Early Time Course Research Articles

Paving the way to a neural fate – RNA signatures in naive and trans-differentiating mesenchymal stem cells

Mesenchymal Stem Cells (MSCs) derived from the embryonic mesoderm persist as a viable source of multipotent cells in adults and have a crucial role in tissue repair. One of the most promising aspects of MSCs is their ability to trans-differentiate into cell types outside of the mesodermal lineage, such as neurons. This characteristic positions MSCs as potential therapeutic tools for neurological disorders. However, the definition of a clear MSC signature is an ongoing topic of debate. Likewise, there is still a significant knowledge gap about functional alterations of MSCs during their transition to a neural fate. In this study, our focus is on the dynamic expression of RNA in MSCs as they undergo trans-differentiation compared to undifferentiated MSCs. To track and correlate changes in cellular signaling, we conducted high-throughput RNA expression profiling during the early time-course of human MSC neurogenic trans-differentiation. The expression of synapse maturation markers, including NLGN2 and NPTX1, increased during the first 24 h. The expression of neuron differentiation markers, such as GAP43 strongly increased during 48 h of trans-differentiation. Neural stem cell marker NES and neuron differentiation marker, including TUBB3 and ENO1, were highly expressed in mesenchymal stem cells and remained so during trans-differentiation. Pathways analyses revealed early changes in MSCs signaling that can be linked to the acquisition of neuronal features. Furthermore, we identified microRNAs (miRNAs) as potential drivers of the cellular trans-differentiation process. We also determined potential risk factors related to the neural trans-differentiation process. These factors include the persistence of stemness features and the expression of factors involved in neurofunctional abnormalities and tumorigenic processes. In conclusion, our findings contribute valuable insights into the intricate landscape of MSCs during neural trans-differentiation. These insights can pave the way for the development of safer treatments of neurological disorders.

#2605 Evaluation of cardiac fetal gene program in experimental uremia

Abstract Background and Aims Heart failure (HF) and uremia share several potent cardiac hypertrophic stimuli such as wall stress, sympathetic activation, renin angiotensin system activation and oxidative stress. In heart failure, induction of fetal gene program is one of the major processes through which such stimuli lead to progressive pathological hypertrophy and myocardial dysfunction. The fetal genes are activated by the transcription factor, myocyte enhance factor 2 (MEF2) which is a downstream target of the Ca++- Calmodulin Dependent Kinase II (CAMKII) pathway. The CAMKII pathway has been shown to be the major transduction pathway of the hypertrophic stimuli in HF [1, 2]. We hosphorzed that such mechanisms are also at play in uremic cardiomyopathy and tested the hypothesis in a rodent model of experimental uremia. Method Wistar rats (n = 18) had subtotal nephrectomy (STNx) or sham surgery (sham) and were followed up for 10 weeks. In vivo and in vitro cardiac assessments were performed. Cardiac tissue was extracted, and protein expression of CAMKII and hosphor-CAMKII were quantified using immunoblotting. Protein expression of MEF2 and its target fetal genes were also studied. Histological analyses were performed to quantify myocardial fibrosis. Data was analysed using an independent sample t-test with Welch's correction and expressed as mean± SEM. Results STNx resulted in higher echocardiographic left ventricular mass, heart weight to tibia length ratio and myocardial fibrosis in the STNx group (Fig. 1) demonstrating cardiac pathological hypertrophy. CaMKII signalling was activated and the expression of MEF2 was also increased following STNx (Fig. 1). There was trend towards increased expression of fetal genes (Fig. 1). However, the difference did not reach statistical significance. Conclusion The study shows that experimental uremia induces cardiac pathological hypertrophy along with activation of intracellular pathways involved in fetal gene induction. Further studies evaluating fetal genes at an earlier time course in the evolution of pathological hypertrophy will be worthwhile.

Mapping 18F-FDG Kinetics Together with Patient-Specific Bootstrap Assessment of Uncertainties: An Illustration with Data from a PET/CT Scanner with a Long Axial Field of View.

The purpose of this study was to examine a nonparametric approach to mapping kinetic parameters and their uncertainties with data from the emerging generation of dynamic whole-body PET/CT scanners. Methods: Dynamic PET 18F-FDG data from a set of 24 cancer patients studied on a long-axial-field-of-view PET/CT scanner were considered. Kinetics were mapped using a nonparametric residue mapping (NPRM) technique. Uncertainties were evaluated using an image-based bootstrapping methodology. Kinetics and bootstrap-derived uncertainties are reported for voxels, maximum-intensity projections, and volumes of interest (VOIs) corresponding to several key organs and lesions. Comparisons between NPRM and standard 2-compartment (2C) modeling of VOI kinetics are carefully examined. Results: NPRM-generated kinetic maps were of good quality and well aligned with vascular and metabolic 18F-FDG patterns, reasonable for the range of VOIs considered. On a single 3.2-GHz processor, the specification of the bootstrapping model took 140 min; individual bootstrap replicates required 80 min each. VOI time-course data were much more accurately represented, particularly in the early time course, by NPRM than by 2C modeling constructs, and improvements in fit were statistically highly significant. Although 18F-FDG flux values evaluated by NPRM and 2C modeling were generally similar, significant deviations between vascular blood and distribution volume estimates were found. The bootstrap enables the assessment of quite complex summaries of mapped kinetics. This is illustrated with maximum-intensity maps of kinetics and their uncertainties. Conclusion: NPRM kinetics combined with image-domain bootstrapping is practical with large whole-body dynamic 18F-FDG datasets. The information provided by bootstrapping could support more sophisticated uses of PET biomarkers used in clinical decision-making for the individual patient.

Upregulation of NADPH-oxidase, inducible nitric oxide synthase and apoptosis in the hippocampus following impaired insulin signaling in the rats: Development of sporadic Alzheimer’s disease

NADPH-oxidase (NOX) is a multi-subunit enzyme complex. The upregulation of NOX causes massive production of superoxide (O2¯), which avidly reacts with nitric oxide (NO) and increases cellular reactive oxygen/nitrogen species (ROS/RNS). Increased ROS/RNS plays pivotal role in the sporadic Alzheimer’s disease (sAD) development and brain damage following impaired insulin signaling. Hence, this study aimed to examine early-time course of changes in NOX and NOS expression, and apoptotic proteins in the rats hippocampi following insulin signaling impairment [induced by STZ injection; intraperitoneal (IP) or in cerebral ventricles (ICV)]. Early effects (1, 3, or 6 weeks) on the NOX activity, translocation of NOX subunits from cytosol to the membrane, NO-synthases [neuronal-, inducible- and endothelial-NOS; nNOS, iNOS and eNOS], The Rac-1 protein expression, levels of NO and O2¯, cytochrome c release, caspase-3 and 9 activations (cleavage) were studied. STZ injection (in both models) increased NOX activity, O2¯ production, and enhanced cytosolic subunits translocation into membrane. The iNOS but not nNOS and eNOS expression and NO levels were increased in STZ treated rats. Finally, STZ injection increased cytochrome c release, caspase-3 and 9 activations in a manner that was significantly associated with levels of O2¯ and NO in the hippocampus. ICV-STZ administration resulted in significant profound changes over the IP route. In conclusion, impairment in insulin function induces early changes in ROS/RNS contents through NOX and iNOS upregulation and neuronal apoptosis in the hippocampus. Our results could mechanistically explain the role of impaired insulin function in the development of sAD.

Short- and long-term neuroplasticity interact during the perceptual learning of concurrent speech.

Plasticity from auditory experience shapes the brain's encoding and perception of sound. However, whether such long-term plasticity alters the trajectory of short-term plasticity during speech processing has yet to be investigated. Here, we explored the neural mechanisms and interplay between short- and long-term neuroplasticity for rapid auditory perceptual learning of concurrent speech sounds in young, normal-hearing musicians and nonmusicians. Participants learned to identify double-vowel mixtures during ~ 45min training sessions recorded simultaneously with high-density electroencephalography (EEG). We analyzed frequency-following responses (FFRs) and event-related potentials (ERPs) to investigate neural correlates of learning at subcortical and cortical levels, respectively. Although both groups showed rapid perceptual learning, musicians showed faster behavioral decisions than nonmusicians overall. Learning-related changes were not apparent in brainstem FFRs. However, plasticity was highly evident in cortex, where ERPs revealed unique hemispheric asymmetries between groups suggestive of different neural strategies (musicians: right hemisphere bias; nonmusicians: left hemisphere). Source reconstruction and the early (150-200ms) time course of these effects localized learning-induced cortical plasticity to auditory-sensory brain areas. Our findings reinforce the domain-general benefits of musicianship but reveal that successful speech sound learning is driven by a critical interplay between long- and short-term mechanisms of auditory plasticity, which first emerge at a cortical level.

Early Time Courses of Recurrent Venous Thromboembolism and Bleeding during Apixaban or Dalteparin Therapy for Patients with Cancer.

In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE. The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding. In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group. The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE.

First activity and interactions in thalamus and cortex using raw single-trial EEG and MEG elicited by somatosensory stimulation.

One of the primary motivations for studying the human brain is to comprehend how external sensory input is processed and ultimately perceived by the brain. A good understanding of these processes can promote the identification of biomarkers for the diagnosis of various neurological disorders; it can also provide ways of evaluating therapeutic techniques. In this work, we seek the minimal requirements for identifying key stages of activity in the brain elicited by median nerve stimulation. We have used a priori knowledge and applied a simple, linear, spatial filter on the electroencephalography and magnetoencephalography signals to identify the early responses in the thalamus and cortex evoked by short electrical stimulation of the median nerve at the wrist. The spatial filter is defined first from the average EEG and MEG signals and then refined using consistency selection rules across ST. The refined spatial filter is then applied to extract the timecourses of each ST in each targeted generator. These ST timecourses are studied through clustering to quantify the ST variability. The nature of ST connectivity between thalamic and cortical generators is then studied within each identified cluster using linear and non-linear algorithms with time delays to extract linked and directional activities. A novel combination of linear and non-linear methods provides in addition discrimination of influences as excitatory or inhibitory. Our method identifies two key aspects of the evoked response. Firstly, the early onset of activity in the thalamus and the somatosensory cortex, known as the P14 and P20 in EEG and the second M20 for MEG. Secondly, good estimates are obtained for the early timecourse of activity from these two areas. The results confirm the existence of variability in ST brain activations and reveal distinct and novel patterns of connectivity in different clusters. It has been demonstrated that we can extract new insights into stimulus processing without the use of computationally costly source reconstruction techniques which require assumptions and detailed modeling of the brain. Our methodology, thanks to its simplicity and minimal computational requirements, has the potential for real-time applications such as in neurofeedback systems and brain-computer interfaces.

Early time-course of respiratory mechanics, mechanical power and gas exchange in ARDS patients

PurposeTo describe the clinical course of ARDS during the first three days of mechanical ventilation, to compare ventilatory setting, respiratory mechanics and gas exchange variables collected during the first three days of mechanical ventilation between patients who survived and died during intensive care unit (ICU) stay and to investigate the variables associated with mortality at ICU admission and throughout the first three days of mechanical ventilation. Materials and methodsProspective observational study. Mechanically ventilated ARDS patients were studied at ICU admission and for the following three days. Univariate logistic regression models were performed for PaO2/FiO2 ratio, driving pressure and alveolar dead space fraction and for mechanical power and mechanical power ratio. ResultsMechanical power ratio was higher in non survivors at ICU admission and over time; PaO2/FiO2 ratio was higher in survivors with a similar behavior over time in the two groups while alveolar dead space fraction was similar at ICU admission and over time between groups. Mechanical power ratio was the only physiological variable which remained consistently associated with ICU mortality throughout the study. ConclusionsThe alteration in oxygenation, dead space, and mechanical power ratio should be assessed not at intensive care admission, but during the first days of mechanical ventilation to better predict outcome.

Consistency of left ventricular ejection fraction measurements in the early time course of STEMI.

Early after ST-segment elevation myocardial infarction (STEMI), initial LV reshaping and hypokinesia may affect analysis of LV function. Concomitant microvascular dysfunction may affect LV function as well. To perform a comparative evaluation of left ventricular ejection fraction (LVEF) and stroke volume (SV) by different imaging modalities to assess LV function early after STEMI. LVEF and SV were assessed using serial imaging within 24 h and 5 days after STEMI using cineventriculography (CVG), 2-dimensional echocardiography (2DE), 2D/3D cardiovascular magnetic resonance (CMR) (2D/3D) in 82 patients. 2D analyses of LVEF using CVG, 2DE and 2D CMR yielded uniform results within 24 h and 5 days of STEMI. SV assessment between CVG and 2DE was comparable, whereas values for SV were higher using 2D CMR (p < 0.01 all). This was due to higher LVEDV measurements. LVEF by 2D versus 3D CMR was comparable, 3D CMR yielded higher volumetric values. This was not influenced by infarct location or infarct size. 2D analysis of LVEF yielded robust results across all imaging techniques implying that CVG, 2DE, and 2D CMR can be used interchangeably early after STEMI. SV measurements differed substantially between imaging techniques due to higher intermodality-differences of absolute volumetric measurements.

Parafoveal syntactic processing from word N + 2 during reading: the case of gender-specific German articles

Previous research has suggested that some syntactic information such as word class can be processed parafoveally during reading. However, it is still unclear to what extent early syntactic cueing within noun phrases can facilitate word processing during dynamic reading. Two experiments (total N = 72) were designed to address this question using a gaze-contingent boundary change paradigm to manipulate the syntactic fit within a nominal phrase. Either the article (Experiment 1) or the noun (Experiment 2) was manipulated in the parafovea, resulting in a syntactic mismatch, depending on the condition. Results indicated a substantial elevation of viewing times on both parts of the noun phrase when conflicting syntactic information had been present in the parafovea. In Experiment 1, the article was also fixated more often in the syntactic mismatch condition. These results provide direct evidence of parafoveal syntactic processing. Based on the early time-course of this effect, it can be concluded that grammatical gender is used to generate constraints for the processing of upcoming nouns. To our knowledge, these results also provide the first evidence that syntactic information can be extracted from a parafoveal word N + 2.

FRET-based nanosensor AMPfret distinguishes physiological from toxic stress.

Cells can deal with different kinds of stress by responding with compensatory or detoxifying mechanisms. Only when such systems become saturated or overstrained, the stress may emerge as toxic. In energy metabolism, the AMP-activated protein kinase (AMPK) has evolved to detect physiologically relevant energy stress in form of decreased ATP/AMP and ATP/ADP ratios. Once activated, AMPK induces compensatory measures that increase ATP generation and reduce ATP consumption. We have exploited this naturally evolved energy sensing mechanism by engineering the genetically-encoded, FRET-based nanosensor AMPfret. This sensor allows for direct, real-time monitoring of cellular energy state as the cell perceives it. We further developed clonal cell lines with site-specific integration of the AMPfret genes, showing AMPfret expression at suitable levels (Abi Nahed et al., 2023, Meth Mol Biol). With the example of HEK293T cells treated with nanoparticles or prospective anti-cancer drugs, we show that the early time course of the AMPfret signal is predictive for physiological versus toxic stress. While the former leads to only mild or transient increase in the AMPfret signal, the latter triggers a possibly slow but persistent and strong increase in AMPfret signal. Thus, AMPfret seems to be appropriate for a more generalized energy-linked toxicity screening.

Early time course of oxidative stress in hippocampal synaptosomes and cognitive loss following impaired insulin signaling in rats: Development of sporadic Alzheimer’s disease

Oxidative stress, caused by impaired insulin signaling, plays a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (sAD). We investigated the oxidative stress parameters in the synaptosomes prepared from the hippocampus tissue in order to identify their potential role in sAD development in intraperitoneal (IP) and intracerebroventricular (ICV) streptozotocin (STZ) injections models of insulin signaling impairment. Rats were harvested 1, 3, or 6 weeks post treatment. Spatial learning and memory, several antioxidants and oxidative stress markers were analyzed. Results showed a significant deficit in learning and memory in rats injected with STZ through IP and ICV routes. Glutathione, glutathione/oxidized glutathione, glutathione S-transferase, glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase(SOD)-total, Zn/Cu(SOD), Mn/Fe(SOD) are significantly decreased in IP-STZ and ICV-STZ groups at 1, 3, and 6 weeks after STZ injection. Oxidized glutathione, thiobarbituric acid reactive species, glucose 6-Phosphate dehydrogenase, protein carbonyls, 4-Hydroxynonenal, and 3-Nitrotyrosine are significantly increased in IP-STZ and ICV-STZ groups at 1,3, and 6 weeks after STZ injection. Changes in oxidative stress parameters in ICV-STZ groups are greater than IP-STZ groups. STZ treatment induced cognitive impairments by 3-W and 6-W, and it was significantly correlated with the extent of oxidative damage. In conclusion, STZ administration through ICV route is deleterious in causing early synaptosomal oxidative damage that exacerbated with time and correlated with cognitive impairments. Our data implicate the involvement of oxidative stress as an early feature of sAD and provide insights into the behavioral and biochemical changes over the course of disease development.

Wheat NAM genes regulate the majority of early monocarpic senescence transcriptional changes including nitrogen remobilization genes.

Senescence enables the remobilization of nitrogen and micronutrients from vegetative tissues of wheat (Triticum aestivum L.) into the grain. Understanding the molecular players in this process will enable the breeding of wheat lines with tailored grain nutrient content. The NAC transcription factor NAM-B1 is associated with earlier senescence and higher levels of grain protein, iron, and zinc contents due to increased nutrient remobilization. To investigate how related NAM genes control nitrogen remobilization at the molecular level, we carried out a comparative transcriptomic study using flag leaves at 7 time points (3, 7, 10, 13, 15, 19, and 26 days after anthesis) in wild type and NAM RNA interference lines with reduced NAM gene expression. Approximately 2.5 times more genes were differentially expressed in wild type than NAM RNA interference plants during this early senescence time course (6,508 vs 2,605 genes). In both genotypes, differentially expressed genes were enriched for gene ontology terms related to photosynthesis, hormones, amino acid transport, and nitrogen metabolism. However, nitrogen metabolism genes including glutamine synthetase (GS1 and GS2), glutamate decarboxylase (GAD), glutamate dehydrogenase (GDH), and asparagine synthetase (ASN1) showed stronger or earlier differential expression in wild-type than in NAM RNA interference plants, consistent with higher nitrogen remobilization. The use of time course data identified the dynamics of NAM-regulated and NAM-independent gene expression changes during senescence and provides an entry point to functionally characterize the pathways regulating senescence and nutrient remobilization in wheat.

Physiological basis of brief, intense interval training to enhance maximal oxygen uptake: a mini-review.

Brief, intense interval training describes a style of exercise characterized by short bouts of strenuous effort interspersed with recovery periods. The method increases whole body maximal oxygen uptake (V̇o2max), but the underlying physiological basis is unclear. V̇o2max represents the functional limit of the integrative oxygen cascade, which refers to the physiological steps involved in oxygen transport and utilization from atmospheric air to mitochondrial metabolism. There is insufficient evidence to definitively state which steps in the oxygen cascade are responsible for the improvement in V̇o2max after brief, intense interval training. Studies typically focus on specific physiological variables that are often characterized as "central" or "peripheral" based in part on their location in the body. Recent work suggests that training for ≥6 wk improves V̇o2max in part by increasing maximal cardiac output and expanding blood volume, responses that are expected to augment central oxygen delivery. Other responses to brief, intense interval training, including increased capillary and mitochondrial density, may contribute to increases in V̇o2max via enhanced skeletal muscle oxygen extraction and/or increased muscle diffusing capacity. This is especially evident after relatively short-term training and despite no change in central oxygen delivery factors. Mechanistic investigations, particularly employing contemporary technologies, are needed to advance our understanding of the early time course of the V̇o2max response to brief, intense interval training and the extent to which changes in specific oxygen cascade processes compare with traditional endurance training.

A Prospective Observational Study on Multiplate®-, ROTEM®- and Thrombin Generation Examinations Before and Early After Implantation of a Left Ventricular Assist Device (LVAD).

BackgroundHeart failure patients are frequently on coagulation-active medications before LVAD implantation and perioperative bleeding is a frequent complication after left ventricular assist device (LVAD) implantation. The role of point-of-care coagulation tests in assessing bleeding risk for LVAD implantation and the early postoperative time course of these tests is not well established.MethodsWe prospectively enrolled 25 patients with terminal heart failure undergoing LVAD implantation. Study related TRAP-, ASPI- and ADP- tests of Multiplate® platelet aggregometry, ROTEM® rotational thromboelastometry (INTEM, EXTEM, FIBTEM), thrombin generation assay and conventional laboratory studies were measured at 11 predefined time-points during the first 21 postoperative days. We examined if preoperative TRAP-, ASPI-, ADP- and ROTEM values are correlated with estimated total blood loss (primary outcome parameter) during the first 21 days after LVAD implantation and compared the baseline values of these measurements between patients with a bleeding event to those without. We performed Spearman's correlation and non-parametric tests for paired and non-paired comparisons.Results7 out of 25 (28%) patients experienced a bleeding event of which 4 required surgical revision. Of the preoperatively performed measurements the TRAP test [Spearman's Rho (ρ) = −0.5, p = 0.01], INTEM CFT (ρ = 0.72, p < 0.001), INTEM alpha (−0.7, p < 0.001), EXTEM MCF (ρ = −0.63; p < 0.001), EXTEM alpha (ρ = −0.67; p < 0.001), FIBTEM MCF (ρ = −0.41; p = 0.042), Fibrinogen (Clauss) (ρ = −0.5; p = 0.011), Anti-thrombin activity (ρ = −0.49; p = 0.013) and platelet count (ρ = −0.42; p = 0.034) were significantly correlated to total blood loss. Patients undergoing a surgical bleeding revision had significantly reduced values in TRAP—[31.5 IQR (17.25–43.5U) vs. 69 IQR (52.5–87U); p = 0.004], ASPI—[16.5 IQR (5.5–35.7U) vs. 39 IQR (24.5–62.5U); p = 0.038], ADP—[30 IQR (22–69U) vs. 12.5 IQR (8.7–21.5U); p = 0.01], EXTEM MCF—[63 IQR (57.7–63.7) vs. 67 IQR (65–75.5); p = 0.019] and EXTEM alpha [74 IQR (68.75–74) vs. 79 IQR (78–80.5); p = 0.002] values before LVAD implantation.ConclusionMultiplate® and ROTEM® measurements before LVAD implantation may identify LVAD candidates with platelet dysfunction and alterations of the primary hemostasis and could guide anesthetists and intensive care practitioners in bleeding risk stratification and in the perioperative clinical management.

Early Time Course of Oxidative Stress in Hippocampal Synaptosomes and Cognitive Loss Following Impaired Insulin Signaling in Rats: Development of Sporadic Alzheimer's Disease

Early Time Course of Oxidative Stress in Hippocampal Synaptosomes and Cognitive Loss Following Impaired Insulin Signaling in Rats: Development of Sporadic Alzheimer's Disease

Preliminary Evaluation of Short-Term Abstinence Effects Among Never-Smoking Experienced Users of Modern Electronic Cigarettes.

ECIG use has increased among non-smokers, with the potential negative consequence of developing nicotine dependence. ECIG users report withdrawal symptoms upon abstinence, though the significance of these symptoms has been questioned. This preliminary study aimed to characterize the early timecourse of ECIG withdrawal under forced abstinence. Fifteen never-smoking ECIG users completed two conditions whereby participants either abstained from ECIG use (abstinence) or used their own ECIG (ad lib) for 3 h. Puff topography in this latter condition was measured via video observation. Outcome measures included heart rate, subjective ratings of withdrawal, cognitive performance, and choice behavior. Heart rate was lower during abstinence compared to ad lib use (F = 12.60, p < .01, ƞp2 = 0.47). Higher levels of craving (F = 4.98, p < .05, ƞp2 = 0.26) and lower levels of nicotine effects (e.g., dizzy, F = 4.62, p < .05, ƞp2 = 0.36) were reported during abstinence compared to ad lib use. Interaction effects were observed for both factors of the Questionnaire of Smoking Urges: Brief (Fs > 3.56, ps < .05, ƞp2s = 0.21-0.27), with factor scores increasing from baseline to 90 min in the abstinent condition only. Inhibitory control was impaired at 120 min in the abstinent condition only (F = 7.51, p < .05, ƞp2 = 0.50). Never-smoking ECIG users experienced aversive withdrawal symptoms within 2-3 h of abstinence. Future work should include other control conditions, such as placebo ECIGs or nicotine replacement therapy, and biomarkers of nicotine exposure, as well as examine withdrawal as a function of device type. Never-smoking ECIG users experience some aversive nicotine withdrawal symptoms within two to three hours of abstinence. Relative to ad lib ECIG use, abstinence decreased heart rate and inhibitory control, as well as increased subjective ratings of withdrawal such as craving and intention to vape. Those same symptoms might be suppressed by self-administration of ECIGs. Experiencing withdrawal upon abstinence may indicate that ECIGs can cause dependence without a history of other tobacco use.

Anosmia-related internet search and the course of the first wave of the COVID-19 pandemic in the United States

BackgroundThe current pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China. Although the first case in the United States was reported on Jan 20, 2020 in Washington, the early pandemic time course is uncertain. One approach with the potential to provide more insight into this time course is the examination of search activity. This study analyzed US search data prior to the first press release of anosmia as an early symptom (March 20, 2020). MethodsDaily internet search query data was obtained from Google Trends (September 20th to March 20th for 2015 to 2020) both for the United States and on a state-by-state basis. Normalized anosmia-related search activity for the years prior to the pandemic was averaged to obtain a baseline level. Cross-correlations were performed to determine the time-lag between changes in search activity and SARS-CoV-2 cases/deaths. ResultsOnly New York showed both significant increases in anosmia-related terms during the pandemic year as well as a significant lag (6 days) between increases in search activity and the number of cases/deaths attributed to SARS-CoV-2. ConclusionsThere is no evidence from search activity to suggest earlier spread of SARS-CoV-2 than has been previously reported. The increase in anosmia-related searches preceded increases in SARS-CoV-2 cases/deaths by 6 days, but this was only significant over the background noise of searches for other reasons in the setting of a very large outbreak (New York in the spring of 2020).

Apelin-13 in septic shock: effective in supporting hemodynamics in sheep but compromised by enzymatic breakdown in patients

Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

Prognostic Values of Platelet Distribution Width and Platelet Distribution Width-to-Platelet Ratio in Severe Burns.

ABSTRACTBackground:Platelet distribution width (PDW) and PDW-to-platelet ratio (PPR) have been proven to be good prognostic indicators for many diseases. However, their prognostic values in severe burns have not been reported.Objective:To investigate the early time course of PDW and PPR in severe burn patients and investigate their prognostic values.Methods:This is a 16-year, single-center retrospective study of 590 severe burn patients. The complete blood count parameters on day 1, day 3, and day 7 postburn, including PDW and PPR, were collected. Receiver operating characteristic curves (ROC) analysis, multiple logistic regression analysis and Kaplan–Meier survival analysis were performed to evaluate the prognostic values of PDW and PPR in severe burn patients.Results:According to 120-day follow-up records, 96 patients were nonsurvivors and 494 patients were survivors. ROC and area under the curve (AUC) analysis showed that, for predicting 120-day prognosis, the AUC of PDW (0.782) and PPR (0.816) on day 3 was the highest, followed by the AUC of PDW (0.764) and PPR (0.750) on day 7. The ROC–AUC of PPR (0.816) on day 3 was very close to that of the ABSI score (0.818). Multiple logistic regression analysis showed that the PDW (P = 0.033 and P = 0.009) and PPR (P = 0.052 and P = 0.046) on day 3 and day 7 were all significantly independently positively associated with 120-day mortality. Kaplan–Meier survival analysis showed that high PDW and PPR were both significantly associated with a high 120-day mortality rate on day 3 and day 7.Conclusion:PDW and PPR on day 3 and day 7 were independent risk factors for 120-day mortality in severe burn patients. These objective and readily available prognostic indicators may be more clinically favored.