Food or medicine? A European regulatory perspective on nutritional therapy products to treat inborn errors of metabolism.

Dietary or nutritional management strategies are the cornerstone of treatment for many inborn errors of metabolism (IEMs). Though a vital part of standard of care, the products prescribed for this are often not formally registered as medication. Instead, they are regulated as food or as food supplements, impacting the level of oversight as well as reimbursed policies. This scoping literature review explores the European regulatory framework relevant to these products and its implications for current clinical practice. Searches of electronic databases (PubMed, InfoCuria) were carried out, supplemented by articles identified by experts, from reference lists, relevant guidelines and case-law by the European Court of Justice. In the European Union (EU), nutritional therapy products are regulated as food supplements, food for special medical purposes (FSMPs) or medication. The requirements and level of oversight increase for each of these categories. Relying on lesser-regulated food products to treat IEMs raises concerns regarding product quality, safety, reimbursement and patient access. In order to ascertain whether a nutritional therapy product functions as medication and thus could be classified as such, we developed a flowchart to assess treatment characteristics (benefit, pharmacological attributes, and safety) with a case-based approach. Evaluating nutritional therapy products might reveal a justifiable need for a pharmaceutical product. A flowchart can facilitate systematically distinguishing products that function medication-like in the management of IEMs. Subsequently, finding and implementing appropriate solutions for these products might help improve the quality, safety and accessibility including reimbursement of treatment for IEMs.

A vitamin a day keeps the doctor away: The need for high quality pyridoxal-5'-phosphate.

BACKGROUND: A rare subset of vitamin B6 responsive seizure disorders does not respond to pyridoxine, and requires the active form of vitamin B6, pyridoxal-5'-phosphate (PLP), to maintain seizure control. Patients with PLP-responsive seizures are dependent on chronic PLP treatment, yet no licensed PLP product is available. PLP food supplements, a product category regulated less stringently than medication, may prove of insufficient effectiveness and safety. Here we describe and discuss three patient scenarios which illustrate this conundrum. METHODS: Medical and laboratory records were reviewed with retrospective extraction for three unrelated patients who suffered complications during treatment with PLP food supplements. RESULTS: - Two cases of PNPO deficiency and one case of PLP-dependent epileptic encephalopathy without a (genetic) diagnosis are reported. These patients are critically dependent on PLP for seizure control and have suffered complications due to insufficient quality of these food supplements during the course of treatment. Complications include the occurrence of seizures following the administration of suspected low quality PLP, inactive PLP due to light exposure, a PLP intoxication, resisting administration and post-administration vomiting as a result of the ingestion of large amounts of capsules per day. CONCLUSION: - This case series illustrates that the reliance on food supplements as anti-seizure therapy is not without risk. The treatment of PLP-dependent seizures exemplifies that PLP is administered as medication, thus there is a clear need for licensed vitamin products of pharmaceutical quality.

Gait analysis before and after corrective osteotomy in patients with knee osteoarthritis and a valgus deformity.

PURPOSE: In this prospective study, the changes in kinetics and kinematics of gait and clinical outcomes after a varus osteotomy (tibial, femoral or double osteotomy) in patients with osteoarthritis (OA) of the knee and a valgus leg alignment were analysed and compared to healthy subjects. METHODS: Twelve patients and ten healthy controls were included. Both kinetics and kinematics of gait and clinical and radiographic outcomes were evaluated. RESULTS: The knee adduction moment increased significantly postoperatively (p < 0.05) and almost similar to the control group. Patients showed less knee and hip flexion/extension motion and moment during gait pre- and postoperatively compared to the controls. A significant improvement was found in WOMAC [80.8 (SD 16.1), p = 0.000], KOS [74.9 (SD 14.7), p = 0.018], OKS [21.2 (SD 7.5), p = 0.000] and VAS-pain [32.9 (SD 20.9), p = 0.003] in all patients irrespective of the osteotomy technique used. The radiographic measurements showed a mean hip knee ankle (HKA) angle correction of 10.4° (95 % CI 6.4°-14.4°). CONCLUSION: In patients with knee OA combined with a valgus leg alignment, the varus-producing osteotomy is a successful treatment. Postoperatively, the patients showed kinetics and kinematics of gait similar as that of a healthy control group. A significant increase in the knee adduction moment during stance phase was found, which was related to the degree of correction. The HKA angle towards zero degrees caused a medial shift in the dynamic knee loading. The medial shift will optimally restore cartilage loading forces and knee ligament balance and reduces progression of OA or the risk of OA. A significant improvement in all clinical outcomes was also found. LEVEL OF EVIDENCE: III.

Prediction of walking speed using single stance force or pressure measurements in healthy subjects.

Walking speed is one of the best measures of overall walking capacity. In plantar pressure measurements, walking speed can be assessed using contact time, but it is only moderately correlated with walking speed. The center of pressure might be of more value to indicate walking speed since walking speed alters foot loading. Therefore, the purpose of this study is to assess walking speed using the velocity of the center of pressure (VCOP). Thirty-three subjects walked over a Footscan pressure plate at three speed conditions; slow, preferred, and fast. Walking speed was measured by a motion analysis system. (Multiple) linear regression analysis was used to indicate the relation between walking speed and independent variables derived from the pressure plate such as mean VCOP and stance time for all walking conditions separately and together. The mean VCOP had the highest correlation coefficient value with walking speed for all walking conditions combined (0.94) and for the preferred walking condition (0.80). The multiple regression analysis, based on a number of additional parameters, revealed a small to modest increase in the performance of predicting walking speed (r=0.98 for combined and r=0.93 for preferred). The mean VCOP was the best predictor for walking speed when using a plantar pressure plate. The mean VCOP predicts the walking speed with a 95% accuracy of 0.20m/s when healthy subjects walk at their preferred walking speed.

Monte Carlo simulation of diffusion and ionic conductivity in a simple cubic random alloy via the interstitialcy mechanism.

This Monte Carlo study deals with mass and charge transport in binary ionic alloys governed by interstitialcy defects acting as diffusion vehicles. In particular, we calculate tracer correlation factors f(A) and f(B) in a simple cubic random alloy AB for diffusion via the collinear interstitialcy mechanism as a function of composition and jump frequency ratio wA/wB. [corrected]. Interstitialcy correlation factors f(I), which play a crucial role in the interpretation of ion-conductivity data, are also determined. The evaluation of partial correlation factors provides insight into the types of jumps that mostly contribute to the different transport processes under consideration. Examination of the percolation behaviour yields the site-percolation threshold of the mobile component B for w(A) = 0. Surprisingly, a unique second-order threshold composition is found, which relates to the abundance of different interstitialcy jump types when wA << wB [corrected]. Both numerically obtained threshold values are accurately reproduced by estimated analytical expressions based on simple arguments. Practical implications of the simulation results are explored by calculating tracer diffusivity ratios D*(A)/D*(B) and by comparing self-diffusion with ionic conductivity using the Nernst-Einstein equation.

Foot lengthening and shortening during gait: a parameter to investigate foot function?

INTRODUCTION: Based on the windlass mechanism theory of Hicks, the medial longitudinal arch (MLA) flattens during weight bearing. Simultaneously, foot lengthening is expected. However, changes in foot length during gait and the influence of walking speed has not been investigated yet. METHODS: The foot length and MLA angle of 34 healthy subjects (18 males, 16 females) at 3 velocities (preferred, low (preferred -0.4 m/s) and fast (preferred +0.4 m/s) speed were investigated with a 3D motion analysis system (VICON(®)). The MLA angle was calculated as the angle between the second metatarsal head, the navicular tuberculum and the heel in the local sagittal plane. Foot length was calculated as the distance between the marker at the heel and the 2nd metatarsal head. A General Linear Model for repeated measures was used to indicate significant differences in MLA angle and foot length between different walking speeds. RESULTS: The foot lengthened during the weight acceptance phase of gait and shortened during propulsion. With increased walking speed, the foot elongated less after heel strike and shortened more during push off. The MLA angle and foot length curve were similar, except between 50% and 80% of the stance phase in which the MLA increases whereas the foot length showed a slight decrease. CONCLUSION: Foot length seems to represent the Hicks mechanism in the foot and the ability of the foot to bear weight. At higher speeds, the foot becomes relatively stiffer, presumably to act as a lever arm to provide extra propulsion.

Classification of forefoot pain based on plantar pressure measurements.

BACKGROUND: Plantar pressure is widely used to evaluate foot complaints. However, most plantar pressure studies focus on the symptomatic foot with foot deformities. The purposes of this study were to investigate subjects without clear foot deformities and to identify differences in plantar pressure pattern between subjects with and without forefoot pain. The second aim was to discriminate between subjects with and without forefoot pain based on plantar pressure measurements using neural networks. METHODS: In total, 297 subjects without foot deformities of whom almost 50% had forefoot pain walked barefoot over a pressure plate. Foot complaints and subject characteristics were assessed with a questionnaire and a clinical evaluation. Plantar pressure was analyzed using a recently developed method, which produced pressure images of the time integral, peak pressure, mean pressure, time of activation and deactivation, and total contact time per pixel. After pre-processing the pressure images with principal component analysis, a forward selection procedure with neural networks was used to classify forefoot pain. FINDINGS: The pressure-time integral and mean pressure were significantly larger under the metatarsals II and III for subjects with forefoot pain. A neural network with 14 input parameters correctly classified forefoot pain in 70.4% of the test feet. INTERPRETATION: The differences in plantar pressure parameters between subjects with and without forefoot pain were small. The reasonable performance of forefoot pain classification by neural networks suggests that forefoot pain is related more to the distribution of the pressure under the foot than to the absolute values of the pressure at fixed locations.

Foreign-ion and self-ion diffusion in a crosslinked salt-in-polyether electrolyte.

We present an extensive study of ionic transport in PolyG(30)LiPF(6), which is a crosslinked poly(ethylene oxide)-poly(propylene oxide(PEO-PPO) random copolymer complexed with LiPF(6) to an oxygen-to-cation ratio of 30 : 1. Self-diffusion coefficients of the constituent ions were measured by pulsed field gradient nuclear magnetic resonance (PFG-NMR) as a function of temperature using the signals of (7)Li and (19)F. These data were compared with the charge diffusivity as derived with the Nernst-Einstein equation from the ion conductivity obtained by impedance spectroscopy. In addition, the diffusion behaviour of a foreign cation (sodium) and that of a foreign anion (iodine) in PolyG(30)LiPF(6) were investigated by means of the radiotracers (22)Na and (125)I. All different types of diffusivities were evaluated in a comprehensive ion transport model which allows for the occurrence of charged single ions and neutral ion pairs. Simultaneous fitting of all data within this model yields best values of the model parameters which include Vogel-Tammann-Fulcher parameters and enthalpies/entropies of pair formation. Two distinct variants of the same general model reproduce the experimental data equally well, i.e., with closely similar results for the pair contribution to the migration of each ionic species. In the first variant, this pair contribution is due to a small fraction of ion pairs with a high mobility. By contrast, the second variant results in a very large fraction of pairs characterized by a relatively low mobility. The assumptions and implications connected with both model variants are discussed in detail.

Linear dependence of peak, mean, and pressure-time integral values in plantar pressure images.

Dynamic plantar pressure images are routinely used in clinical gait assessment, and peak pressure, mean pressure, and pressure-time integral are the most frequently used parameters to summarize these images. Many studies report only one parameter, but other studies report all three. The interdependency of these variables has not been explicitly studied previously. The purpose of this study was to describe the linear relation between these three pressure parameters. 327 subjects walked normally over a pressure plate. Peak pressure, mean pressure and pressure-time integral were calculated for 10 different anatomical areas and, after applying a previously described spatial normalization procedure, these variables were also calculated for each pixel. Mean pressure was highly correlated with peak pressure (r=0.90+/-0.09) and pressure-time integral (r=0.81+/-0.13) for pixels. Peak pressure and pressure-time integral showed a linear correlation coefficient of r=0.78+/-0.21. The pressure parameters of the forefoot pixels were more highly correlated than the heel pixels. The current results have two major implications: (1) plantar pressure parameters (peak, mean, and impulse) can be reasonably compared across studies, even across parameters, and (2) the variables most commonly used to characterize plantar pressures are highly inter-correlated, implying that a smaller set of parameters may more efficiently capture the biomechanical behavior of interest.

A new method to normalize plantar pressure measurements for foot size and foot progression angle.

Plantar pressure measurement provides important information about the structure and function of the foot and is a helpful tool to evaluate patients with foot complaints. In general, average and maximum plantar pressure of 6-11 areas under the foot are used to compare groups of subjects. However, masking the foot means a loss of important information about the plantar pressure distribution pattern. Therefore, the purpose of this study was to develop and test a simple method that normalizes the plantar pressure pattern for foot size, foot progression angle, and total plantar pressure. Moreover, scaling the plantar pressure to a standard foot opens the door for more sophisticated analysis techniques such as pattern recognition and machine learning. Twelve subjects walked at preferred and half of the preferred walking speed over a pressure plate. To test the method, subjects walked in a straight line and in an approaching angle of approximately 40 degrees . To calculate the normalized foot, the plantar pressure pattern was rotated over the foot progression angle and normalized for foot size. After normalization, the mean shortest distance between the contour lines of straight walking and walking at an angle had a mean of 0.22 cm (SD: 0.06 cm) for the forefoot and 0.14 cm (SD: 0.06 cm) for the heel. In addition, the contour lines of normalized feet for the various subjects were almost identical. The proposed method appeared to be successful in aligning plantar pressure of various feet without losing information.

Mass and charge transport in the PEO-NaI polymer electrolyte system: effects of temperature and salt concentration.

Ionic transport in amorphous complexes of poly(ethylene oxide) (PEO) and sodium iodide (NaI) was investigated by means of radiotracer diffusion and electrical conductivity measurements for three different compositions characterised by O-to-Na ratios of 20, 30, and 60. The diffusivity of 22Na and 125I as well as the charge diffusivity each show a systematic dependence on both temperature and salt concentration. The experimental data can be described within a transport model based on the occurrence of neutral ion pairs in addition to charged single cations and anions. It is found that both the enthalpy and entropy of ion pair formation decrease with increasing salt concentration. This indicates that the state of coordination between cations and polymer chain segments correlates with the number of available oxygen atoms per cation.

Radiotracer diffusion and ionic conduction in a PEO-NaI polymer electrolyte.

We studied ion transport in amorphous PEO30NaI consisting of poly(ethylene oxide) and sodium iodide in a Na-to-O ratio of 30. Diffusion coefficients of the radiotracers 22Na and 125I were measured for temperatures between 67 and 180 degrees C and compared with the overall charge diffusivity deduced from dc conductivity data. To explain the observed discrepancy between the sum of the tracer diffusivities and the charge diffusivity we propose a detailed model which is based on the formation of neutral ion pairs. Evaluating simultaneously all experimental data within this model yields not only the true diffusion coefficient of all individual species but also the ion-pairing reaction constant as a function of temperature.