Integrated decentralized blood culture incubation: A step towards a 24/7 microbiology service?

To have an impact on the mortality of bloodstream infections, microbiological diagnostics of blood cultures (BC) should provide first results within 12 h. Here, we show how a decentralized BC incubation connected to the central BC incubators via a browser-based application significantly reduces turnaround times.

Making acute ischemic stroke thrombi visible in MRI imaging.

Knowledge of thrombus behavior and visualization on MRI in acute ischemic stroke is less than optimal. However, MRI sequences could be enhanced based on the typical T1 and T2 relaxation times of the target tissues, which mainly determine their signal intensities on imaging. We studied the relaxation times of a broad spectrum of clot analogs along with their image characteristics of three sequences analyzed: a T1-weighted turbo inversion-recovery sequence (T1w Turbo IR), a T1-weighted turbo spin echo with fat suppression (T1w TSE SPIR), and a T2-weighted 3D TSE with magnetization refocusing to remove T1 dependence (T2w TSE DRIVE). We compared their imaging behavior with the intensity values of normal brain tissue using the same imaging protocols as for clots. Each histological and biochemical clot component contributed to each of the relaxation times. Overall, histological composition correlated strongly with T1 times, and iron content, specifically, with T2 relaxation time. Using decision trees, fibrin content was selected as the primary biomarker for T1 relaxation times, inducing an increase. Up to four clot subgroups could be defined based on its distinctive T1 relaxation time. Clot signal intensity in the T1 and T2-weighted images varied significantly according to T1 and T2 relaxation times. Moreover, in comparison with normal brain tissue intensity values, T2w DRIVE images depict thrombi according to the principle of the more fibrin, the higher the intensity, and in T1w TSE, the more erythrocytes, the higher the intensity. These findings could facilitate improvements in MRI sequences for clot visualization and indicate that T2w DRIVE and T1w TSE sequences should depict the vast majority of acute ischemic stroke thrombi as more hyperintense than surrounding tissues.

Anaplerotic Therapy Using Triheptanoin in Two Brothers Suffering from Aconitase 2 Deficiency.

Citric acid cycle deficiencies are extremely rare due to their central role in energy metabolism. The ACO2 gene encodes the mitochondrial isoform of aconitase (aconitase 2), the second enzyme of the citric acid cycle. Approximately 100 patients with aconitase 2 deficiency have been reported with a variety of symptoms, including intellectual disability, hypotonia, optic nerve atrophy, cortical atrophy, cerebellar atrophy, and seizures. In this study, a homozygous deletion in the ACO2 gene in two brothers with reduced aconitase 2 activity in fibroblasts has been described with symptoms including truncal hypotonia, optic atrophy, hyperopia, astigmatism, and cerebellar atrophy. In an in vivo trial, triheptanoin was used to bypass the defective aconitase 2 and fill up the citric acid cycle. Motor abilities in both patients improved.

The Potential for Foreign Body Reaction of Implanted Poly-L-Lactic Acid: A Systematic Review.

Poly-L-lactic acid (PLLA) implants have been used for bone fixation for decades. However, upon insertion, they can cause a foreign body reaction (FBR) that may lead to complications. On 15 December 2023, a systematic review was conducted to search for articles on the PubMed, MeSH term, and Scopus databases using the keywords 'PLLA' and 'foreign body reaction'. The articles were reviewed not only for the question of FBR, its severity, and the manifestation of symptoms but also for the type of implant and its location in the body, the species, and the number of individuals included. A total of 71 original articles were identified. Of these, two-thirds reported on in vivo trials, and one-third reported on clinical applications. The overall majority of the reactions were mild in more than half of the investigations. Symptoms of extreme and extensive FBR mainly include osteolysis, ganglion cysts, and swelling. The localization of PLLA implants in bone can often result in osteolysis due to local acidosis. This issue can be mitigated by adding hydroxyapatite. There should be no strong FBR when PLLA is fragmented to 0.5-4 µm by extracorporeal shock wave.

Development and validation of a bioanalytical method for the quantification of methotrexate from serum and capillary blood using volumetric absorptive microsampling (VAMS) and on-line solid phase extraction (SPE) LC-MS.

High-dose methotrexate is part of the polychemotherapy protocols for the treatment of Acute lymphoblastic leukaemia (ALL) with therapeutic drug monitoring (TDM) to adjust leucovorin rescue. An immunoassay is commonly used to analyse serum samples collected via venous blood sampling. However, immunoassays cannot distinguish between the parent drug and its metabolites. Besides, the blood volume required by venous blood sampling is high. Therefore, the aim of this project was to develop a fast, simple, reliable and cost-efficient micro sampling bioanalytical method using capillary blood to minimize the harm of children and to analyse both methotrexate and its metabolites. To achieve this aim, a LC-MS method with on-line solid phase extraction (SPE) for the simultaneous detection of methotrexate and its metabolites from capillary blood using volumetric-absorptive-microsampling (VAMS) technology was developed and fully validated. Besides, the method was also validated and modified for serum samples to compare the results with the immunoassay. A single-quadrupole MS detector was used for detection. Through the use of on-line SPE technology, a lower limit of quantitation of 0.03 µM for MTX and 7-OH-MTX and of 0.05 µM for DAMPA from a 10 µL capillary blood sample was achieved. The accuracy is between 90.0 and 104% and the precision between 4.7 and 12% for methotrexate and its metabolites, respectively. Because of the cross reactivity of the immunoassay a cross-validation was not successful. Besides, a correlation factor of 0.46 for MTX between plasma and whole-blood was found. A fast, simple, reliable and cost-efficient extraction and analysis LC-MS method could be developed and validated, which is applicable in ambulatory and clinical care.

Shock Wave-Activated Silver-Loaded Biopolymer Implant Coating Eliminates Staphylococcus epidermidis on the Surface and in the Surrounding of Implants.

Bacterial biofilms on foreign surfaces are considered a primary cause of implant-related infections, which are challenging to treat. A new implant coating was developed, containing anti-infective silver within a biocompatible polymer carrier substance. In addition to its passive effect on the implant surface, highly concentrated anti-infective silver can be released as needed via the application of high-energy shock waves. This intervention could be applied transcutaneously in a clinical setting without the need for additional surgery. We investigated the inhibition of biofilm formation and the effectiveness of eradication after activation of the coating via shock waves in an in vitro biofilm model using Staphylococcus epidermidis RP62A. This was performed via scanning electron microscopy and quantitative microbiology. Additionally, we examined the cytotoxicity of the new coating on normal human fibroblasts and Saos-2 osteoblast-like cells, depending on the silver concentration. All studies were compared to uncoated titanium surfaces Ti6Al4V and a conventional electroplated silver coating. Cytotoxicity toward normal human fibroblasts and Saos-2 osteoblast-like cells increased with higher silver content but remained tolerable at 6%. Compared to uncoated Ti6Al4V and the electroplated silver coating, the new coating with a silver content of 4% and 6% exhibited a significant reduction in adherent bacteria by a factor of approximately 1000. This was also evident via microscopic examination of the surface morphology of the biofilms. Furthermore, following shock wave activation, no bacteria were detectable on either the implant or in the surrounding fluid after a 24 h period.

On-Demand Release of Anti-Infective Silver from a Novel Implant Coating Using High-Energy Focused Shock Waves.

Implant-related infections are a significant concern in orthopedic surgery. A novel anti-infective implant coating made of bioresorbable polymer with silver nitrate was developed. A controlled release of silver ions into the vicinity of the prosthesis can be triggered on-demand by extracorporeal shock waves to effectively combat all clinically relevant microorganisms. Microscopy techniques were used to examine the effects of shock wave application on coated titanium discs. Cytotoxicity was measured using a fibroblast proliferation assay. The anti-infective effect was assessed by monitoring the growth curves of three bacterial strains and by conventional culture. Microscopic analysis confirmed surface disruption of the coatings, with a complete release of silver in the focus area after shock wave application. Spectrometry detected an increase in silver concentration in the surrounding of the discs that surpassed the minimum inhibitory concentration (MIC) for both S. epidermidis RP62A and E. coli ATCC 25922. The released silver demonstrated an anti-infective effect, significantly inhibiting bacterial growth, especially at 6% and 8% silver concentrations. Cytotoxicity testing showed decreasing fibroblast viability with increasing silver concentration in the coating, with 6% silver maintaining viability above 25%. Compared to a commonly used electroplated silver coating on the market, the new coating demonstrated superior antimicrobial efficacy and lower cytotoxicity.

Analysis of Urinary Glycosaminoglycans to Predict Outcome in COVID-19 and Community-Acquired Pneumonia-A Proof-of-Concept Study.

Although coronavirus disease 2019 (COVID-19) is considered a systemic disease associated with vascular inflammation and eventual destruction of the protective endothelial glycocalyx (eGC), biomarkers of eGC damage are not yet available in the clinic. The most prominent components of eGC are sulphated glycosaminoglycans (sGAGs) attached to core proteoglycans. We hypothesised that the amount of sGAG fragments shed in urine (as a surrogate for systemic eGC damage) would correlate with disease severity and outcome. Total urinary sGAG concentration was measured using an in-house optimised 1,9-dimethylmethylene blue (DMMB) assay, which is highly accurate and insensitive to interferences. The median urinary sGAG concentration was significantly higher in 67 hospitalised patients with COVID-19 compared to 72 hospitalised patients with community-acquired pneumonia (CAP). In both groups, urinary sGAG concentrations predicted a combined endpoint (including intubation and death) with an area under the receiver operator characteristic curve of 0.72 (95% CI 0.55-0.88, p = 0.01) and 0.70 (95% CI 0.57-0.83, p = 0.007), respectively. In conclusion, the inexpensive and easy-to-perform DMMB assay provides a surrogate parameter for eGC damage that may be useful for risk stratification of patients with COVID-19 and CAP.

Assessment of Intestinal Permeability and Inflammation Bio-Markers in Patients with Rheumatoid Arthritis.

Increased intestinal permeability and inflammation, both fueled by dysbiosis, appear to contribute to rheumatoid arthritis (RA) pathogenesis. This single-center pilot study aimed to investigate zonulin, a marker of intestinal permeability, and calprotectin, a marker of intestinal inflammation, measured in serum and fecal samples of RA patients using commercially available kits. We also analyzed plasma lipopolysaccharide (LPS) levels, a marker of intestinal permeability and inflammation. Furthermore, univariate, and multivariate regression analyses were carried out to determine whether or not there were associations of zonulin and calprotectin with LPS, BMI, gender, age, RA-specific parameters, fiber intake, and short-chain fatty acids in the gut. Serum zonulin levels were more likely to be abnormal with a longer disease duration and fecal zonulin levels were inversely associated with age. A strong association between fecal and serum calprotectin and between fecal calprotectin and LPS were found in males, but not in females, independent of other biomarkers, suggesting that fecal calprotectin may be a more specific biomarker than serum calprotectin is of intestinal inflammation in RA. Since this was a proof-of-principle study without a healthy control group, further research is needed to validate fecal and serum zonulin as valid biomarkers of RA in comparison with other promising biomarkers.

Beta-Hydroxybutyrate (BHB), Glucose, Insulin, Octanoate (C8), and Decanoate (C10) Responses to a Medium-Chain Triglyceride (MCT) Oil with and without Glucose: A Single-Center Study in Healthy Adults.

MCTs are increasingly being used to promote ketogenesis by patients on ketogenic diet therapy, but also by people with other conditions and by the general public for the perceived potential benefits. However, consumption of carbohydrates with MCTs and untoward gastrointestinal side effects, especially at higher doses, could decrease the sustainability of the ketogenic response. This single-center study investigated the impact of consuming carbohydrate as glucose with MCT oil compared to MCT alone on the BHB response. The effects of MCT oil versus MCT oil plus glucose on blood glucose, insulin response, levels of C8, C10, BHB, and cognitive function were determined, and side effects were monitored. A significant plasma BHB increase with a peak at 60 min was observed in 19 healthy participants (24.4 ± 3.9 years) after consuming MCT oil alone, and a more delayed but slightly higher peak was observed after consuming MCT oil plus glucose. A significant increase in blood glucose and insulin levels occurred only after MCT oil plus glucose intake. The overall mean plasma levels of C8 and C10 were higher with the intake of MCT oil alone. MCT oil plus glucose consumption showed improved scores for the arithmetic and vocabulary subtests.

Mechanical and microbiological testing concept for activatable anti-infective biopolymer implant coatings.

An anti-infective bilayer implant coating with selectively activatable properties was developed to prevent biofilm formation and to support the treatment of periprosthetic infection as a local adjunct to current treatment concepts. In a first step, Ti6Al4V discs were coated with a permanent layer of Poly(l-lactide) (PLLA) including silver ions. The PLLA could be optionally released by the application of extracorporeal shock waves. In a second step, a resorbable layer of triglyceride (TAG) with incorporated antibiotics was applied. The second layer is designed for resorption within weeks. Prior to approval and clinical application, a comprehensive evaluation process to determine mechanical/physical and microbiological properties is obligate. To date, none of the existing test standards covers both drug-releasing and activatable coatings for orthopedic implants. Therefore, a comprehensive test concept was developed to characterize the new coating in a pilot series. The coatings were homogeneously applied on the Ti6Al4V substrate, resulting in an adhesion strength sufficient for non-articulating surfaces for PLLA. Proof of the extracorporeal shockwave activation of PLLA was demonstrated both mechanically and microbiologically, with a simultaneous increase of biocompatibility compared to standard electroplated silver coating. Wettability was significantly reduced for both layers in comparison to the Ti6Al4V substrate. Thus, potentially inhibiting biofilm formation. Furthermore, the TAG coating promoted cell proliferation and bacterial eradication. In conclusion, the testing concept is applicable for similar biopolymer coating systems. Furthermore, the extracorporeal activation could represent a completely new supportive approach for the treatment of periprosthetic joint infections.

Microvascular and proteomic signatures overlap in COVID-19 and bacterial sepsis: the MICROCODE study.

AIMS: Although coronavirus disease 2019 (COVID-19) and bacterial sepsis are distinct conditions, both are known to trigger endothelial dysfunction with corresponding microcirculatory impairment. The purpose of this study was to compare microvascular injury patterns and proteomic signatures in COVID-19 and bacterial sepsis patients. METHODS AND RESULTS: This multi-center, observational study included 22 hospitalized adult COVID-19 patients, 43 hospitalized bacterial sepsis patients, and 10 healthy controls from 4 hospitals. Microcirculation and glycocalyx dimensions were quantified via intravital sublingual microscopy. Plasma proteins were measured using targeted proteomics (Olink). Coregulation and cluster analysis of plasma proteins was performed using a training-set and confirmed in a test-set. An independent external cohort of 219 COVID-19 patients was used for validation and outcome analysis. Microcirculation and plasma proteome analysis found substantial overlap between COVID-19 and bacterial sepsis. Severity, but not disease entity explained most data variation. Unsupervised correlation analysis identified two main coregulated plasma protein signatures in both diseases that strictly counteract each other. They were associated with microvascular dysfunction and several established markers of clinical severity. The signatures were used to derive new composite biomarkers of microvascular injury that allow to predict 28-day mortality or/and intubation (area under the curve 0.90, p < 0.0001) in COVID-19. CONCLUSION: Our data imply a common biological host response of microvascular injury in both bacterial sepsis and COVID-19. A distinct plasma signature correlates with endothelial health and improved outcomes, while a counteracting response is associated with glycocalyx breakdown and high mortality. Microvascular health biomarkers are powerful predictors of clinical outcomes.

Significantly Reduced Retinol Binding Protein 4 (RBP4) Levels in Critically Ill COVID-19 Patients.

The SARS-CoV-2 virus is the causative agent of the COVID-19 pandemic. The disease causes respiratory failure in some individuals accompanied by marked hyperinflammation. Vitamin A (syn. retinol) can exist in the body in the storage form as retinyl ester, or in the transcriptionally active form as retinoic acid. The main function of retinol binding protein 4 (RBP4), synthesized in the liver, is to transport hydrophobic vitamin A to various tissues. Vitamin A has an important role in the innate and acquired immune system. In particular, it is involved in the repair of lung tissue after infections. In viral respiratory diseases such as influenza pneumonia, vitamin A supplementation has been shown to reduce mortality in animal models. In critically ill COVID-19 patients, a significant decrease in plasma vitamin A levels and an association with increased mortality have been observed. However, there is no evidence on RBP4 in relation to COVID-19. This prospective, multicenter, observational, cross-sectional study examined RBP4 (enzyme-linked immunosorbent assay) and vitamin A plasma levels (high-performance liquid chromatography) in COVID-19 patients, including 59 hospitalized patients. Of these, 19 developed critical illness (ARDS/ECMO), 20 developed severe illness (oxygenation disorder), and 20 developed moderate illness (no oxygenation disorder). Twenty age-matched convalescent patients following SARS-CoV-2 infection, were used as a control group. Reduced RBP4 plasma levels significantly correlated with impaired liver function and elevated inflammatory markers (CRP, lymphocytopenia). RBP4 levels were decreased in hospitalized patients with critical illness compared to nonpatients (p < 0.01). In comparison, significantly lower vitamin A levels were detected in hospitalized patients regardless of disease severity. Overall, we conclude that RBP4 plasma levels are significantly reduced in critically ill COVID-19 patients during acute inflammation, and vitamin A levels are significantly reduced in patients with moderate/severe/critical illness during the acute phase of illness.

Prevalence of autoantibodies in patients with juvenile idiopathic arthritis: results from the German inception cohort ICON-JIA.

BACKGROUND: An association of different autoimmune diseases is suspected. In juvenile idiopathic arthritis (JIA), only few and partially conflicting data on the co-existence of other autoimmune disorders are available. The prevalence of autoantibodies in patients with JIA in Germany is not known. METHODS: Samples from 499 patients (median age at time of blood collection 11 years, median disease duration 4.4 years) in the prospective, multicenter inception cohort of children newly diagnosed with JIA (ICON-JIA) were analysed for the presence of anti-thyroid antibodies, celiac disease-specific antibodies (anti-tTG IgA, anti-tTG IgG), and connective tissue disease-associated antibodies (CTD-screen). RESULTS: A total of 76 (15.2%) patients had either clinically diagnosed autoimmune comorbidity or elevated autoantibodies. Of 21 patients with clinical autoimmune comorbidity, only 8 were also serologically positive at the time of testing, while 55 patients had autoantibodies without clinical diagnosis. Thus, 63 patients (12.6%) had at least one elevated autoantibody. Antibodies against thyroglobulin were found in 3% and against thyreoperoxidase in 4% of the samples. TSH receptor antibodies could not be detected in any of the 499 patients. Tissue transglutaminase antibodies were elevated in 0.4% of the patients. A positive screen for CTD-specific antinuclear antibodies was found in 7%, but only rarely specific antibodies (anti-dsDNA 1.4%, anti-SS-A and -SS-B 0.2% each, anti-CENP-B 0.4%) were confirmed. CONCLUSIONS: In our study, a specific correlation between JIA and other autoimmune phenomena could not be confirmed. The lack of well-matched control groups makes interpretation challenging. Further data need to corroborate the suspected increased risk of developing other autoimmune phenomena in JIA patients.

Impact of disease-modifying therapies on humoral and cellular immune-responses following SARS-CoV-2 vaccination in MS patients.

The impact of distinct disease-modifying therapies (DMTs) on severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination efficacy in patients with multiple sclerosis (MS) is still enigmatic. In this prospective comparative study, we investigated humoral and cellular immune-responses in patients with MS receiving interferon beta, natalizumab, and ocrelizumab pre-vaccination and 6 weeks post second SARS-CoV-2 vaccination. Healthy individuals and interferon beta-treated patients generated robust humoral and cellular immune-responses. Although humoral immune responses were diminished in ocrelizumab-treated patients, cellular immune-responses were reduced in natalizumab-treated patients. Thus, both humoral and cellular immune responses should be closely monitored in patients on DMTs. Whereas patients with a poor cellular immune-response may benefit from additional vaccination cycles, patients with a diminished humoral immune-response may benefit from a treatment with SARS-CoV-2 antibodies in case of an infection.

Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia.

Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p.

Iron Deficiency Caused by Intestinal Iron Loss-Novel Candidate Genes for Severe Anemia.

The adult human body contains about 4 g of iron. About 1-2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient.

Short-Term Influence of Caffeine and Medium-Chain Triglycerides on Ketogenesis: A Controlled Double-Blind Intervention Study.

BACKGROUND: Ketone bodies are a highly relevant topic in nutrition and medicine. The influence of medium-chain triglycerides (MCT) on ketogenesis is well known and has been successfully used in ketogenic diets for many years. Nevertheless, the effects of MCTs and coconut oil on the production of ketone bodies have only partially been investigated. Furthermore, the increased mobilisation of free fatty acids and release of catabolic hormones by caffeine suggest an influence of caffeine on ketogenesis. METHODS: In a controlled, double-blind intervention study, seven young healthy subjects received 10 mL of tricaprylin (C8), tricaprin (C10), C8/C10 (50% C8, 50% C10), or coconut oil with or without 150 mg of caffeine, in 250 mL of decaffeinated coffee, over ten interventions. At baseline and after every 40 minutes, for 4 h, ßHB and glucose in capillary blood as well as caffeine in saliva were measured. Furthermore, questionnaires were used to survey sensory properties, side effects, and awareness of hunger and satiety. RESULTS: The interventions with caffeine caused an increase in ßHB levels-in particular, the interventions with C8 highly impacted ketogenesis. The effect decreased with increased chain lengths. All interventions showed a continuous increase in hunger and diminishing satiety. Mild side effects (total = 12) occurred during the interventions. CONCLUSIONS: The present study demonstrated an influence of caffeine and MCT on ketogenesis. The addition of caffeine showed an additive effect on the ketogenic potential of MCT and coconut oil. C8 showed the highest ketogenicity.

Vitamin A Plasma Levels in COVID-19 Patients: A Prospective Multicenter Study and Hypothesis.

COVID-19 is a pandemic disease that causes severe pulmonary damage and hyperinflammation. Vitamin A is a crucial factor in the development of immune functions and is known to be reduced in cases of acute inflammation. This prospective, multicenter observational cross-sectional study analyzed vitamin A plasma levels in SARS-CoV-2 infected individuals, and 40 hospitalized patients were included. Of these, 22 developed critical disease (Acute Respiratory Distress Syndrome [ARDS]/Extracorporeal membrane oxygenation [ECMO]), 9 developed severe disease (oxygen supplementation), and 9 developed moderate disease (no oxygen supplementation). A total of 47 age-matched convalescent persons that had been earlier infected with SARS-CoV-2 were included as the control group. Vitamin A plasma levels were determined by high-performance liquid chromatography. Reduced vitamin A plasma levels correlated significantly with increased levels of inflammatory markers (CRP, ferritin) and with markers of acute SARS-CoV-2 infection (reduced lymphocyte count, LDH). Vitamin A levels were significantly lower in hospitalized patients than in convalescent persons (p < 0.01). Of the hospitalized patients, those who were critically ill showed significantly lower vitamin A levels than those who were moderately ill (p < 0.05). Vitamin A plasma levels below 0.2 mg/L were significantly associated with the development of ARDS (OR = 5.54 [1.01-30.26]; p = 0.048) and mortality (OR 5.21 [1.06-25.5], p = 0.042). Taken together, we conclude that vitamin A plasma levels in COVID-19 patients are reduced during acute inflammation and that severely reduced plasma levels of vitamin A are significantly associated with ARDS and mortality.

3-Hydroxyisobutyrate dehydrogenase (HIBADH) deficiency-A novel disorder of valine metabolism.

3-Hydroxyisobutyric acid (3HiB) is an intermediate in the degradation of the branched-chain amino acid valine. Disorders in valine degradation can lead to 3HiB accumulation and its excretion in the urine. This article describes the first two patients with a new metabolic disorder, 3-hydroxyisobutyrate dehydrogenase (HIBADH) deficiency, its phenotype and its treatment with a low-valine diet. The detected mutation in the HIBADH gene leads to nonsense-mediated mRNA decay of the mutant allele and to a complete loss-of-function of the enzyme. Under strict adherence to a low-valine diet a rapid decrease of 3HiB excretion in the urine was observed. Due to limited patient numbers and intrafamilial differences in phenotype with one affected and one unaffected individual, the clinical phenotype of HIBADH deficiency needs further evaluation.