Increased erythroferrone levels in malarial anaemia.

We assessed the diagnostic potential of erythroferrone as a biomarker for iron homeostasis comparing iron deficiency cases with anaemia of inflammation and controls. The dysregulation of the hepcidin axis was observed by Latour et al. in a mouse model of malarial anaemia induced by prolonged Plasmodium infection leading to increased erythroferrone concentrations. In line with that, we found significantly higher erythroferrone levels in cases with malaria and anaemia in an African population, compared to asymptomatic controls. Therefore, our findings extend the previous ones of the mouse model, suggesting also a dysregulation of the hepcidin axis in humans, which should be further corroborated in prospective studies and may lay the basis for the development of improved treatment strategies according to ERFE concentrations in such patients.

Therapy-Associated Saliva and Taste change Evaluation (TASTE) in head & neck cancer patients undergoing radiotherapy: a study protocol.

BACKGROUND: One of the main side effects of radiation therapy to the head and neck region is altered taste sensation. This causes significant morbidity and has profound effects on the quality of life (QoL) of patients. While radiation-associated toxicities like xerostomia and dysphagia are part of large investigations, data on taste impairment is sparse. Small cohort sizes in the majority of studies and a variety of analysis methods limit our current understanding of the underlying processes. None of the studies published to date used a taste-specific QoL questionnaire with differentiation of the different taste qualities (e.g. sour, bitter). Furthermore, data regarding the correlation of taste impairment with radiation-associated change in saliva composition is currently not available. The aim of the TASTE study is to fill this gap. Based on the acquired data, a normal tissue complication probability (NTCP) model for late radiation-associated taste impairment will be developed. METHODS: In this prospective, observational multicenter study 150 head and neck cancer patients undergoing radiation therapy will be recruited and undergo repetitive (semi-) objective and subjective assessment of their taste, smell and salivary function (questionnaires, taste and smell assessment, saliva analysis). Primary endpoint will be patient-reported taste impairment 12 months post radiation therapy using a standardized questionnaire. Secondary endpoints will include taste impairment measured using taste strips at 12 months and 2 years post radiation therapy. Differences between subgroups (radiation side, chemotherapy, etc.) and changes over time will be assessed while adjusting for confounding factors (e.g. age, sex, smoking history). DISCUSSION: This study sets out to further our understanding of taste impairment in patients undergoing radiation therapy to the head and neck region with the goal to prevent this common side effect in future patients. The results of the study may be used to evaluate taste-preserving radiotherapy for patients with head and neck cancer, which may significantly reduce the long-term burden in this patient cohort.

Exploring the host factors affecting asymptomatic Plasmodium falciparum infection: insights from a rural Burkina Faso study.

BACKGROUND: Asymptomatic Plasmodium falciparum parasitaemia forms a reservoir for the transmission of malaria disease in West Africa. Certain haemoglobin variants are known to protect against severe malaria infection. However, data on the potential roles of haemoglobin variants and nongenetic factors in asymptomatic malaria infection is scarce and controversial. Therefore, this study investigated the associations of iron homeostasis, inflammation, nutrition, and haemoglobin mutations with parasitaemia in an asymptomatic cohort from a P. falciparum-endemic region during the high transmission season. METHODS: A sub-study population of 688 asymptomatic individuals (predominantly children and adolescents under 15 years, n = 516) from rural Burkina Faso previously recruited by the NOVAC trial (NCT03176719) between June and October 2017 was analysed. Parasitaemia was quantified with conventional haemocytometry. The haemoglobin genotype was determined by reverse hybridization assays targeting a selection of 21 HBA and 22 HBB mutations. Demographics, inflammatory markers (interleukins 6 and 10, hepcidin), nutritional status (mid upper-arm circumference and body mass index), and anaemia (total haemoglobin, ferritin, soluble transferrin receptor) were assessed as potential predictors through logistic regression. RESULTS: Malaria parasites were detected in 56% of subjects. Parasitaemia was associated most strongly with malnutrition. The effect size increased with malnutrition severity (OR = 6.26, CI95: 2.45-19.4, p < 0.001). Furthermore, statistically significant associations (p < 0.05) with age, cytokines, hepcidin and heterozygous haemoglobin S were observed. CONCLUSIONS: According to these findings, asymptomatic parasitaemia is attenuated by haemoglobin S, but not by any of the other detected genotypes. Aside from evidence for slight iron imbalance, overall undernutrition was found to predict parasitaemia; thus, further investigations are required to elucidate causality and inform strategies for interventions.

Efficiency evaluation of a SARS-CoV-2 diagnostic strategy combining high throughput quantitative antigen immunoassay and real time PCR.

OBJECTIVES: Laboratory testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has played an important role in the effort to prevent and contain local outbreaks. The aim of this study was to assess the diagnostic accuracy of a new fully automated SARS-CoV-2 laboratory-based antigen assay (CoV2Ag) and to explore the efficiency of a diagnostic algorithm combining antigen and conventional high-throughput molecular assays to address potential future challenges of the SARS-CoV-2 pandemic. METHODS: One thousand two hundred and twenty four consecutive nasopharyngeal swabs were tested using RT-PCR and CoV2Ag assay. RESULTS: The overall sensitivity and specificity of CoV2Ag were 79.1 and 97.8%, respectively. When the analysis was restricted to cases with Ct values ≤30, the sensitivity of the assay improved to 98.1%. Acceptable sensitivity was found when the analysis was limited to patients presenting within one or two to four days of symptom onset (80.5 and 84.8%, respectively). A retrospective analysis of the use of a two-step diagnostic approach combining the CoV2Ag assay and RT-PCR during an acute pandemic phase of 97 days showed a potential reduction in the number of RT-PCR tests by 36.1%, corresponding to savings in reagent costs and technician workload of approximately €8,000 and 10.5 h per day, respectively. CONCLUSIONS: Our data show that the proposed algorithm represents a valid alternative diagnostic approach to increase testing efficiency during future pandemic phases with high positivity rates (>20%) and elevated numbers of RT-PCR test requests.

Optimizing hepcidin measurement with a proficiency test framework and standardization improvement.

Objectives: Hepcidin measurement advances insights in pathophysiology, diagnosis, and treatment of iron disorders, but requires analytically sound and standardized measurement procedures (MPs). Recent development of a two-level secondary reference material (sRM) for hepcidin assays allows worldwide standardization. However, no proficiency testing (PT) schemes to ensure external quality assurance (EQA) exist and the absence of a high calibrator in the sRM set precludes optimal standardization. Methods: We developed a pilot PT together with the Dutch EQA organization Stichting Kwaliteitsbewaking Medische Laboratoriumdiagnostiek (SKML) that included 16 international hepcidin MPs. The design included 12 human serum samples that allowed us to evaluate accuracy, linearity, precision and standardization potential. We manufactured, value-assigned, and validated a high-level calibrator in a similar manner to the existing low- and middle-level sRM. Results: The pilot PT confirmed logistical feasibility of an annual scheme. Most MPs demonstrated linearity (R2>0.99) and precision (duplicate CV>12.2%), although the need for EQA was shown by large variability in accuracy. The high-level calibrator proved effective, reducing the inter-assay CV from 42.0% (unstandardized) to 14.0%, compared to 17.6% with the two-leveled set. The calibrator passed international homogeneity criteria and was assigned a value of 9.07±0.24 nmol/L. Conclusions: We established a framework for future PT to enable laboratory accreditation, which is essential to ensure quality of hepcidin measurement and its use in patient care. Additionally, we showed optimized standardization is possible by extending the current sRM with a third high calibrator, although international implementation of the sRM is a prerequisite for its success.

Trimethylamine-N-oxide (TMAO) predicts short- and long-term mortality and poor neurological outcome in out-of-hospital cardiac arrest patients.

Objectives: Prior research found the gut microbiota-dependent and pro-atherogenic molecule trimethylamine-N-oxide (TMAO) to be associated with cardiovascular events as well as all-cause mortality in different patient populations with cardiovascular disease. Our aim was to investigate the prognostic value of TMAO regarding clinical outcomes in patients after out-of-hospital cardiac arrest (OHCA). Methods: We included consecutive OHCA patients upon intensive care unit admission into this prospective observational study between October 2012 and May 2016. We studied associations of admission serum TMAO with in-hospital mortality (primary endpoint), 90-day mortality and neurological outcome defined by the Cerebral Performance Category (CPC) scale. Results: We included 258 OHCA patients of which 44.6% died during hospitalization. Hospital non-survivors showed significantly higher admission TMAO levels (µmol L-1) compared to hospital survivors (median interquartile range (IQR) 13.2 (6.6-34.9) vs. 6.4 (2.9-15.9), p<0.001). After multivariate adjustment for other prognostic factors, TMAO levels were significantly associated with in-hospital mortality (adjusted odds ratios (OR) 2.1, 95%CI 1.1-4.2, p=0.026). Results for secondary outcomes were similar with significant associations with 90-day mortality and neurological outcome in univariate analyses. Conclusions: In patients after OHCA, TMAO levels were independently associated with in-hospital mortality and other adverse clinical outcomes and may help to improve prognostication for these patients in the future. Whether TMAO levels can be influenced by nutritional interventions should be addressed in future studies.

Derivatization-free determination of short-chain volatile amines in human plasma and urine by headspace gas chromatography-mass spectrometry.

BACKGROUND: Short-chain volatile amines (SCVA) are an interesting compound class playing crucial roles in physiological and toxicological human settings. Dimethylamine (DMA), trimethylamine (TMA), diethylamine (DEA), and triethylamine (TEA) were investigated in detail. METHODS: Headspace gas chromatography coupled to mass spectrometry (HS-GC-MS) was used for the simultaneous qualitative and quantitative determination of four SCVA in different human body fluids. Four hundred microliters of Li-heparin plasma and urine were analyzed after liberation of volatile amines under heated conditions in an aqueous alkaline and saline environment. Target analytes were separated on a volatile amine column and detected on a Thermo DSQ II mass spectrometer scheduled in single ion monitoring mode. RESULTS: Chromatographic separation of selected SCVA was done within 7.5 minutes. The method was developed and validated with respect to accuracy, precision, recovery and stability. Accuracy and precision criteria were below 12% for all target analytes at low and high levels. The selected extraction procedure provided recoveries of more than 92% from both matrices for TMA, DEA and TEA. The recovery of DMA from Li-heparin plasma was lower but still in the acceptable range (>75%). The newly validated method was successfully applied to plasma and urine samples from healthy volunteers. Detected concentrations of endogenous metabolites DMA and TMA are comparable to already known reference ranges. CONCLUSION: Herein, we describe the successful development and validation of a reliable and broadly applicable HS-GC-MS procedure for the simultaneous and quantitative determination of SCVA in human plasma and urine without relying on derivatization chemistry.

Metabolomics and Their Ability to Distinguish Thyroid Disorders: A Retrospective Pilot Study.

Early diagnosis of thyroid disorders is key to further treatment. We assessed the ability of a high-throughput proton NMR metabolomic profile to distinguish disease type amongst of Graves' disease (n=87), Hashimoto's thyroiditis (n=17), toxic goiter (n=11), and autoimmune thyroiditis [i. e., subacute thyroiditis (n=4), postpartum thyroiditis (n=1)]. This observational study was conducted investigating patients presenting with a thyroid disorder at a Swiss hospital endocrine referral center and an associated endocrine outpatient clinic. The main outcome was diagnosis of thyroid disorder based on classical parameters. Blood draws took place as close as possible to treatment initiation. We performed one-way ANOVA and partial least squares discriminant analysis (PLS-DA) as multivariate classification and feature ranking method. One-way ANOVA analysis yielded following significantly different metabolites, triglycerides in small VLDL, triglycerides in very small VLDL, and triglycerides in large LDL (FDR=0.04). There was no distinct separation of any of the 4 diagnoses by PLS-DA. We did not find a metabolomic biomarker combination capable of predicting diagnosis. Preanalytical issues might have influenced our results. We strongly suggest replicating our work in another cohort.

Radiation-associated changes in saliva composition of head and neck cancer patients: A systematic review.

Xerostomia is a common radiation-associated toxicity in patients with head and neck cancer. Although several studies examined the decrease in saliva production due to radiotherapy (RT) and investigated the factors associated with this side effect, little is known about the change in radiation-associated saliva composition. This systematic review is the first to summarize existing data and give an overview of the change in pH/buffer capacity, electrolytes, proteins, enzymes, and mucins due to radiation to the salivary glands. Literature search was performed in PubMed and Embase with 47 articles finally eligible for the review, analyzing the saliva composition at several time points before, during and/or after RT, or comparing findings in irradiated patients to a healthy control group. Overall, RT leads to a substantial decrease in salivary pH and buffer capacity. For sodium, chloride and calcium ion, as well as amylase, an increased concentration or activity during RT was reported in most of the studies, followed by a subsequent decrease either already during RT or after the end of treatment. Different trends have been described for the total protein concentration during and after RT. Lactoferrin, however, increased considerably, especially in the first phase of RT. Mucin 5B (MUC5B) concentrations showed a slight increase during RT and concentrations around baseline values again six months post-radiotherapy.

Association of tryptophan pathway metabolites with mortality and effectiveness of nutritional support among patients at nutritional risk: secondary analysis of a randomized clinical trial.

Tryptophan is an essential amino acid and is the precursor of many important metabolites and neurotransmitters. In malnutrition, the availability of tryptophan is reduced, potentially putting patients at increased risks. Herein, we investigated the prognostic implications of the tryptophan metabolism in a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized, controlled trial comparing individualized nutritional support to usual care in patients at risk for malnutrition. Among 238 patients with available measurements, low plasma levels of metabolites were independently associated with 30-day mortality with adjusted hazard ratios (HR) of 1.77 [95% CI 1.05-2.99, p 0.034] for tryptophan, 3.49 [95% CI 1.81-6.74, p < 0.001] for kynurenine and 2.51 [95% CI 1.37-4.63, p 0.003] for serotonin. Nutritional support had more beneficial effects on mortality in patients with high tryptophan compared to patients with low tryptophan levels (adjusted HR 0.61 [95% CI 0.29-1.29] vs. HR 1.72 [95% CI 0.79-3.70], p for interaction 0.047). These results suggest that sufficient circulating levels of tryptophan might be a metabolic prerequisite for the beneficial effect of nutritional interventions in this highly vulnerable patient population.

The Association of the Essential Amino Acids Lysine, Methionine, and Threonine with Clinical Outcomes in Patients at Nutritional Risk: Secondary Analysis of a Randomized Clinical Trial.

Lysine, methionine, and threonine are essential amino acids with vital functions for muscle and connective tissue health, metabolic balance, and the immune system. During illness, the demand for these amino acids typically increases, which puts patients at risk for deficiencies with harmful clinical consequences. In a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), which compared individualized nutritional support to usual care nutrition in patients at nutritional risk, we investigated the prognostic impact of the lysine, methionine, and threonine metabolism. We had complete clinical and amino acid data in 237 patients, 58 of whom reached the primary endpoint of death at 30 days. In a model adjusted for comorbidities, sex, nutritional risk, and trial intervention, low plasma methionine levels were associated with 30-day mortality (adjusted HR 1.98 [95% CI 1.16 to 3.36], p = 0.01) and with a decline in functional status (adjusted OR 2.06 [95% CI 1.06 to 4.01], p = 0.03). The results for lysine and threonine did not show statistically significant differences regarding clinical outcomes. These findings suggest that low levels of methionine may be critical during hospitalization among patients at nutritional risk. Further studies should investigate the effect of supplementation of methionine in this patient group to improve outcomes.

Association of leucine and other branched chain amino acids with clinical outcomes in malnourished inpatients: a secondary analysis of the randomized clinical trial EFFORT.

BACKGROUND: The essential branched-chain amino acids leucine, isoleucine and valine are considered anabolic and stimulate protein synthesis in the muscles as well in the liver. They also promote muscle recovery and contribute to glucose homeostasis. Recent studies in critically ill patients have demonstrated that depletion of plasma leucine is associated with increased mortality, but data in the non-critical care setting is lacking. METHODS: This secondary analysis of the randomized controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT), investigated the impact of leucine, isoleucine, and valine metabolism on clinical outcomes. The primary endpoint was 180-day all-cause mortality. RESULTS: Among 238 polymorbid patients with available metabolite measurements, low serum leucin levels were associated with a doubled risk of 180-day all-cause mortality in a fully adjusted regression model (adjusted HR 2.20 [95% CI 1.46-3.30], p < 0.001). There was also an association with mortality for isoleucine (1.56 [95% CI 1.03-2.35], p = 0.035) and valine (1.69 [95% CI 1.13-2.53], p = 0.011). When comparing effects of nutritional support on mortality in patients with high and low levels of leucine, there was no evidence of significant differences in effectiveness of the intervention. The same was true for isoleucine and valine. CONCLUSION: Our data suggest that depletion of leucine, isoleucine, and valine among malnourished polymorbid patients is associated with increases in long-term mortality. However, patients with low metabolite levels did not show a pronounced benefit from nutritional support. Further research should focus on the clinical effects of nutritional support in patients with depleted stores of essential branched-chain amino acids. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov as NCT02517476 (registered 7 August 2015).

Prognostic implications of the arginine metabolism in patients at nutritional risk: A secondary analysis of the randomized EFFORT trial.

BACKGROUND: Arginine, a conditionally essential amino acid, is key component in metabolic pathways including immune regulation and protein synthesis. Depletion of arginine contributes to worse outcomes in severely ill and surgical patient populations. We assessed prognostic implications of arginine levels and its metabolites and ratios in polymorbid medical inpatients at nutritional risk regarding clinical outcomes and treatment response. METHODS: Within this secondary analysis of the randomized controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT), we investigated the association of arginine, its metabolites and ratios (i.e., ADMA and SDMA, ratios of arginine/ADMA, arginine/ornithine, and global arginine bioavailability ratio) measured on hospital admission with short-term and long-term mortality by means of regression analysis. RESULTS: Among the 231 patients with available measurements, low arginine levels ≤90.05 µmol/l (n = 86; 37 %) were associated with higher all-cause mortality at 30 days (primary endpoint, adjusted HR 3.27, 95 % CI 1.86 to 5.75, p < 0.001) and at 5 years (adjusted HR 1.50, 95 % CI 1.07 to 2.12, p = 0.020). Arginine metabolites and ratios were also associated with adverse outcome, but had lower prognostic value. There was, however, no evidence that treatment response was influenced by admission arginine levels. CONCLUSION: This secondary analysis focusing on medical inpatients at nutritional risk confirms a strong association of low plasma arginine levels and worse clinical courses. The potential effects of arginine-enriched nutritional supplements should be investigated in this population of patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov as NCT02517476 (registered 7 August 2015).

Association of Glutamine and Glutamate Metabolism with Mortality among Patients at Nutritional Risk-A Secondary Analysis of the Randomized Clinical Trial EFFORT.

Glutamine and its metabolite glutamate serve as the main energy substrates for immune cells, and their plasma levels drop during severe illness. Therefore, glutamine supplementation in the critical care setting has been advocated. However, little is known about glutamine metabolism in severely but not critically ill medical patients. We investigated the prognostic impact of glutamine metabolism in a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized controlled trial comparing individualized nutritional support to usual care in patients at nutritional risk. Among 234 patients with available measurements, low plasma levels of glutamate were independently associated with 30-day mortality (adjusted HR 2.35 [95% CI 1.18-4.67, p = 0.015]). The impact on mortality remained consistent long-term for up to 5 years. No significant association was found for circulating glutamine levels and short- or long-term mortality. There was no association of glutamate nor glutamine with malnutrition parameters or with the effectiveness of nutritional support. This secondary analysis found glutamate to be independently prognostic among medical inpatients at nutritional risk but poorly associated with the effectiveness of nutritional support. In contrast to ICU studies, we found no association between glutamine and clinical outcome.

Aluminum and other chemical elements in parenteral nutrition components and all-in-one admixtures.

BACKGROUND & AIMS: Parenteral nutrition (PN) can lead to high or even toxic exposure to aluminum (Al). We aimed to quantify concentrations of Al and other chemical elements of all-in-one (AIO) PN admixtures for adults prepared from commercial multichamber bags (Olimel® 5.7%, Omegaflex® special, SmofKabiven®, all with and without electrolytes) and vitamin and trace element additives over a 48-h period. Secondly, we determined the level of Al contamination resulting from admixing and infusion set use. METHODS: We used dynamic reaction cell and kinetic energy discrimination inductively coupled plasma mass spectrometry (ICP-MS) to quantify Al, arsenic (As), cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), nickel (Ni), antimony (Sb), selenium (Se), tin (Sn), vanadium (V), and zinc (Zn) in AIO PN admixtures. We extracted samples for analysis via the bag injection ports and infusion sets over a 48-h period after admixing. We compared the measured Al concentrations of AIO PN admixtures with calculated values based on the measured concentrations of individual chamber contents and additives. RESULTS: Mean (standard deviation) baseline Al concentrations in AIO PN admixtures ranged from 10.5 (0.5) to 59.3 (11.4) µg/L and decreased slightly over the 48 h (estimate [standard error] -0.09 [0.02] µg/L/hour, p <0.001). Thus, certain products exceeded the widely accepted limit of 25 µg/L. There was no significant difference in Al concentrations between samples extracted via the bag injection ports or infusion sets (p = 0.33), nor between measured and calculated Al concentrations of AIO PN admixtures (p = 0.91). CONCLUSION: Because certain commercially available PN admixtures for adults proved to contain excessively high levels of Al in our study, regulations and corresponding quality requirements at the authority level (e.g., Pharmacopoeia and regulatory authorities) are urgently required. Our results showed that the PN handling process (admixing and supplementing additives) or the materials of the infusion set did not lead to additional Al contamination to any extent. Moreover, calculated Al concentrations of AIO PN admixtures derived from individual chamber contents and additives are valid.

Prevalence of Micronutrient Deficiencies in Patients Hospitalized with COVID-19: An Observational Cohort Study.

BACKGROUND: A higher risk for severe clinical courses of coronavirus disease 2019 (COVID-19) has been linked to deficiencies of several micronutrients. We therefore studied the prevalence of deficiencies of eight different micronutrients in a cohort of hospitalized COVID-19-patients. METHODS: We measured admission serum/plasma levels of vitamins A, B12, D, and E, as well as folic acid, zinc, selenium, and copper in 57 consecutively admitted adult patients with confirmed COVID-19 and analyzed prevalence of micronutrient deficiencies and correlations among micronutrient levels. Further, we studied associations of micronutrient levels with severe disease progression, a composite endpoint consisting of in-hospital mortality and/or need for intensive care unit (ICU) treatment with logistic regression. RESULTS: Median age was 67.0 years (IQR 60.0, 74.2) and 60% (n = 34) were male. Overall, 79% (n = 45) of patients had at least one deficient micronutrient level and 33% (n = 19) had ≥3 deficiencies. Most prevalent deficiencies were found for selenium, vitamin D, vitamin A, and zinc (51%, 40%, 39%, and 39%, respectively). We found several correlations among micronutrients with correlation coefficients ranging from r = 0.27 to r = 0.42. The strongest associations with lower risk for severe COVID-19 disease progression (adjusted odds ratios) were found for higher levels of vitamin A (0.18, 95% CI 0.05-0.69, p = 0.01), zinc (0.73, 95% CI 0.55-0.98, p = 0.03), and folic acid (0.88, 95% CI 0.78-0.98, p = 0.02). CONCLUSIONS: We found a high prevalence of micronutrient deficiencies in mostly older patients hospitalized for COVID-19, particularly regarding selenium, vitamin D, vitamin A, and zinc. Several deficiencies were associated with a higher risk for more severe COVID-19 courses. Whether supplementation of micronutrients is useful for prevention of severe clinical courses or treatment of COVID-19 warrants further research.

Activation of the kynurenine pathway predicts mortality and neurological outcome in cardiac arrest patients: A validation study.

PURPOSE: Activation of the kynurenine pathway (KP) has been shown to predict outcome in cardiac arrest (CA) patients. We validated these findings in a Swiss cohort. METHODS: We measured admission tryptophan and kynurenine levels in 270 consecutive CA patients (38 in-hospital CA) and investigated associations with in-hospital mortality and neurological outcome at hospital discharge. RESULTS: 120 of 270 (44%) patients died in the hospital. Compared to survivors, non-survivors showed higher median initial kynurenine levels (5.28 µmol/l [IQR 2.91 to 7.40] vs 3.58 µmol/l [IQR 2.47 to 5.46]; p < 0.001) and a higher median kynurenine/tryptophan ratio (0.10 µmol/l [IQR 0.07 to 0.17] vs 0.07 µmol/l [IQR 0.05 to 0.1]; p < 0.001). In a model adjusted for age, gender and comorbidities, kynurenine (OR 1.16, 95% CI 1.05 to 1.27; p = 0.001) and kynurenine/tryptophan ratio (OR 1.19, 95% CI 1.08 to 1.31; p = 0.003) were significantly associated with mortality. Results were similar for neurological outcome. CONCLUSIONS: Our findings validate a previous study and show associations of the activation of the KP with unfavorable outcomes after CA. Future studies should evaluate whether therapeutic modulation of the KP may impact clinical outcomes after CA.

Physicochemical Stability and Compatibility Testing of Voriconazole in All-in-One Parenteral Nutrition Admixtures.

(1) Drug compatibility with all-in-one (AiO) parenteral nutrition (PN) admixtures is a very important pharmaceutical quality issue to be answered based on appropriate laboratory testing. We assessed voriconazole (V), a poorly water-soluble (logP ≈ 1) single-daily dosed antifungal drug monitored in patients and thus candidate for AiO PN admixing for convenient and safe patient care. We evaluated V compatibility and stability in AiO PN admixtures through adapted therapeutic drug monitoring method (drug stability) and visual microscopic emulsion stability by lipid droplets analysis improved by an automated microscopic digital assessment. (2) V was added in concentrations of 0.05/0.25/0.5 mg/mL (143.1/715.7/1431.5 µM), correlating to daily therapeutic dosing, to three commercially available industrial AiO PN admixtures. Three aliquots were stored in the refrigerator (4 °C), at room temperature (24 °C) and under stress conditions in a water bath (37 °C). Samples taken at 0/24/48/72/168 h after admixing were subjected to a stability-indicating one-week analysis. Assessment included visual examination, lipid droplet measurement according to an established and validated method (bright-field microscopy using oil immersion), pH measurement (glass electrode) and V identification/quantification (LC-MS/MS). (3) After one week, all samples at 37 °C showed slight yellow discoloration. The pH values remained stable. All samples met specifications for lipid droplets according to size (upper size ≤8 µm, mean size <4.5 ± 2 µm) and number (n ≤ 9 lipid droplets >5 µm). V concentrations were within an acceptable range, calculated for every timepoint as percent of the theoretical concentration spiked into the AiO PN. The median recovery was 98.2% (min-max, 90-112%). (4) At therapeutic doses, commercial V formulations were compatible and stable within specifications over one week in commonly used volumes of commercial AiO PN admixtures at 4-37 °C.

Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest-Results from the Prospective, Observational COMMUNICATE Trial.

(1) Background: In patients with shock, the L-arginine nitric oxide pathway is activated, causing an elevation of nitric oxide, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels. Whether these metabolites provide prognostic information in patients after out-of-hospital cardiac arrest (OHCA) remains unclear. (2) Methods: We prospectively included OHCA patients, recorded clinical parameters and measured plasma ADMA, SDMA and Arginine levels by liquid chromatography tandem mass spectrometry (LC-MS). The primary endpoint was 90-day mortality. (3) Results: Of 263 patients, 130 (49.4%) died within 90 days after OHCA. Compared to survivors, non-survivors had significantly higher levels of ADMA and lower Arginine and Arginine/ADMA ratios in univariable regression analyses. Arginine levels and Arginine/ADMA ratio were significantly associated with 90-day mortality (OR 0.51 (95%CI 0.34 to 0.76), p < 0.01 and OR 0.40 (95%CI 0.26 to 0.61), p < 0.001, respectively). These associations remained significant in several multivariable models. Arginine/ADMA ratio had the highest predictive value with an area under the curve (AUC) of 0.67 for 90-day mortality. Results for secondary outcomes were similar with significant associations with in-hospital mortality and neurological outcome. (4) Conclusion: Arginine and Arginine/ADMA ratio were independently associated with 90-day mortality and other adverse outcomes in patients after OHCA. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated.

Association of Taurine with In-Hospital Mortality in Patients after Out-of-Hospital Cardiac Arrest: Results from the Prospective, Observational COMMUNICATE Study.

BACKGROUND: Studies have suggested that taurine may have neuro- and cardio-protective functions, but there is little research looking at taurine levels in patients after out-of-hospital cardiac arrest (OHCA). Our aim was to evaluate the association of taurine with mortality and neurological deficits in a well-defined cohort of OHCA patients. METHODS: We prospectively measured serum taurine concentration in OHCA patients upon admission to the intensive care unit (ICU) of the University Hospital Basel (Switzerland). We analyzed the association of taurine levels and in-hospital mortality (primary endpoint). We further evaluated neurological outcomes assessed by the cerebral performance category scale. We calculated logistic regression analyses and report odds ratios (OR) and 95% confidence intervals (CI). We calculated different predefined multivariable regression models including demographic variables, comorbidities, initial vital signs, initial blood markers and resuscitation measures. We assessed discrimination by means of area under the receiver operating curve (ROC). RESULTS: Of 240 included patients, 130 (54.2%) survived until hospital discharge and 110 (45.8%) had a favorable neurological outcome. Taurine levels were significantly associated with higher in-hospital mortality (adjusted OR 4.12 (95%CI 1.22 to 13.91), p = 0.02). In addition, a significant association between taurine concentration and a poor neurological outcome was observed (adjusted OR of 3.71 (95%CI 1.13 to 12.25), p = 0.03). Area under the curve (AUC) suggested only low discrimination for both endpoints (0.57 and 0.57, respectively). CONCLUSION: Admission taurine levels are associated with mortality and neurological outcomes in OHCA patients and may help in the risk assessment of this vulnerable population. Further studies are needed to assess whether therapeutic modulation of taurine may improve clinical outcomes after cardiac arrest.