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The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine β-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-β-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: In 2019, pegvaliase was approved in Europe for the treatment of phenylketonuria (PKU) in patients aged 16 years and older with blood phenylalanine (Phe) concentrations above 600 μmol/L despite prior management with available treatment options. Since its European approval, German metabolic centres have gained valuable experience, which may be of benefit to other treatment centres managing patients on pegvaliase., Methods: After a virtual meeting that was attended by nine German physicians, three German dietitians and one American physician, a follow-up discussion was held via an online platform to develop a set of recommendations on the use of pegvaliase in Germany. Eight German physicians contributed to the follow-up discussion and subsequent consensus voting, using a modified Delphi technique. The recommendations were supported by literature and retrospectively collected patient data., Results: Consensus (≥75% agreement) was achieved on 25 recommendations, covering seven topics deemed relevant by the expert panel when considering pegvaliase an option for the treatment of patients with PKU. In addition to the recommendations, a retrospective chart review was conducted in seven of the centres and included 71 patients who initiated treatment with pegvaliase. Twenty-seven patients had been treated for at least 24 months and 23 (85.2%) had achieved blood Phe ≤600 μmol/L with some degree of diet normalisation. Of these patients, 14 had physiological blood Phe on a normalised diet., Conclusion: The practical consensus recommendations provide guidance on the different steps along the pegvaliase journey from clinical site requirements to treatment goals and outcomes. The recommendations are intended to support less experienced European metabolic centres with the implementation of pegvaliase, emphasising that a core treatment team consisting of at least a dietitian and metabolic physician is sufficient to initiate pegvaliase and support patients during their treatment journey., Competing Interests: Declaration of Competing Interest JK received consulting payments and speaker fees from Amicus, BioMarin and Sanofi, as well as speakers fees from Shire and research grants from Danone. CB received consulting payments from BioMarin, participated as a clinical trial investigator for BioMarin and received speaker fees from Sanofi-Genzyme, Sobi and Vitaflo. CH and AR are employees of BioMarin Deutschland GmbH. CK received consulting payments from BioMarin. KGP received consulting payments from BioMarin and research fees as well as speaker fees from Vitaflo. FR received consulting payments from BioMarin, Elastrin Therapeutics and Inozyme Pharma, research grants and patents from Inozyme Pharma, speaker fees from BioMarin, Inozyme Pharma and Recordati Rare Diseases and participated as a clinical trial investigator for Aeglea BioTherapeutics, BioMarin, Inozyme Pharma and PTC Therapeutics. SS received consulting payments from BioMarin, Leadiant GmbH and Vertex, speaker fees and travel support from Sobi, and participated as clinical trial investigator for BioMarin. NW received consulting payments from BioMarin, Sanofi and Takeda, speaker fees from Sanofi and Takeda, travel support from Nutricia and Takeda and participated as a clinical trial investigator for BioMarin. ACM received consulting payment from Atheneum, Nestlé and PTC Therapeutics, speaker fees from AIM-PHAMRA Ltd., APR and Nutricia, travel support from Nutricia and participated as a clinical trial investigator for BioMarin and PTC Therapeutics., (Copyright © 2023 BioMarin Deutschland GmbH and BioMarin Pharmaceutical Inc. Published by Elsevier Inc. All rights reserved.)

The aim of the study was a systematic evaluation of cognitive development in individuals with glutaric aciduria type 1 (GA1), a rare neurometabolic disorder, identified by newborn screening in Germany. This national, prospective, observational, multi-centre study includes 107 individuals with confirmed GA1 identified by newborn screening between 1999 and 2020 in Germany. Clinical status, development, and IQ were assessed using standardized tests. Impact of interventional and non-interventional parameters on cognitive outcome was evaluated. The majority of tested individuals (n = 72) showed stable IQ values with age (n = 56 with IQ test; median test age 11 years) but a significantly lower performance (median [IQR] IQ 87 [78-98]) than in general population, particularly in individuals with a biochemical high excreter phenotype (84 [75-96]) compared to the low excreter group (98 [92-105]; p = 0.0164). For all patients, IQ results were homogenous on subscale levels. Sex, clinical motor phenotype and quality of metabolic treatment had no impact on cognitive functions. Long-term neurologic outcome in GA1 involves both motor and cognitive functions. The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. These findings implicate the necessity of new treatment concepts., (© 2021. The Author(s).)

Isovaleric aciduria (IVA), a metabolic disease with severe (classic IVA) or attenuated phenotype (mild IVA), is included in newborn screening (NBS) programs worldwide. The long-term clinical benefit of screened individuals, however, is still rarely investigated. A national, prospective, observational, multi-center study of individuals with confirmed IVA identified by NBS between 1998 and 2018 was conducted. Long-term clinical outcomes of 94 individuals with IVA were evaluated, representing 73.4% (for classic IVA: 92.3%) of the German NBS cohort. In classic IVA (N = 24), NBS prevented untimely death except in one individual with lethal neonatal sepsis (3.8%) but did not completely prevent single (N = 10) or recurrent (N = 7) metabolic decompensations, 13 of them occurring already neonatally. IQ (mean ± SD, 90.7 ± 10.1) was mostly normal but below the reference population (P = .0022) and was even lower in individuals with severe neonatal decompensations (IQ 78.8 ± 7.1) compared to those without crises (IQ 94.7 ± 7.5; P = .01). Similar results were obtained for school placement. In contrast, individuals with mild IVA had excellent neurocognitive outcomes (IQ 105.5 ± 15.8; normal school placement) and a benign disease course (no metabolic decompensation, normal hospitalization rate), which did not appear to be impacted by metabolic maintenance therapy. In conclusion, NBS reduces mortality in classic IVA, but does not reliably protect against severe neonatal metabolic decompensations, crucial for favorable neurocognitive outcome. In contrast, individuals with mild IVA had excellent clinical outcomes regardless of metabolic maintenance therapy, questioning their benefit from NBS. Harmonized stratified therapeutic concepts are urgently needed., (© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Overcrowding in emergency departments (EDs) is inefficient, especially if it is caused by inappropriate visits for which primary care physicians could be equally effective as a hospital ED. Our paper investigates the extent to which both ambulatory ED visits and inpatient ED admissions are substitutes for primary care emergency services (PCES) in Germany. We use extensive longitudinal data and fixed effects models. Moreover, we add interaction terms to investigate the influence of various determinants on the strength of the substitution. Our results show significant substitution between PCES and ambulatory ED visits. Regarding the determinants, we find the largest substitution for younger patients. The more accessible the hospital ED is, the significantly larger the substitution. Moreover, substitution is larger among better-educated patients. For inpatient ED admission, we find significant substitution that is eight times smaller than the substitution for ambulatory ED visits. With regard to the determinants, we find the strongest substitution for non-urgent, short-stay admission and elderly patients. Countries with no gate-keeping system (such as Germany) have difficulties redirecting the patients streaming to EDs. Our estimated elasticities can help policy makers to resolve this issue, as our findings indicate where incentivizing the utilization of PCES is particularly effective., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

In this study, we investigated the relationship between changes in demand-side determinants and changes in hospital admissions. We used longitudinal market-wide data, including a novel detailed measure of population morbidity. To assess the effect of ageing, we interacted age with shifts in the population structure for both the surviving population and the population in their last year of life. We used fixed effects models and addressed the endogeneity of morbidity with instrumental variables. We found that changes in morbidity had the largest impact on changes in hospital admissions. Changes in the size of the surviving population had the second largest impact, which differed substantially across the age spectrum. There was a large response in admissions to changes in the size of the population aged 60-79 years. The end-of-life effect had the smallest impact and began to play a greater role only in the population aged 80 years and older. In many studies, end of life presumably approximates high morbidity. Our results demonstrated robustness in several tests. We performed estimations in separate major diagnostic categories and included changes in personal preferences. We argue that the determinants included in our estimations capture the vast majority of change on the demand side. Taken together, our findings provide evidence that these determinants explain one-fifth of changes in hospital admissions.

The aim of this study was to investigate the impact of myocardial fibrosis in Fabry disease. Seventy-three patients with genetically confirmed Fabry disease were followed for 4.8 ± 2.4 years. In accordance with current guidelines, 57 patients received enzyme replacement therapy (ERT) after study inclusion, whereas 16 did not. At baseline and latest possible follow-up, myocardial fibrosis was assessed noninvasively by cardiac magnetic resonance, and biomarkers of collagen metabolism were determined. Holter electrocardiography and clinical follow-up at yearly intervals were used to monitor malignant ventricular arrhythmias (MVAs; nonsustained and sustained ventricular tachycardia and sudden cardiac death). In total, 48 patients (66%) showed fibrosis assessed by late enhancement (LE) at baseline, and 4 patients developed new LE during follow-up, 2 of them despite ERT. The 2 patients receiving ERT (1.4 ± 1.9% vs 2.5 ± 2.6%, p <0.001) and the patients not receiving ERT (0.5 ± 0.8% vs 0.7 ± 1.0%, p = 0.035) showed a progression of LE during follow-up. None of the patients displayed reductions of LE during follow-up. Collagen biomarkers were elevated in patients with and without LE but did not correlate with LE amount. Thirteen LE-positive patients at the baseline examination had documented MVAs (including 5 sudden cardiac deaths), whereas none of the patients without LE had MVAs. The yearly increase in fibrosis was 0.9 ± 0.6% in patients with MVAs and 0.2 ± 0.3% in patients without MVAs (p <0.001). Logistic multivariate regression analysis revealed that the annual increase in fibrosis during follow-up was the only independent predictor of MVAs. In conclusion, myocardial fibrosis in Fabry disease is progressive, apparently not modified by ERT, and a crucial outcome determinant., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: The aim of this paper is to present an update of the Back School concept including recent randomised controlled studies, systematic reviews and guidelines., Method: After definition and classification of the origins of the Back School concept, results of randomised controlled studies and systematic reviews within the framework of the Cochrane Collaboration Back Review Group are presented with their consequences with regard to German and International guidelines for the rehabilitation and prevention of low-back pain., Results: The Back School, integrated into a multidisciplinary programme, is effective in the rehabilitation and prevention of recurrent and chronic low-back pain. It is not effective for acute back problems when compared to other treatment modalities. There is moderate evidence suggesting that back schools in an occupational setting reduce pain and improve function and return to work status., Conclusion: The classic structure of the Back School with information, back protection exercises and gymnastics can be practiced successfully for chronic low-back pain and in an occupational setting. Insurance companies should consider the low-cost technology. For children, adolescents and for older people with osteoporosis and lumbar spinal stenosis, a special age-orientated design of the Back School is necessary.

Since 1993 occupational influences of the spine are included into the German workman's compensation law (Berufskrankheitenverordnung). Because it is difficult to differentiate degenerative from occupational disc diseases only 3 % of the proposals have been accepted in the last years. Unfortunately most of the epidemiologic studies only consider morphologic changes of the spine but not discogenic diseases. More efforts have to be made to prevent spine diseases in the working place by exercises and back training. Our results of medical opinions in 256 cases of occupational spine diseases are presented and analysed.

It is difficult to find medical evidence of a correlation between a lumbar disk disease and trauma. One should consider whether the individual degeneration of lumbar disks or the trauma lead to the typical complaints. Disk disease in the population are very common. Therefore the relevance of the individual affection before trauma has to be considered. Spinal trauma with its sudden, incidental onset needs to be differentiated from purposeful and conscious movements. An intervertebral disk disease can be classified as accident related only in cases involving adequate trauma, with no previous complains, and a sudden onset of pain.

The concentration of extracellular polysaccharides (EPS) of 80 cereal grain samples of the German harvest 1995 was investigated. In addition to this, the total as well as the inherent mycoflora of two winter wheat and two winter rye brands which showed the highest EPS-concentration was detected on maltsalt agar (NaCl 5%). Surface disinfection with 1% NaOCl for the determination of the internal mycoflora caused a significant reduction in number and kind of fungi. However, the mycoflora of all samples was dominated by fungi of the genera Alternaria spp. and Cladosporium spp., Aureobasidium pullulans, Fusarium spp. and Epicoccum purpurascens (in decreasing order) occurred to a minor extent. A possible contamination of the cereal grains with mycotoxins of Alternaria and Cladosporium is discussed.

In the last few years many reports have documented that human pathogenic viruses are transmitted via food and can cause epidemics. Between November 1994 and February 1995 a HAV epidemic was recorded in the village and agricultural area of Euskirchen (Germany). 49 persons with HAV infections were registered. It seems that the epidemic started in a bakery and was caused by an employee who had spent his holidays in the Dominican Republic and came back already excreting the virus via his faeces. Two weeks later he developed a symptomatic illness. HAV is transmitted via a fecal-oral cycle. Lack of hygiene in food production and distribution cause the risk of secondary virus contamination. Virus transmission via food is first of all a problem in uncooked food. To ensure success in food safety in respect of foodborne human pathogenic viruses it is important to establish personal hygienic education, cleaning and disinfection plans and preventive measures such as immunization to avoid viruses in the food.