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BACKGROUND High levels of inflammation pre- and post-percutaneous coronary intervention (PCI) are associated with worse outcomes. Recent trials have suggested a benefit from treating inflammation with colchicine in coronary artery disease. In this randomised pilot COPE-PCI sub-study, we aimed to determine if administration of colchicine pre-PCI, would attenuate the inflammatory effect of PCI. METHODS PCI patients were randomised to colchicine or placebo, 6 to 24-hours pre-procedure. Study blood samples were taken immediately pre-PCI, and 24-hours post-procedure. Samples were tested for a broad array of inflammatory biomarkers including high-sensitive(hs)-CRP, leucocyte counts, and hs-troponin-. Periprocedural Myocardial Injury (PM-Injury) was defined as per the ESC Third Universal Definitions of Myocardial Infarction. RESULTS Thirty-six were randomised to colchicine and 39 to placebo. Treatment groups were similar for baseline variables. The median time from drug administration to pre-PCI blood sampling was 18-hours. Overall inflammation was low across the patient population, pre- & post-PCI hsCRP was

Background Intravascular imaging has defined various vulnerable plaque (VP) phenotypes that predict future clinical events. Atherosclerosis is an inflammatory process and inflammation, measured by systemic biomarkers can also predict events and anti-inflammatory therapy is beneficial. We were interested to assess the relationship between plaque phenotypes and key inflammatory biomarkers, measured close to the coronary. Methods Ninety-two patients scheduled for elective percutaneous coronary intervention (PCI) underwent virtual histology intravascular ultrasound, optical coherence tomography, pressure wire and blood sampling from the guide catheter (GC), coronary sinus (CS) to determine trans-myocardial gradient (TMG = CS-GC) and from peripheral blood. Procedure related troponin release was assessed at 6-hours post-PCI from peripheral venous blood. Biomarker data were analysed and compared with coronary data. Results Interleukin (IL)-6 was associated with increased levels of tumour necrosis factor (TNF)-α and C-reactive protein (CRP) and the pre-PCI IL-6 TMG correlated with plaque features of vulnerability: plaque burden - PB (r = 0.253, p = 0.04) and minimal lumen area - MLA (r = −0.438, p = 0.007), although no relationship existed for thin-capped fibroatheroma defined by either imaging modality. Peripheral IL-6 levels had no correlation with post PCI troponin, although the pre-PCI IL-6 TMG was related (r = 0.334, p = 0.006), as was PB (r = 0.27, p = 0.029). Conclusion IL-6 TMG pre-PCI correlates with plaque burden and MLA that have been shown to predict future clinical events and is correlated with post-PCI troponin release. These associations were not apparent from peripheral blood and suggest that local coronary biomarker signatures may help further define vulnerability and risk.

Background Gastric and colorectal cancer (CRC) are both one of the most common cancers worldwide. In many countries fecal immunochemical tests (FIT)-based CRC screening has been implemented. We investigated if FIT can also be applied for detection of H. pylori, the main risk factor for gastric cancer. Methods This prospective study included participants over 18 years of age referred for urea breath test (UBT). Patients were excluded if they had used antibiotics/bismuth in the past 4 weeks, or a proton pomp inhibitor (PPI) in the past 2 weeks. Participants underwent UBT, ELISA stool antigen test in standard feces tube (SAT), ELISA stool antigen test in FIT tube (Hp-FIT), and blood sampling, and completed a questionnaire on user friendliness. UBT results were used as reference. Results A total of 182 patients were included (37.4% male, median age 52.4 years (IQR 22.4)). Of these, 60 (33.0%) tested H. pylori positive. SAT and Hp-FIT showed comparable overall accuracy 71.1% (95%CI 63.2–78.3) vs. 77.6% (95%CI 70.4–83.8), respectively (p = 0.97). Sensitivity of SAT was 91.8% (95%CI 80.4–97.7) versus 94.2% (95%CI 84.1–98.9) of Hp-FIT (p = 0.98). Serology scored low with an overall accuracy of 49.7% (95%CI 41.7–57.7). Hp-FIT showed the highest overall user convenience. Conclusions FIT can be used with high accuracy and sensitivity for diagnosis of H. pylori and is rated as the most convenient test. Non-invasive Hp-FIT test is highly promising for combined upper and lower gastrointestinal (pre-) cancerous screening. Further research should investigate the clinical implications, benefits and cost-effectiveness of such an approach.

OBJECTIVE 1) Describe the progression of diabetes mellitus over time in an observational study of Wolfram syndrome, a rare, genetic, neurodegenerative disorder which often includes diabetes mellitus and is typically diagnosed during childhood or adolescence. 2) Determine whether C-peptide could be used as a marker of diabetes progression in interventional trials for Wolfram syndrome. METHODS N=44 (25F/19M) participants with genetically-confirmed Wolfram syndrome attended the Washington University Wolfram Research Clinic annually from 2010-2019. Medical history, physical examinations, blood sampling, and questionnaires were used to collect data about diabetes mellitus and other components of Wolfram syndrome. Beta-cell function was assessed by determination of C-peptide during a mixed meal tolerance test. Random coefficients models evaluated the rate of progression of C-peptide over time, and power analyses were used to estimate the number of subjects needed to detect a change in C-peptide decline during an intervention trial. RESULTS 93.2% of patients had diabetes mellitus. Mean HbA1c across all study visits was 7.9%. C-peptide significantly decreased with increasing duration of diabetes mellitus (p

AIM Birth asphyxia can lead to organ dysfunction, varying from isolated biological acidosis to hypoxic-ischemic encephalopathy (HIE). Pathophysiology of moderate or severe HIE is now well known and guidelines exist regarding the care required in this situation. However, for newborns without moderate or severe HIE, no consensus is available. Our objective was to describe the immediate neonatal consequences and need for care of asphyxiated newborns without moderate or severe HIE. METHODS Multicentre retrospective study from January 2015 to December 2017 in two academic centres, including neonates ≥37 gestational weeks with pathological foetal acidemia (umbilical arterial pH

This study monitored the long-term immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in patients who had recovered from coronavirus disease (COVID)-19. Anti-nucleocapsid immunoglobulin G (anti-N IgG) titer in serum samples collected at a single (N = 302) or multiple time points (N = 229) 3–12 months after COVID-19 symptom onset or SARS-CoV-2 detection in respiratory specimens was measured by semiquantitative chemiluminescent microparticle immunoassay. The 531 patients (966 specimens) were classified according to the presence or absence of pneumonia symptoms. Anti N IgG was detected in 87.5% of patients (328/375) at 3 months, 38.6% (93/241) at 6 months, 23.7% (49/207) at 9 months, and 26.6% (38/143) at 12 months. The anti-N IgG seropositivity rate was significantly lower at 6, 9, and 12 months than at 3 months (P P P = 0.04), and 12 months (P = 0.04). The rate started to decline 6–12 months after symptom onset. Anti-N IgG sample/cutoff index was positively correlated with age (r = 0.192, P P

Background Dried blood spot (DBS) microsampling has gained interest in different clinical fields, owing to its many advantages compared to conventional blood sampling. However, whilst being applied for decades for screening purposes, some challenges, such as the hematocrit (Hct) effect, hinder further widespread use of DBS for quantitative purposes in clinical practice. Amongst the approaches that were developed to cope with this issue, is the Hct prediction of DBS using near-infrared (NIR) spectroscopy. Methods Using left-over EDTA-anticoagulated patient samples, the accuracy and precision, stability, and robustness were assessed. Furthermore, applicability of the method on capillary DBS was evaluated via finger prick samples. Results A maximal bias, respectively CV, of 0.012 L/L and 4.5% were obtained. The method was robust towards several aspects, including storage (except for storage at 60°C), measurement location, type of filter paper and spotted volume. Furthermore, the potential to predict the Hct of capillary DBS was demonstrated. Conclusion A commercially available NIR set-up was extensively and successfully validated, allowing non-contact Hct prediction of DBS with excellent accuracy and precision. This allows to correct for the Hct-based bias observed in partial-punch DBS analysis and the set-up of blood-plasma conversion factors, increasing the application potential of patient-centric sampling.

Purpose Inpatient diabetes management involves frequent assessment of glucose levels for treatment decisions. Here we describe a program for inpatient real-time continuous glucose monitoring (rtCGM) at a community hospital and the accuracy of rtCGM-based glucose estimates. Methods Adult inpatients with preexisting diabetes managed with intensive insulin therapy and a diagnosis of coronavirus disease 2019 (COVID-19) were monitored via rtCGM for safety. An rtCGM system transmitted glucose concentration and trending information at 5-minute intervals to nearby smartphones, which relayed the data to a centralized monitoring station. Hypoglycemia alerts were triggered by rtCGM values of ≤85 mg/dL, but rtCGM data were otherwise not used in management decisions; insulin dosing adjustments were based on blood glucose values measured via fingerstick blood sampling. Accuracy was evaluated retrospectively by comparing rtCGM values to contemporaneous point-of-care (POC) blood glucose values. Results A total of 238 pairs of rtCGM and POC data points from 10 patients showed an overall mean absolute relative difference (MARD) of 10.3%. Clarke error grid analysis showed 99.2% of points in the clinically acceptable range, and surveillance error grid analysis showed 89.1% of points in the lowest risk category. It was determined that for 25% of the rtCGM values, discordances in rtCGM and POC values would likely have resulted in different insulin doses. Insulin dose recommendations based on rtCGM values differed by 1 to 3 units from POC-based recommendations. Conclusion rtCGM for inpatient diabetes monitoring is feasible. Evaluation of individual rtCGM-POC paired values suggested that using rtCGM data for management decisions poses minimal risks to patients. Further studies to establish the safety and cost implications of using rtCGM data for inpatient diabetes management decisions are warranted.

Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.

Background Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. Methods This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. Discussion This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. Trial registration ClinicalTrials.gov NCT04385719. Registered 13 May 2020.

Introduction Serologic testing can provide a safe and fast approach for assessing SARS-CoV-2 antibodies. These tests can be utilized as a complementary method in diagnosis and patients' follow-up, and can also be helpful in epidemiological studies. This study aimed to describe temporal changes in the incidence of COVID-19 IgM and IgG antibodies in emergency medical technicians (EMTs) within a specified time period. Methods All EMTs working for Tehran Emergency Medical Service (EMS) center during May to September 2020 were eligible for this study. Those EMTs who were suspected/probable/confirmed cases of COVID-19, based on WHO defined criteria and were willing to participate, entered the study. The EMTs underwent serology testing four weeks after the occurrence of exposure (in suspected cases) or onset of their symptoms (in probable/confirmed cases). Cases were further confirmed by RT-PCR and/or lung CT, and antibody testing was performed for the second and third time with 12-week intervals. Finger-stick blood sampling was utilized for the specimen collection in three different phases. Samples were then analyzed by a commercial immunochromatography-based kit for qualitative measurement of serum IgM and IgG antibodies against the COVID-19 S-protein antigen. Results Two hundred eighty-four participants met the inclusion criteria; their mean age was 35.9 (SD = 7.6) years and consisted of 244 (85.9%) males. COVID-19 was confirmed in 169 out of 284 participants. Subsequently, 142 and 122 participants were included in phases 2 and 3 of the study, respectively. The number of seronegative patients exceeded seropositive ones in all three phases. At baseline, 162 (57%) patients were seronegative, 27 (9.5%) were only positive for IgG, 3 (1.1%) were only positive for IgM, and 92 (32.4%) were positive for both antibodies; Seventy-eight (54.9%) were seronegative, and 31 (21.8%) were positive for both antibodies in the second phase; These values were 85 (69.6%) and 8 (6.6%) for the third phase, respectively. Among the people who were positive IgG in the first phase (80 people), 56.3% were still positive in the second phase and 27.5% in both subsequent phases. Conclusion The results of our study show that there is a significant reduction in COVID-19 antibody seropositivity over time.

Exercise is beneficial for brain health, inducing neuroplasticity and vascular plasticity in the hippocampus, which is possibly mediated by brain-derived neurotrophic factor (BDNF) levels. Here we investigated the short-term effects of exercise, to determine if a 1-week intervention is sufficient to induce brain changes. Fifteen healthy young males completed five supervised exercise training sessions over seven days. This was preceded and followed by a multi-modal magnetic resonance imaging (MRI) scan (diffusion-weighted MRI, perfusion-weighted MRI, dual-calibrated functional MRI) acquired 1 week apart, and blood sampling for BDNF. A diffusion tractography analysis showed, after exercise, a significant reduction relative to baseline in restricted fraction—an axon-specific metric—in the corpus callosum, uncinate fasciculus, and parahippocampal cingulum. A voxel-based approach found an increase in fractional anisotropy and reduction in radial diffusivity symmetrically, in voxels predominantly localised in the corpus callosum. A selective increase in hippocampal blood flow was found following exercise, with no change in vascular reactivity. BDNF levels were not altered. Thus, we demonstrate that 1 week of exercise is sufficient to induce microstructural and vascular brain changes on a group level, independent of BDNF, providing new insight into the temporal dynamics of plasticity, necessary to exploit the therapeutic potential of exercise.

We examined in a rat model of Gulf War illness (GWI), the potential of (−)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicle and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi partially reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function.

A long-acting granulocyte colony-stimulating factor, tripegfilgrastim, was approved in Korea for the prevention of chemotherapy-induced neutropenia in adult patients. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and safety of tripegfilgrastim in pediatric patients. A phase I, open-label, single ascending-dose study was performed in pediatric patients with solid tumors or lymphoma (ClinicalTrials.gov, NCT02963389). The patients were stratified according to age groups (aged 6 to 12 or 12 to 19 years) and received a single subcutaneous dose of tripegfilgrastim 60 μg/kg or 100 μg/kg. Tripegfilgrastim was administered 24 hours after the end of the chemotherapy, and serial blood sampling and safety monitoring were conducted. Twenty-seven patients with solid tumors were enrolled in this study. Tripegfilgrastim was detectable in plasma for an extended period (terminal half-life > 40 hours), and plasma concentrations increased slightly less than dose proportionally. The mean duration of grade 4 neutropenia was reduced as the average tripegfilgrastim concentration during the initial neutrophil recovery process increased. No substantial differences in the pharmacokinetic and pharmacodynamic responses were observed between the two age groups. When stratified by body weight, weighing more than 45 kg has a higher risk of a prolonged neutropenia period when receiving the lower dose (60 μg/kg) of tripegfilgrastim. Tripegfilgrastim was generally safe and well-tolerated in the pediatric patients. These results justify further clinical investigations of tripegfilgrastim at 100 μg/kg dose in pediatric patients.

Introduction Postpartum depression (PPD) is a multifactor disorder caused by psychological, social, and also biological factors. 5-HTTLPR polymorphism in the promoter region of serotonin transporter gene seems to influence PPD onset. In this study, we examined the effect of 5-HTTLPR polymorphism on prenatal and postnatal symptoms of depression and posttraumatic stress in women. Methods A longitudinal design with three points - time 1 (32-40 weeks gestation); time 2 (2 or 3 weeks after birth), and time 3 (3 months after birth) - was made. A total of 141 women were recruited during childbirth preparation courses. At time 1, women completed the Beck Depression Inventory (BDI) and the Los Angeles Symptoms Checklist (LASC). At time 2, they fulfilled BDI and Edinburgh Postnatal Depression Scale (EDPS), LASC and the Perinatal Posttraumatic stress disorder (PTSD) Questionnaire (PPQ); midwives and nurses collected biological test tubes by blood sampling for the genetic analysis. At time 3, the women were reassessed for BDI, LASC, EDPS, and PPQs. Analysis of variance and moderation analysis were used to correlate genotype and psychological investigations. Results Results showed that, compared with LL/LS genotypes, SS genotype moderated cognitive depressive symptoms onset at T2 and T3. Moreover, this genotype correlated, directly or indirectly, with PTSD postpartum aspects (re-experience, avoidance, and hyperarousal). Discussion Findings revealed that a lower expression of serotonin transporter gene, associated with SS genotype, seems to render women more vulnerable to depressive and PTSD symptoms after childbirth.

Supplemental Digital Content is Available in the Text., Purpose: Innovative and sustainable sampling strategies for bioanalytical quantification of drugs and metabolites have gained considerable interest. Scavenging can be stratified as a sustainable sampling strategy using residual material because it aligns with the green principles of waste reduction and sampling optimization. Scavenged sampling includes all biological fluids' (eg, blood, liquor, and urine) leftover from standard clinical care. This review elaborates on the past and current landscape of sustainable sampling within therapeutic drug monitoring, with a focus on scavenged sampling. Methods: In February 2021, 4 databases were searched to assess the literature on the clinical use of innovative and sustainable sampling techniques without applying publication date restrictions. Studies reporting the clinical use of scavenged blood sampling and bridging studies of scavenged sampling and normal blood sampling were eligible for inclusion. Results: Overall, 19 eligible studies concerning scavenged sampling were identified from 1441 records. Scavenged sampling is mainly applied in the pediatric population, although other patient groups may benefit from this strategy. The infrastructure required for scavenged sampling encounters several challenges, including logistic hurdles, storage and handling conditions, and documentation errors. A workflow is proposed with identified opportunities that guide the implementation of scavenged sampling. Conclusions: This review presents current evidence on the clinical use of scavenged sampling strategies. Scavenged sampling can be a suitable approach for drug quantification to improve dosage regimens, perform pharmacokinetic studies, and explore the value of therapeutic drug monitoring without additional sample collection.

Xanthine oxidoreductase (XOR) is known as an enzyme related to purine metabolism, catalysing the oxidation of hypoxanthine to xanthine and of xanthine to uric acid. We investigated the relationship between plasma XOR activity in stable kidney transplantation (KT) recipients and carotid artery lesions.A total of 42 KT patients visiting our outpatient clinic on regular basis were recruited. Associations between plasma XOR activity and the existence of plaque in the common carotid artery (CCA) or internal carotid artery (ICA) and maximum intima-medial thickness (IMT) of CCA (max-CIMT) 0.9 mm were examined using univariate and multivariate analyses.At blood sampling, the mean and SD patient age was 52.7 ± 13.8 years old. Plasma XOR(pmol/h/ml) activity was significantly higher in patients with CCA/ICA plaque or max-CIMT0.9 mm than those without. [23.9 (11.8, 38.3) vs. 8.29 (6.67, 17.5), p .01, 23.9 (16.9, 71.2) vs. 9.16 (6.67, 28.2), p = .01] Univariate and multivariate logistic regression analyses revealed age and plasma XOR activity as independent predictors of CCA/ICA plaque or max-CIMT0.9 mm. Receiver operator characteristic curve analyses revealed that the cutoff value of plasma XOR activity for the diagnosis of CCA/ICA plaque or CCA-IMT 0.9 mm was 16.3 pmol/h/ml.Plasma XOR activity is associated independently with atherosclerotic changes in the carotid artery of stable post-KT patients.

Background and Objective High lipoprotein(a) is a genetically determined causal risk factor for cardiovascular disease, and 20% of the adult population has high levels (ie, >42 mg/dL, >88 nmol/L). We investigated whether early life lipoprotein(a) levels measured in cord blood may serve as a proxy for neonatal venous blood levels, whether lipoprotein(a) birth levels (ie, cord or venous) predict levels later in life, and whether early life and parental levels correlate. Methods The Compare study is a prospective cohort study of newborns (N = 450) from Copenhagen, Denmark, including blood sampling of parents. Plasma lipoprotein(a) was measured in cord blood (N = 402), neonatal venous blood (N = 356), and at 2 (N = 320) and 15 months follow-up (N = 148) of infants, and in parents (N = 705). Results Mean lipoprotein(a) levels were 2.2 (95% CI, 1.9-2.5), 2.4 (2.0-2.7), 4.1 (3.4-4.9), and 14.6 (11.4-17.9) mg/dL in cord, neonatal venous, and 2- and 15-month venous samples, respectively. Lipoprotein(a) levels in cord blood correlated strongly with neonatal venous blood levels (R2 = 0.95, P 42 mg/dL at 15 months with positive predictive values of 89% and 85% for neonatal venous and cord blood. Neonatal and infant levels correlated weakly with parental levels, most pronounced at 15 months (R2 = 0.22, P Conclusions Lipoprotein(a) levels are low in early life, cord blood may serve as a proxy for neonatal venous blood, and birth levels ≥ 90th percentile can identify newborns at risk of developing high levels.

Purpose of review To date, prognostication of patients after acute traumatic spinal cord injury (SCI) mostly relies on the neurological assessment of residual function attributed to lesion characteristics. With emerging treatment candidates awaiting to be tested in early clinical trials, there is a need for wholistic high-yield prognostic biomarkers that integrate both neurogenic and nonneurogenic SCI pathophysiology as well as premorbid patient characteristics. Recent findings It is becoming clearer that effective prognostication after acute SCI would benefit from integrating an assessment of pathophysiological changes on a systemic level, and with that, extend from a lesion-centric approach. Immunological markers mirror tissue injury as well as host immune function and are easily accessible through routine blood sampling. New studies have highlighted the value of circulating white blood cells, neutrophils and lymphocytes in particular, as prognostic systemic indicators of SCI severity and outcomes. Summary We survey recent advances in methods and approaches that may allow for a more refined diagnosis and better prognostication after acute SCI, discuss how these may help deepen our understanding of SCI pathophysiology, and be of use in clinical trials.

Background and Objective Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation. Methods Critically ill children (aged 0–18 years) treated with intravenous ceftriaxone (100 mg/kg once daily, infused in 30 minutes) and a central or arterial line in place were eligible. Opportunistic blood sampling for total and unbound ceftriaxone concentrations was used. Population pharmacokinetic analysis was performed using non-linear mixed-effects modeling on NONMEM™ Version 7.4.3. Simulations were performed to select optimal doses using probability of target attainment for two pharmacokinetic targets of the minimum inhibitory concentration (MIC) reflecting the susceptibility of pathogens (f T > MIC 100% and fT > 4 × MIC 100%). Results Two hundred and five samples for total and 43 time-matched samples for unbound plasma ceftriaxone concentrations were collected from 45 patients, median age 2.5 (range 0.1–16.7) years. A two-compartment model with bodyweight as the co-variate for volume of distribution and clearance, and creatinine-based estimated glomerular filtration rate as an additional covariate for clearance, best described ceftriaxone pharmacokinetics. For a typical patient (2.5 years, 14 kg) with an estimated glomerular filtration rate of 80 mL/min/1.73 m2, the current 100-mg/kg once-daily dose results in a probability of target attainment of 96.8% and 60.8% for a MIC of 0.5 mg/L and 4 × MIC (2 mg/L), respectively, when using fT > MIC 100% as a target. For a 50-mg/kg twice-daily regimen, the probability of target attainment was 99.9% and 93.4%, respectively. Conclusions The current dosing regimen of ceftriaxone provides adequate exposure for susceptible pathogens in most critically ill children. In patients with an estimated glomerular filtration rate of > 80 mL/min/1.73 m2 or in areas with a high prevalence of less-susceptible pathogens (MIC ≥ 0.5 mg/L), a twice-daily dosing regimen of 50 mg/kg can be considered to improve target attainment. Clinical Trial Registration POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018). Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01035-9.

Introduction:\ud Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.\ud \ud Methods:\ud A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.\ud \ud Results:\ud A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557–0.664], p = 0.0015) and 0.516 [0.443–0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.\ud \ud Conclusions:\ud SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.

Hyper- or hypoventilation are commonly occurring stress responses to arterial puncture around the time of blood sampling and have been shown to rapidly alter arterial blood acid-base parameters. This study aimed to evaluate a physiology-based mathematical method to transform peripheral venous blood acid-base values into mathematically arterialised equivalents following acute, transient changes in ventilation. Data from thirty patients scheduled for elective surgery were analysed using the physiology-based method. These data described ventilator changes simulating 'hyper-' or 'hypoventilation' at arterial puncture and included acid-base status from simultaneously drawn blood samples from arterial and peripheral venous catheters at baseline and following ventilatory change. Venous blood was used to calculate mathematically arterialised equivalents using the physiology-based method; baseline values were analysed using Bland-Altman plots. When compared to baseline, measured arterial and calculated arterialised values at each time point within limits of pH: ± 0.03 and PCO2: ± 0.5 kPa, were considered 'not different from baseline'. Percentage of values considered not different from baseline were calculated at each sampling timepoint following hyper- and hypoventilation. For the physiological method, bias and limits of agreement for pH and PCO2 were -0.001 (-0.022 to 0.020) and -0.02 (-0.37 to 0.33) kPa at baseline, respectively. 60 s following a change in ventilation, 100% of the mathematically arterialised values of pH and PCO2 were not different from baseline, compared to less than 40% of the measured arterial values at the same timepoint. In clinical situations where transient breath-holding or hyperventilation may compromise the accuracy of arterial blood samples, arterialised venous blood is a stable representative of steady state arterial blood.

Background Personal glucose meters, primarily designed for self-control of glucose concentration in patients with diabetes, are frequently used in clinical practice as point-of-care equipment. The procedure of washing hands with water and soap before testing, as recommended by the manufacturer of personal glucose meters, in hospital wards is often difficult to fulfil and is replaced by disinfecting the place of blood sampling with isopropyl alcohol. Aim The purpose of the research was to evaluate the effect of different disinfecting procedures on glycemia measurement in capillary blood using personal glucose meters. Materials and methods Four measurements of glycemia were taken in each of 50-volunteer group using Accu-Check Performa (Roche, Swiss) glucose meter using different procedures: washing hands with soap and drying them (1), disinfection with isopropyl alcohol and waiting for the disinfectant to evaporate (2) and the immediate puncture after disinfection. In the latter case two kind of single-use lancets were use – typical for adult (3) and smaller preferred by diabetics or children (4). Results Paired T-student test showed no statistically significant difference between measurements 1st and 2nd 95% CI (−4.282 to 0.322), p = 0.09. However, the comparison between 1st/3rd and 1st/4th showed statistically significant difference, 95% CI (−4.964 to −0.796), p = 0,0077 (p Conclusions The procedure of disinfection when fluid completely evaporates has no effect on glucose measurements. Sampling the wet finger influences results of glucose measurement but observed changes were clinically irrelevant.

Objective To understand whether polycystic ovarian morphology (PCOM) represents a transient phase, and whether an increased stroma could help to characterize the phenotype of the ovary in adolescence. Methods Cross-sectional population-based study on high-school students in Cagliari, Italy. The study population consisted of 257 normocyclic non-hyperandrogenic girls selected from a sample of 600 healthy volunteers recruited from 2012 to 2016. Clinical examination, medical history, blood sampling, and pelvic ultrasound (US) were performed. Postmenarchal years and body mass index (BMI) were estimated. Follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β estradiol (E2), total testosterone (tT), delta-4-androstenedione (A), and 17-hydroxyprogesterone (17-OHP) were measured. Ovarian volume, follicular number per section (FNPS), and S/A ratio were measured by pelvic US. Results Following the Rotterdam guidelines for US PCOS diagnosis and setting the normal S/A ratio at ≤0.3, subjects were categorized into 3 groups: (1) normal ovarian morphology (NOM; n = 154, 60%); (2) polycystic ovarian morphology (PCOM) with normal S/A ratio (PCOM-NS; n = 70, 27%); and (3) PCOM with increased S/A ratio (PCOM-IS; n = 33, 13%). The NOM group had more postmenarchal years and a lower LH than both the PCOM groups, and lower A and tT than the PCOM-IS group. The PCOM-NS group had fewer postmenarchal years and lower A than the PCOM-IS group. Interestingly, unlike NOM and PCOM-NS, the prevalence of PCOM-IS remained constant among the 3 phases of postmenarchal age (10% vs 16% vs 15%, P = not significant). Conclusion This study demonstrates that PCOM can be a transient condition, whereas a high S/A ratio is a stable US alteration present from early postmenarchal years.

Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram.

Female sexual dysfunction (FSD) may be a mirror of a poor cardiometabolic state. In a small pilot study enrolling 71 women with FSD, we previously demonstrated that clitoral Pulsatility Index (PI) evaluated by using color Doppler ultrasound (CDU), reflecting vascular resistance, was associated with cardiometabolic risk factors. Data on uterine CDU in this context are lacking. First, to confirm previously reported data on the direct association between clitoral PI and cardiometabolic risk factors on a larger study population of women consulting for sexual symptoms; second, to investigate eventual similar correlations between cardiometabolic risk factors and CDU parameters of the uterine artery. We also ascertained whether uterine artery PI, similarly to what had previously been observed for clitoral artery PI, was directly related to body image uneasiness and psychopathological symptoms, assessed by validated questionnaires. N = 230 women consulting our clinic for sexual symptoms were examined with clitoral CDU and blood sampling and were asked to fill out the Female Sexual Function Index, the Middlesex Hospital Questionnaire (MHQ) and the Body Uneasiness Test (BUT). In a subgroup of women (n = 164), we also performed transvaginal CDU with measurement of uterine artery parameters. At multivariate analysis, we found a direct association between clitoral PI and body mass index (BMI) (p = 0.004), waist circumference (WC) (p = 0.004), triglycerides (p = 0.006), insulin (p = 0.029) and HOMA-IR (p = 0.009). Furthermore, a correlation between obesity and Metabolic Syndrome (MetS) and a higher clitoral PI was observed (p = 0.003 and p = 0.012, respectively). Clitoral PI was also correlated with MHQ-S (p = 0.010), a scale exploring somatized anxiety symptoms, and BUT-B Positive Symptom Distress Index (p = 0.010), a measure of body image concerns. Similarly, when investigating the uterine artery, we were able to demonstrate an association between its PI and BMI (p p = 0.001), insulin (p = 0.006), glycated haemoglobin (p = p = 0.009). Women diagnosed with obesity and MetS showed significantly higher uterine PI values vs. those without obesity or MetS (p = 0.001 and p = 0.004, respectively). Finally, uterine PI was associated with BUT-A Global Severity Index (p

ObjectivesTo investigate the prevalence and quantity of aortic valve calcium (AVC) in two large cohorts, stratified according to age and lipoprotein(a) (Lp(a)), and to assess the association between Lp(a) and AVC.MethodsWe included 2412 participants from the population-based Rotterdam Study (52% women, mean age=69.6±6.3 years) and 859 apparently healthy individuals from the Amsterdam University Medical Centers (UMC) outpatient clinic (57% women, mean age=45.9±11.6 years). All individuals underwent blood sampling to determine Lp(a) concentration and non-enhanced cardiac CT to assess AVC. Logistic and linear regression analyses were performed to investigate the associations of Lp(a) with the presence and amount of AVC.ResultsThe prevalence of AVC was 33.1% in the Rotterdam Study and 5.4% in the Amsterdam UMC cohort. Higher Lp(a) concentrations were independently associated with presence of AVC in both cohorts (OR per 50 mg/dL increase in Lp(a): 1.54 (95% CI 1.36 to 1.75) in the Rotterdam Study cohort and 2.02 (95% CI 1.19 to 3.44) in the Amsterdam UMC cohort). In the Rotterdam Study cohort, higher Lp(a) concentrations were also associated with increase in aortic valve Agatston score (β 0.19, 95% CI 0.06 to 0.32 per 50 mg/dL increase).ConclusionsLp(a) is robustly associated with presence of AVC in a wide age range of individuals. These results provide further rationale to assess the effect of Lp(a) lowering interventions in individuals with early AVC to prevent end-stage aortic valve stenosis.

Objective/Background Individuals with sickle cell anaemia (SCA) may manifest various forms of renal abnormalities. Proteinuria is an early marker of renal dysfunction and a strong risk factor for chronic kidney disease (CKD) progression in both patients with SCA and non-SCA population. Currently, the degree of attention given to proteinuric CKD far exceeds that of nonproteinuric CKD, and risk factors that might trigger a progressive decline of the glomerular filtration rate (GFR) in the absence of proteinuria have not been well evaluated in SCA. The aim of this study was to compare the clinical and laboratory parameters among SCA patients with proteinuric and nonproteinuric CKD. Methods This was a cross-sectional study conducted at the University of Maiduguri Teaching Hospital in north-eastern Nigeria between January 2013 and April 2018. Clinical variables including age of diagnosis of SCA, frequency of vaso-occlusive crises, number of hospitalizations per annum and transfusion therapy were collected. Laboratory data including haematological profile and renal function test were obtained from routine blood sampling. Results A total of 257 patients with SCA (HbSS) were enrolled during the study period of which 42 had proteinuric CKD, and 48 had nonproteinuric CKD. The two groups were matched for the number of hospital admission (p = .063) and blood transfusion per year (p = .450), frequency of painful crisis (p = .210), systolic blood pressure (p = .084) and diastolic blood pressure (p = .400). In the proteinuric CKD group, the mean serum creatinine was higher (332.17 µmol/L, p = .001) and the estimated GFR was lower (31.88 mL/min, p = .046). The serum alkaline phosphatase was higher in the nonproteinuric CKD group (81.81 IU/L, p = .012). Conclusion Nonproteinuric CKD was more frequent than proteinuric CKD in our study population; however, the proteinuric group presented with more advanced disease.

Praziquantel pharmacokinetics studies in schistosomiasis infected children are scarce partly due to the challenges/complexity of intensive blood sampling in the target population. This study was aimed to investigate the optimal single sampling time-point for monitoring praziquantel exposure. This was intensive pharmacokinetic study conducted among 32 Schistosoma mansoni infected children treated with an oral standard single-dose 40 mg/kg praziquantel. Plasma samples were collected at 0, 1, 2, 4, 6 and 8 h post-praziquantel administration. Quantification of praziquantel and its enantiomers (R- and S-praziquantel) concentrations was done by Liquid chromatography-tandem mass spectrometer (LC–MS/MS). The correlation between area under the plasma concentration–time curve from 0 to 8 h (AUC8) and plasma concentrations at each specific sampling time-point was determined by Pearson’s correlation coefficient (r2). The median age (range) of the study population was 12.5 years (10–17). The study participants were 17 males and 15 females. Both total praziquantel and its enantiomers (R- and S-praziquantel) displayed a wide inter-individual pharmacokinetic variability. Regression analysis indicated that, plasma concentrations collected at 4 h post-dose had a significantly highest correlation with the AUC8 for both total praziquantel (r2 = 0.81, p S-praziquantel (r2 = 0.84, p R-praziquantel, plasma concentrations collected at 6 h sampling time-point had a significantly highest correlation with the AUC8 (r2 = 0.79, p R-praziquantel enantiomer.

Erectile dysfunction (ED) is one of the most common sexual disorders in men. During the past 30 years, there has been no new drug development for ED. Thus, exploring the genetic basis of ED deserves further study, in hope of developing new pharmacological treatments for ED. In this study, Real-Time PCR analysis was used to assess the expression of androgen regulatory protein (Andpro) and pyruvate dehydrogenase kinase 4 (Pdk4) genes in ED. For this purpose, the experiment was performed on 20 men with severe ED and 20 potent men. IIEF-15 was used to determine the ED severity. The study was conducted in the Department of Sexual Medicine of the Kermanshah University of Medical Sciences, Kermanshah, Iran. The EDTA-Na vacuum blood tube was taken from ED patients and controls. Informed consent was obtained from all participants. After blood sampling, RNA was extracted from whole blood. Then cDNA was synthesized. The gene expression was analyzed through the qPCR method. The ß-actin was used as a reference gene. To further study these two proteins, their three-dimensional structures were predicted through I-TASSER. Compared with controls, in ED patients, the expression of the Andpro gene decreased, while the expression of the Pdk4 gene increased (p

Background Persistent hypoglycemia is common in the newborn and is associated with poor neurodevelopmental outcome. Adequate monitoring is critical in prevention, but is dependent on frequent, often hourly blood sampling. Continuous glucose monitoring (CGM) is increasingly being used in children with type 1 diabetes mellitus, but use in neonatology remains limited. We aimed to introduce real-time CGM to provide insights into patterns of dysglycemia and to support the management of persistent neonatal hypoglycemia. Methods This is a single-center retrospective study of real-time CGM use over a 4-year period in babies with persistent hypoglycemia. Results CGMs were inserted in 14 babies: 8 term and 6 preterm infants, 9 with evidence of congenital hyperinsulinism (CHI). A total of 224 days of data was collected demonstrating marked fluctuations in glucose levels in babies with CHI, with a higher sensor glucose SD (1.52 ± 0.79 mmol/L vs 0.77 ± 0.22 mmol/L) in infants with CHI compared with preterm infants. A total of 1254 paired glucose values (CGM and blood) were compared and gave a mean absolute relative difference of 11%. Conclusion CGM highlighted the challenges of preventing hypoglycemia in these babies when using intermittent blood glucose levels alone, and the potential application of CGM as an adjunct to clinical care.

Context Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons). Objective We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood–brain barrier) and impedes their downstream effects. Design Case/control. Setting Academic medical center. Participants Mice. Interventions Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature. Main Outcome Measures LH pulse parameters and body temperature. Results First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals’ elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity. Conclusion The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.

Skin rash is a common adverse event associated with erlotinib therapy. In severe conditions, the rash could affect patients' QOL. If the rash occurrence can be predicted, erlotinib treatment failures can be prevented. We designed an in vivo study that applied erlotinib regimens resembling its clinical application to evaluate possible erlotinib-induced skin rash biomarkers for humans and simultaneously observe the effects of erlotinib discontinuation, followed with or without dose reduction, on rash development. Rats were divided into four groups: placebo, constant (erlotinib 35 mg/kg on d1-d21), intermittent (erlotinib 70 mg/kg on d1-d7 and d15-d21), and mimic (erlotinib 70 mg/kg on d1-d7 and erlotinib 35 mg/kg on d15-d21). Blood sampling was performed on d1, d8, d15, and d22. The samples were used to measure erlotinib concentrations, the level of hepatic and renal function markers, immune cell percentages, and immune cells' CD45 expression levels. Erlotinib 70 mg/kg generated high mean circulating erlotinib concentrations (>1800 ng/mL) that led to severe rashes. Erlotinib dose reduction following rash occurrence reduced circulating erlotinib concentration and rash severity. After the treatment, the escalation of neutrophil percentages and reduction of neutrophils' CD45 expression levels were observed, which were significantly correlated with the rash occurrence. This study is the first to show that erlotinib-induced skin rash may be affected by the reduction of neutrophils' CD45 expression levels, and this is a valuable finding to elucidate the erlotinib-induced skin rash formation mechanism.

Background Seroprevalence of anti-SARS-CoV-2 antibodies is now available in several world regions to better estimate transmission dynamics. However, to date, there is no epidemiological data regarding anti-SARS-CoV-2 prevalence in Mexico. Therefore, we aimed to determine the prevalence of anti-SARS-CoV-2 antibodies and define the clinical and demographic characteristics associated with seroprevalence. Methods We conducted a cross-sectional serological survey in Ciudad Guadalupe, NL, Mexico. City government employees voluntarily participated during July 2020. Demographic and clinical characteristics were collected at the time of blood sampling to analyze the associated characteristics. IgM/IgG antibodies were determined using a qualitative chemiluminescent immunoassay. Descriptive statistics were used for categorical and continuous variables. Statistical significance was tested using the Chi-squared test, Student’s t-test and the Mann–Whitney. Logistic regression models and the odds ratios (adjusted and unadjusted) were used to estimate the association of demographic and clinical characteristics. Results Of the 3,268 participants included, 193 (5.9%, 95% CI 5.1–6.8) tested positive for IgM/IgG against SARS-CoV-2. Sex, city of residence, and comorbidities did not show any association with having IgM/IgG antibodies. A total of 114 out of 193 (59.1%) subjects with a positive test were asymptomatic, and the odds of being positive were higher in those who reported symptoms of COVID-19 in the previous four weeks to the survey (OR 4.1, 95% CI 2.9–5.5). Conclusions There is a low rate of SARS-CoV-2 infection among government employees that have continuously been working during the pandemic. Six in ten infections were asymptomatic, and seroprevalence is low and still far from herd immunity. Epidemiological surveillance and preventive measures should be mandatory.

Background The Fetal Blood Sample (FBS) is used as an indicator of fetal acidosis during labor. Its place is discussed through the lack of randomized trials, as well as the limitations related to the technical procedure. An alternative could be the Fetal Scalp Stimulation (FSS). Aim Our objective was to describe the FSS diagnostic value to predict fetal wellbeing defined from FBS. Methods The FSS consisted in a digital scalp stimulation for 15 s. Test was negative when an acceleration and/or a normal variability were elicited in the 2 min following. FSS was performed before each FBS which was classified as normal when pH was > 7.25. The diagnostic value was assessed by sensibility, specificity, positive and negative predictive values. Findings 148 women were included in our center from February to December 2019. Of the 191 FBS procedures, when accelerations were elicited sensibility was 58,3 (36.8–77.1), specificity was 67,5 (59.3–75), positive predictive value was 20,9 (12.5–32.9) and negative predictive value was 91.7 % (95 %CI, 85–95.5). Discussion FBS is considered as the gold standard in our study which could be discussed as it is abandoned in some countries because of its questioned reliability and the lack of controlled randomized trials. Conclusion This study suggests that FSS could be an interesting alternative adjunctive test to perform in the first instance as it seems to be reliable, non-invasive and easy to perform in order to limit FBS only to absence of acceleration after FSS.

BACKGROUND & AIMS: The aim was to measure fractional hepatic blood volume (HBV) and hepatic blood flow (HBF) before and after a meal in patients with cirrhosis (n = 7) and healthy persons (n = 6).METHODS: Catheters were placed in a radial artery and a hepatic vein for blood sampling and a peripheral vein for indocyanine green (ICG) infusion. A 6-min positron emission tomography (PET) liver scan was performed after inhalation of 1000 MBq 15O-CO and repeated after ingestion of a standard meal. HBV was calculated as the 15O-CO concentration in liver tissue (PET) divided by that in arterial blood. HBF was calculated from ICG infusion rate and arterial and hepatic venous blood concentrations according to Fick's principle.RESULTS: Mean fasting HBV was 14 mL blood/100 mL liver tissue in patients with cirrhosis and 21 mL blood/100 mL liver tissue in healthy subjects (p CONCLUSIONS: Fasting HBV was lower in patients with cirrhosis and did not decrease postprandially as it did in the healthy controls although the HBF increased equally. Patients with cirrhosis thus have a disturbed hemodynamic response to normo-physiological changes such as a meal.

Background and Aims Because of COVID-19 public health restrictions, telemedicine has replaced conventional outpatient follow up for most patients with chronic immune-mediated inflammatory disorders treated with biologic drugs. Innovative solutions to facilitate remote therapeutic drug monitoring are therefore required. Low-volume intracapillary blood sampling can be undertaken by patients at home and samples returned by post to central laboratories. We sought to report the effect of the COVID-19 pandemic on requests for therapeutic drug monitoring and the equivalence, acceptability and effectiveness of low volume Patient-led Remote IntraCapillary pharmacoKinetic Sampling [fingerPRICKS] compared to conventional venepuncture. Methods We undertook a cross-sectional blood sampling methods comparison study and compared sample types using linear regression models. Drug and antidrug antibody levels were measured using standard ELISAs. Acceptability was assessed using a purpose-designed questionnaire. Results Therapeutic drug monitoring requests for adalimumab (96.5 [70.5–106] per week to 52 [33.5–57.0], p < 0.001) but not infliximab (184.5 [161.2–214.2] to 161 [135–197.5], p = 0.34) reduced during the first UK stay-at-home lockdown compared with the preceding 6 months. Fingerprick sampling was equivalent to conventional venepuncture for adalimumab, infliximab, vedolizumab and ustekinumab drug, and anti-adalimumab and anti-infliximab antibody levels. The median [interquartile range] volume of serum obtained using intracapillary sampling was 195 µL [130–210]. More than 87% [90/103] of patients agreed that intracapillary testing was easy and 69% [71/103] preferred it to conventional venepuncture. In routine care, 75.3% [58/77] of patients returned two blood samples within 14 days to permit remote assessment of biologic therapeutic drug monitoring. Conclusions Therapeutic drug monitoring can be undertaken using patient-led remote intracapillary blood sampling and has the potential to be a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.

Various biomarkers of oxidative stress and redox status have been used in a number of clinical and epidemiological studies related to diseases and conditions that involve disturbances of the redox balance. However, a comprehensive study of diurnal variations of a set of biomarkers has not been conducted so far. Therefore, the aim of this study is to investigate circadian rhythm and time-of-day-effects of a set of frequently used biomarkers of oxidative stress, redox and antioxidant status in serum/plasma. These biomarkers include Reactive Oxygen Metabolites (ROM), Biological Antioxidant Potency (BAP), Total Thiols in Proteins (TTP), high-sensitive C-Reactive Protein (CRP) and Uric Acid (UA). During a 24-hr study, blood sampling was conducted 6 times at 4-hr intervals. The presence of circadian rhythm was analyzed with CircWave analysis, whereas the effect of time was analyzed with Repeated Measures ANOVA (RM-ANOVA). Thereby, the main focus was on the time points in working hours (8, 12 and 16 hr), which are used frequently in practice. Of all investigated biomarkers, only TTP in males demonstrated statistically significant circadian rhythm (p = 0.040). A statistically significant effect between all six time points with RM-ANOVA was observed for ROM, TTP and UA in both genders, and for BAP in females only. No statistically significant differences were observed between the time points 8 hr and 12 hr for any of the biomarkers that were assessed in our study. In conclusion, diurnal variations in some of the studied biomarkers that we demonstrate here should be taken into account when designing and conducting clinical and epidemiological studies. It is advised to standardize the time of sampling with a preference in the morning hours.

The missense variant, breast cancer resistance protein (BCRP) p.Q141K, which encodes a reduced function BCRP, has been linked to poor response to allopurinol. Using a multifaceted approach, we aimed to characterize the relationship(s) between BCRP p.Q141K, the pharmacokinetics (PK) and pharmacodynamics (PD) of oxypurinol (the active metabolite of allopurinol), and serum uric acid (SUA) levels. A prospective clinical study (NCT02956278) was conducted in which healthy volunteers were given a single oral dose of 300mg allopurinol followed by intensive blood sampling. Data were analyzed using noncompartmental analysis and population PK/PD modeling. Additionally, electronic health records were analyzed to investigate whether clinical inhibitors of BCRP phenocopied the effects of the p.Q141K variant with respect to SUA. Subjects homozygous for p.Q141K had a longer half-life (34.2±12.2h vs. 19.1±1.42h) of oxypurinol. The PK/PD model showed that women had a 24.8% lower volume of distribution. Baseline SUA was affected by p.Q141K genotype and renal function; that is, it changed by 48.8% for every 1mg/dl difference in serum creatinine. Real-world data analyses showed that patients prescribed clinical inhibitors of BCRP have higher SUA levels than those that have not been prescribed inhibitors of BCRP, consistent with the idea that BCRP inhibitors phenocopy the effects of p.Q141K on uric acid levels. This study identified important covariates of oxypurinol PK/PD that could affect its efficacy for the treatment of gout as well as a potential side effect of BCRP inhibitors on increasing uric acid levels, which has not been described previously.

The promise of using induced pluripotent stem cells (iPSCs) for cellular therapies has been hampered by the lack of easily isolatable and well characterized source cells whose genomes have undergone minimal changes during their processing. Blood-derived late-outgrowth endothelial progenitor cells (EPCs) are used for disease modeling and have potential therapeutic uses including cell transplantation and the translation of induced pluripotent stem cell (iPSC) derivatives. However, the current isolation of EPCs has been inconsistent and requires at least 40-80 mL of blood, limiting their wider use. In addition, previous EPC reprogramming methods precluded the translation of EPC-derived iPSCs to the clinic. Here a series of clinically-compatible advances in the isolation and reprogramming of EPCs is presented, including a reduction of blood sampling volumes to 10 mL and use of highly efficient RNA-based reprogramming methods together with autologous human serum, resulting in clinically relevant iPSCs carrying minimal copy number variations (CNVs) compared to their parent line.

Relatively little is known about associations between peripheral inflammation and neural function in humans. Neuroimaging studies in adults have suggested that elevated peripheral inflammatory markers are associated with altered resting state functional connectivity (rsFC) in several brain networks associated with mood and cognition. Few studies have examined these associations in adolescents, yet scarce data from adolescents point to different networks than adult studies. The current study examined the associations between peripheral inflammation and rsFC in a community sample of adolescents (n = 70; age, 12–15 years; 32 female, 36 male, 2 nonbinary). After blood sampling, an fMRI scan was performed to assess rsFC. Assay for serum inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP), was performed. Results indicated that higher TNF-α was associated with altered rsFC between the right amygdala and left striatum and between the right inferior frontal gyrus and left parietal cortex (p < 0.05 whole-brain corrected). Associations with IL-6 and CRP were not significant. In contrast with findings in adults, inflammation may have unique links with the connectivity of the developing adolescent brain. Results have implications for understanding how peripheral inflammation may influence connectivity during adolescence, when neural networks are undergoing major developmental changes.

Background The influence of regular breath-hold training on hematological variables is not fully understood. We monitored hematological variables in breath-hold divers' (BHDs) and active controls over a year expecting both breath-hold training and seasonal effects. Methods In 11 recreational BHDs (36 ± 9 yrs, 177 ± 8 cm, 72 ± 9 kg) and 12 active controls (22 ± 2 yrs, 174 ± 8 cm, 70 ± 13 kg) monthly blood samples were analyzed with the hematological module of WADA's athlete biological passport. Hemoglobin mass and plasma volume were measured indirectly by the CO-rebreathing method for the last eight months of the study. Breath-hold training sessions were recorded online. Days without breath-hold training, or the number of hours prior to blood sampling when training was realized within the last 24 h, were recorded. Results Hematology did not differ significantly between BHDs and controls over the study time (P > 0.05). However, hematological values varied significantly over time for both groups suggesting seasonal effects. Blood sampling 19h or more after a breath hold training did not indicate any acute effects of breath holding training. Conclusions In comparison with a physically active lifestyle, regular breath-hold training does not induce significant variations over one year for the hematological module of the ABP.

BACKGROUND: Increased plasma aldehyde dehydrogenase 1 (ALDH1) levels have been proposed to predict cancer chemoresistance. However, studies have reported inconsistent results, depending on the type of cancer cells used. OBJECTIVE: This study aimed to investigate the correlation between plasma levels of ALDH1 and chemotherapy responses to the taxane–adriamycin–cyclophosphamide (TAC) regimen in breast cancer patients. METHODS: Thirty breast cancer patients who underwent chemotherapy using the TAC regimen were included in this study. Blood sampling was performed before chemotherapy was initiated and after the first and third cycles of chemotherapy administration. After 3 cycles of chemotherapy, patients were categorized as non-responsive if the tumor size was reduced

ContextAdult obesity is associated with chronic low-grade inflammation and may give rise to future chronic disease. However, it is unclear whether adiposity-related inflammation is already apparent in childhood.ObjectiveTo study associations between child adiposity measures with circulating monocytes and naive and memory subsets in CD4, CD8, and γδ T cell lineages.MethodsTen-year-old children (n = 890) from the Generation R Cohort underwent dual-energy x-ray absorptiometry and magnetic resonance imaging for body composition (body mass index [BMI], fat mass index [FMI], android-to-gynoid fat mass ratio, visceral fat index, liver fat fraction). Blood samples were taken for detailed immunophenotyping of leukocytes by 11-color flow cytometry.ResultsSeveral statistically significant associations were observed. A 1-SD increase in total FMI was associated with +8.4% (95% CI 2.0, 15.2) Vδ2+Vγ9+ and +7.4% (95% CI 2.4, 12.5) CD8+TEMRO cell numbers. A 1-SD increase in visceral fat index was associated with +10.7% (95% CI 3.3, 18.7) Vδ2+Vγ9+ and +8.3% (95% CI 2.6, 14.4) CD8+TEMRO cell numbers. Higher android-to-gynoid fat mass ratio was only associated with higher Vδ2+Vγ9+ T cells. Liver fat was associated with higher CD8+TEMRO cells but not with Vδ2+Vγ9+ T cells. Only liver fat was associated with lower Th17 cell numbers: a 1-SD increase was associated with −8.9% (95% CI −13.7, −3.7) Th17 cells. No associations for total CD8+, CD4+ T cells, or monocytes were observed. BMI was not associated with immune cells.ConclusionHigher Vδ2+Vγ9+ and CD8+TEMRO cell numbers in children with higher visceral fat index could reflect presence of adiposity-related inflammation in children with adiposity of a general population.

Background and aims: Today, Sleeve gastrectomy (SG) has recently become the most common bariatric procedure among various bariatric surgical procedures due to its advantages. The aim of this study is to investigate nutritional status, body composition and biochemical parameters following SG. Methods: This was a prospective study, the subjects were patients who underwent SG at a special obesity clinic in Istanbul, Turkey, between 01.05.2017 and 01.11.2017. The mean body mass index (BMI) of the participants was 42.15 +/- 4.84 kg/m(2) for men and 41.44 +/- 4.34 kg/m(2) for women, preoperatively. Nutritional status, some anthropometric measurements and blood sampling were taken at each visit. Data were collected and analyzed for the present study at the following periods: pre-operation (pre-op), 1 month, 3 months and 6 months after surgery. Results: A total of 47 SG patients (20 men, 27 women) were evaluated. The mean BMI was 30.23 +/- 3.56 kg/m(2) for men and 30.35 +/- 4.36 kg/m(2) for women after 6 months and the amount of excess weight loss (EWL) increased in the 3 months (p

Background Associations between sugar consumption and cardiometabolic health, taking into account the physical form of sugar-containing foods (liquid vs. solid) and the type of sugars consumed [free sugars (FSs) vs. naturally occurring sugars (NOSs)], remain to be thoroughly documented. Objective The objective was to examine whether FS and NOS intakes from drinks and solid foods are associated with cardiometabolic risk factors in a sample of French-speaking adults from the province of Quebec, Canada. Methods Data were collected as part of the cross-sectional PREDISE (PREDicteurs Individuels, Sociaux et Environnementaux) study (n = 1019, 18-65 y old; 50% women). FS and NOS intakes were assessed by three 24-h dietary recalls using a self-administered, web-based application. Diet quality was assessed using the Alternative Healthy Eating Index-2010. Participants underwent on-site clinical assessment of cardiometabolic risk factors, including blood pressure, waist circumference, BMI, and fasting blood sampling (glucose, insulin, C-reactive protein, blood lipids). Multivariable linear regression models were performed to examine the associations between sugar intake and cardiometabolic risk factors with sociodemographic characteristics, lifestyle variables, and diet quality entered as covariates. Results In fully adjusted models, FS intake from drinks was associated with fasting insulin (1.06%; 95% CI: 0.30%, 1.84%; P = 0.006) and with insulin resistance as estimated using the HOMA model (1.01%; 95% CI: 0.19%, 1.84%; P = 0.02). All metabolic variables that were significantly associated with NOS intake from solid foods in minimally adjusted models were no longer significant after entering sociodemographic and lifestyle variables (e.g., educational and income levels, smoking, physical activity, daily energy intake) and diet quality in the models. Conclusions Our data from an adult sample showed that unfavorable and favorable associations with cardiometabolic risk factors observed, respectively, for FS intake from drinks and NOS intake from foods are mostly explained by sociodemographic and lifestyle variables, as well as by diet quality.

Several strategies exist to prevent and control echinococcosis, a global parasitic disease. However, most treatments are ineffective and adverse effects are common. Therefore, we aimed to screen protoscolex antigen molecules of Echinococcus granulosus to identify a diagnostic biomarker for hydatid disease. Published E. granulosus transcriptome sequencing data were analyzed to screen for antigen molecules that are highly expressed in protoscoleces but not in oncospheres. The membrane protein EG-06283 (annotated as Frizzled-4) was selected from 16 antigens, and its gene fragment was subjected to codon optimization and synthesis. rEG-06283 expression was induced in the pET-24a/EG-06283/BL21 strain; subsequently, the protein was purified and subcutaneously injected into ICR mice at weeks 0, 2, 4, and 6. Blood sampling occurred periodically to quantify serum immunoglobulin G (IgG) levels via enzyme-linked immunosorbent assays (ELISA). Immunogenicity was determined by western blot assays using sera from normal mice and mice with secondary hydatid infections. The antigen’s immune reactivity and diagnostic value were validated using sera of patients with hydatid disease. ELISA results confirmed that the antigen molecule induced specific IgG production in mice, resulting in significantly higher levels than those in the adjuvant and control groups (P

Overview Objective: Fetal Inflammatory Response Syndrome (FIRS) is a serious complication accompanied by increased neonatal mortality and morbidity. Early dia­gnosis of FIRS is essential to detect high risk infants. The aim of the study was to evaluate the correlation between interleukin-6 (IL-6), procalcitonin (PCT), C-reactive protein (CRP) in cord blood and histologically proven funisitis/ chorioamnionitis in high-risk infants after preterm birth. Methods: Blood sampling for the measurement of inflammatory bio­markers was performed immediately after placental delivery and umbilical cutting. Umbilical and placental inflammatory changes were assessed using a recently released scoring system (Amsterdam Placental Workshop Group Consensus). Results: One hundred preterm infants (30.5 ± 2.5 gestational week, birth weight 1,443 ± 566 grams) and 21 health term infants were analyzed. Histologic chorioamnionitis was confirmed in 19% cases and chorioamnionitis with funisitis in 7% cases. Thirty-three infants (33%) fulfilled criteria of FIRS (funistis and/ or umbilical IL-6 > 11 ng/ L). The presence of FIRS correlated significantly with maternal leukocytosis (P < 0.001), preterm premature rupture of membrane (P < 0.001) and preterm uterine contraction (P < 0.0001). In comparison to preterm and healthy term infants we found statistically significant higher levels of umbilical inflammatory bio­markers (IL-6, PCT, CRP) in FIRS group (P < 0.0001). Composite mortality and morbidity (bronchopulmonary dysplasia, intraventricular haemorrhage, periventricular leukomalacia) was higher in FIRS group (28.1 vs 22.4% in preterm group). However, the difference was not statistically significant (P = 0.53). Conclusion: Our study confirmed the correlation of umbilical inflammatory bio­markers levels (IL-6, PCT, CRP) and the presence of FIRS. We did not find significant adverse impact of FIRS on neonatal mortality and morbidity. Nevertheless, our results could be influenced by the size of study group and strict inclusion criteria (only cases after C-section were analyzed). Keywords: fetal inflammatory response syndrome – neonatal mortality – morbidity – interleukin-6 – C-reactive protein – procalcitonin – chorioamnionitis and funisitis