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Background: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. Results: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29–13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. Conclusion: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases. [ABSTRACT FROM AUTHOR]

An important focus in discussions of immunity to error through misidentification (IEM) is on what explains putative cases of it, and correspondingly, on what significance its presence should be taken to have. This focus is important for the literature: the interest of the phenomenon naturally depends on why it is supposed to be significant when it arises. This paper looks to the claimed IEM of memory-based judgments as a case study to advocate for a pluralist account of explanations of IEM. I argue that Evans was right that Shoemakerian q-memories fail to undermine the supposed IEM of memory-based first personal judgments, but that he was wrong about why. In fact, cases of q-memory reveal a surprising referential underdetermination in first person thought, which subvenes an underdetermination of the explanation of IEM for memory-based judgments. Given this plurality of explanations active in just a single case study, we should be cautious about claims to IEM having just one source of significance. [ABSTRACT FROM AUTHOR]

Abstract Background Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. Results Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of β-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), β-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29–13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. Conclusion The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

I defend the view that episodic memory judgments do not depend on any kind of identification of oneself as the person whose past is being remembered, and are therefore logically (rather than merely de facto) immune from error through misidentification relative to “I”. There are two challenges to this view that have been pressed in the literature. One appeals to the idea of background presuppositions of identity and says that “I am the person from whom my memory impression derives” is a background presupposition of any memory judgment. The other appeals to wh-misidentification and says there are possible cases in which memory goes astray that should be counted as cases of error through wh-misidentification. Although the details are different, the core thought behind both challenges is the same: Shoemaker’s thought that there could be a memory-like relation that one stands in to another’s past. I think this thought is a mistake. [ABSTRACT FROM AUTHOR]

Classical homocystinuria is an inborn amino acid metabolism disorder resulting from mutations in the Cystathionine-β-Synthase (CBS) gene. These mutations lead to elevated homocysteine and methionine levels and reduced cysteine levels in the blood. Typically, diagnosis occurs after patients display symptoms, and various lab methods confirm it. DNA sequencing is the best option for early detection of genetic variants in asymptomatic suspected individuals. Unfortunately, its high cost can hinder its use, especially in low-income countries like Pakistan. Aim of this study was to devise a robust low-cost diagnostic/screening assay based on Tetra-ARMS-PCR for five prevalent genetic variants found in Pakistani classical homocystinuria patients. In the current study, T-ARMS-PCR assays were developed for five mutations (c.975G > C, c.770C > T, c.752T > C, c.1039 + 1G > T, c.451 + 1GG > TA), which were characterized previously in classical homocystinuria patients. These low-cost T-ARMS-PCR assays were then used to screen the affected individuals and their family members to identify their genotypes for pathogenic variations in the asymptomatic patients and carriers in their respective families. The outcomes were entirely consistent with those obtained from Sanger DNA sequencing, confirming the sensitivity, specificity, and reliability of the T-ARMS-PCR assay for detecting CBS mutations. T-ARMS-PCR has wide applications for low-income countries for the screening and early diagnosis of asymptomatic patients and carriers in the homocystinuria affected families as well as other inherited diseases. [ABSTRACT FROM AUTHOR]

In this paper, the current field modulation is described using a solution of the wave action equation. Using an integrated equation model (IEM), a current field modulated scattering model is established. The sea surface backscattering coefficient decreases with increasing current speed. At high wind speeds, the change of backscattering coefficient under 1 m $ \cdot $ ⋅ s−1 current field modulation is about 1 dB. An increase of 60° in the angle between wind and current direction leads to a decrease of 1.5 dB in the modulation coefficient. Finally, the model is verified using satellite data. [ABSTRACT FROM AUTHOR]

Inborn errors of metabolism (IEMs) are inherited biochemical/metabolic disorders that are commonly present in the immediate neonatal period. The aim of this retrospective study was to determine the incidence and distribution of IEMs in newborn infants delivered in our hospital and to evaluate its outcome. A total of 16 494 (99.9%) newborn infants were screened for IEMs. We found 29 newborn infants diagnosed with IEMs, representing an incidence of 1 per ~569 live births and a cumulative incidence of 176 per 100 000 live births of the IEM-positive newborn infants. We detected 11 different types of IEMs, and the top 6 categories were endocrinopathies followed by carbohydrates disorders, vitamin-responsive disorders, organic acid defects, and ketogenesis and ketolysis defects. This study does reflect upon the importance of educating the general population about the perils of Consanguineous Marriages (CMs) in order to reduce related disorders significantly, especially in families who have a history of IEMs. [ABSTRACT FROM AUTHOR]

Objective To evaluate the knowledge and experiences of healthcare workers in the management of neurometabolic disorders. Methods A cross-sectional study was carried out among the 132 participants of a continued medical education program conducted in the Department of Pediatrics at a tertiary-care teaching hospital. A questionnaire-based feedback form was circulated among the participants, and their responses were analyzed. Results Ninety-three responses were analyzed. The most common pediatric illnesses identified were infections (91%), nutritional (91%), birth-related injuries (44.4%) and metabolic disorders (44.4%). Consanguinity (81.5%) and genetic heterogeneity (42.4%) were recognized as most important causes of neurometabolic disorders. Important steps identified for prevention were prenatal testing (65.6%) and newborn screening at birth (61%); while for improving the diagnosis were routine availability of metabolic investigations (65.3%) and screening at birth (46.6%). Most respondents (58.7%) expressed discomfort in managing a case with inherited metabolic defect due to a lack of knowledge (46.8%) and diagnostic facilities (44.6%). Despite access to testing in the majority, a high cost of testing was noticed for biochemical and genetic investigations. The majority of participants (73%) considered some of the inherited metabolic disorders as treatable. Dietary substitution (89.3%), enzyme replacement (69%), cofactor replacement (53.6%), gene therapy (35.7%) and regular dialysis (16.7%) were considered the treatment options. Conclusion In spite of growing awareness of inherited metabolic disorders, there are still gaps in knowledge among healthcare workers. It is challenging to diagnose and manage these disorders. Cost-reduction of diagnostic tests, routine newborn screening and increased educational activities are key challenges to be addressed. [ABSTRACT FROM AUTHOR]

Background: The incidence of inborn errors of metabolism (IEM) varies across countries and areas. Currently, there are no studies on IEM using newborn screening (NBS) in eastern coastal areas of China. We aimed to estimate the incidence and genetic variants of IEM and understand the spectrum of diseases caused by IEM and variants among them in this area. Methods: The NBS performed by tandem mass spectrometry (MS/MS) from 2016 to 2021 was retrospectively reviewed. Heel blood was collected from all newborns 72 h after birth. Targeted massively parallel sequencing was performed for genetic analysis. Results: Among 245,194 newborns, 95 were diagnosed with IEM, the overall incidence observed was—IEM: 1/2581; amino acid metabolism disorder: 1/4715; organic acid metabolism disorder: 1/11676; and fatty acid metabolism disorder: 1/11145. The incidence of different IEM was in the range of 1/245194 to 1/6452. Phenylketonuria (PKU, 1/7211) was the most common IEM, followed by methylmalonic acidemia (MMA, 1/27244), short‐chain acyl‐CoA dehydrogenase deficiency (SCADD, 1/30649), and citrin deficiency (CD, 1/35028). For genetic variants, the common hotspot variants found were—PAH gene for PKU: c.728G > A, c.442‐1G > A, c.611A > G, c.721C > T; PTS gene for non‐classical PKU: c.259C > T; MMACHC gene for MMA: c.658_660delAAG, c.609G > A; MMUT gene for MMA: c.1663G > A; ACADS gene for SCADD: c.1031A > G and c.1130C > T; and SLC25A13 gene for CD: c.1638_1660dup, c.852_855del. Conclusion: This study displayed the diseases and varied spectrum of IEM in eastern coastal areas of China. Implementing NBS for IEM by MS/MS combined with massively parallel sequencing can offer an improved plan for NBS to detect IEM. [ABSTRACT FROM AUTHOR]

There are about 1500 genetic metabolic diseases. A small number of treatable diseases are diagnosed by newborn screening programs, which are continually being developed. However, most diseases can only be diagnosed based on clinical symptoms or metabolic findings. The main biological fluids used are urine, plasma and, in special situations, cerebrospinal fluid. In contrast to commonly used methods such as gas chromatography and high performance liquid chromatography mass spectrometry, ex vivo proton spectroscopy (1H‐NMR) is not yet used in routine clinical practice, although it has been recommended for more than 30 years. Automatic analysis and improved NMR technology have also expanded the applications used for the diagnosis of inborn errors of metabolism. We provide a mini‐overview of typical applications, especially in urine but also in plasma, used to diagnose common but also rare genetic metabolic diseases with 1H‐NMR. The use of computer‐assisted diagnostic suggestions can facilitate interpretation of the profiles. In a proof of principle, to date, 182 reports of 59 different diseases and 500 reports of healthy children are stored. The percentage of correct automatic diagnoses was 74%. Using the same 1H‐NMR profile‐targeted analysis, it is possible to apply an untargeted approach that distinguishes profile differences from healthy individuals. Thus, additional conditions such as lysosomal storage diseases or drug interferences are detectable. Furthermore, because 1H‐NMR is highly reproducible and can detect a variety of different substance categories, the metabolomic approach is suitable for monitoring patient treatment and revealing additional factors such as nutrition and microbiome metabolism. Besides the progress in analytical techniques, a multiomics approach is most effective to combine metabolomics with, for example, whole exome sequencing, to also diagnose patients with nondetectable metabolic abnormalities in biological fluids. In this mini review we also provide our own data to demonstrate the role of NMR in a multiomics platform in the field of inborn errors of metabolism. [ABSTRACT FROM AUTHOR]

Untargeted metabolomics (UM) is increasingly being deployed as a strategy for screening patients that are suspected of having an inborn error of metabolism (IEM). In this study, we examined the potential of existing outlier detection methods to detect IEM patient profiles. We benchmarked 30 different outlier detection methods when applied to three untargeted metabolomics datasets. Our results show great differences in IEM detection performances across the various methods. The methods DeepSVDD and R-graph performed most consistently across the three metabolomics datasets. For datasets with a more balanced number of samples-to-features ratio, we found that AE reconstruction error, Mahalanobis and PCA reconstruction error also performed well. Furthermore, we demonstrated the importance of a PCA transform prior to applying an outlier detection method since we observed that this increases the performance of several outlier detection methods. For only one of the three metabolomics datasets, we observed clinically satisfying performances for some outlier detection methods, where we were able to detect 90% of the IEM patient samples while detecting no false positives. These results suggest that outlier detection methods have the potential to aid the clinical investigator in routine screening for IEM using untargeted metabolomics data, but also show that further improvements are needed to ensure clinically satisfying performances. [ABSTRACT FROM AUTHOR]

Abstract Background The incidence of inborn errors of metabolism (IEM) varies across countries and areas. Currently, there are no studies on IEM using newborn screening (NBS) in eastern coastal areas of China. We aimed to estimate the incidence and genetic variants of IEM and understand the spectrum of diseases caused by IEM and variants among them in this area. Methods The NBS performed by tandem mass spectrometry (MS/MS) from 2016 to 2021 was retrospectively reviewed. Heel blood was collected from all newborns 72 h after birth. Targeted massively parallel sequencing was performed for genetic analysis. Results Among 245,194 newborns, 95 were diagnosed with IEM, the overall incidence observed was—IEM: 1/2581; amino acid metabolism disorder: 1/4715; organic acid metabolism disorder: 1/11676; and fatty acid metabolism disorder: 1/11145. The incidence of different IEM was in the range of 1/245194 to 1/6452. Phenylketonuria (PKU, 1/7211) was the most common IEM, followed by methylmalonic acidemia (MMA, 1/27244), short‐chain acyl‐CoA dehydrogenase deficiency (SCADD, 1/30649), and citrin deficiency (CD, 1/35028). For genetic variants, the common hotspot variants found were—PAH gene for PKU: c.728G > A, c.442‐1G > A, c.611A > G, c.721C > T; PTS gene for non‐classical PKU: c.259C > T; MMACHC gene for MMA: c.658_660delAAG, c.609G > A; MMUT gene for MMA: c.1663G > A; ACADS gene for SCADD: c.1031A > G and c.1130C > T; and SLC25A13 gene for CD: c.1638_1660dup, c.852_855del. Conclusion This study displayed the diseases and varied spectrum of IEM in eastern coastal areas of China. Implementing NBS for IEM by MS/MS combined with massively parallel sequencing can offer an improved plan for NBS to detect IEM.

The dual polarimetric study including degree of polarization ( m L ) and energy span (λ1+ λ2) for vegetation targets infer the accuracy of vegetation algorithms. The Sentinel − 1 A and ALOS − 2 satellite data were utilized for dual polarimetric radar vegetation index (DPRVI), polarimetric radar vegetation index (PRVI) and radar vegetation index (RVI) computation and simulation of backscattering coefficient (σ0 (dB)) at VV polarization. The DPRVI, PRVI and RVI were computed at VV + VH and HH + HV polarizations, respectively. The simulation of σ0 (dB) at HH + HV can be show better results than VV + VH polarization using derived radar vegetation descriptors (V). The DPRVI, PRVI and RVI showed higher R2 and lower RMSE values at L – band than C - band. The DPRVI at L – band (HH + HV polarization) was indicated highest R2 = 0.91 and lower RMSE = 0.31 (dB) among all proposed V in the algorithm. [ABSTRACT FROM AUTHOR]

[vstplugin~] is a cross-platform Pure Data external for hosting VST 2 and VST 3 plugins that has been developed at the IEM in Graz. The external provides an extensive set of features which span several topics, such as channel layout, plugin search, real-time safety, GUI editor, parameter automation, preset management, MIDI events, transport and timing, bridging and sandboxing, multithreading and offline processing. We show the development process and discuss previous work in this area. We also cover the history of the VST technology, explain the differences between the VST 2 and VST 3 SDK and offer insight into their inner workings. Finally, we discuss possible improvements and extensions for the future.

There is insufficient data about esophageal body dysmotility in patients with refractory gastroesophageal reflux disease (RGERD) who have inadequate response to proton pump inhibitors (PPIs) treatment. This study aimed to assess esophageal motility disorder and reflux parameters among these patients by high-resolution manometry (HRM) and intraluminal impedance and pH (MII‐pH) monitoring after stopping PPI therapy. A retrospective study was conducted among 100 RGERD patients admitted to Taleghani Hospital (Tehran, Iran) during one year. More than half of them were males (55%). The mean age of patients was 47.10 ± 6.92 and 50% of them had ineffective esophageal motility (IEM). Middle, distal, and proximal esophageal pressure (MEP, DEP, and PEP), integrated relaxation pressure (IRP), lower esophageal sphincter (LES) basal pressure (LESP), distal contractile integral (DCI), large breaks, upper esophageal sphincter basal pressure (UESP), and LES length (LESL) in the patients with IEM were significantly lower than the patients with normal esophageal motility (P

Objective: To study the clinicoetiological profile of children presenting with acute noninfectious encephalopathy (NIE) and identify the proportion of children having inborn errors of metabolism (IEM). Method: This descriptive cross sectional study was conducted in a tertiary care centre in Northern India. Consecutive children, aged more than 28 d and less than 12 y, with acute encephalopathy were enrolled after ruling out CNS infection. All children were evaluated on an internally validated structured proforma. A sequential pre-decided battery of tests was applied to determine the cause of encephalopathy. IEM suspects were subjected to TMS/GCMS followed by mutation analysis for confirmation. Results: Fifty children with noninfectious encephalopathy (NIE) were recruited and metabolic causes were detected in 9 of these children (18%), aged 3 to 42 mo, with female preponderance. The IEMs included lactic acidosis (4), glutaric aciduria (3), isovaleric academia (1), and hyperhomocysteinemia (1). History of previously affected siblings and consanguinity between the parents were important indicators of IEM. MS/MS and mutation analysis were the mainstay of diagnosis in these patients. IEMs contributed to the most common cause amongst cases of NIE. Conclusion: IEMs constitute a significant proportion of NIE in India and a high index of suspicion is required to make the diagnosis. [ABSTRACT FROM AUTHOR]

We have developed a fast and accurate method that uses a small volume of sample to determine over 25 of the typically reported amino acids in human plasma. Samples were prepped with a single step using a spin filter to remove proteins, avoiding the decreased sensitivity from dilution in acid precipitation. Using a reverse phase (RP) High Performance Liquid Chromatography (HPLC) system with O-phthaldehyde (OPA) as the pre-column derivatization reagent, and UV detection at 338 nm, we did a direct comparison with the most common ion exchange/ninhydrin method used in clinical labs on the same plasma samples with 95% concurrence, analysis of amino acid standard solutions returned 99% concurrence. With a sample preparation time of 30 min, utilizing less than 25 μl of sample and with a chromatography run of 30 min, this method can substantially increase access to analysis in both clinical and research laboratories using instruments that are more widely available. Synopsis: We describe a rapid and easily deployed method for sensitive amino measurement in biological samples.

Biotin-thiamine-responsive basal ganglia disease is a rare, autosomal recessive, treatable, neurometabolic disorder associated with biallelic pathogenic variations in the SLC19A3 gene. The condition may present as an early-childhood encephalopathy, an early-infantile lethal encephalopathy with lactic acidosis, with or without infantile spasms, or a late-onset Wernicke-like encephalopathy. The key radiological features are bilateral, symmetrical lesions in the caudate, putamen, and medial thalamus, with variable extension into the brain stem, cerebral cortex, and cerebellum. Treatment is life long and includes initiation of high dose biotin and thiamine. Genetic testing confirms the diagnosis. The prognosis depends on the time from diagnosis to the time of vitamin supplementation. The genotype-phenotype correlations are not clear yet, but the early infantile phenotype portends a poorer prognosis. We provide a brief overview of the disorder and emphasize the initiation of high-dose biotin and thiamine in infants and children with unexplained encephalopathy and basal ganglia involvement.

Untargeted metabolomics (UM) is increasingly being deployed as a strategy for screening patients that are suspected of having an inborn error of metabolism (IEM). In this study, we examined the potential of existing outlier detection methods to detect IEM patient profiles. We benchmarked 30 different outlier detection methods when applied to three untargeted metabolomics datasets. Our results show great differences in IEM detection performances across the various methods. The methods DeepSVDD and R-graph performed most consistently across the three metabolomics datasets. For datasets with a more balanced number of samples-to-features ratio, we found that AE reconstruction error, Mahalanobis and PCA reconstruction error also performed well. Furthermore, we demonstrated the importance of a PCA transform prior to applying an outlier detection method since we observed that this increases the performance of several outlier detection methods. For only one of the three metabolomics datasets, we observed clinically satisfying performances for some outlier detection methods, where we were able to detect 90% of the IEM patient samples while detecting no false positives. These results suggest that outlier detection methods have the potential to aid the clinical investigator in routine screening for IEM using untargeted metabolomics data, but also show that further improvements are needed to ensure clinically satisfying performances.

In the last two decades, the introduction of tandem mass spectrometry in clinical laboratories has enabled simultaneous testing of numerous acylcarnitines and amino acids from dried blood spots for detecting many aminoacidopathies, organic acidurias and fatty acid oxidation disorders. The expanded newborn screening was introduced in Slovenia in September 2018. Seventeen metabolic diseases have been added to the pre-existing screening panel for congenital hypothyroidism and phenylketonuria, and the newborn screening program was substantially reorganized and upgraded.

Hemophagocytic lymphocytosis (HLH) is a rare disease caused by inborn errors of immunity (IEI), secondary to infection, lymphoma or autoimmune disorders, but we often overlook the fact that HLH can be secondary to inborn errors of metabolism (IEM). Here, we describe a patient who was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. The diagnosis of glutaric aciduria type IIC, a IEM, was confirmed by whole exome sequencing. The patient was treated with coenzyme Q10 and riboflavin which effectively improved her liver function. During treatment, the patient developed severe anemia and thrombocytopenia. Persistent fever, splenomegaly, cytopenias, increased ferritin, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis in the bone marrow pointed to the diagnosis of HLH; however, the patient eventually died of gastrointestinal bleeding. After other potential causes were ruled out, the patient was diagnosed with glutaric aciduria type IIC complicated by features suggestive of possible HLH. When cytopenias occurs in IEM patients, HLH is a possible complication that cannot be ignored. This case suggests a possible relationship between IEM and risk for immune dysregulation.

Introduction: Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of acid β-glucosidase encoded by the GBA gene. In patients with GD, childhood onset parkinsonian features have been rarely described.Methods: Twin siblings with GD are described, including clinical follow-up and treatment response. Bone marrow, enzyme activity studies and genotyping were performed.Results: By age 9 months, symptoms at onset were thrombocytopenia and splenomegaly. By age 2, hypokinesia, bradykinesia and oculomotor apraxia were observed. By age 5 a complete rigid hypokinetic syndrome was stablished in both patients, including bradykinesia, tremor and rigidity. Treatment with imiglucerase, miglustat, ambroxol and levodopa were performed. Levodopa showed a good response with improvement in motor and non-motor skills. Foamy cells were found in the bone marrow study. Glucocerebrosidase activity was 28% and 26%. Sanger sequencing analysis identified a missense mutation and a complex allele (NP_000148: p.[(Asp448His)]; [(Leu422Profs*4)]) in compound heterozygosity in GBA gene.Conclusions: Two siblings with neuronopathic GD with an intermediate form between type 2 and 3, with a systemic and neurological phenotype are described. The complex neurological picture included a hypokinetic-rigid and tremor syndrome that improved with levodopa treatment. These conditions together have not been previously described in pediatric GD. We suggest that in children with parkinsonian features, lysosomal storage disorders must be considered, and a levodopa trial must be performed. Moreover, this report give support to the finding that GBA and parkinsonian features share biological pathways and highlight the importance of lysosomal mechanisms in parkinsonism pathogenesis, what might have therapeutic implications. [ABSTRACT FROM AUTHOR]

Introduction: Ineffective esophageal motility (IEM) is a physiologic diagnosis and is a component of the Chicago Classification. It has a strong association with gastroesophageal reflux and may be found during work-up for anti-reflux surgery. IEM implies a higher risk of post-op dysphagia if a total fundoplication is done. We hypothesized that IEM is not predictive of dysphagia following fundoplication and that it is safe to perform total fundoplication in appropriately selected patients. Methods: Retrospective chart review of patients who underwent total fundoplication between September 2012 and December 2018 in a single foregut surgery center and who had IEM on preoperative manometry. We excluded patients who had partial fundoplication, previous foregut surgery, other causes of dysphagia or an esophageal lengthening procedure. Dysphagia was assessed using standardized Dakkak score ≤ 40 and GERD-HRQL question 7 ≥ 3. Results: Two hundred patients were diagnosed with IEM and 31 met the inclusion criteria. Median follow-up: 706 days (IQR 278–1348 days). No preoperative factors, including subjective dysphagia, transit on barium swallow, or individual components of manometry showed statistical correlation with postoperative dysphagia. Of 9 patients with preoperative dysphagia, 2 (22%) had persistent postoperative dysphagia and 7 had resolution. Of 22 patients without preoperative dysphagia, 3 (14%) developed postoperative dysphagia; for a combined rate of 16%. No patient needed re-intervention beyond early recovery or required reoperation for dysphagia during the follow-up period. Conclusion: In appropriately selected patients, when total fundoplication is performed in the presence of preoperative IEM, the rate of long-term postoperative dysphagia is similar to the reported rate of dysphagia without IEM. With appropriate patient selection, total fundoplication may be performed in patients with IEM without a disproportionate increase in postoperative dysphagia. The presence of preoperative IEM should not be rigidly applied as a contraindication to a total fundoplication. [ABSTRACT FROM AUTHOR]

Inborn errors of metabolism (IEM), otherwise known as inherited metabolic disorders (IMD), are individually rare, but collectively common. IEM pose a challenge to diagnosis, as neonates present with nonspecific signs. A high index of suspicion is essential. Knowledge on clinical presentation may be life saving, especially for conditions that are treatable. It is important for the first-line physicians not to miss treatable disorders. Simplified classification and algorithmic approach help in the clinical setting. This article describes the classification of IEM into three groups, namely group 1 - intoxication disorders, group 2 - energy defects, and group 3 - storage disorders. Clinical presentations of IEM in the neonatal period, a quick guide to the diagnosis with the help of baseline investigations (glucose, arterial blood gas, lactate, ammonia, and ketone abbreviated as GALAK), a tabulated guide to the diagnosis with the help of tandem mass spectrometry (TMS), and gas chromatography and mass spectrometry (GCMS) are summarized in this article. Four principles of therapy that include substrate reduction, provision of deficient metabolites, disposal of toxic metabolites, and increase in enzyme activity are elaborated with particular stress to the diet management. In addition, a list of medications used in the treatment of different disorders classified according to Society for the Study of IEM (SSIEM) is presented. [ABSTRACT FROM AUTHOR]

[vstplugin~] is a cross-platform Pure Data external for hosting VST 2 and VST 3 plugins that has been developed at the IEM in Graz. The external provides an extensive set of features which span several topics, such as channel layout, plugin search, real-time safety, GUI editor, parameter automation, preset management, MIDI events, transport and timing, bridging and sandboxing, multithreading and offline processing. We show the development process and discuss previous work in this area. We also cover the history of the VST technology, explain the differences between the VST 2 and VST 3 SDK and offer insight into their inner workings. Finally, we discuss possible improvements and extensions for the future. [ABSTRACT FROM AUTHOR]

Summary: Cation exchange membranes need to have high permselectivity for protons to make these membranes suitable for, for example, energy storage devices. Here, we present the proof of concept for a proton selective membrane made of hydrochloric acid‐doped ice. The proton selectivity of this acid‐doped ice membrane is the result of defects in the ice structure, caused by the acid. Ice membranes were made from different hydrochloric acid concentrations (0.1‐2.0 M). The proton permselectivity of all ice membranes was above 99.7% when both Na+ and K+ were present. The resistivity decreased exponentially with the concentration of acid in the ice membrane, reaching a value of 12 Ω.cm. The ice membranes were tested in an electrochemical cell using the Fe/Fe2+ and Fe2+/Fe3+ redox couples, and a power density of 7 W/m2 and OCV of 0.87 V were measured. The resistance of the ice membrane increased with time as protons moved from the ice structure, as determined from the higher pH of the ice after melting. These expelled protons (and corresponding counter charged ions) were not replaced by other mobile cations, indicating a permanent loss in conductivity, but not selectivity. To apply the ice membrane as a selective separator for protons in energy storage devices in the future, the membrane thickness should be reduced and the protons should be retained inside the ice. [ABSTRACT FROM AUTHOR]

Biotin-thiamine-responsive basal ganglia disease is a rare, autosomal recessive, treatable, neurometabolic disorder associated with biallelic pathogenic variations in the SLC19A3 gene. The condition may present as an early-childhood encephalopathy, an early-infantile lethal encephalopathy with lactic acidosis, with or without infantile spasms, or a late-onset Wernicke-like encephalopathy. The key radiological features are bilateral, symmetrical lesions in the caudate, putamen, and medial thalamus, with variable extension into the brain stem, cerebral cortex, and cerebellum. Treatment is life long and includes initiation of high dose biotin and thiamine. Genetic testing confirms the diagnosis. The prognosis depends on the time from diagnosis to the time of vitamin supplementation. The genotype-phenotype correlations are not clear yet, but the early infantile phenotype portends a poorer prognosis. We provide a brief overview of the disorder and emphasize the initiation of high-dose biotin and thiamine in infants and children with unexplained encephalopathy and basal ganglia involvement. [ABSTRACT FROM AUTHOR]

Spencer E Thomas,1,2,* Jeffrey Comer,1,* Min Jung Kim,1 Shanna Marroquin,1 Vaibhav Murthy,1 Meghana Ramani,1 Tabetha Gaile Hopke,2 Jayden McCall,1 Seong-O Choi,1 Robert K DeLong1 1Nanotechnology Innovation Center of Kansas State, Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA; 2Department of Biomedical Science, Missouri State University, Springfield, MO, USA *These authors contributed equally to this work Introduction: Biomedical applications of nanoparticles (NPs) as enzyme inhibitors have recently come to light. Oxides of metals native to the physiological environment (eg, Fe, Zn, Mg, etc.) are of particular interest—especially the functional consequences of their enzyme interaction. Materials and methods: Here, Fe2O3, zinc oxide (ZnO), magnesium oxide (MgO) and nickel oxide (NiO) NPs are compared to copper (Cu) and boron carbide (B4C) NPs. The functional impact of NP interaction to the model enzyme luciferase is determined by 2-dimensional fluorescence difference spectroscopy (2-D FDS) and 2-dimensional photoluminescence difference spectroscopy (2-D PLDS). By 2-D FDS analysis, the change in maximal intensity and in 2-D FDS area under the curve (AUC) is in the order Cu~B4C>ZnO>NiO>>Fe2O3>MgO. The induced changes in protein conformation are confirmed by tryptic digests and gel electrophoresis. Results: Analysis of possible trypsin cleavage sites suggest that cleavage mostly occurs in the range of residues 112–155 and 372–439, giving a major 45 kDa band. By 2-D PLDS, it is found that B4C NPs completely ablate bioluminescence, while Cu and Fe2O3 NPs yield a unique bimodal negative decay rate, -7.67×103 and -3.50×101 relative light units respectively. Cu NPs, in particular, give a remarkable 271% change in enzyme activity. Molecular dynamics simulations in water predicted that the surfaces of metal oxide NPs become capped with metal hydroxide groups under physiological conditions, while the surface of B4C becomes populated with boronic acid or borinic acid groups. These predictions are supported by the experimentally determined zeta potential. Thin layer chromatography patterns further support this conception of the NP surfaces, where stabilizing interactions were in the order ionic>polar>non-polar for the series tested. Conclusion: Overall the results suggest that B4C and Cu NP functional dynamics on enzyme biochemistry are unique and should be examined further for potential ramifications on other model, physiological or disease-relevant enzymes. Keywords: 2-dimensional fluorescence difference, 2-D FDS, AUC, corrected light intensity emitted, emission wavelength, excitation wavelength, wavelength of max intensity, RLU

In countries characterized by arid and semi-arid climates, a precise determination of soil moisture conditions on the field scale is critically important, especially in the first crop growth stages, to schedule irrigation and to avoid wasting water. The objective of this study was to apply the operative methodology that allowed surface soil moisture (SSM) content in a semi-arid environment to be estimated. SSM retrieval was carried out by combining two scattering models (IEM and WCM), supplied by backscattering coefficients at the VV polarization obtained from the C-band Synthetic Aperture Radar (SAR), a vegetation descriptor NDVI obtained from the optical sensor, among other essential parameters. The inversion of these models was performed by Neural Networks (NN). The combined models were calibrated by the Sentinel 1 and Sentinel 2 data collected on bare soil, and in cereal, pea and onion crop fields. To retrieve SSM, these scattering models need accurate measurements of the roughness surface parameters, standard deviation of the surface height (hrms) and correlation length (L). This work used a photogrammetric acquisition system carried on Unmanned Aerial Vehicles (UAV) to reconstruct digital surface models (DSM), which allowed these soil roughness parameters to be acquired in a large portion of the studied fields. The obtained results showed that the applied improved methodology effectively estimated SSM on bare and cultivated soils in the principal early growth stages. The bare soil experimentation yielded an R2 = 0.74 between the estimated and observed SSMs. For the cereal field, the relation between the estimated and measured SSMs yielded R2 = 0.71. In the experimental pea fields, the relation between the estimated and measured SSMs revealed R2 = 0.72 and 0.78, respectively, for peas 1 and peas 2. For the onion experimentation, the highest R2 equaled 0.5 in the principal growth stage (leaf development), but the crop R2 drastically decreased to 0.08 in the completed growth phase. The acquired results showed that the applied improved methodology proves to be an effective tool for estimating the SSM on bare and cultivated soils in the principal early growth stages.

Background: Outcomes for severe hyperammonemia treated with renal replacement therapy (RRT) reported in the literature vary widely. This has created differing recommendations regarding when RRT is beneficial for hyperammonemic patients. Methods: To evaluate our institution's experience with RRT in pediatric patients with inborn errors of metabolism (IEMs) and potential prognostic indicators of a better or worse outcome, we performed a retrospective chart review of patients who received RRT for hyperammonemia. Our cohort included 19 patients with confirmed IEMs who received RRT between 2000 and 2017. Descriptive statistics are presented as medians with interquartile ranges with appropriate statistical testing assuming unequal variance. Results: There were 16 males (84%) and 3 females (16%) identified for inclusion in this study. There were 9 survivors (47%) and 10 non-survivors (53%). The average age of survivors was 67 months (age range from 3 days to 15.6 years). The average age of non-survivors was 1.8 months (age range from 2 days to 18.7 months). Peak ammonia, ammonia on admission, and at RRT initiation were higher in non-survivors compared with survivors. Higher ammonia levels and no change in ammonia between admission and RRT initiation were associated with an increased risk of mortality. Conclusions: Hyperammonemia affects two distinct patient populations; neonates with markedly elevated ammonia levels on presentation and older children who often have established IEM diagnoses and require RRT after failing nitrogen-scavenging therapy. Our experience demonstrates no significant change in mortality associated with neonatal hyperammonemia, which remains high despite improvements in RRT and intensive care. [ABSTRACT FROM AUTHOR]

(AAV)-mediated episomal gene replacement therapy for monogenic liver disorders is currently limited in pediatric settings due to the loss of vector DNA, associated with hepatocyte duplication during liver growth. Genome editing is a promising strategy leading to a permanent and specific genome modification that is transmitted to daughter cells upon proliferation. Using genome targeting, we previously rescued neonatal lethality in mice with Crigler-Najjar syndrome. This rare monogenic disease is characterized by severe neonatal unconjugated hyperbilirubinemia, neurological damage, and death. Here, using the CRISPR- Staphylococcus aureus Cas9 ( Sa Cas9) platform, we edited the disease-causing mutation present in the Ugt1a locus of these mice. Newborn mice were treated with two AAV8 vectors: one expressing the Sa Cas9 and single guide RNA, and the other carrying the Ugt1a homology regions with the corrected sequence, while maintained in a temporary phototherapy setting rescuing mortality. We observed a 50% plasma bilirubin reduction that remained stable for up to 6 months. We then tested different Cas9:donor vector ratios, with a 1:5 ratio showing the greatest efficacy in lowering plasma bilirubin, with partial lethality rescue when more severe, lethal conditions were applied. In conclusion, we reduced plasma bilirubin to safe levels and partially rescued neonatal lethality by correcting the mutant Ugt1a1 gene of a Crigler-Najjar mouse model., Competing Interests: G.B. and A.F.M. are inventors of patents describing liver gene transfer approaches for metabolic diseases and/or treatment of hyperbilirubinemia. The remaining authors declare no competing interests., (© 2023 The Author(s).)

The purpose of this study is to estimate the surface roughness (rms) using TerraSar-X data in HH polarization. Simulation of data is carried out at a wide range of moisture and roughness using the Integral Equation Model (IEM). The inversion method is based on Multi-Layer Perceptron neural network. Inversion technique is performed in two steps. In the first step, the neural network is trained using synthetic data. The inputs of the first neural network are the backscattering coefficient and incidence angle, and the moisture is the output. In the next step, three neural networks are built based on a prior and without prior information on roughness. The inputs of three neural network are backscattering coefficient, estimated moisture in the first step and incidence angle and the roughness is output. The validation of the proposed methods is carried out based on synthetic and real data. Ground roughness measurements are extracted from Digital Terrain Model (DTM) using the fractal method. The accuracy of moisture from synthetic data is 6.1 vol% without prior information on moisture and roughness. The roughness (rms) accuracy of synthetic datasets is 0. 61 cm without prior information and is 0.31 cm and 0.38 cm for rms lower than 2 cm and rms between 2 and 4 cm, with prior information on roughness. The result's analysis of the simulated data showed that the prior information on roughness strongly improves the accuracy of roughness and moisture estimates. The accuracy of rms estimates for the TerraSar-X image in the HH polarization is about 0.9 cm in the case of no prior information on roughness. The accuracy improves to 0.57 cm for rms lower than 2 cm and 0.54 cm for rms between 2 and 4 cm with prior information on roughness. An overestimation of rms for rms lower than 2 cm and an underestimation of rms for rms higher than 2 cm are observed. The results of the accuracy of the synthetic and real data showed that the X band in HH polarization has a very good potential to estimate the soil roughness. [ABSTRACT FROM AUTHOR]

Introduction: Ineffective esophageal motility (IEM) is the most commonly diagnosed abnormality on high-resolution manometry (HRM). However, the clinical significance of IEM and associated reflux burden remains unclear.Aim: Our primary aim was to compare reflux patterns between IEM versus normal motility on HRM.Methods: HRM and reflux studies in patients with IEM and normal motility were retrospectively reviewed. Esophageal pressure topography parameters, reflux variables, and patient-reported outcome questionnaires were explored.Results: A total of 239 patients with IEM were explored. Of these, 146 underwent reflux monitoring. Additionally, 100 patients with normal HRM all of whom had undergone reflux monitoring were included. IEM patients were more likely to have an abnormal number of reflux events compared to normal (22.7% vs. 9.0%, p < 0.01). Including only off-proton pump inhibitor (PPI) testing, IEM patients had higher mean total acid exposure time (AET) and total reflux events compared to normal motility (p = 0.02). Within IEM patients, higher AET modestly correlated with increased percentage of impaired swallows. Increased reflux events modestly correlated with higher impaired swallows and decreased lower esophageal sphincter (LES) resting pressure. Reflux burden increased with higher esophagogastric junction (EGJ) subtype, driven mostly by subtype III, although there was no difference in the distribution of EGJ subtypes between the IEM and normal HRM cohorts.Conclusions: Patients with HRM diagnosis of IEM may be more prone to acid reflux while off-PPI and non-acid reflux while on-PPI. Reflux burden appears to be worse in IEM patients who have lower resting LES pressure, higher EGJ subtype, or higher percentage of impaired swallows. [ABSTRACT FROM AUTHOR]

For inborn errors of metabolism (IEM), metabolomics is performed for three main purposes: 1) development of next generation metabolic screening platforms, 2) identification of new biomarkers in predefined patient cohorts and 3) for identification of new IEM. To date, plasma, urine and dried blood spots are used. We anticipate that cerebrospinal fluid (CSF) holds additional – valuable – information, especially for IEM with neurological involvement. To expand metabolomics to CSF, we here tested whether direct-infusion high-resolution mass spectrometry (DI-HRMS) based non-quantitative metabolomics could correctly capture the biochemical profile of patients with an IEM in CSF. Eleven patient samples, harboring eight different IEM, and thirty control samples were analyzed using DI-HRMS. First we assessed whether the biochemical profile of the control samples represented the expected profile in CSF. Next, each patient sample was assigned a 'most probable diagnosis' by an investigator blinded for the known diagnoses of the patients. the biochemical profile identified using DI-HRMS in CSF samples resembled the known profile, with – among others – the highest median intensities for mass peaks annotated with glucose, lactic acid, citric acid and glutamine. Subsequent analysis of patient CSF profiles resulted in correct 'most probable diagnoses' for all eleven patients, including non-ketotic hyperglycinaemia, propionic aciduria, purine nucleoside phosphorylase deficiency, argininosuccinic aciduria, tyrosinaemia type I, hyperphenylalaninemia and hypermethioninaemia. We here demonstrate that DI-HRMS based non-quantitative metabolomics accurately captures the biochemical profile of this set of patients in CSF, opening new ways for using metabolomics in CSF in the metabolic diagnostic laboratory. Unlabelled Image [ABSTRACT FROM AUTHOR]

Introduction: Introduction: Inborn errors of metabolism (IEM) represent a small, yet unknown, fraction of idiopathic causes of persistent pulmonary hypertension of the newborn (PPHN). The treatment of a neonate presenting with PPHN follows a well-described pattern until standard medical therapies do not improve the patient's condition. Once these therapies are exhausted, and pulmonary hypertension, as well as acidosis, persists, the search for a more unlikely etiology of PPHN is undertaken. Extracorporeal membrane oxygenation (ECMO) allows for the treatment of PPHN and respiratory acidosis while allowing time for diagnosis and treatment of the IEM. Case Presentation: This is the case of a term Hispanic female exhibiting symptoms consistent with PPHN. After initial stabilization with CPAP, antibiotics and inhaled nitric oxide, she deteriorated, requiring intubation. Serial echocardiograms demonstrated worsening pulmonary hypertension along with hemodynamic instability and severe acidosis. Given the failure to respond to maximal medical therapy, she was placed on venovenous ECMO. Despite achieving hemodynamic stability on ECMO, the acidosis persisted leading to exploration of a metabolic cause. A thorough evaluation revealed a diagnosis of methylmalonic acidemia, an inborn error of metabolism. Treatment was started with levocarnitine, hydroxocobalamin, and cessation of proteins. Once treatment was initiated, the patient's metabolic acidosis resolved rapidly, and she was weaned from ECMO support twenty-four hours after initiation. Ultimate diagnosis after genetic testing was cobalamin-C methylmalonic acidemia (Cbl-C) and homocystinuria. Discussion: There is evidence that IEM's like Cbl-C represent a subset of idiopathic causes of PPHN, and early diagnosis is crucial to prevent rapid, progressive deterioration. Recognition of an association between IEM, pulmonary hypertension, and the need for ECMO support would lead to a search for underlying IEM and aggressive treatment. [ABSTRACT FROM AUTHOR]

Biochemical testing serves as a first indication of the general metabolic routes that the alterations can be involved in. The objective was to screen for aromatic and branched chain amino acids disorder in symptomatic children. This cross sectional study included 520 symptomatic children from infants to 15 years of age over a period of 3 years. Routine biochemical tests included for aromatic and branched chain amino acids along with TLC and HPLC of urine and plasma samples. Out of 520 symptomatic cases, 150 (28.8%) had inherited metabolic disorders. Among the cases positive for metabolic disorders, thirty six (36/150, 24%) suffered from aminoacidopathies with overall frequency of 6.92% (36/520). Preponderance of males (60%) was more as compared to females (40%). Significant family history (consanguinity and sibling deaths) was present (36.7%). The most common presentation was lethargy followed by recurrent vomiting, developmental delay and convulsion. Prevalence of aromatic and branched aminoacidopathies was more in females than males (80% versus 20%), of which 30% children were from consanguineous marriages. This study will help to emphasize on routine screening in neonates and children at initial age for detection of various IEM, since they are not only economic but also reliable in countries with high birth rate. Awareness should be increased in developing countries by including them in their health policies. This will help in early initiation of rehabilitation and management which can reduce frequent hospitalization of patients later in their life. [ABSTRACT FROM AUTHOR]

Adenylosuccinate lyase deficiency is a rare inherited disorder of purine metabolism causing severe neurological impairment ranging from early-onset neonatal epileptic encephalopathy to progressive psychomotor retardation and autism in later life. Diagnostic workup involves the measurement of toxic succinyl purines in body fluids and gene sequencing. The authors describe a 13-mo-old girl with compound heterozygous variants in the ADSL gene, presenting as early-onset seizures, severe neurological impairment, development delay, and hypotonia. Neuroimaging revealed cerebral atrophy, delayed myelination and diffusion restriction in bilateral basal ganglia, thalamus and periventricular white matter. The present case highlights ADSL deficiency as a rare cause of metabolic epilepsy that needs timely recognition and prevention of unnecessary investigations. [ABSTRACT FROM AUTHOR]

Background: In 2012, the first Nigerian Hepatitis B Virus (HBV) immune escape mutant (IEM) case was detected in a pregnant woman in southwestern Nigeria. Consequently, this study was designed to investigate the presence and possible circulation of IEMs amongst asymptomatic community dwellers in southwestern Nigeria. Methods: Blood specimens collected from 438 asymptomatic community dwellers were screened for HBsAg using ELISA technique. Subsequently, the S-gene was amplified in HBsAg positive samples by a nested PCR protocol, and amplicons sequenced. Isolates were then subtyped by amino acid residues at positions 122, 127, 134 and 160, and genotyped by phylogenetic analysis. Results: Of the 31 (7.08%) samples positive for HBsAg, the ∼408 bp Sgene fragment was successfully amplified and sequenced in 27. Samples obtained from 4 patients could not be amplified due to low titres. Sequence data from only 15 of the isolates could be analysed further as eight of the remaining 12 had multiple peaks while the rest three showed no similarity to any HBV gene when subjected to BLAST analysis. Thirteen of the 15 isolates were identified as genotype E. Eleven of which were subtyped as ayw4 while the remaining two could not be subtyped due to sR122Q/P substitutions. The last two isolates that could not be genotyped and subtyped had other mutations in the “a” determinant associated with IEMs. Conclusions: This study confirmed presence and circulation of HBV IEM in Nigeria, the country's inclusion in the genotype E crescent, and the value of phylogenetic analysis in HBV identification.

This study aimed to analyze existing microwave surface (Oh, Dubois, Water Cloud Model “WCM”, Integral Equation Model “IEM”) and canopy (Water Cloud Model “WCM”, Single Scattering Radiative Transfer “SSRT”) Radiative Transfer (RT) models and assess advantages and disadvantages of different model combinations in terms of VV polarized radar backscatter simulation of wheat fields. The models are driven with field measurements acquired in 2017 at a test site near Munich, Germany. As vegetation descriptor for the canopy models Leaf Area Index (LAI) was used. The effect of empirical model parameters is evaluated in two different ways: (a) empirical model parameters are set as static throughout the whole time series of one growing season and (b) empirical model parameters describing the backscatter attenuation by the canopy are treated as non-static in time. The model results are compared to a dense Sentinel-1 C-band time series with observations every 1.5 days. The utilized Sentinel-1 time series comprises images acquired with different satellite acquisition geometries (different incidence and azimuth angles), which allows us to evaluate the model performance for different acquisition geometries. Results show that total LAI as vegetation descriptor in combination with static empirical parameters fit Sentinel-1 radar backscatter of wheat fields only sufficient within the first half of the vegetation period. With the saturation of LAI and/or canopy height of the wheat fields, the observed increase in Sentinel-1 radar backscatter cannot be modeled. Probable cause are effects of changes within the grains (both structure and water content per leaf area) and their influence on the backscatter. However, model results with LAI and non-static empirical parameters fit the Sentinel-1 data well for the entire vegetation period. Limitations regarding different satellite acquisition geometries become apparent for the second half of the vegetation period. The observed overall increase in backscatter can be modeled, but a trend mismatch between modeled and observed backscatter values of adjacent time points with different acquisition geometries is observed.

Untargeted metabolomics may become a standard approach to address diagnostic requests, but, at present, data interpretation is very labor-intensive. To facilitate its implementation in metabolic diagnostic screening, we developed a method for automated data interpretation that preselects the most likely inborn errors of metabolism (IEM). The input parameters of the knowledge-based algorithm were (1) weight scores assigned to 268 unique metabolites for 119 different IEM based on literature and expert opinion, and (2) metabolite Z-scores and ranks based on direct-infusion high resolution mass spectrometry. The output was a ranked list of differential diagnoses (DD) per sample. The algorithm was first optimized using a training set of 110 dried blood spots (DBS) comprising 23 different IEM and 86 plasma samples comprising 21 different IEM. Further optimization was performed using a set of 96 DBS consisting of 53 different IEM. The diagnostic value was validated in a set of 115 plasma samples, which included 58 different IEM and resulted in the correct diagnosis being included in the DD of 72% of the samples, comprising 44 different IEM. The median length of the DD was 10 IEM, and the correct diagnosis ranked first in 37% of the samples. Here, we demonstrate the accuracy of the diagnostic algorithm in preselecting the most likely IEM, based on the untargeted metabolomics of a single sample. We show, as a proof of principle, that automated data interpretation has the potential to facilitate the implementation of untargeted metabolomics for metabolic diagnostic screening, and we provide suggestions for further optimization of the algorithm to improve diagnostic accuracy.