Background: Treatment of hypoxemic respiratory failure (HRF) and Acute Respiratory Distress Syndrome (ARDS) is complex. Standardized management of HRF and ARDS may improve adherence to evidence informed practice and improve outcomes.

Research question: To examine the effect of standardized management compared to usual care on survival in HRF and ARDS patients.

Methods: MEDLINE, EMBASE, Cochrane, CINAHL, Scopus, and Web-of-Science were searched (inception to 2018). Included studies were randomized clinical trials or quasi-experimental studies that examined the effect of standardized management (care-protocol, care-pathway, or bundle) compared with usual management among mechanically ventilated adult patients admitted to an intensive care unit (ICU) with HRF or ARDS. Study characteristics, pathway components, and patient outcomes were abstracted independently by two reviewers.

Results: From 15,932 unique citations, 14 studies were included in the systematic review (3 RCTs and 11 quasi-experimental studies). Twelve studies (including 5,767 patients) were included in the meta-analysis. Standardized management of HRF was associated with a 23% relative reduction in mortality (relative risk (RR) 0.77, 95% CI 0.65-0.91, I² 70%, p=0.002). In studies targeting ARDS patients (n=8), a 21% pooled mortality reduction was observed (RR 0.79, 95% CI 0.71-0.88, I² 3.1%). Standardized management was associated with increased 28-day ventilator-free days (weighted-mean difference, 3.48 days, 95% CI 2.43-4.54 p< 0.001). Standardized management was also associated with a reduction in tidal volume (weighted mean difference -1.80 mL/kg predicted body weight, 95% CI -2.80 to -0.80, p<0.001). Meta-regression demonstrated that the reduction in mortality was associated with provision of lower tidal volume (p=0.045).

Interpretation: When compared to usual management, standardized management of HRF and ARDS patients is associated with increased ventilator-free days, lower tidal volume ventilation, and lower mortality. Intensive care units should consider the use of standardized management to improve the processes and outcomes of care for patients with HRF and ARDS.

Keywords: Acute Respiratory Distress Syndrome (ARDS); care bundles and pathways; hypoxemic respiratory failure; mechanical ventilation; systematic review.

Glaucoma is an eye disease initiated due to excessive intraocular pressure inside it and caused complete sightlessness at its progressed stage. Whereas timely glaucoma screening-based treatment can save the patient from complete vision loss. Accurate screening procedures are dependent on the availability of human experts who performs the manual analysis of retinal samples to identify the glaucomatous-affected regions. However, due to complex glaucoma screening procedures and shortage of human resources, we often face delays which can increase the vision loss ratio around the globe. To cope with the challenges of manual systems, there is an urgent demand for designing an effective automated framework that can accurately identify the Optic Disc (OD) and Optic Cup (OC) lesions at the earliest stage. Efficient and effective identification and classification of glaucomatous regions is a complicated job due to the wide variations in the mass, shade, orientation, and shapes of lesions. Furthermore, the extensive similarity between the lesion and eye color further complicates the classification process. To overcome the aforementioned challenges, we have presented a Deep Learning (DL)-based approach namely EfficientDet-D0 with EfficientNet-B0 as the backbone. The presented framework comprises three steps for glaucoma localization and classification. Initially, the deep features from the suspected samples are computed with the EfficientNet-B0 feature extractor. Then, the Bi-directional Feature Pyramid Network (BiFPN) module of EfficientDet-D0 takes the computed features from the EfficientNet-B0 and performs the top-down and bottom-up keypoints fusion several times. In the last step, the resultant localized area containing glaucoma lesion with associated class is predicted. We have confirmed the robustness of our work by evaluating it on a challenging dataset namely an online retinal fundus image database for glaucoma analysis (ORIGA). Furthermore, we have performed cross-dataset validation on the High-Resolution Fundus (HRF), and Retinal Image database for Optic Nerve Evaluation (RIM ONE DL) datasets to show the generalization ability of our work. Both the numeric and visual evaluations confirm that EfficientDet-D0 outperforms the newest frameworks and is more proficient in glaucoma classification.

Keywords: EfficientDet; EfficientNet; fundus images; glaucoma.

Diabetic retinopathy (DR) is the main cause of blindness in diabetic patients. Early and accurate diagnosis can improve the analysis and prognosis of the disease. One of the earliest symptoms of DR are the hemorrhages in the retina. Therefore, we propose a new method for accurate hemorrhage detection from the retinal fundus images. First, the proposed method uses the modified contrast enhancement method to improve the edge details from the input retinal fundus images. In the second stage, a new convolutional neural network (CNN) architecture is proposed to detect hemorrhages. A modified pre-trained CNN model is used to extract features from the detected hemorrhages. In the third stage, all extracted feature vectors are fused using the convolutional sparse image decomposition method, and finally, the best features are selected by using the multi-logistic regression controlled entropy variance approach. The proposed method is evaluated on 1509 images from HRF, DRIVE, STARE, MESSIDOR, DIARETDB0, and DIARETDB1 databases and achieves the average accuracy of 97.71%, which is superior to the previous works. Moreover, the proposed hemorrhage detection system attains better performance, in terms of visual quality and quantitative analysis with high accuracy, in comparison with the state-of-the-art methods.

Keywords: deep learning; diabetic retinopathy; feature fusion; hemorrhage detection; medical image processing; retinal fundus image.

Purpose: To quantitatively explore the correlation between optical coherence tomography (OCT) parameters and vision impairment in patients with diabetic macular edema (DME).

Methods: This study was a retrospective observational case series. One-hundred eyes from 66 patients with DME were retrospectively included. OCT parameters, including central macular thickness (CMT), height of intraretinal cystoid, subretinal fluid and sponge-like retinal swelling, density of hyperreflective foci (HRF), and integrity of the ellipsoidal zone (EZ), were assessed. Correlation analyses and multiple linear regression analysis were performed to quantitatively explore the relationship between best-corrected visual acuity (BCVA) and OCT parameters.

Results: Among all OCT parameters, CMT, height of intraretinal cystoid, height of sponge-like retinal swelling, and density of HRF and EZ integrity were significantly correlated with BCVA (r = -0.550, -0.526, -0.411, -0.277, and -0.501, respectively; P < 0.01). In multiple linear regression analysis, CMT, density of HRF, and EZ integrity fit a significant linear equation (β = 0.482, 0.184, and 0.447, respectively), with the adjusted R square reaching 0.522 (P < 0.001). In eyes without SRF, the height of intraretinal cystoid, density of HRF, and EZ integrity were included in the model and an adjusted R square of 0.605 (P < 0.001) was obtained.

Conclusion: In DME eyes, OCT parameters, including the density of HRF, the EZ integrity together with CMT, or the height of intraretinal cystoid, could explain 52.2% to 60.5% of the variation in BCVA and were weighted approximately 2 : 1 : 2, respectively.

Purpose: We aimed to determine the correlation between optical coherence tomography (OCT)- and demographic features and baseline best corrected visual acuity (BCVA) in treatment-naïve patients with retinal vein occlusion (RVO).

Methods: This was a cross-sectional posthoc analysis of OCT images that included RVO patients from two prospective, open-label, multicentre studies. The morphological grading was done manually, in the standardized setting of a reading centre. Main outcome measure was the estimated difference in Early Treatment Diabetic Retinopathy Study letters associated with each individual biomarker.

Results: Included were 381/301 treatment-naïve patients with BRVO/CRVO. For BRVO, statistically significant correlations with BCVA were seen for a 100 µm increase in central subfield thickness (CST; -3.1 letters), intraretinal cysts at centre point (CP; +4.1), subretinal fluid (SRF) at CP (+3.0) and hyperreflective foci (HRF) at the central B-scan (-2.2). In CRVO, a 100 µm increase in CST was associated with a loss of -3.4 letters. In the total cohort, 100 µm increase in CST, SRF at CP and HRF at the central B-scan correlated with a difference of -3.2,+3.2 and -2.0 letters. A 10-year increase in age and female gender yielded a -2.0 and -2.5 letter decrease in the total cohort. Adjusted multiple R² for the respective group was 18.3%/26.3%/23.5%.

Conclusions: Of all parameters studied, only CST and age were consistently associated with worse BCVA in treatment-naïve RVO patients. Morphology on OCT explained only a modest part of functional loss in this patient cohort.

Keywords: biomarker; function; morphology; optical coherence tomography; retinal vein occlusion.

This perspectives article discusses the use of a novel set of dynamical biomarkers in the assessment of biological versus chronological age. The basis for this development is a recently delineated property of altered sinoatrial pacemaker-neuroautonomic function, termed heart rate fragmentation (HRF). Fragmented rhythms manifest as an increase in the density of changes in heart rate acceleration sign, not mechanistically explicable by physiological cardiac vagal tone modulation. We reported that HRF increased monotonically with cross-sectional age and that HRF measures, but not conventional heart rate variability metrics, were significantly associated with major incident cardiovascular events in the Multi-Ethnic Study of Atherosclerosis (MESA). Furthermore, HRF measures added value to both Framingham and MESA cardiovascular risk indices. Here, we propose that interventions that fundamentally slow or reverse the pace of biological aging, via system-wide effects, should be associated with a decrease in the degree of HRF and possibly with a reemergence of the nonfragmented ("fluent") patterns associated with more youthful heart rate dynamics.

Purpose: To assess whether the combination of intra-abdominal hypertension (IAH, intra-abdominal pressure ≥ 12 mmHg) and hypoxic respiratory failure (HRF, PaO2/FiO2 ratio < 300 mmHg) in patients receiving invasive ventilation is an independent risk factor for 90- and 28-day mortality as well as ICU- and ventilation-free days.

Methods: Mechanically ventilated patients who had blood gas analyses performed and intra-abdominal pressure measured, were included from a prospective cohort. Subgroups were defined by the absence (Group 1) or the presence of either IAH (Group 2) or HRF (Group 3) or both (Group 4). Mixed-effects regression analysis was performed.

Results: Ninety-day mortality increased from 16% (Group 1, n = 50) to 30% (Group 2, n = 20) and 27% (Group 3, n = 100) to 49% (Group 4, n = 142), log-rank test p < 0.001. The combination of IAH and HRF was associated with increased 90- and 28-day mortality as well as with fewer ICU- and ventilation-free days. The association with 90-day mortality was no longer present after adjustment for independent variables. However, the association with 28-day mortality, ICU- and ventilation-free days persisted after adjusting for independent variables.

Conclusions: In our sub-analysis, the combination of IAH and HRF was not independently associated with 90-day mortality but independently increased the odds of 28-day mortality, and reduced the number of ICU- and ventilation-free days.

Keywords: Acute respiratory distress syndrome; Critically ill; Intra-abdominal hypertension; Intra-abdominal pressure; Mechanical ventilation; Outcome; Oxygenation; Respiratory failure; Risk factors.

Three hexachloronorbornene-based flame retardants and five polybrominated diphenyl ethers (PBDEs) were measured in 414 human plasma samples, (169 from children, 167 from mothers, and 78 from fathers), collected from 200 families between 2014 and 2016. The median concentration of ∑PBDEs (sum of BDE-47, -99, -100, -153 and -183) was 13.2 ng/g lipid for child, 9.03 ng/g lipid for mother and 12.7 ng/g lipid for father, respectively. Among the hexachloronorbornene-based flame retardants, Dec 602 was the most frequently detected chemical. Significant and positive correlations between the concentrations of PBDE congeners as well as between Dec 602 and Dec 603 were observed. Concentrations of PBDE congeners also showed significant and positive correlations in paired samples from family members (child-mother-father), while Dec 602 was the only hexachloronorbornene-based flame retardant whose concentrations correlated between family members, and only in mother-father paired samples. This is the largest study to date focusing on measuring and correlating HRFs in children and their parents living in the same household. The results convey important information on human exposure to measured HFRs, which can help researchers and regulators more clearly understand the influence of diet and the home environment.

Tai chi (TC) has been shown to positively influence health-related fitness (HRF) of elderly participants by affording them a means to increase musculoskeletal strength. The objective of this study was to examine TC intervention effects on HRF and whether ethnic groups not culturally related to TC experienced a barrier to participation in a community-based program for low-income older adults. Seventy-eight older mixed-ethnicity adults (age 55 and older) who were not culturally affiliated with TC were recruited for this study. HRF measures were taken before and after a 16-week TC program that offered seven sessions per week. Significant improvements were found in upper and lower musculoskeletal fitness and partial curl-ups, with TC being embraced by the participants. These results suggest that TC can be effective for improving HRF and that non-TC culturally related ethnic groups did not experience a barrier to participation in an older low-socioeconomic population sample.

This retrospective study evaluated the association of hyperreflective foci (HRF) with treatment response in diabetic macular oedema (DME) after anti-vascular endothelial growth factor (VEGF) therapy. The medical records, including of ophthalmologic examinations and optical coherence tomography (OCT) images, of 106 patients with DME treated with either intravitreal ranibizumab or aflibercept were reviewed. The correlations between best-corrected visual acuity (BCVA) changes and HRF along with other OCT biomarkers were analysed. The mean logMAR BCVA improved from 0.696 to 0.461 after an average of 6.2 injections in 1 year under real-world conditions. Greater visual-acuity gain was noted in patients with a greater number of HRF in the outer retina at baseline (p = 0.037), along with other factors such as poor baseline vision (p < 0.001), absence of epiretinal membrane (p = 0.048), and presence of subretinal fluid at baseline (p = 0.001). The number of HRF after treatment was correlated with the presence of hard exudate (p < 0.001) and baseline haemoglobin A1C (p = 0.001). Patients with proliferative diabetic retinopathy had greater HRF reduction after treatment (p = 0.018). The number of HRF in the outer retina, in addition to other baseline OCT biomarkers, could be used to predict the treatment response in DME after anti-VEGF treatment.

The hemodynamic response function (HRF) characterizes temporal variations of blood oxygenation level-dependent (BOLD) signals. Although a variety of HRF models have been proposed for gray matter responses to functional demands, few studies have investigated HRF profiles in white matter particularly under resting conditions. In the present work we quantified the nature of the HRFs that are embedded in resting state BOLD signals in white matter, and which modulate the temporal fluctuations of baseline signals. We demonstrate that resting state HRFs in white matter could be derived by referencing to intrinsic avalanches in gray matter activities, and the derived white matter HRFs had reduced peak amplitudes and delayed peak times as compared with those in gray matter. Distributions of the time delays and correlation profiles in white matter depend on gray matter activities as well as white matter tract distributions, indicating that resting state BOLD signals in white matter encode neural activities associated with those of gray matter. This is the first investigation of derivations and characterizations of resting state HRFs in white matter and their relations to gray matter activities. Findings from this work have important implications for analysis of BOLD signals in the brain.

Keywords: BOLD; fMRI; hemodynamic response function; resting state; white matter.

Fat-water magnetic resonance (MR) images allow automated noninvasive analysis of morphological properties and fat fractions of vertebral bodies (VBs) and intervertebral discs (IVDs) that constitute an important part of human biomechanical systems. In this paper, we propose a fully automated approach for simultaneously segmenting multiple VBs and IVDs on fat-water MR images without prior localization or geometry estimation. This method involved a hierarchical random forest (HRF) classifier and a hierarchical conditional random field (HCRF) that encoded amulti-resolution image pyramid based on a set of multiscale local and contextual features. The HRF classifier employed penalized multivariate linear discriminants and SMOTEBagging to handle limited and imbalanced training data with large feature dimension. The HCRF estimated optimum labels according to their spatial and hierarchical consistencies by using the layer-wise significant features determined over the trained HRF classifier. To handle variable sample numbers at different resolutions, resolutionspecific hyperparameters were used. This method was trained and evaluated for segmenting 15 thoracic and lumbar VBs and their IVDs on fat-water MR images of a subset of a large cohort data set. It was further evaluated for segmenting 7 IVDs of the lower spine on fat-water images of a public grand challenge. These evaluations revealed the comparable accuracy of this method with the state-ofthe-art while requiring less computational burden due to a simultaneous localization and segmentation.

Nitrapyrin, a nitrification inhibitor, produces liver tumors in mice at high doses. Several experiments were performed to investigate molecular, cellular, and apical endpoints to define the key events leading to the tumor formation. These data support a mode-of-action (MoA) characterized by constitutive androstane receptor (CAR) nuclear receptor activation, increased hepatocellular proliferation leading to hepatocellular foci and tumor formation. Specifically, nitrapyrin induced a dose-related increase in the Cyp2b10/CAR-associated transcript and protein. Interestingly, the corresponding enzyme activity (7-pentoxyresorufin-O-dealkylase (PROD) was not enhanced due to nitrapyrin-mediated suicide inhibition of PROD activity. Nitrapyrin exposure elicited a clear dose-responsive increase in hepatocellular proliferation in wild-type mice, but not in CAR knock-out mice, informing that CAR activation is an obligatory key event in this test material-induced hepatocarcinogenesis. Furthermore, nitrapyrin exposure induced a clear, concentration-responsive increase in cell proliferation in mouse, but not human, hepatocytes in vitro. Evaluation of the data from repeat dose and MoA studies by the Bradford Hill criteria and a Human Relevance Framework (HRF) suggested that nitrapyrin-induced mouse liver tumors are not relevant to human health risk assessment because of qualitative differences between these two species.

Glaucoma is an optic neuropathy that gradually steals the patient's sight by damaging the optic nerve head (which is responsible for transferring images from the eye to the brain). Causing an estimated 12.3% of global blindness, glaucoma is considered as the first leading cause of irreversible blindness in the world. This paper presents a novel eye fundus image analysis algorithm for the automatic measurement of fundus related glaucoma indicators; Cup to Disc Ratio (CDR), verification of the ISNT rule, Disc Damage Likelihood Scale (DDLS), and the classification of the input fundus into glaucoma or non-glaucoma case using a random forest model. The proposed method is applied on the public image database 'HRF', and a local database containing both, normal and glaucoma cases, and resulted sensitivity, specificity, and accuracy of 1, 0.93 and 0.97 respectively. This technique presented the highest classification accuracy compared to previous works studied in the state of the art; hence, it can be used as a computer aided glaucoma diagnosis system by ophthalmologists to assist in their screening routine.

Keywords: Cup to disc ratio; DDLS; Eye fundus; Glaucoma; ISNT rule; Optic nerve head.

Whole brain estimation of the haemodynamic response function (HRF) in functional magnetic resonance imaging (fMRI) is critical to get insight on the global status of the neurovascular coupling of an individual in healthy or pathological condition. Most of existing approaches in the literature works on task-fMRI data and relies on the experimental paradigm as a surrogate of neural activity, hence remaining inoperative on resting-stage fMRI (rs-fMRI) data. To cope with this issue, recent works have performed either a two-step analysis to detect large neural events and then characterize the HRF shape or a joint estimation of both the neural and haemodynamic components in an univariate fashion. In this work, we express the neural activity signals as a combination of piece-wise constant temporal atoms associated with sparse spatial maps and introduce an haemodynamic parcellation of the brain featuring a temporally dilated version of a given HRF model in each parcel with unknown dilation parameters. We formulate the joint estimation of the HRF shapes and spatio-temporal neural representations as a multivariate semi-blind deconvolution problem in a paradigm-free setting and introduce constraints inspired from the dictionary learning literature to ease its identifiability. A fast alternating minimization algorithm, along with its efficient implementation, is proposed and validated on both synthetic and real rs-fMRI data at the subject level. To demonstrate its significance at the population level, we apply this new framework to the UK Biobank data set, first for the discrimination of haemodynamic territories between balanced groups (n=24 individuals in each) patients with an history of stroke and healthy controls and second, for the analysis of normal aging on the neurovascular coupling. Overall, we statistically demonstrate that a pathology like stroke or a condition like normal brain aging induce longer haemodynamic delays in certain brain areas (e.g. Willis polygon, occipital, temporal and frontal cortices) and that this haemodynamic feature may be predictive with an accuracy of 74 % of the individual's age in a supervised classification task performed on n=459 subjects.

Keywords: BOLD signal; Dictionary learning; HRF; Low-rank decomposition; Multivariate modeling; Sparsity; UK Biobank.

Objective: Transcatheter Aortic Valve Implantation (TAVI) is a consolidated procedure showing a low operative risk and excellent long-term outcomes in patients with aortic stenosis. Patients presenting a bicuspid aortic valve (BAV) often require valve replacement due to the highly calcific nature of the aortic leaflets. However, BAV patients have usually been contraindicated for TAVI due to their complex valve anatomy. The aim of this work was to compare the performance of devices featuring high conformability (HC) against those with high radial force (HRF).

Methods: Four BAV patients undergoing TAVI were retrospectively selected. The aortic roots including the native leaflets and calcifications were reconstructed from pre-operative Computed Tomography scans. In each patient, both HC and HRF devices were virtually implanted using Finite Element Analysis simulations. After implantation, paravalvular orifice area, von Mises stress distribution, root contact area, and device eccentricity were calculated.

Results: Simulations showed good agreement with intraoperative imaging. In 3 out of 4 patients, the HRF device resulted in a lower paravalvular area than the HC. Stress distribution was also more homogeneously distributed in the HRF group as compared with the HC group. Despite their lower adaptability, HRF devices showed consistently higher stent-root contact area.

Conclusion: HRF devices showed improved results with respect to HC valves after being deployed in BAV anatomies. We hypothesize that the ability to reshape the annulus is the major determinant of success in this subgroup of patients featuring highly calcified leaflets.

Keywords: Bicuspid aortic valve; Finite element analysis; Paravalvular leakage; Patient-specific modeling; Self-expandable devices; Transcatheter aortic valve implantation.

BACKGROUND

We previously reported that the biologically active form of histamine releasing factor (HRF) is dimerized translationally controlled tumor protein (dTCTP) which is involved in a number of allergic diseases.

UNASSIGNED

Hoping that agents that modulate dTCTP may provide new therapeutic targets to allergic inflammatory diseases, we screened a library of natural products for substances that inhibit dTCTP. One such inhibitor we found was dehydrocostus lactone (DCL), a natural sesquiterpene present in rhizome of Saussurea lappa Clarke, the subject of this study.

METHODS

We evaluated the therapeutic efficacy of DCL in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation, employing the ELISA system using BEAS-2B cells and splenocytes, and confirmed that DCL interacts with dTCTP using SPR assay.

RESULTS

DCL inhibited dTCTP-induced secretion of IL-8 in BEAS-2B cells. From kinetic analysis of dTCTP and DCL, we found that KD value was 5.33 ± 0.03 μM between dTCTP and DCL. DCL also significantly reduced inflammatory lung eosinophilia, type 2 cytokines in BALF, as well as OVA specific IgE and mucus production in a mouse model of ovalbumin induced allergy. Moreover, DCL suppressed NF-κB activation.

CONCLUSIONS

DCL's therapeutic potential in allergic airway inflammation is based on its anti-inflammatory activity of suppressing the function of dTCTP.

BACKGROUND

Thin layer chromatography (TLC) is frequently used to obtain the fingerprint of a plant extract. Although the retardation factor and the response to visualisation give primary information about compound identification, the direct TLC-mass spectrometry (MS) coupling allows a more detailed characterisation of samples.

OBJECTIVE

To demonstrate the potential for the flavonoid dereplication using an inorganic matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) method with and without TLC separation.

METHODS

Samples derived from wine, apple or rose were deposited on an aluminium-backed silica gel TLC sheet compatible with the MS adapter. Unlike the wine sample, for apple and rose samples compound derivatisation was necessary. These two samples were deposited twice and the plate was cut in two parts. One half was oversprayed with Neu-Peg reagent to visualise flavonoids while the inorganic matrix was deposited on each flavonoid zone on the second half for MS ionisation.

RESULTS

Mass spectra obtained for samples without plate development showed numerous ions corresponding to glycosylated flavonoids. The lower m/z observed could be due either to aglycone flavonoids or to in-source fragment ions. After plate development, a separation of many spots was observed and each spot was analysed separately leading to a deeper identification of the present flavonoids. Moreover, isobaric flavonoids with different hRf values could be differentiated.

CONCLUSIONS

TLC-MALDI-TOF-MS using an inorganic matrix enabled the analysis of anthocyanins in positive mode and of flavonols, flavanols, dihydrochalcones and phenolic acids in negative mode, reducing adduct, aggregate forms giving thus simple and reliable spectra for the dereplication approach of flavonoids in complex samples.

Pharmacological functional magnetic resonance imaging (phMRI) is a valuable tool for the investigation of pharmacological effects of a drug on pain processing. We hypothesized that the ibuprofen-arginine combination, in line with its characteristic analgesic properties, may influence the phMRI response at the central level, as compared to placebo. Ten healthy subjects underwent a double-blind, placebo-controlled, randomized, cross-over phFMRI study with somatosensory painful stimulation of the right median nerve. We measured the blood oxygen level dependent (BOLD) signal variations induced in conditions of pain after oral administration of either ibuprofen-arginine or placebo formulations. Independent component analysis (ICA) was used for the analysis of the fMRI data, without assuming a specific hemodynamic response function (HRF), which may be altered by drug administration. Median nerve electrical painful stimulation mainly activated the primary contralateral and the secondary somatosensory cortices, the insula, the supplementary motor area, and the middle frontal gyrus. Placebo and ibuprofen-arginine administration induced activation bilaterally in the premotor cortex, and an overall reduction in the other pain-related areas, which was more prominent in the left hemisphere. A task-related increase of BOLD signal between drug and placebo was observed bilaterally in the primary somatosensory area and the middle frontal gyrus without any changes in subjective pain scores. Overall, our findings show that ibuprofen-arginine, in line with the characteristic analgesic properties of ibuprofen, influences the BOLD response in specific pain-related brain areas with respect to placebo, with a vasoactive effect possibly due to arginine.

Objective: Characterize the impact of milrinone on arterial pressure of neonates with persistent hypoxemic respiratory failure (HRF) and hypoxic ischemic encephalopathy (HIE) treated with inhaled nitric oxide and therapeutic hypothermia (TH).

Study design: Retrospective cohort study. Arterial pressure was assessed hourly for 24 h. The primary outcome was change in diastolic arterial pressure (DAP).

Results: 56 patients were included [(i) cases: HIE/TH who received milrinone (n = 9), (ii) Milrinone controls (n = 17), (iii) HIE controls (n = 30)]. Baseline demographics, severity of HRF and arterial pressure were comparable between groups. Only milrinone treated patients with HIE/TH had a marked drop in DAP in the first hour, which persisted for more than 12 h despite escalation in inotropes (p = 0.008).

Conclusion: Milrinone treated patients with HRF and HIE/TH develop profound reduction in DAP and require escalation of cardiovascular support. The risk benefit profile of milrinone should be considered and pharmacological studies are warranted to evaluate drug metabolism and clearance in this population.

In functional near infrared spectroscopy (fNIRS), deconvolution analysis of oxy and deoxy-hemoglobin concentration changes allows estimating specific hemodynamic response functions (HRF) elicited by neuronal activity, taking advantage of the fNIRS excellent temporal resolution. Diffuse optical tomography (DOT) is also becoming the new standard reconstruction procedure as it is more accurate than the modified Beer Lambert law approach at the sensor level. The objective of this study was to assess the relevance of HRF deconvolution after DOT constrained along the cortical surface. We used local personalized fNIRS montages which consists in optimizing the position of fNIRS optodes to ensure maximal sensitivity to subject specific target brain regions. We carefully evaluated the accuracy of deconvolution when applied after DOT, using realistic simulations involving several HRF models at different signal to noise ratio (SNR) levels and on real data related to motor and visual tasks in healthy subjects and from spontaneous pathological activity in one patient with epilepsy. We demonstrated that DOT followed by deconvolution was able to accurately recover a large variability of HRFs over a large range of SNRs. We found good performances of deconvolution analysis for SNR levels usually encountered in our applications and we were able to reconstruct accurately the temporal dynamics of HRFs in real conditions.

Persistent DNA damage is responsible for mutagenesis, aging, and disease. Repair of the prototypic oxidatively damaged guanine lesion 8-oxo-7,8-dihydroguanine (8-oxoG) is initiated by oxoguanine glycosylase (hOGG1 in humans). In this work, we examine hOGG1 activity on DNA packaged as it is in chromatin, in a nucleosome core particle (NCP). We use synthetic methods to generate a population of NCPs with G to 8-oxoG substitutions and evaluate the global profile of hOGG1 repair in packaged DNA. For several turns of the helix, we observe that solution accessible 8-oxoGs are sites of activity for hOGG1. At the dyad axis, however, hOGG1 activity is suppressed, even at lesions predicted to be solution accessible by hydroxyl radical footprinting (HRF). We predict this diminished activity is due to the properties of the DNA unique to the dyad axis and/or the local histone environment. In contrast to the dyad axis, the DNA ends reveal hOGG1 activity at sites predicted by HRF to be both solution accessible and inaccessible. We attribute the lack of correlation between hOGG1 activity and solution accessibility at the ends of the DNA to transient unwrapping of the DNA from the protein core, thus exposing the inward-facing lesions.