Elevated Plasma Levels of Arginines During Labor Among Women with Spontaneous Preterm Birth: A Prospective Cohort Study.

PROBLEM: Preterm birth (PTB) is a leading cause of infant mortality and morbidity. The pathogenesis of PTB is complex and involves many factors, including socioeconomy, inflammation and infection. Asymmetric dimethylarginine, ADMA and symmetric dimethylarginine, SDMA are involved in labor as inhibitors of nitric oxide, a known relaxant of the uterine smooth muscles. Arginines are scarcely studied in relation to PTB and we aimed to investigate arginines (ADMA, SDMA and L-arginine) in women with spontaneous PTB and term birth. METHODS OF THE STUDY: The study was based on data from the population-based, prospective cohort BASIC study conducted in Uppsala County, Sweden, between September 2009 and November 2018. Arginines were analyzed by Ultra-High Performance Liquid Chromatography using plasma samples taken at the onset of labor from women with spontaneous PTB (n = 34) and term birth (n = 45). We also analyzed the inflammation markers CRP, TNF-R1 and TNF-R2 and GDF-15. RESULTS: Women with spontaneous PTB had higher plasma levels of ADMA (p < 0.001), and L-Arginine (p = 0.03). In addition, inflammation marker, TNF-R1 (p = 0.01) was higher in spontaneous PTB compared to term birth. Further, in spontaneous PTB, no significant correlations could be observed when comparing levels of arginines with inflammation markers, except ADMA versus CRP. CONCLUSIONS: These findings provide novel evidence for the potential involvement of arginines in the pathogenesis of spontaneous PTB and it seems that arginine levels at labor vary independently of several inflammatory markers. Further research is warranted to investigate the potential of arginines as therapeutic targets in the prevention and management of spontaneous PTB.

Body mass index is associated with pulmonary gas and blood distribution mismatch in COVID-19 acute respiratory failure. A physiological study.

Background: The effects of obesity on pulmonary gas and blood distribution in patients with acute respiratory failure remain unknown. Dual-energy computed tomography (DECT) is a X-ray-based method used to study regional distribution of gas and blood within the lung. We hypothesized that 1) regional gas/blood mismatch can be quantified by DECT; 2) obesity influences the global and regional distribution of pulmonary gas and blood; 3) regardless of ventilation modality (invasive vs. non-invasive ventilation), patients' body mass index (BMI) has an impact on pulmonary gas/blood mismatch. Methods: This single-centre prospective observational study enrolled 118 hypoxic COVID-19 patients (92 male) in need of respiratory support and intensive care who underwent DECT. The cohort was divided into three groups according to BMI: 1. BMI<25 kg/m2 (non-obese), 2. BMI = 25-40 kg/m2 (overweight to obese), and 3. BMI>40 kg/m2 (morbidly obese). Gravitational analysis of Hounsfield unit distribution of gas and blood was derived from DECT and used to calculate regional gas/blood mismatch. A sensitivity analysis was performed to investigate the influence of the chosen ventilatory modality and BMI on gas/blood mismatch and adjust for other possible confounders (i.e., age and sex). Results: 1) Regional pulmonary distribution of gas and blood and their mismatch were quantified using DECT imaging. 2) The BMI>40 kg/m2 group had less hyperinflation in the non-dependent regions and more lung collapse in the dependent regions compared to the other BMI groups. In morbidly obese patients, gas and blood were more evenly distributed; therefore, the mismatch was lower than in other patients (30% vs. 36%, p < 0.05). 3) An increase in BMI of 5 kg/m2 was associated with a decrease in mismatch of 3.3% (CI: 3.67% to -2.93%, p < 0.05). Neither the ventilatory modality nor age and sex affected the gas/blood mismatch (p > 0.05). Conclusion: 1) In a hypoxic COVID-19 population needing intensive care, pulmonary gas/blood mismatch can be quantified at a global and regional level using DECT. 2) Obesity influences the global and regional distribution of gas and blood within the lung, and BMI>40 kg/m2 improves pulmonary gas/blood mismatch. 3) This is true regardless of the ventilatory mode and other possible confounders, i.e., age and sex. Trial Registration: Clinicaltrials.gov, identifier NCT04316884, NCT04474249.

Increased levels of thymidine kinase 1 in malignant cell-derived extracellular vesicles.

Extracellular vesicles (EVs), whose main subtypes are exosomes, microparticles, and apoptotic bodies, are secreted by all cells and harbor biomolecules such as DNA, RNA, and proteins. They function as intercellular messengers and, depending on their cargo, may have multiple roles in cancer development. Thymidine kinase 1 (TK1) is a cell cycle-dependent enzyme used as a biomarker for cell proliferation. TK1 is usually elevated in cancer patients' serum, making the enzyme a valuable tumor proliferation biomarker that strongly correlates with cancer stage and metastatic capabilities. Here, we investigated the presence of TK1 in EVs derived from three prostate cancer cell lines with various p53 mutation statuses (LNCaP, PC3, and DU145), EVs from the normal prostate epithelial cell line RWPE-1 and EVs isolated from human seminal fluid (prostasomes). We measured the TK1 activity by a real-time assay for these EVs. We demonstrated that the TK1 enzyme activity is higher in EVs derived from the malignant cell lines, with the highest activity from cells deriving from the most aggressive cancer, compared to the prostasomes and RWPE-1 EVs. The measurement of TK1 activity in EVs may be essential in future prostate cancer studies.

Eleven neurology-related proteins measured in serum are positively correlated to the severity of diabetic neuropathy.

About 20% of patients with diabetes suffer from chronic pain with neuropathic characteristics. We investigated the multivariate associations between 92 neurology-related proteins measured in serum from 190 patients with painful and painless diabetic neuropathy. Participants were recruited from the Pain in Neuropathy Study, an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the exploration cohort, two groups were defined by hierarchical cluster analyses of protein data. The proportion of painless vs painful neuropathy did not differ between the two groups, but one group had a significantly higher grade of neuropathy as measured by the Toronto Clinical Scoring System (TCSS). This finding was replicated in the replication cohort. Analyzing both groups together, we found that a group of 11 inter-correlated proteins (TNFRSF12A, SCARB2, N2DL-2, SKR3, EFNA4, LAYN, CLM-1, CD38, UNC5C, GFR-alpha-1, and JAM-B) were positively associated with TCSS values. Notably, EFNA4 and UNC5C are known to be part of axon guidance pathways. To conclude, although cluster analysis of 92 neurology-related proteins did not distinguish painful from painless diabetic neuropathy, we identified 11 proteins which positively correlated to neuropathy severity and warrant further investigation as potential biomarkers.

Patient result monitoring of HbA1c shows small seasonal variations and steady decrease over more than 10 years.

OBJECTIVES: Internal and external quality assurance materials often use highly processed matrixes. This can render the materials non-commutable. Monitoring laboratory methods with patient medians helps in identifying and correcting systematic errors that may affect diagnostic accuracy. The aim of the present study was to use HbA1c patient results for monitoring of method performance over time. METHODS: Test HbA1c results from 2010 to 2022 was analyzed (n=722,553) regarding changes over time and seasonal variation. The HbA1c testing was initially performed on a Cobas 501 instrument using immunological detection but in May 2017 the method was replaced by capillary electrophoresis on Capillarys 3 Tera. RESULTS: There was a steady decrease in HbA1c values. From 2011 to 2021 the decrease was for 0.10 percentile 6.6 %, lower quartile 7.9 %, median 10.2 %, mean values 9 %, upper quartile 11.2 %, and 0.90 percentile 9.3 %. No clear shift in HbA1c levels was observed due to the shift in methods. The median HbA1c values per month was approximately 44 mmol/mol (6.2 %, DCCT/NGSP). The only month with a median HbA1c that differed by more than 1 mmol/mol was July with a median value of 42 mmol/mol (6.0 %). CONCLUSIONS: The patient data showed a similar decrease as in the National Diabetes Register which indicates that the method is stable over time without any sudden changes and that the seasonal variation is low. The continuous decrease in HbA1c values over time is most likely to a shift towards earlier detection of patient with diabetes and improved treatment.

Cerebrospinal fluid and plasma concentrations of the inflammatory marker soluble CD27 in a large surgical population.

Soluble CD27 (sCD27) is a potential biomarker for diseases involving immune dysfunction. As there is currently little data on cerebrospinal fluid (CSF) sCD27 concentrations in the general population we measured CSF and plasma concentrations in 486 patients (age range 18-92 years, 57% male) undergoing spinal anesthesia for elective surgery. Across the complete cohort the median [range] sCD27 concentrations were 163 [<50 to 7474] pg/mL in CSF and 4624 [1830 to >400,000] pg/mL in plasma. Plasma sCD27, age and Qalb were the factors most strongly associated with CSF sCD27 levels. Reference sCD27 concentration intervals (central 95% of values) in a sub-group without the indication of neuropsychiatric, inflammatory or systemic disease (158 patients) were <50 pg/mL - 419 pg/mL for CSF and 2344-36422 pg/mL for plasma. These data provide preliminary reference ranges that could inform future studies of the validity of sCD27 as a biomarker for neuro- and systemic inflammatory disorders.

The predictive value of cardiovascular outcomes and mortality assessed by the C-reactive protein to albumin ratio in the UK Biobank.

BACKGROUND: The C-reactive protein/albumin ratio (CAR) seems to mirror disease severity and prognosis in several acute disorders particularly in elderly patients, yet less is known about if CAR is superior to C-reactive protein (CRP) in the general population. METHODS: Prospective study design on the UK Biobank, where serum samples of CRP and Albumin were used. Cox regression analyses were conducted to assess all-cause and cardiovascular mortality, myocardial infarction, ischemic stroke, and heart failure over a follow-up period of approximately 12.5 years. The Cox model was adjusted for established cardiovascular disease (CVD) risk factors, including age, sex, smoking habits, physical activity level, BMI level, systolic blood pressure, LDL-cholesterol, statin treatment, diabetes, and previous CVD, with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Analyses were also stratified by sex, CRP level (< 10 and ≥ 10 mg/ml) and age (< 60 and ≥ 60 years). RESULTS: In total, 411,506 individuals (186,043 men and 225,463 women) were included. In comparisons between HRs for all adverse outcomes, the results were similar or identical for CAR and CRP. For example, both CAR and CRP, adjusted HRs for all-cause mortality were 1.13 (95% CI 1.12-1.14). Regarding CVD mortality, the adjusted HR for CAR was 1.14 (95% CI 1.12-1.15), while for CRP, it was 1.13 (95% CI 1.11-1.15). CONCLUSIONS: Within this study CAR was not superior to CRP in predictive ability of mortality or CVD disorders. CLINICAL TRIAL REGISTRATION NUMBER: Not applicable (cohort study).

Role of NO in Disease: Good, Bad or Ugly.

This Special Issue of Biomedicines (https://www [...].

Different distances between central venous catheter tips can affect antibiotic clearance during continuous renal replacement therapy.

BACKGROUND: The aim of this experimental study was to elucidate whether different distances between central venous catheter tips can affect drug clearance during continuous renal replacement therapy (CRRT). Central venous catheters (CVCs) are widely used in intensive care patients for drug infusion. If a patient receives CRRT, a second central dialysis catheter (CDC) is required. Where to insert CVCs is directed by guidelines, but recommendations regarding how to place multiple catheters are scarce. There are indications that a drug infused in a CVC with the tip close to the tip of the CDC, could be directly aspirated into the dialysis machine, with a risk of increased clearance. However, studies on whether clearance is affected by different CVC and CDC tip positions, when the two catheters are in the same vessel, are few. METHODS: In this model with 18 piglets, gentamicin (GM) and vancomycin (VM) were infused through a CVC during CRRT. The CVC tip was placed in different positions in relation to the CDC tip from caudal, i.e., proximal to the heart, to cranial, i.e., distal to the heart. Serum and dialysate concentrations were sampled after approximately 30 min of CRRT at four different positions: when the CVC tip was 2 cm caudally (+ 2), at the same level (0), and at 2 (- 2) and 4 (- 4) cm cranially of the tip of the CDC. Clearance was calculated. A mixed linear model was performed, and level of significance was set to p < 0.05. RESULTS: Clearance of GM had median values at + 2 cm, 0 cm, - 2 cm and - 4 cm of 17.3 (5.2), 18.6 (7.4), 20.0 (16.2) and 26.2 (12.2) ml/min, respectively (p = 0.04). Clearance of VM had median values at + 2 cm, 0 cm, - 2 cm and - 4 cm of 16.2 (4.5), 14.7 (4.9), 19.0 (10.2) and 21.2 (11.4) ml/min, respectively (p = 0.02). CONCLUSIONS: The distance between CVC and CDC tips can affect drug clearance during CRRT. A cranial versus a caudal tip position of the CVC in relation to the tip of the CDC led to the highest clearance.

Orthostatic hypotension is associated with higher levels of circulating endostatin.

Aims: The pathophysiology of orthostatic hypotension (OH), a common clinical condition, associated with adverse outcomes, is incompletely understood. We examined the relationship between OH and circulating endostatin, an endogenous angiogenesis inhibitor with antitumour effects proposed to be involved in blood pressure (BP) regulation. Methods and results: We compared endostatin levels in 146 patients with OH and 150 controls. A commercial chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin. Linear and multivariate logistic regressions were conducted to test the association between endostatin and OH. Endostatin levels were significantly higher in OH patients (59 024 ± 2513 pg/mL) vs. controls (44 090 ± 1978pg/mL, P < 0.001). A positive linear correlation existed between endostatin and the magnitude of systolic BP decline upon standing (P < 0.001). Using multivariate analysis, endostatin was associated with OH (adjusted odds ratio per 10% increase of endostatin in the whole study population = 1.264, 95% confidence interval 1.141-1.402), regardless of age, sex, prevalent cancer, and cardiovascular disease, as well as traditional cardiovascular risk factors. Conclusion: Circulating endostatin is elevated in patients with OH and may serve as a potential clinical marker of increased cardiovascular risk in patients with OH. Our findings call for external validation. Further research is warranted to clarify the underlying pathophysiological mechanisms.

Exhaled Nitric Oxide Reflects the Immune Reactions of the Airways in Early Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA) have altered levels of exhaled nitric oxide (NO) compared with healthy controls. Here, we investigated whether the clinical features of and immunological factors in RA pathogenesis could be linked to the NO lung dynamics in early disease. A total of 44 patients with early RA and anti-citrullinated peptide antibodies (ACPAs), specified as cyclic citrullinated peptide 2 (CCP2), were included. Their exhaled NO levels were measured, and the alveolar concentration, the airway compartment diffusing capacity and the airway wall concentration of NO were estimated using the Högman-Meriläinen algorithm. The disease activity was measured using the Disease Activity Score for 28 joints. Serum samples were analysed for anti-CCP2, rheumatoid factor, free secretory component, secretory component containing ACPAs, antibodies against Porphyromonas gingivalis (Rgp) and total levels of IgA, IgA1 and IgA2. Significant negative correlations were found between the airway wall concentration of NO and the number of swollen joints (Rho -0.48, p = 0.004), between the airway wall concentration of NO and IgA rheumatoid factor (Rho -0.41, p = 0.017), between the alveolar concentration and free secretory component (Rho -0.35, p = 0.023) and between the alveolar concentration and C-reactive protein (Rho -0.36, p = 0.016), but none were found for anti-CCP2, IgM rheumatoid factor or the anti-Rgp levels. In conclusion, altered NO levels, particularly its production in the airway walls, may have a role in the pathogenesis of ACPA-positive RA.

Sustained IFN signaling is associated with delayed development of SARS-CoV-2-specific immunity.

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity.

The Human Phospholipase B-II Precursor (HPLBII-P) in Urine as a Novel Biomarker of Glomerular Activity in COVID-19 and Diabetes Mellitus.

Background: The human phospholipase B-II precursor (HPLBII-P) was originally purified from white blood cells but is also found in other cellular structures, such as kidney glomeruli and tubuli. The objective of this report was to investigate the relationship of HPLBII-P in urine to acute kidney injury in patients with COVID-19. Methods: Urine was collected at admission from 132 patients with COVID-19 admitted to the intensive care units (ICUs) because of respiratory failure. HPLBII-P was measured using a sensitive ELISA. For comparison, human neutrophil lipocalin (HNL) was measured in urine, using the ELISA configured with the monoclonal antibody 763/8F, as a sign of tubular affection in addition to routine biomarkers of kidney disease. Results: Overall, the concentrations of urinary HPLBII-P were almost 3-fold higher in patients with COVID-19 compared to healthy controls (p < 0.0001) and with significantly higher concentrations even in patients with COVID-19 without signs of acute kidney injury (AKI) (p < 0.001). HPLBII-P was further increased in patients with AKI (p < 0.02). HPLBII-P was significantly increased in patients with diabetes mellitus (p = 0.0008) and correlated to plasma glucose (r = 0.29, p = 0.001) and urine albumin concentrations (r = 0.55, p < 0.001). Conclusions: Urine concentrations of HPLBII-P are highly raised in the urine of patients with COVID-19 and relate to AKI and diabetes mellitus. HPLBII-P may reflect glomerular injury and/or increased glomerular cell activity in SARS-CoV-2 infections.

The Human Phospholipase B-II Precursor (HPLBII-P) in Urine as a Novel Biomarker of Increased Glomerular Production or Permeability in Diabetes Mellitus?

Background: A previous report showed that the urine output of HPLBII-P in patients with diabetes mellitus and SARS-CoV-2 infection was increased as a sign of glomerular dysfunction. The aim of this report was to investigate the relation of the urine output of HPLBII-P to diabetes mellitus in two large community-based elderly populations, i.e., the ULSAM and PIVUS cohorts. Methods: HPLBII-P was measured by an ELISA in the urine of a community-based cohort of 839 men (ULSAM) collected at 77 years of age and in the urine of a community-based cohort of 75-year-old men, n = 387, and women, n = 401 (PIVUS). KIM-1, NGAL, and albumin were measured in urine and cathepsin S and cystatin C in serum. Results: HPLBII-P was significantly raised among males with diabetes in the ULSAM (p < 0.0001) and PIVUS cohorts (p ≤ 0.02), but not in the female cohort of PIVUS. In the female subpopulation of insulin-treated diabetes, HPLBII-P was raised (p = 0.02) as compared to women treated with oral antidiabetics only. In the ULSAM cohort, HPLBII-P was correlated to NGAL, KIM-1, and albumin in urine both in non-DM (all three biomarkers; p < 0.0001) and in DM (NGAL; p = 0.002, KIM-1; p = 0.02 and albumin; p = 0.01). Plasma glucose and HbA1c in blood showed correlations to U-HPLBII-P (r = 0.58, p < 0.001 and r = 0.42, p = 0.004, respectively). U-HPLBII-P and cathepsin S were correlated in the ULSAM group (r = 0.50, p < 0.001). No correlations were observed between U-HPLBII-P and serum creatinine or cystatin C. Conclusions: The urine measurement of HPLBII-P has the potential to become a novel and useful biomarker in the monitoring of glomerular activity in diabetes mellitus.

Supplementation with selenium and coenzyme Q10 in an elderly Swedish population low in selenium - positive effects on thyroid hormones, cardiovascular mortality, and quality of life.

BACKGROUND: Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q10 on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL). METHODS: Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses. RESULTS: In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q10 for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group. CONCLUSIONS: Supplementation with selenium and coenzyme Q10 had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

Impact of respiratory cycle during mechanical ventilation on beat-to-beat right ventricle stroke volume estimation by pulmonary artery pulse wave analysis.

BACKGROUND: The same principle behind pulse wave analysis can be applied on the pulmonary artery (PA) pressure waveform to estimate right ventricle stroke volume (RVSV). However, the PA pressure waveform might be influenced by the direct transmission of the intrathoracic pressure changes throughout the respiratory cycle caused by mechanical ventilation (MV), potentially impacting the reliability of PA pulse wave analysis (PAPWA). We assessed a new method that minimizes the direct effect of the MV on continuous PA pressure measurements and enhances the reliability of PAPWA in tracking beat-to-beat RVSV. METHODS: Continuous PA pressure and flow were simultaneously measured for 2-3 min in 5 pigs using a high-fidelity micro-tip catheter and a transonic flow sensor around the PA trunk, both pre and post an experimental ARDS model. RVSV was estimated by PAPWA indexes such as pulse pressure (SVPP), systolic area (SVSystAUC) and standard deviation (SVSD) beat-to-beat from both corrected and non-corrected PA signals. The reference RVSV was derived from the PA flow signal (SVref). RESULTS: The reliability of PAPWA in tracking RVSV on a beat-to-beat basis was enhanced after accounting for the direct impact of intrathoracic pressure changes induced by MV throughout the respiratory cycle. This was evidenced by an increase in the correlation between SVref and RVSV estimated by PAPWA under healthy conditions: rho between SVref and non-corrected SVSD - 0.111 (0.342), corrected SVSD 0.876 (0.130), non-corrected SVSystAUC 0.543 (0.141) and corrected SVSystAUC 0.923 (0.050). Following ARDS, correlations were SVref and non-corrected SVSD - 0.033 (0.262), corrected SVSD 0.839 (0.077), non-corrected SVSystAUC 0.483 (0.114) and corrected SVSystAUC 0.928 (0.026). Correction also led to reduced limits of agreement between SVref and SVSD and SVSystAUC in the two evaluated conditions. CONCLUSIONS: In our experimental model, we confirmed that correcting for mechanical ventilation induced changes during the respiratory cycle improves the performance of PAPWA for beat-to-beat estimation of RVSV compared to uncorrected measurements. This was demonstrated by a better correlation and agreement between the actual SV and the obtained from PAPWA.

Overfeeding polyunsaturated fat compared with saturated fat does not differentially influence lean tissue accumulation in individuals with overweight: a randomized controlled trial.

BACKGROUND: Fatty acids may influence lean tissue volume and skeletal muscle function. We previously reported in young lean participants that overfeeding PUFA compared with SFA induced greater lean tissue accumulation despite similar weight gain. OBJECTIVES: In a double-blind randomized controlled trial, we aimed to investigate if the differential effects of overfeeding SFA and PUFA on lean tissue accumulation could be replicated in individuals with overweight and identify potential determinants. Further, using substitution models, we investigated associations between SFA and PUFA concentrations with lean tissue volume in a large population-based sample (UK Biobank). METHODS: Sixty-one males and females with overweight [BMI (kg/m2): 27.3 (interquartile range (IQR), 25.4-29.3); age: 43 (IQR, 36-48)] were overfed SFA (palm oil) or n-6 (ω-6) PUFA (sunflower oil) for 8 wk. Lean tissue was assessed by MRI. We had access to n = 13,849 participants with data on diet, covariates, and MRI measurements of lean tissue, as well as 9119 participants with data on circulating fatty acids in the UK Biobank. RESULTS: Body weight gain mean (SD) was similar in PUFA (2.01 ± 1.90 kg) and SFA (2.31 ± 1.38 kg) groups. Lean tissue increased to a similar extent [0.54 ± 0.93 L and 0.67 ± 1.21 L for PUFA and SFA groups, respectively, with a difference between groups of 0.07 (-0.21, 0.35)]. We observed no differential effects on circulating amino acids, myostatin, or IL-15 and no clear determinants of lean tissue accumulation. Similar nonsignificant results for SFA and PUFA were observed in UK Biobank, but circulating fatty acids demonstrated ambiguous and sex-dependent associations. CONCLUSIONS: Overfeeding SFA or PUFA does not differentially affect lean tissue accumulation during 8 wk in individuals with overweight. A lack of dietary fat type-specific effects on lean tissue is supported by specified substitution models in a large population-based cohort consuming their habitual diet. This trial was registered at clinicaltrials.gov identifier as NCT02211612.

Anti-histone and anti-nucleosome rather than anti-dsDNA antibodies associate with IFN-induced biomarkers in Sudanese and Swedish Systemic Lupus Erythematosus patients.

OBJECTIVES: In SLE, anti-dsDNA can co-occur with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies induce type-1 interferon production, a hallmark of SLE. We measured antinuclear antibody (ANA) sub-specificities and investigated their associations to inflammatory biomarkers including interferon-regulated chemokines. METHODS: We included 93 Sudanese and 480 Swedish SLE patients and matched controls (N = 104 + 192). Autoantibodies targeting ANA-subspecificites: dsDNA, Sm, Sm/U1RNPcomplex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified in all subjects, anti-nucleosome only in the Swedish patients, with a bead-based multiplex immunoassay. Levels of 72 plasma biomarkers were determined with Proximity Extension Assay technique or ELISA. RESULTS: Among Sudanese patients, the investigated antibodies significantly associated with 9/72 biomarkers. Anti-histone antibodies showed the strongest positive correlations with MCP-3 and S100A12 as well as with interferon I-inducible factors MCP-1 and CXCL10. Anti-dsDNA antibodies associated with CXCL10 and S100A12, but in multivariate analyses, unlike anti-histone, associations lost significance.Among Swedish patients, MCP-1, CXCL10, SA100A12 also demonstrated stronger associations to anti-histone and anti-nucleosome antibodies, compared with anti-dsDNA and other ANA sub-specificities. In multiple regression models, anti-histone/nucleosome retained the strongest associations. When excluding anti-histone or anti-nucleosome positive patients, the associations between MCP-1/CXCL10 and anti-dsDNA were lost. In contrast, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome remained significant. CONCLUSION: In two cohorts of different ethnical origin, autoantibodies targeting chromatin correlate stronger with IFN-induced inflammatory biomarkers than anti-dsDNA or other ANA sub-specificities. Our results suggest that anti-histone/nucleosome autoantibodies may be main drivers of type-1 interferon activity in SLE.

Plasma neutrophil gelatinase-associated lipocalin independently predicts dialysis need and mortality in critical COVID-19.

Neutrophil gelatinase-associated lipocalin (NGAL) is a novel kidney injury and inflammation biomarker. We investigated whether NGAL could be used to predict continuous renal replacement therapy (CRRT) and mortality in critical coronavirus disease 2019 (COVID-19). This prospective multicenter cohort study included adult COVID-19 patients in six intensive care units (ICUs) in Sweden between May 11, 2020 and May 10, 2021. Blood was sampled at admission, days two and seven in the ICU. The samples were batch analyzed for NGAL, creatinine, and cystatin c after the end of the study period. Initiation of CRRT and 90-day survival were used as dependent variables in regression models. Of 498 included patients, 494 were analyzed regarding CRRT and 399 were analyzed regarding survival. Seventy patients received CRRT and 154 patients did not survive past 90 days. NGAL, in combination with creatinine and cystatin c, predicted the subsequent initiation of CRRT with an area under the curve (AUC) of 0.95. For mortality, NGAL, in combination with age and sex, had an AUC of 0.83. In conclusion, NGAL is a valuable biomarker for predicting subsequent initiation of CRRT and 90-day mortality in critical COVID-19. NGAL should be considered when developing future clinical scoring systems.

Pediatric reference intervals for serum folate and cobalamin based on a European population without exposure to folic acid fortification.

The aim of the present study was to define pediatric reference intervals for serum cobalamin and folate utilizing data generated from a population not exposed to food fortified with folic acid. Folate and cobalamin results analyzed by electrochemiluminescence immunoassay (Roche Cobas) were obtained from 2375 children (2 months to 17.99 years of age). The serum samples were collected between 2011 and 2015 as part of the LIFE (Leipzig Research Centre for Civilization Diseases) Child cohort study in Germany, where folic acid fortification of food is not mandated. These results were used to generate age- and gender-specific reference intervals presented as non-parametric 2.5 and 97.5 percentiles. Because of a subsequent restandardisation of the Roche folate assay in 2016, folate values were recalculated accordingly for adaptation to results obtained using the present calibration. In both genders, folate concentrations decreased continuously with age, whereas cobalamin concentrations peaked at five years of age and then declined. Teenage females had higher concentrations of cobalamin in the age group 12-17.99 years.