The daily updated Dutch national database on COVID-19 epidemiology, vaccination and sewage surveillance.

The Dutch national open database on COVID-19 has been incrementally expanded since its start on 30 April 2020 and now includes datasets on symptoms, tests performed, individual-level positive cases and deaths, cases and deaths among vulnerable populations, settings of transmission, hospital and ICU admissions, SARS-CoV-2 variants, viral loads in sewage, vaccinations and the effective reproduction number. This data is collected by municipal health services, laboratories, hospitals, sewage treatment plants, vaccination providers and citizens and is cleaned, analysed and published, mostly daily, by the National Institute for Public Health and the Environment (RIVM) in the Netherlands, using automated scripts. Because these datasets cover the key aspects of the pandemic and are available at detailed geographical level, they are essential to gain a thorough understanding of the past and current COVID-19 epidemiology in the Netherlands. Future purposes of these datasets include country-level comparative analysis on the effect of non-pharmaceutical interventions against COVID-19 in different contexts, such as different cultural values or levels of socio-economic disparity, and studies on COVID-19 and weather factors.

Influence of fetal blood flow redistribution on fetal and childhood growth and fat distribution: the Generation R Study.

OBJECTIVE: A suboptimal intrauterine environment leads to fetal blood flow redistribution and fetal growth restriction. Not much is known about childhood growth consequences. We examined the associations of fetal blood flow redistribution with birth outcomes, and repeatedly measured fetal and childhood growth and fat mass measures. DESIGN: Prospective cohort study. SETTING: Population-based. POPULATION: One thousand one hundred and ninety-five pregnant women and their children. METHODS: We measured umbilical and cerebral artery blood flow at a gestational age of 30.3 weeks (95% range, 28.5-32.6 weeks). A higher umbilical/cerebral (U/C) pulsatility index ratio is an indicator of preferential blood flow to the brain cerebral circulation at the expense of the lower body parts. MAIN OUTCOME MEASURES: Fetal and childhood growth were repeatedly measured from the third trimester until childhood. We measured the total body fat mass, lean fat mass and android/gynoid fat mass ratio by dual-energy X-ray absorptiometry and preperitoneal fat by ultrasound at 6 years. RESULTS: A higher fetal U/C ratio was associated with increased risks of preterm birth and small size for gestational age at birth [odds ratios, 1.41 (95% confidence interval, 1.08-1.85) and 1.63 (95% confidence interval, 1.21-2.19), respectively, per SDS increase in U/C ratio]. Longitudinal growth analyses showed that a higher fetal U/C ratio was associated with persistently lower head circumference, length and weight from third trimester fetal life until childhood (all P < 0.05). The fetal U/C ratio was not associated with total body and abdominal fat measures at 6 years. CONCLUSION: Our results suggest that fetal blood flow redistribution affects fetal development and has persistent consequences for childhood growth. TWEETABLE ABSTRACT: Fetal blood flow redistribution affects fetal development and has persistent consequences for childhood growth.

The risk-based approach to ATMP development - generally accepted by regulators but infrequently used by companies.

Advanced therapy medicinal products (ATMPs) are the cutting edge of drug innovation. ATMPs have different challenges than other drug classes. To accommodate these challenges and facilitate science-driven development, flexibility in the requirements to demonstrate the safety and efficacy of this rapidly evolving drug class is necessary. To create flexibility, the European Union introduced the risk-based approach. This approach provides the possibility of omitting guideline-based studies based on risk analyses. To gain insight into the effect of the risk-based approach on the non-clinical development of ATMPs, two questions are addressed in this paper. Firstly, "Do companies use a risk-based approach for the non-clinical development of ATMPs?" and, secondly, "Does the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) accept non-clinical development programs based on the risk-based approach?" Scientific advice letters formulated by the CHMP were analyzed. The risk-based approach was used to justify deviations from the guidelines in the majority (75%) of the cases. The CHMP accepted 40% of the proposals to omit studies and stated that additional data was necessary to make an informed decision for 35% of the proposals. This indicates that the risk-based approach facilitates the science-driven development of ATMPs.

Levels of lead, arsenic, mercury and cadmium in clays for oral use on the Dutch market and estimation of associated risks.

Pregnant women in Africa, Asia and Suriname, and some immigrants in Western societies, traditionally consume clay products known by a variety of names such as mabele, calabash chalk, sikor and pimba. Furthermore, clay is used for health purposes in Western societies. Because certain clays can contain high levels of metals and metalloids, the aim of this study was to determine lead, arsenic, mercury and cadmium in clay products for oral use available on the Dutch market. Traditional clays originating from Africa (n = 10) and Suriname (n = 26), and health clays (n = 27) were sampled from 2004 up to and including 2012. Total metal and metalloid contents were measured by ICP-MS and showed maximum levels of lead, arsenic, mercury and cadmium of 99.7, 45.1, 2.2 and 0.75 mg kg⁻¹, respectively. In the absence of maximum limits for these type of clays, the potential exposure was estimated from the determined concentration, the estimated daily use level of the clays, and the estimated bioaccessibility of the different metals and arsenic. The intake estimates were compared with existing health-based guidance values. For lead, the use of 34 of the 36 traditional clays and two of the 27 health clays would result in intake levels exceeding the toxicological limit by up to 20-fold. Use of 15 of the 35 traditional clays and 11 of the 27 health clays would result in intake levels exceeding the toxicological limit for inorganic arsenic by up to 19-fold. Although limited bioaccessibility from the clay may limit the exposure and exceedance of the health-based guidance values, it was concluded that lead and arsenic intakes from some clay products could be of concern also because of their use by pregnant women and the potential developmental toxicity. As a result the use of these products, especially by pregnant women, should be discouraged.

The role of the alpha-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress.

AIM: The prompt increase in peripheral vascular resistance, mediated by sympathetic alpha-adrenergic stimulation, is believed to be the key event in blood pressure control during postural stress. However, despite the absence of central sympathetic control of the leg vasculature, postural leg vasoconstriction is preserved in spinal cord-injured individuals (SCI). This study aimed at assessing the contribution of both central and local sympathetically induced alpha-adrenergic leg vasoconstriction to head-up tilt (HUT) by including healthy individuals and SCI, who lack central sympathetic baroreflex control over the leg vascular bed. METHODS: In 10 controls and nine SCI the femoral artery was cannulated for drug infusion. Upper leg blood flow (LBF) was measured bilaterally using venous occlusion strain gauge plethysmography before and during 30 degrees HUT throughout intra-arterial infusion of saline or the non-selective alpha-adrenergic receptor antagonist phentolamine respectively. Additionally, in six controls the leg vascular response to the cold pressor test was assessed during continued infusion of phentolamine, in order to confirm complete alpha-adrenergic blockade by phentolamine. RESULTS: During infusion of phentolamine HUT still caused vasoconstriction in both groups: leg vascular resistance (mean arterial pressure/LBF) increased by 10 +/- 2 AU (compared with 12 +/- 2 AU during saline infusion), and 13 +/- 3 AU (compared with 7 +/- 3 AU during saline infusion) in controls and SCI respectively. CONCLUSION: Effective alpha-adrenergic blockade did not reduce HUT-induced vasoconstriction, regardless of intact baroreflex control of the leg vasculature. Apparently, redundant mechanisms compensate for the absence of sympathetic alpha-adrenoceptor leg vasoconstriction in response to postural stress.

Endothelium-dependent and -independent vasodilation of the superficial femoral artery in spinal cord-injured subjects.

Extreme inactivity of the legs in spinal cord-injured (SCI) individuals does not result in an impairment of the superficial femoral artery flow-mediated dilation (FMD). To gain insight into the underlying mechanism, the present study examined nitric oxide (NO) responsiveness of vascular smooth muscles in controls and SCI subjects. In eight healthy men (34 +/- 13 yr) and six SCI subjects (37 +/- 10 yr), superficial femoral artery FMD response was assessed by echo Doppler. Subsequently, infusion of incremental dosages of sodium nitroprusside (SNP) was used to assess NO responsiveness. Peak diameter was examined on a second day after 13 min of arterial occlusion in combination with sublingual administration of nitroglycerine. Resting and peak superficial femoral artery diameter in SCI subjects were smaller than in controls (P < 0.001). The FMD response in controls (4.2 +/- 0.9%) was lower than in SCI subjects (8.2 +/- 0.9%, P < 0.001), but not after correcting for area under the curve for shear rate (P = 0.35). When expressed as relative change from baseline, SCI subjects demonstrate a significantly larger diameter increase compared with controls at each dose of SNP. However, when expressed as a relative increase within the range of diameter changes [baseline (0%) - peak diameter (100%)], both groups demonstrate similar changes in response to SNP. Changes in diameter during SNP infusion and FMD response are larger in SCI subjects compared with controls. When these results are corrected, superficial femoral artery FMD and NO sensitivity in SCI subjects are not different from those in controls. This illustrates the importance of appropriate data presentation and suggests that, subsequent to structural inward remodeling of conduit arteries as a consequence of extreme physical inactivity, arterial function is normalized.

Flow-mediated dilatation in the superficial femoral artery is nitric oxide mediated in humans.

Flow-mediated dilatation (FMD) of the brachial and radial arteries is an important research tool for assessment of endothelial function in vivo, and is nitric oxide (NO) dependent. The leg skeletal muscle vascular bed is an important territory for studies in exercise physiology. However, the role of endothelial NO in the FMD response of lower limb arteries has never been investigated. The purpose of this study was to examine the contribution of NO to FMD in the superficial femoral artery in healthy subjects. Since physical inactivity may affect endothelial function, and therefore NO availability, spinal cord-injured (SCI) individuals were included as a model of extreme deconditioning. In eight healthy men (34 +/- 13 years) and six SCI individuals (37 +/- 10 years), the 5 min FMD response in the superficial femoral artery was assessed by echo-Doppler, both during infusion of saline and during infusion of the NO synthase blocker N(G)-monomethyl-L-arginine (L-NMMA). In a subset of the controls (n = 6), the 10 min FMD response was also examined using the same procedure. The 5 min FMD response in controls (4.2 +/- 0.3%) was significantly diminished during L-NMMA infusion (1.0 +/- 0.2%, P < 0.001). In SCI, L-NMMA also significantly decreased the FMD response (from 8.2 +/- 0.4% during saline to 2.4 +/- 0.5% during L-NMMA infusion). The hyperaemic flow response during the first 45 s after cuff deflation was lower in both groups during infusion of L-NMMA, but the effect of L-NMMA on FMD persisted in both groups after correction for the shear stress stimulus. The 10 min FMD was not affected by L-NMMA (saline: 5.4 +/- 1.6%, L-NMMA: 5.6 +/- 1.5%). Superficial femoral artery FMD in response to distal arterial occlusion for a period of 5 min is predominantly mediated by NO in healthy men and in the extremely deconditioned legs of SCI individuals.

Local vasoconstriction in spinal cord-injured and able-bodied individuals.

Local vasoconstriction plays an important role in maintaining blood pressure in spinal cord-injured individuals (SCI). We aimed to unravel the mechanisms of local vasoconstriction [venoarteriolar reflex (VAR) and myogenic response] using both limb dependency and cuff inflation in SCI and compare these with control subjects. Limb blood flow was measured in 11 male SCI (age: 24-55 yr old) and 9 male controls (age: 23-56 yr old) using venous occlusion plethysmography in forearm and calf during three levels of 1) limb dependency, and 2) cuff inflation. During limb dependency, vasoconstriction relies on both the VAR and the myogenic response. During cuff inflation, the decrease in blood flow is caused by the VAR and by a decrease in arteriovenous pressure difference, whereas the myogenic response does not play a role. At the highest level of leg dependency, the percent increase in calf vascular resistance (mean arterial pressure/calf blood flow) was more pronounced in SCI than in controls (SCI 186 +/- 53%; controls 51 +/- 17%; P = 0.032). In contrast, during cuff inflation, no differences were found between SCI and controls (SCI 17 +/- 17%; controls 14 +/- 10%). Percent changes in forearm vascular resistance in response to either forearm dependency or forearm cuff inflation were equal in both groups. Thus local vasoconstriction during dependency of the paralyzed leg in SCI is enhanced. The contribution of the VAR to local vasoconstriction does not differ between the groups, since no differences between groups existed for cuff inflation. Therefore, the augmented local vasoconstriction in SCI during leg dependency relies, most likely, on the myogenic response.

Triple osteotomy of the pelvis for acetabular dysplasia: results at a mean follow-up of 15 years.

We report the long-term results of 51 pelvic osteotomies in 43 patients with a mean follow-up of 15 years (13 to 20). The mean age of the patients was 28 years (14 to 46). At review three patients were lost to follow-up, and six had received a total hip arthroplasty. Of 48 hips, 42 (88%) were preserved, with good to excellent clinical results in 27 (64%). Pre-operatively, 41 (80%) of the treated hips had shown no sign of osteoarthritis. Thirty-one (65%) hips showed no progression of osteoarthritis after follow-up for 15 years. Significant negative factors for good long-term results were the presence of osteoarthritic changes and a fair or poor clinical score pre-operatively. Pelvic reorientation osteotomy for symptomatic hip dysplasia can give satisfactory and reproducible long-term clinical results.

Oral aspects of porphyria.

Porphyria is a diverse group of diseases in which the biosynthesis of heme is disrupted by either genetic defects or environmental factors. This review gives an overview of the different types of porphyria and describes possible causes, clinical signs, diagnosis and therapy. In addition, the oral manifestations of porphyria and the potential implications of the disease for dental management are discussed.

[Oral aspects of porphyria]. / Orale aspecten van porfyrie.

Porphyria is a disease of specific enzymes in the biosynthesis of heme, caused by either genetic defects or environmental factors. This review of the literature presents the different types of porphyria and describes their possible causes, clinical signs, diagnosis and therapy. In addition, oral findings observed in patients with porphyria and the potential implications of the disease for dental treatment are discussed.

Teardrop-femoral head distance after shelf acetabuloplasty for Perthes' disease.

Shelf acetabuloplasty is an accepted treatment for Perthes' disease. Favourable outcomes have been reported. This study aimed at determining whether changes in femoral head subluxation after shelf acetabuloplasty occur and whether they predict outcome. We assumed that reduction of subluxation after shelf acetabuloplasty would improve the long-term outcome. During follow-up, growth presented as a source of error when comparing the amount of absolute subluxation. Correction for growth was achieved by calculating a subluxation index. This index showed a significant reduction during follow-up. There was no correlation between clinical and radiological outcome, but the fact that the subluxation index showed a decreasing trend could be promising regarding outcome. This might be one of the reasons why shelf acetabuloplasty produces its effect. Following shelf acetabuloplasty the enlarged acetabulum could possibly direct the growth of the femoral head to a better-contained joint. This could result in better joint congruity and lesser tendency to degenerative arthritis.

Shelf acetabuloplasty for Perthes' disease: 12-year follow-up.

The goal of all therapies for Perthes' disease is to achieve an optimal shape of the acetabulum and an optimal coverage of the femoral head. Thirty patients who were included in this follow-up study (mean follow-up 12 years) underwent a shelf acetabuloplasty for Catterall group III or IV. The mean IOWA hip score at follow-up was 96 (max. 100 points, range 74-100). The mean acetabular-head quotient increased from 82.9% pre-operatively to 107.9% postoperatively, and remained 102.4% at follow-up. There was a decrease in mean lateral subluxation ratio from 1.44 pre-operatively to 1.27 postoperatively, which remained 1.23 at follow-up. According to the Stulberg classification in the 18 adult hips, 6 hips had a good result (Stulberg 1 or 2), 10 hips had a fair result (Stulberg 3), and 2 hips had a poor result (Stulberg 4 or 5). These results appear to be better than the natural history as described by Stulberg. Shelf acetabuloplasty can be considered as an appropriate surgical treatment for severe cases of Perthes' disease.

Treatment of idiopathic scoliosis with side-shift therapy: an initial comparison with a brace treatment historical cohort.

A group of 44 patients with idiopathic scoliosis (mean age 13.6 years) with an initial Cobb angle between 20 degrees and 32 degrees received side-shift therapy (mean treatment duration 2.2 years). A group of 120 brace patients (mean age 13.6 years) with an initial Cobb angle in the same range (mean brace treatment 3.0 years) was the historical reference group. Failure was defined as an increase of Cobb angle greater than 5 degrees within 4 months or a Cobb angle greater than 35 degrees or a total increase of Cobb angle greater than 10 degrees. The chance of success was not significantly different between the side-shift and the brace groups, whether tested for efficiency (66% vs 68%) or efficacy (85% vs 90%). The difference in the mean progression of the Cobb angle for the respective groups is small (for efficiency: 3 degrees vs -2 degrees, for efficacy: 2 degrees vs -1 degrees ). Side-shift therapy appears to be a promising additional treatment for idiopathic scoliosis in adolescents with an initial Cobb angle between 20 degrees and 32 degrees.

Acetabular coverage of the femoral head after triple pelvic osteotomy: no relation to outcome in 51 hips followed for 8-15 years.

In developmental dysplasia of the hip in adolescents and young adults, pelvic osteotomies aim to improve acetabular coverage of the femoral head by reorienting the acetabulum. We determined whether acetabular coverage is related to long-term clinical results after triple osteotomy of the pelvis. We used a previously published computer program (Konishi and Mieno 1993) which calculates three-dimensional coverage of the femoral head from plain anteroposterior radiographs. We studied the pelvic radiographs of 51 hips in 43 patients and the results were correlated with studies on clinical outcome (de Kleuver et al. 1997). Total acetabular coverage improved from a mean of 56% to 70%. We did not find a relationship between total acetabular coverage and long-term outcome, nor could we determine an optimal coverage. Reduced coverage of the posterolateral quadrant of the femoral head was related to a reduced score for walking ability (p = 0.03), and therefore care should be taken not to overcorrect the acetabulum forwards when attempting to improve the deficient anterior coverage. We challenge the concept that total acetabular coverage is a prerequisite for a good long-term outcome after triple pelvic osteotomy, and hypothesize that other factors such as the change in load across the hip are probably more important in determining the outcome.

Pelvic osteotomies: anatomic pitfalls at the ischium. A cadaver study.

Pelvic osteotomies for acetabular dysplasia include an osteotomy of the ischium. The potential anatomical hazards of three different osteotomies of the ischium were assessed by performing a triple osteotomy in a series of 8 fresh cadaver pelvises. An oblique osteotomy above the sacrospinous ligament using a posterior approach requires that the inferior gluteal and pudendal neurovascular bundles be mobilised and retracted. A transverse osteotomy below the sacrospinous ligament using a posterior approach can be performed in a relatively safe area between the pudendal and sciatic nerves. A transverse osteotomy from anterior can be performed through a modified Smith Peterson approach. The pudendal nerve medially, the sciatic nerve laterally and the medial circumflex artery distally are not visualised and are prone to damage.

Anatomic basis of Tönnis' triple pelvic osteotomy for acetabular dysplasia.

Dysplasia of the hip in adults can be treated by a pelvic osteotomy. In order to assess pelvic anatomy in relation to surgical approach and osteotomy sites, 12 cadaver hips were studied. A triple pelvic osteotomy as described by Tönnis [6] through ilium, pubis and ischium was performed, followed by an intrapelvic and anterior and posterior dissection of the hip. At the ischium, the pudendal and inferior gluteal neurovascular bundles are most at risk medially and proximally respectively. Much less in danger is the sciatic n. as it runs 1 to 3 cm lateral to the osteotomy site. At the pubis osteotomy the femoral v. lies close on the bone and is prone to damage. The artery lies further off the bone. The ilium osteotomy starts just proximal to the anterior inferior iliac spine and exits posteriorly at the sciatic notch. Here the sciatic n. and the superior gluteal neurovascular bundle may be damaged. The practical surgical implications of these three osteotomies are discussed, especially with respect to the requirement of meticulous subperiostal dissection and accurate placement of retractors.

Pelvic osteotomies: anatomic pitfalls at the pubic bone. A cadaver study.

Pelvic osteotomies for acetabular dysplasia include an osteotomy of the pubic bone. The anatomical consequences of two different approaches to the pubic bone were assessed by performing a triple osteotomy on a series of 12 fresh cadaver hemipelvises. The medial approach through a separate incision over the pubic symphysis was compared with the lateral approach through the incision used for the innominate osteotomy. Although the medial approach appears technically easy, there are several anatomical structures at risk, such as the femoral vein and the corona mortis. The lateral approach is safer, and it is easier to make the osteotomy close to the hip joint. The closer the osteotomy is to the hip joint, the smaller the chance of developing a non-union.