, the sampled variation). The GP-related excess variation was calculated as the ratio between the observed variation and sampled variation. The linear correlation between the observed/expected ratio for each of the criteria and the observed/expected ratio of total PIM time (for each clinic) was measured by Pearson's rho.

Results: Overall, 294 542 individuals were exposed to 1 44 117 years of PIMs. The two most prevalent PIMs were long-term use (>3 months) of non-steroidal anti-inflammatory drugs (51 074 years of PIMs) or benzodiazepines (48 723 years of PIMs). These two criteria showed considerable excess variation of 2.33 and 3.05, respectively; for total PIMs, this figure was 1.65. For more than half of the criteria, we observed a positive correlation between the specific PIM and the sum of remaining PIMs.

Conclusions: This study documents considerable variations in the prescribing practice of GPs for certain PIMs. These findings highlight a need for exploring the causal explanations for such variations, which could be markers of suboptimal GP-prescribing strategies.
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July 2021

Effectiveness of the population-based 'check your health preventive programme' conducted in a primary care setting: a pragmatic randomised controlled trial.

J Epidemiol Community Health 2021 Jun 18. Epub 2021 Jun 18.

Public Health, Aarhus Universitet, Aarhus, Denmark.

Background: Health checks have been suggested as an early detection approach aiming at lowering the risk of chronic disease development. This study aimed to evaluate the effectiveness of a health check programme offered to the general population, aged 30-49 years.

Methods: The entire population aged 30-49 years (N=26 216) living in the municipality of Randers, Denmark, was invited to a health check during 5 years. A pragmatic household cluster-randomised controlled trial was conducted in 10 505 citizens. The intervention group (IG, N=5250) included citizens randomised to the second year and reinvited in the 5th year. The comparison group (CG, N=5255) included citizens randomised to the 5th year. Outcomes were modelled cardiovascular disease (CVD) risk; self-reported physical activity (PA) and objectively measured cardio respiratory fitness (CRF); self-rated health (short-form 12 (SF-12)), self-rated mental health (SF-12_Mental Component Score (MCS)) and, registry information on sick-leave and employment. Due to low participation, we compared groups matched on propensity scores for participation when reinvited.

Results: Participation in the first health check was 51% (N=2698) in the IG and 40% (N=2120) in the CG. In the IG 26% (N=1340) participated in both the first and second health checks. No intervention effects were found comparing IG and CG. Mean differences were (95% CI): modelled CVD risk: -0.052 (95% CI -0.107 to 0.003)%, PA: -0.156 (-0.331 to 0.019) days/week with 30 min moderate PA, CRF: 0.133 (-0.560 to 0.826) mL O/min/kg, SF-12: -0.003 (-0.032 to 0.026), SF-12_MCS: 0.355 (-0.423 to 1.132), sick leave periods ≥3 weeks: -0.004 (-0.025 to 0.017), employment: -0.004 (-0.032 to 0.024).

Conclusions: Preventive health checks offered to the general population, aged 30-49 years, had no effects on a wide range of indicators of chronic disease risk.

Trial Registration Number: NCT02028195.
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June 2021

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun 2021 06 9;12(1):3505. Epub 2021 Jun 9.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
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June 2021

Diabetic Polyneuropathy Early in Type 2 Diabetes Is Associated With Higher Incidence Rate of Cardiovascular Disease: Results From Two Danish Cohort Studies.

Diabetes Care 2021 May 26. Epub 2021 May 26.

Steno Diabetes Center Aarhus, Aarhus, Denmark.

Objective: Symptoms indicative of diabetic polyneuropathy (DPN) early in type 2 diabetes may act as a marker for cardiovascular disease (CVD) and death.

Research Design And Methods: We linked data from two Danish type 2 diabetes cohorts, the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) and the Danish Centre for Strategic Research in Type 2 Diabetes (DD2), to national health care registers. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was completed at diabetes diagnosis in ADDITION-Denmark and at a median of 4.6 years after diagnosis of diabetes in DD2. An MNSIq score ≥4 was considered as indicative of DPN. Using Poisson regressions, we computed incidence rate ratios (IRRs) of CVD and all-cause mortality comparing MNSIq scores ≥4 with scores <4. Analyses were adjusted for a range of established CVD risk factors.

Results: In total, 1,445 (ADDITION-Denmark) and 5,028 (DD2) individuals were included in the study. Compared with MNSIq scores <4, MNSIq scores ≥4 were associated with higher incidence rate of CVD, with IRRs of 1.79 (95% CI 1.38-2.31) in ADDITION-Denmark, 1.57 (CI 1.27-1.94) in the DD2, and a combined IRR of 1.65 (CI 1.41-1.95) in a fixed-effect meta-analysis. MNSIq scores ≥4 did not associate with mortality; combined mortality rate ratio was 1.11 (CI 0.83-1.48).

Conclusions: The MNSIq may be a tool to identify a subgroup within individuals with newly diagnosed type 2 diabetes with a high incidence rate of subsequent CVD. MNSIq scores ≥4, indicating DPN, were associated with a markedly higher incidence rate of CVD, beyond that conferred by established CVD risk factors.
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May 2021