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Pain assessment is challenging in neonates. Behavioral and physiological pain scales do not assess neocortical nociception, essential to pain encoding and central pain pathway development. Functional near-infrared spectroscopy (fNIRS) can assess neocortical activation to noxious stimuli from changes in oxy-(HbO) and total-hemoglobin concentrations (HbT). This study aims to assess fNIRS nociceptive functional activation in the prefrontal cortex of neonates undergoing circumcision through changes in HbO and HbT, and the correlation between changes in fNIRS and Neonatal Infant Pain Scale (NIPS), a behavioral pain assessment scale.In healthy term neonates, HbO, HbT, and NIPS were recorded during sequential circumcision events 1-Prep before local anesthetic injection; 2-Local anesthetic injection; 3-Prep before incision; 4-Oral sucrose; 5-Incision; 6-Gomco (hemostatic device) attached; 7-Gomco twisted on; and 8-Gomco removed. fNIRS and NIPS changes after each event were assessed with Wilcoxon signed-rank test and summarized as median and interquartile range (IQR). Changes in fNIRS vs. NIPS were correlated with Spearman coefficient.In 31 neonates fNIRS increased (median [IQR] µmol/L) with noxious events: Local injection (HbO: 1.1 [0.5, 3.1], p .001; HbT: 2.3 [0.2, 7.6], p .001), Gomco attached (HbO: 0.7 [0.1, 1.7], p = .002; HbT: 0.7 [-0.2, 2.9], p = .02), and Gomco twisted on (HbO: 0.5 [-0.2, 1.7], p = .03; HbT: 0.8 [-0.1, 3.3], p = .02). fNIRS decreased with non-noxious event: Prep before incision (HbO: -0.6 [-1.2, -0.2] p .001; HbT: -1 [-1.8, -0.4], p .001). Local anesthetic attenuated fNIRS increases to subsequent sharp stimuli. NIPS increased with subsequent sharp stimuli despite local anesthetic. Although fNIRS and NIPS changed in the same direction, there was not a strong correlation between them.During neonatal circumcision, changes in fNIRS differed between different types of painful stimuli, which was not the case for NIPS, suggesting that fNIRS may complement NIPS to assess the quality of pain.

The present study examined the relationships between people's romantic loneliness, parasocial love (PSL), and imagined interaction (II) with media figures they viewed as romantic partners. Two hundred and twenty four college students in a Chinese university participated in the survey study. Romantic loneliness was negatively related to PSL moderated by gender. The negative relationship only emerged in males but not in females. People who had II with the personae had stronger PSL in contrast those who didn’t. PSL was positively related to II's attributes of frequency and valence and functions of compensation and relationship maintenance. Frequency of II negatively mediated the relationship between romantic loneliness and PSL.

BACKGROUND: Ketamine has traditionally been avoided as an induction agent for tracheal intubation in patients with neurologic conditions at risk for intracranial hypertension due to conflicting data in the literature. The objective of this study was to evaluate and compare the effects of ketamine versus other medications as the primary induction agent on peri-intubation neurologic, hemodynamic and respiratory associated events in pediatric patients with neurologic conditions at risk for intracranial hypertension. METHODS: This retrospective observational study enrolled patients < 18 years of age at risk for intracranial hypertension who were admitted to a quaternary children’s hospital between 2015 and 2020. Associated events included neurologic, hemodynamic and respiratory outcomes comparing primary induction agents of ketamine versus non-ketamine for tracheal intubation. RESULTS: Of 143 children, 70 received ketamine as the primary induction agent prior to tracheal intubation. Subsequently after tracheal intubation, all the patients received adjunct analgesic and sedative medications (fentanyl, midazolam, and/or propofol) at doses that were inadequate to induce general anesthesia but would keep them comfortable for further diagnostic workup. There were no significant differences between associated neurologic events in the ketamine versus non-ketamine groups (p = 0.42). This included obtaining an emergent computed tomography scan (p = 0.28), an emergent trip to the operating room within 5 h of tracheal intubation (p = 0.6), and the need for hypertonic saline administration within 15 min of induction drug administration for tracheal intubation (p = 0.51). There were two patients who had clinical and imaging evidence of herniation, which was not more adversely affected by ketamine compared with other medications (p = 0.49). Of the 143 patients, 23 had pre-intubation and post-intubation intracranial pressure values recorded; 11 received ketamine, and 3 of these patients had intracranial hypertension that resolved or improved, whereas the remaining 8 children had intracranial pressure within the normal range that was not exacerbated by ketamine. There were no significant differences in overall associated hemodynamic or respiratory events during tracheal intubation and no 24-h mortality in either group. CONCLUSIONS: The administration of ketamine as the primary induction agent prior to tracheal intubation in combination with other agents after tracheal intubation in children at risk for intracranial hypertension was not associated with an increased risk of peri-intubation associated neurologic, hemodynamic or respiratory events compared with those who received other induction agents.

How does the presence of a robot affect pedestrians and crowd dynamics, and does this influence vary across robot type? In this paper, we took the first step towards answering this question by performing a crowd-robot gate-crossing experiment. The study involved 28 participants and two distinct robot representatives: A smart wheelchair and a Pepper humanoid robot. Collected data includes: video recordings; robot and participant trajectories; and participants’ responses to post-interaction questionnaires. Quantitative analysis on the trajectories suggests the robot affects crowd dynamics in terms of trajectory regularity and interaction complexity. Qualitative results indicate that pedestrians tend to be more conservative and follow “social rules” while passing a wheelchair compared to a humanoid robot. These insights can be used to design a social navigation strategy that allows more natural interaction by considering the robot effect on the crowd dynamics.

Gelsemiumelegans(Gardner.Chapm.) Benth. has long been considered a traditional Chinese medicine effective against rheumatoid pain, cancer, cirrhosis, and skin diseases. Koumine (KM), the most abundant alkaloid in G.elegans Benth., demonstrates a variety of biological effects, including antitumor, analgesic, anxiolytic, anti-inflammatory, antidepressant, antioxidant, immunoregulatory, and hepatoprotective effects. Furthermore, the relatively low toxicity of KM makes it a promising drug candidate. This study aimed to investigate the protective effects of KM and its possible mechanisms using a concanavalin A (Con A)-induced autoimmune hepatitis (AIH) model in mice. Mice were orally administered different doses of KM for 14 d before Con A tail vein injections. The effects of KM on serum biochemical markers and liver histopathology were then evaluated 12 h after Con A exposure. The Nrf2 and NF-κB signaling pathways and alterations in gut microbiota were determined using western blotting, immunohistochemistry, and 16S rRNA sequencing to explore the underlying mechanisms of KM exposure. KM pretreatment dose-dependently decreased serum liver injury markers (Alanine aminotransferase, and aspartate aminotransferase) and cytokine levels (Tumor necrosis factor-α and interleukin-6), as well as the liver pathological damage triggered by Con A. Furthermore, the results of the multi-technique analysis indicated that KM activated the Nrf2 pathway, upregulated the expression of anti-oxidation factors HO-1 and Nrf2, and downregulated the expression of Keap1. Moreover, the NF-κB signaling pathway was inhibited. Interestingly, pre-treatment with KM also significantly improved the composition of the gut microbiota probably because it increases the richness of probiotics. Our findings suggest that KM pretreatment could attenuate Con A-induced AIH, the Nrf2 and NF-κB signaling pathways, and that gut microbiota are involved in the process of the hepatoprotective effect. This study provides a theoretical basis for the development of KM as an effective agent against AIH.

We present the optical photometric and spectroscopic observations of the nearby Type Ia supernova (SN) 2021hpr. The observations covered the phase of $-$14.37 to +63.68 days relative to its maximum luminosity in the $B$ band. The evolution of multiband light/color curves of SN 2021hpr is similar to that of normal Type Ia supernovae (SNe Ia) with the exception of some phases, especially a plateau phase that appeared in the $V-R$ color curve before peak luminosity, which resembles that of SN 2017cbv. The first spectrum we observed at t $\sim -$14.4 days shows a higher velocity for the Si II $\lambda$6355 feature ($\sim$ 21,000 km s$^{-1}$) than that of other normal Velocity (NV) SNe Ia at the same phase. Based on the Si II $\lambda$6355 velocity of $\sim$ 12,420 km s$^{-1}$ around the maximum light, we deduce that SN 2021hpr is a transitional object between high velocity (HV) and NV SNe Ia. Meanwhile, the Si II $\lambda$6355 feature shows a high velocity gradient (HVG) of about 800 km s$^{-1}$ day$^{-1}$ from roughly $-$14.37 to $-$4.31 days relative to the $B$-band maximum, which indicates that SN 2021hpr can also be classified as an HVG SN Ia. The evolution of SN 2021hpr is similar to that of SN 2011fe. Including SN 2021hpr, there have been six supernovae observed in the host galaxy NGC 3147, and the supernovae explosion rate in the last 50 yr is slightly higher for SNe Ia, while lower for SNe Ibc and SNe II it is lower than expected rate from the radio data. Inspecting the spectra, we find that SN 2021hpr has a metal-rich (12 + log(O/H) $\approx$ 8.648) circumstellar environment, where HV SNe tend to reside. Based on the decline rate of SN 2021hpr in the $B$ band, we determine the distance modulus of the host galaxy NGC 3147 using the Phillips relation to be 33.46 $\pm$ 0.21 mag, which is close to that found by previous works., Comment: 25 pages, 12 figures, 5 tables, published by Publications of the Astronomical Society of the Pacific

Background Structural brain abnormalities in newborn animals after prolonged exposure to all routinely used general anaesthetics have raised substantial concerns for similar effects occurring in millions of children undergoing surgeries annually. Combining a general anaesthetic with non-injurious sedatives may provide a safer anaesthetic technique. We tested dexmedetomidine as a mitigating therapy in a sevoflurane dose-sparing approach. Methods Neonatal rats were randomised to 6 h of sevoflurane 2.5%, sevoflurane 1% with or without three injections of dexmedetomidine every 2 h (resulting in 2.5, 5, 10, 25, 37.5, or 50 μg kg−1 h−1), or fasting in room air. Heart rate, oxygen saturation, level of hypnosis, and response to pain were measured during exposure. Neuronal cell death was quantified histologically after exposure. Results Sevoflurane at 2.5% was more injurious than at 1% in the hippocampal cornu ammonis (CA)1 and CA2/3 subfields; ventral posterior and lateral dorsal thalamic nuclei; prefrontal, retrosplenial, and somatosensory cortices; and subiculum. Although sevoflurane 1% did not provide complete anaesthesia, supplementation with dexmedetomidine dose dependently increased depth of anaesthesia and diminished responses to pain. The combination of sevoflurane 1% and dexmedetomidine did not reliably reduce neuronal apoptosis relative to an equianaesthetic dose of sevoflurane 2.5%. Conclusions A sub-anaesthetic dose of sevoflurane combined with dexmedetomidine achieved a level of anaesthesia comparable with that of sevoflurane 2.5%. Similar levels of anaesthesia caused comparable programmed cell death in several developing brain regions. Depth of anaesthesia may be an important factor when comparing the neurotoxic effects of different anaesthetic regimens.

Background: Gout could result in irreversible bone erosion, and chondrocyte might be involved in the process. Increased soluble urate is the early stage of gout and is strongly oxidative. Objective: To explore the effect of intracellular urate on the oxidative status of chondrocytes Methods: A chondrocyte model was used. Serial concentrations of exogenous urate were incubated with chondrocytes for increasing amounts of time. Reactive oxygen species (ROS), oxidant, and anti-oxidant molecules were measured with biochemical assays, rt-PCR, and western blot. A urate transport inhibitor and oxidative inhibitors were used to confirm the effect of exogenous urate. Results: All concentrations of exogenous urate stimulated the production of ROS in a time- and concentration-dependent manner, as well as oxidant molecules, including hydrogen peroxide (H2O2), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nitric oxide (NO) inducible nitric oxide synthase (iNOS), and these effects, could be inhibited by oxidant inhibitors. However, anti-oxidant molecules, including acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), ataxia-telangiectasia mutated (ATM), heme oxygenase-1 (HO-1), and the transcription factor nuclear factor erythroid 2 (NF-E2)-related (Nrf2), was decreased by high concentrations of exogenous urate after prolonged incubation, but not by low to medium concentrations of exogenous urate. By inhibiting soluble urate trafficking, benzbromarone significantly suppressed the effect of urate stimulus on the oxidant and anti-oxidant molecules. Conclusion: Intracellular soluble urate could regulate chondrocyte redox balance in a time and concentration-dependent manner, and would be a target for regulating and protecting chondrocyte function in the early gout stage.

Carbapenem-resistant Gram-negative bacterial pathogens continue to threaten public health. Avibactam (AVI), a novel non-β-lactam β-lactamase inhibitor, has been approved for use with ceftazidime (CAZ) mainly against carbapenem-resistant Enterobacteriaceae. Therapeutic drug monitoring (TDM) is urgently needed to optimize dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. This study aims to develop and validate a rapid, simple, and economical LC-MS/MS method for simultaneous determination of CAZ/AVI in human plasma.Samples were processed by simple protein precipitation, and gradient elution strategy was applied to separate CAZ and AVI on a reverse-phase C18 column; with subsequent detection by the mass spectrometer in a positive and negative ion switching mode. Plasma samples from patients were analysed.A 4-min run of LC-MS/MS was developed. The precision, trueness, matrix effect, extraction recovery, carry-over, dilution integrity, and stability were all acceptable for a bioanalytical method. The method was successfully applied to the determination of CAZ and AVI in patients, and a considerable PK variability of CAZ/AVI was observed among patients.A robust, rapid, simple, and economical LC-MS/MS method for the simultaneous determination of CAZ and AVI was developed. The considerable PK variability of CAZ/AVI among patients demonstrates the clinical significance of TDM.

Gaseous and particulate chlorine species play an important role in modulating tropospheric oxidation capacity, aerosol water uptake, visibility degradation, and human health. The lack of recent global continental chlorine emissions has hindered modeling studies of the role of chlorine in the atmosphere. Here, we develop a comprehensive global emission inventory of gaseous HCl and particulate Cl-(pCl), including 35 sources categorized in six source sectors based on published up-to-date activity data and emission factors. These emissions are gridded at a spatial resolution of 0.1° × 0.1° for the years 1960 to 2014. The estimated emissions of HCl and pCl in 2014 are 2354 (1661-3201) and 2321 (930-3264) Gg Cl a-1, respectively. Emissions of HCl are mostly from open waste burning (38%), open biomass burning (19%), energy (19%), and residential (13%) sectors, and the major sources classified by fuel type are combustion of waste (43%), biomass (32%), and coal (25%). Emissions of pCl are mostly from biofuel (29%) and open biomass burning processes (44%). The sectoral and spatial distributions of HCl and pCl emissions are very heterogeneous along the study period, and the temporal trends are mainly driven by the changes in emission factors, energy intensity, economy, and population.

Medication poisoning, also called drug poisoning, is a harmful effect on health caused by certain therapeutic drugs. Even as an increasing number of people are seeking information on YouTube, the quality of videos remains unknown. This study aimed to identify whether YouTube is an educational resource for medication poisoning. Videos were systematically searched through YouTube on April 22, 2020. Video demographics such as views, duration, likes, and dislikes were extracted. Each video was assessed and scored by two independent pharmacists. A 5-point global quality scale, a 4-point accuracy scale, and six content-specific items were used to score the videos. Cohen’s kappa coefficient and the intraclass correlation coefficient were calculated to determine the degree of agreement between the two raters. The videos were categorized as “slightly useful,” “useful,” and “very useful” by the total score. The videos were further categorized according to content styles and sources. There was no difference in the scores given by the two viewers. Only 12.71% of the videos were deemed very useful, and 93.33% of the very useful videos belonged to the educational style. Educational videos had a significantly longer duration and higher scores than the other content styles. A remarkable correlation was observed among the videos of the different styles or source categories regarding the usefulness. YouTube is a promising educational source regarding medication poisoning. Given a minimal number of these videos were considered as very useful, physicians, pharmacists, nurses, and other health care organizations should be encouraged to upload more high-quality videos to meet the needs of the growing population of netizens.

Objectives Determine level of agreement among clinical signs of shock type, identify which signs clinicians prioritize to determine shock type and select vasoactive medications, and test the association of shock type-vasoactive mismatch with prolonged organ dysfunction or death (complicated course). Design Retrospective observational study. Setting Single large academic PICU. Patients Patients less than 18 years treated on a critical care sepsis pathway between 2012 and 2016. Interventions None. Measurements and main results Agreement among clinical signs (extremity temperature, capillary refill, pulse strength, pulse pressure, and diastolic blood pressure) was measured using Fleiss and Cohen's κ. Association of clinical signs with shock type and shock type-vasoactive mismatch (e.g., cold shock treated with vasopressor rather than inotrope) with complicated course was determined using multivariable logistic regression. Of 469 patients, clinicians determined 307 (65%) had warm and 162 (35%) had cold shock. Agreement across all clinical signs was low (κ, 0.25; 95% CI, 0.20-0.30), although agreement between extremity temperature, capillary refill, and pulse strength was better than with pulse pressure and diastolic blood pressure. Only extremity temperature (adjusted odds ratio, 26.6; 95% CI, 15.5-45.8), capillary refill (adjusted odds ratio, 15.7; 95% CI, 7.9-31.3), and pulse strength (adjusted odds ratio, 21.3; 95% CI, 8.6-52.7) were associated with clinician-documented shock type. Of the 86 patients initiated on vasoactive medications during the pathway, shock type was discordant from vasoactive medication (κ, 0.14; 95% CI, -0.03 to 0.31) and shock type-vasoactive mismatch was not associated with complicated course (adjusted odds ratio, 0.3; 95% CI, 0.1-1.02). Conclusions Agreement was low among common clinical signs used to characterize shock type, with clinicians prioritizing extremity temperature, capillary refill, and pulse strength. Although clinician-assigned shock type was often discordant with vasoactive choice, shock type-vasoactive mismatch was not associated with complicated course. Categorizing shock based on clinical signs should be done cautiously.

OBJECTIVES To evaluate the effect of providing early attending physician involvement via telemedicine to improve the decision process of rapid response teams. DESIGN Quasi-experimental; three pairs of control/intervention months: June/July; August/October; November/December. SETTING Single-center, urban, quaternary academic children's hospital with three-member rapid response team: critical care fellow or nurse practitioner, nurse, respiratory therapist. Baseline practice: rapid response team leader reviewed each evaluation with an ICU attending physician within 2 hours after return to ICU. SUBJECTS 1) Patients evaluated by rapid response team, 2) rapid response team members. INTERVENTIONS Implementation of a smartphone-based telemedicine platform to facilitate early co-assessment and disposition planning between the rapid response team at the patient's bedside and the attending in the ICU. MEASUREMENTS AND MAIN RESULTS As a marker of efficiency, the primary provider outcome was time the rapid response team spent per patient encounter outside the ICU prior to disposition determination. The primary patient outcome was percentage of patients requiring intubation or vasopressors within 60 minutes of ICU transfer. There were three pairs of intervention/removal months. In the first 2 pairs, the intervention was associated with the rapid response team spending less time on rapid response team calls (June/July: point estimate -5.24 min per call; p < 0.01; August/October: point estimate -3.34 min per call; p < 0.01). During the first of the three pairs, patients were significantly less likely to require intubation or vasopressors within 60 minutes of ICU transfer (adjusted odds ratio, 0.66; 95 CI, 0.51-0.84; p < 0.01). CONCLUSIONS Early in the study, more rapid ICU attending involvement via telemedicine was associated with rapid response team providers spending less time outside the ICU, and among patients transferred to the ICU, a significant decrease in likelihood of patients requiring vasopressors or intubation within the first 60 minutes of transfer. These findings provide evidence that early ICU attending involvement via telemedicine can improve efficiency of rapid response team evaluations.

BACKGROUND Prophylactic analgesic administration reduces pain behavior after pediatric bilateral myringotomy and pressure equalization tube placement (BMT). We hypothesized that postoperative pain in children treated with intraoperative ketorolac would, among several exposures of interest, be strongly associated with ear condition. METHODS We conducted a retrospective cohort study of healthy children (9 months to 7 years) who underwent BMT at the Children's Hospital of Philadelphia or its ambulatory surgery centers from 2013 to 2016. Anesthetic care included preoperative oral midazolam, sevoflurane/nitrous oxide (N2O)/air/oxygen (O2) by mask, and intramuscular ketorolac. Demographic and procedural information included left and right tympanic membrane (normal, retracted, or bulging) and middle ear (normal/no, serous, mucoid, or purulent effusion) conditions. Because tympanic membrane and middle ear conditions were highly concordant and mean maximum Face, Legs, Activity, Cry and Consolability (FLACC) scores (0-10) were not different across the array of abnormal findings, we categorized each ear as normal or abnormal based on middle ear effusion alone. We then defined the ear condition of each child (primary exposure) using bilateral findings: normal/normal, normal/abnormal, and abnormal/abnormal. Secondary exposures included age, BMT history, procedure duration, facility location, and attending surgeon/anesthesiologist pair. The primary outcome was maximum postanesthesia care unit FLACC score: 4-10 (moderate-to-severe pain) versus 0-3 (no-to-low pain). Rescue oxycodone, acetaminophen administration, and emergence agitation were secondary outcomes. Statistical analysis incorporated generalized linear mixed models with random intercepts accounting for the clustering effect of provider pairs. Adjusting for multiple comparisons, significance level was set at P = .004. RESULTS Excluding recurrent cases, 1922 unique evaluable subjects remained. The probability of moderate-to-severe pain behavior (FLACC, 4-10) was 52.4% (95% confidence interval [CI], 50.2-54.6) overall. In a confounder-adjusted model, ear condition was significantly associated with moderate-to-severe pain: compared to bilateral abnormal (effusions), odds ratio (OR) (95% CI) for bilateral normal was 2.2 (1.6-2.9), P < .0001. Younger age (OR, 1.1 [1.1-1.2] per year; P = .001) and longer procedure duration (OR, 1.1 [1.0-1.2] per minute; P = .0008) were likewise related to higher pain. With surgeon added to the model, variance explained by provider pairs decreased from 9.60% to 1.05%. Two secondary outcome associations also emerged: comparing bilateral normal to abnormal ears, ORs were 1.7 (1.3-2.2), P = .0001, for rescue oxycodone and 2.0 (1.2-3.3), P = .008, for emergence agitation. CONCLUSIONS Pain behavior after BMT varies by surgeon and is strongly associated with ear condition. Ketorolac as a single prophylactic analgesic appears less effective in younger children with normal middle ear findings.

An efficient Ni2P–CdS photocatalyst for photocatalytic hydrogen evolution was synthesized by phosphorizing β-Ni(OH)2 nanosheet with exposed (001) facets on CdS nanorods. The obtained Ni2P–CdS composite displays an outstanding and stable photocatalytic hydrogen generation rate of 68.47 mmol g−1 h−1 in 10 vol% lactic acid under visible light irradiation, more than 17 times higher than that for pure CdS nanorods. The transient photocurrent response, EIS measurement, Mott-Schottky plots, acidic LSV measurement, and PL spectra have proved that Ni2P loading can significantly improve the separation of photo-excited electron-hole pairs in CdS nanorods and enhance the hydrogen evolution capability for CdS. These improvements are achieved by features of Ni2P such as the high capability of trapping photo-generated electrons from CdS, lifting the total Fermi level and lowering the hydrogen evolution overpotential of the composite. The results show that β-Ni(OH)2 precursor with a high exposure degree of (001) facet is contributed to the epitaxial formation of (001)-facet-exposed Ni2P co-catalyst on CdS nanorods, resulting in that the Fermi level and the hydrogen evolution overpotential of the composite can be further lifted and lowered. This study has provided a novel precursor-derived route to fabricate high-performance co-catalysts with highly exposed active facets on CdS nanorods for effective photocatalytic hydrogen evolution.

Carboxylic contained zeolitic imidazolate frameworks (ZIF-COOH) were designed and synthesized using 1H-Imidazole-2-carboxylic acid and Zn(NO3)2·6H2O. The ZIF-COOH was then applied in the fabrication of composite membranes with sulfonated polyether ether ketone (SPEEK) (SPEEK/ZIF-COOH). The properties of the composite membranes, including mechanical strength, proton conductivity, and methanol permeability were studied. The incorporation of ZIF-COOH generated a significant effect on SPEEK/ZIF-COOH composite membranes, due to the special structure and compositional characteristics of ZIF-COOH. In particular, the tensile strength of SPEEK/ZIF-COOH-5 showed an enhancement of 44.1 MPa, which was 42% higher than the pristine SPEEK. Simultaneously, the proton conductivity displayed an improvement of 46% as compared to the SPEEK. Most importantly, the methanol permeability values decreased to 1.1 × 10−7 cm2 s−1, which was only a tenth of the value of SPEEK.

Objective: Tuberous sclerosis complex (TSC) is a multisystem disease. Variants in the TSC1 and TSC2 genes have been reported to be associated with TSC and are considered pathogenic. The purpose of ...

Solar hydrogen peroxide (H2O2) produced through the selective two-electron (2e−) oxygen reduction pathway is an ideal alternative to liquid fuel in addition to being a versatile chemical. Up to now, low photocatalytic activity, low selectivity and serious competing reactions have been big hurdles in the production of solar H2O2 in an efficient way. Herein, we report that polyterthiophene (pTTh), a metal-free narrow-bandgap polymeric semiconductor, is an efficient photocathode for H2O2 production in alkaline solution. We found that 2e− selectivity for the ORR is dependent on the pH of electrolytes and approaches 100% at pH ∼ 13. A record-high H2O2 concentration of 110 mmol L−1 is achieved, which is two orders of magnitude higher than the previous photosynthesized H2O2. Furthermore, NiFeOx/BiVO4–pTTh dual-photoelectrodes in photoelectrochemical devices enabled bias-free synthesis of solar H2O2 of concentration ∼90 mmol L−1 for several cycles without any noticeable decay. This extremely high 2e− selectivity is attributed to the intrinsic electrochemical properties of pTTh. Theoretical calculations suggested that the selectivity-determining step in the 2e− process is over ∼200 times faster than that in the 4e− pathway. Our work paves an alternative way of generating liquid solar fuel that is very promising for practical applications.

In this paper we deal with model-based control design in the presence of uncertainties. We use Stochastic Dynamic Programming to solve two problems, called longitudinal and lateral vehicle control. The goal is to allow safe driving (navigation) of a moving vehicle in an environment with static obstacles. We show how to define the optimization problems given the stochastic driver behavior and environment. The vehicle dynamics model is deterministic (obeys physical laws) and is explicitly integrated into the optimization problem. In terms of results, the numerically computed control policies provide best-on-average performance (according to the expected value operator). In simulation, it is shown that the vehicle effectively avoids obstacles, thus ensuring a safe drive experience.

BACKGROUND Increasing evidence has suggested that gut flora play an important role in tumor progression and prognosis. However, the relationship between fecal microbiota and hematologic malignancy requires further investigation. This study aimed to characterize the relationship of the fecal microbial community in multiple myeloma (MM) patients. MATERIAL AND METHODS A total of 40 MM patients and healthy controls (n=17) were retrospectively collected from the First Affiliated Hospital of Sun Yat-sen University between October 2018 and May 2019. The fecal samples were collected for 16S rRNA high-throughput sequencing for the fecal microbial community, as well as diversity and correlation analysis. Furthermore, 21 MM patients and their family members were selected for the matched pair analysis to confirm the fecal microbiota taxonomic changes by qRT-PCR assay. RESULTS Diversity analysis showed that diversity measured by Shannon index was lower in MM patients compared with healthy controls. At the phylum level, higher abundances of Proteobacteria but lower abundances of Actinobacteria were identified in the MM group in comparison with the healthy control group. At the genus level, the proportion of Bacteroides, Faecalibacterium, and Roseburia was significantly higher in the MM group. The matched pair analysis showed that Pseudomonas aeruginosa and Faecalibacterium were significantly more abundant in the MM group. Further analysis on prognostic risk factors revealed that the Faecalibacterium prausnitzii level was significantly correlated with ISS stage. CONCLUSIONS Our study highlights the imbalanced composition and diversity of the gastrointestinal microbiome in MM patients, which could be further used as a potential biomarker for MM risk screening, therapeutic strategies, and prognostic prediction.

Objectives: Deficiency of adenosine deaminase 2 (DADA2) is a rare disease with varying phenotypes and disease outcomes. We evaluated the treatment of DADA2 and explored the factors associated with disease outcome. Methods: A systemic literature review of DADA2 was conducted. Cases were included if they had documented detailed genotypes, phenotypes, treatment protocols, and outcomes. Patients were categorized as having uncontrolled and controlled disease. Factors associated with disease outcome were analyzed using logistic regression models. Results: The study population comprised 242 DADA2 patients with data on treatment protocols and responses, of whom 17 required no treatment. Tumor necrosis factor a inhibitors (TNFi) were effective in 78.6% (103/131). Hematological abnormalities and increased acute phase reactants are independently associated with the effectiveness of TNFi (OR, 0.21 [95%CI, 0.07-0.661; P=.007] and 9.62 [95%CI, 2.31-40.00; P=.002, respectively). Among the 225 patients requiring active treatment, 157 (69.8%) had controlled disease and 68 (30.2%) uncontrolled disease. Neither age of disease onset nor genotype was associated with disease outcome. Increased acute phase reactant values, constitutional symptoms, neurological symptoms, and treatment with TNFi were independently associated with disease control, while recurrent infections and severe vascular events were the main causes of mortality (10/21 and 6/21, respectively). Conclusion: In patients requiring treatment, symptoms of systemic inflammation and vasculitis and treatment with TNFi are associated with disease control. Recurrent infections and severe vascular events should be treated intensively, as they are the main causes of death. Hematological abnormalities should be monitored, as they decrease the effectiveness of TNFi.

BackgroundAutoinflammatory phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) is a rare autoinflammatory disease caused by gain-of-function mutations in the PLCG2 gene. Here we report a rare case of APLAID patient carrying a novel heterozygous missense PLCG2 I169V mutation with gangrenous pyoderma and concomitant high serum immunoglobulin (Ig) E level.MethodsThe patient was diagnosed as APLAID and has been treated in our department. His phenotype and genotype were carefully documented and studied. We also conducted a comprehensive literature review on APLAID.ResultsA 23-year-old Chinese Han man presented with recurrent fever for 18 years and vesiculopustular rashes for 9 years, along with chronic bronchitis, leukocytosis, increased C-reactive protein, immunodeficiency and high serum IgE. Skin biopsy showed chronic inflammatory cells infiltration. A paternal heterozygous missense variant in exon 6 of the PLCG2 gene p. I169V was identified. His vesiculopustular and IgE level responded to medium dose corticosteroids. After withdrawal of steroids, he developed severe arthritis and a large deteriorating ulceration resembling pyoderma gangrenosum on the left knee. Large dose corticosteroids were suboptimal. Then he received adalimumab with satisfactory response for arthritis and skin lesion. But he got an immunodeficiency-associated lymphoproliferative disorder 2 months later. Through literature review, there were a total of 10 APLAID patients reported by six English-language publications. Vesiculopustular rashes, sinopulmonary infection and immunodeficiency were the most frequent symptoms of APLAID patients. Glucocorticoids, intravenous immunoglobulin and biologics were clinically used to treat APLAID but none of these patients had a complete recovery.ConclusionsThe rarity and diversity of APLAID make it difficult to be diagnosed. Our study reported the first case of APLAID with gangrenous pyoderma and concomitant high IgE carrying a novel PLCG2 mutation, which may expand the clinical phenotype and genotype of APLAID.

BACKGROUND: Beckwith-Wiedemann Syndrome is the most common congenital overgrowth disorder with an incidence of approximately 1 in 10,000 live births. The condition is characterized by lateralized overgrowth, abdominal wall defects, macroglossia, and predisposition to malignancy. Historically, children with Beckwith-Wiedemann Syndrome have been presumed to be difficult airways; however, most of the evidence to support this has been anecdotal and derived from case reports. Our study aimed to determine the prevalence of difficult airway in patients with Beckwith-Wiedemann Syndrome. We hypothesized that most patients with Beckwith-Wiedemann Syndrome would not have difficult airways. METHODS: We retrospectively reviewed the electronic medical records of patients enrolled in our institution’s Beckwith-Wiedemann Syndrome registry. Patients with a molecular diagnosis of Beckwith-Wiedemann Syndrome who were anesthetized between January 2012 and July 2019 were included for analysis. The primary outcome was the presence of difficult airway, defined as difficult facemask ventilation, difficult intubation or both. We defined difficult intubation as the need for 3 or more tracheal intubation attempts, the need for advanced airway techniques (non-direct laryngoscopy) to perform tracheal intubation or a Cormack and Lehane grade ≥ 3 during direct laryngoscopy. Secondary objectives were to define predictors of difficult intubation and difficult facemask ventilation, and the prevalence of adverse airway events. Generalized linear-mixed effect models were used to account for multiple anesthesia events per patients. RESULTS: Of 201 Beckwith-Wiedemann Syndrome patients enrolled in the registry, 60% (n=122) had one or more documented anesthetics for a total of 310 anesthetics. A pre-existing airway was present in 22 anesthetics. The prevalence of difficult airway was 5.3% (95% confidence interval [CI] 3.0%-9.3%,18/288) of the cases. The prevalence of difficult intubation was 5.2% (95%CI 2.9%-9.4%,12/226). The prevalence of difficult facemask ventilation was 2.9% (95%CI 1.4%-6.2%, 12/277) and facemask ventilation was not attempted in 42 anesthetics. Age < 1 year, macroglossia, lower weight, endocrine comorbidities, plastics/craniofacial surgery, tongue reduction surgery, and obstructive sleep apnea were associated with difficult airways in cases without a pre-existing airway. 83.8% (95%CI 77.6%-88.5%) of the cases were intubated with a single attempt. Hypoxemia was the most common adverse event. CONCLUSION: The prevalence of difficult tracheal intubation and difficult facemask ventilation in children with Beckwith-Wiedemann Syndrome was 5.2% and 2.9% respectively. We identified factors associated with difficult airway which included age < 1 year, macroglossia, endocrine abnormalities, plastics/craniofacial surgery, tongue reduction surgery and obstructive sleep apnea. Clinicians should anticipate difficult airways in patients with these factors.

Stereoelectroencephalography (SEEG) has been widely used in the presurgical evaluation of patients with medically intractable epilepsy. In the past, SEEG was commonly used as a method for mapping and localizing the epileptogenic zone (EZ). Since 2004, several studies have been conducted to examine the effectiveness of SEEG-guided radiofrequency thermocoagulation (RF-TC) in treating refractory epilepsy. However, the seizure-free and responder rates varied greatly across studies. We aimed to analyze the outcome of 56 patients who were treated with SEEG-guided RF-TC to evaluate the effectiveness of this treatment. SEEG-guided RF-TC can be considered as a treatment for refractory epilepsy. However, due to its limited efficacy, SEEG-guided RF-TC might be regarded as a temporary treatment performed under SEEG rather than a promising treatment for refractory epilepsy.

Despite the growing interest in green products in the interior wall decorative material market, knowledge gaps exist because determining which product is more environmental and user friendly than the others is difficult. This work assesses the environmental and human health profiles of interior latex and wallpaper. Two interior latex products of different raw material ratios and one non-woven wallpaper product are considered. The environmental impact assessment follows life cycle assessment (LCA) methodology and applies Building Environmental Performance Analysis System (BEPAS). The human health impact is based on impact-pathway chain and is performed using Building Health Impact Analysis System (BHIAS). The assessment scope, associated emissions, and territorial scope of various emissions are defined to facilitate comparison study of interior wall decorative products. The impacts are classified into 15 categories belonging to three safeguard areas: ecological environment, natural resources, and human health. The impacts of categories are calculated and monetized using willingness to pay (WTP) and disability-adjusted life year (DALY) and summarized as an integrated external cost of environmental and human health impacts. Assessment results reveal that the integrated impact of interior latex is lower than that of non-woven wallpaper, and the interior latex of low quality causes low life cycle integrated impact. The most impacted categories are global warming, respiratory effects, and water consumption. Hotspots of product manufacturing are recognized to promote green product design.

Objective The present study investigated the electroclinical features and epileptogenic networks of parietal operculum seizures (POS) by using stereoelectroencephalography (SEEG) intracerebral recordings. Methods Comprehensive presurgical evaluation data of seven patients with drug-resistant epilepsy with POS were analyzed retrospectively. Stereoelectroencephalography-recorded seizures were processed visually and quantitatively by using epileptogenicity mapping (EM), which has been proposed to ergonomically quantify the epileptogenicity of brain structures with a neuroimaging approach. Results Six patients reported initial somatosensory or viscerosensitive symptoms. Ictal clinical signs comprised frequently nocturnal hypermotor seizures and contralateral focal motor seizures, including tonic, tonic–clonic, or dystonic seizures of the face and limbs. Interictal and ictal scalp EEG provided information regarding lateralization in the majority of patients, but the discharges were widely distributed over perisylvian or “rolandic-like” regions and the vertex. Furthermore, two subgroups of epileptogenic network organization were identified within POS by SEEG, visually and quantitatively, using an EM approach: group 1 (mesial frontal/cingulate networks) was observed in three patients who mainly exhibited hypermotor seizures; group 2 (perisylvian networks) was observed in four patients who mainly exhibited contralateral focal motor seizures. Conclusion This study indicated that POS could be characterized by initial specific somatosensory sensations, followed by either frequently nocturnal hypermotor seizures or contralateral focal motor seizures. The distinctive seizure semiology depended on the organization of two primary epileptogenic networks. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond.

Biomedical research has been struck with the problem of study findings that are not reproducible. With the advent of large databases and powerful statistical software, it has become easier to find associations and form conclusions from data without forming an a-priori hypothesis. This approach may yield associations without clinical relevance, false positive findings, or biased results due to "fishing" for the desired results. To improve reproducibility, transparency, and validity among clinical trials, the National Institute of Health recently updated its grant application requirements, which mandates registration of clinical trials and submission of the original statistical analysis plan (SAP) along with the research protocol. Many leading journals also require the SAP as part of the submission package. The goal of this article and the companion article detailing the SAP of an actual research study is to provide a practical guide on writing an effective SAP. We describe the what, why, when, where, and who of a SAP, and highlight the key contents of the SAP.

Three-dimensional palladium nanoflowers (Pd NF) composed of ultrathin Pd nanosheets had been synthesized by a solvothermal approach in our previous work. Here, the effects of preparation conditions on the morphology and electrochemical performance of palladium nanostructures were investigated. The explored conditions are as follows: the ratio of reducing agent to capping agent, the concentration of PdCl2 precursor, the amount of HCl (used for PdCl2 dissolution), the reaction temperature and time. Only when these conditions are strictly controlled, the obtained Pd material displays a uniformly nanoflower-like morphology, otherwise the Pd samples with nanoparticles or incomplete flowers can only be obtained. Then, the relationship between the morphology of Pd and its electrocatalytic activity was further studied. The results indicate that the Pd with perfect nanoflowers morphology possesses superior activity for formic acid electro-oxidation, while the Pd with incomplete flowers and ordinary (or irregular) particle morphology shows moderate and inferior activity. Therefore, the morphology-dependent electrocatalytic activity has been demonstrated in this work.

We report the photoelectrochemical (PEC) oxidation of glucose at tungsten trioxide nanoplate (WO3NP) electrode for glucose sensing application and photo fuel cell (PFC) application. The WO3-based PEC sensor shows high sensitivity of 68.15 μA cm−2 mM−1 in glucose detection for the concentrations in the range of 0.1~0.5 mM and displays good selectivity toward the interferents of ascorbic acid (AA) and uric acid (UA). Moreover, electricity can be extracted from photo-oxidizing of glucose on WO3NP electrode in a PFC device and the output strongly depends on the concentration of glucose fuel. In addition, the power performance of PFC obtained under irradiation shows 60-fold higher than that of achieved in the dark, indicating that photo-oxidation of glucose on the WO3NP anode is the essence for this fuel cell electricity generation. The work expands the application of WO3 in the field of glucose analysis and provides a possible way to detect glucose without inputting external power.

Aims Assessment of brain injury severity early after cardiac arrest (CA) may guide therapeutic interventions and help clinicians counsel families regarding neurologic prognosis. We aimed to determine whether adding EEG features to predictive models including clinical variables and examination signs increased the accuracy of short-term neurobehavioral outcome prediction. Methods This was a prospective, observational, single-center study of consecutive infants and children resuscitated from CA. Standardized EEG scoring was performed by an electroencephalographer for the initial EEG timepoint after return of spontaneous circulation (ROSC) and each 12-h segment from the time of ROSC up to 48 h. EEG Background Category was scored as: (1) normal; (2) slow-disorganized; (3) discontinuous or burst-suppression; or (4) attenuated-featureless. The primary outcome was neurobehavioral outcome at discharge from the Pediatric Intensive Care Unit. To develop the final predictive model, we compared areas under the receiver operating characteristic curves (AUROC) from models with varying combinations of Demographic/Arrest Variables, Examination Signs, and EEG Features. Results We evaluated 89 infants and children. Initial EEG Background Category was normal in 9 subjects (10%), slow-disorganized in 44 (49%), discontinuous or burst suppression in 22 (25%), and attenuated-featureless in 14 (16%). The final model included Demographic/Arrest Variables (witnessed status, doses of epinephrine, initial lactate after ROSC) and EEG Background Category which achieved AUROC of 0.9 for unfavorable neurobehavioral outcome and 0.83 for mortality. Conclusions The addition of standardized EEG Background Categories to readily available CA variables significantly improved early stratification of brain injury severity after pediatric CA.

Background Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. Gelsemium elegans Benth (GEB) is a traditional Chinese medicine commonly used for treatment for gastrointestinal cancer, including CRC. However, the underlying active ingredients and mechanism remain unknown. This study aims to explore the active components and the functional mechanisms of GEB in treating CRC by network pharmacology-based approaches. Methods Candidate compounds of GEB were collected from the Traditional Chinese Medicine@Taiwan, Traditional Chinese Medicines Integrated Database, Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine, and published literature. Potentially active targets of compounds in GEB were retrieved from SwissTargetPrediction databases. Keywords “colorectal cancer”, “rectal cancer” and “colon cancer” were used as keywords to search for related targets of CRC from the GeneCards database, then the overlapped targets of compounds and CRC were further intersected with CRC related genes from the TCGA database. The Cytoscape was applied to construct a graph of visualized compound-target and pathway networks. Protein-protein interaction networks were constructed by using STRING database. The DAVID tool was applied to carry out Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis of final targets. Molecular docking was employed to validate the interaction between compounds and targets. AutoDockTools was used to construct docking grid box for each target. Docking and molecular dynamics simulation were performed by Autodock Vina and Gromacs software, respectively. Results Fifty-three bioactive compounds were successfully identified, corresponding to 136 targets that were screened out for the treatment of CRC. Functional enrichment analysis suggested that GEB exerted its pharmacological effects against CRC via modulating multiple pathways, such as pathways in cancer, cell cycle, and colorectal cancer. Molecular docking analysis showed that the representative compounds had good affinity with the key targets. Molecular dynamics simulation indicated that the best hit molecules formed a stable protein-ligand complex. Conclusion This network pharmacology study revealed the multiple ingredients, targets, and pathways synergistically involved in the anti-CRC effect of GEB, which will enhance our understanding of the potential molecular mechanism of GEB in treatment for CRC and lay a foundation for further experimental research.

OBJECTIVES We developed a tool, Serial Neurologic Assessment in Pediatrics, to screen for neurologic changes in patients, including those who are intubated, are sedated, and/or have developmental disabilities. Our aims were to: 1) determine protocol adherence when performing Serial Neurologic Assessment in Pediatrics, 2) determine the interrater reliability between nurses, and 3) assess the feasibility and acceptability of using Serial Neurologic Assessment in Pediatrics compared with the Glasgow Coma Scale. DESIGN Mixed-methods, observational cohort. SETTING Pediatric and neonatal ICUs. SUBJECTS Critical care nurses and patients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Serial Neurologic Assessment in Pediatrics assesses Mental Status, Cranial Nerves, Communication, and Motor Function, with scales for children less than 6 months, greater than or equal to 6 months to less than 2 years, and greater than or equal to 2 years old. We assessed protocol adherence with standardized observations. We assessed the interrater reliability of independent Serial Neurologic Assessment in Pediatrics assessments between pairs of trained nurses by percent- and bias- adjusted kappa and percent agreement. Semistructured interviews with nurses evaluated acceptability and feasibility after nurses used Serial Neurologic Assessment in Pediatrics concurrently with Glasgow Coma Scale during routine care. Ninety-eight percent of nurses (43/44) had 100% protocol adherence on the standardized checklist. Forty-three nurses performed 387 paired Serial Neurologic Assessment in Pediatrics assessments (149 < 6 mo; 91 ≥ 6 mo to < 2 yr, and 147 ≥ 2 yr) on 299 patients. Interrater reliability was substantial to near-perfect across all components for each age-based Serial Neurologic Assessment in Pediatrics scale. Percent agreement was independent of developmental disabilities for all Serial Neurologic Assessment in Pediatrics components except Mental Status and lower extremity Motor Function for patients deemed "Able to Participate" with the assessment. Nurses reported that they felt Serial Neurologic Assessment in Pediatrics, compared with Glasgow Coma Scale, was easier to use and clearer in describing the neurologic status of patients who were intubated, were sedated, and/or had developmental disabilities. About 92% of nurses preferred to use Serial Neurologic Assessment in Pediatrics over Glasgow Coma Scale. CONCLUSIONS When used by critical care nurses, Serial Neurologic Assessment in Pediatrics has excellent protocol adherence, substantial to near-perfect interrater reliability, and is feasible to implement. Further work will determine the sensitivity and specificity for detecting clinically meaningful neurologic decline.

Introduction/Hypothesis The outcome of cardiopulmonary resuscitation (CPR) depends on timely recognition of the underlying cause of cardiac arrest. Ventricular fibrillation (VF) waveform analysis to differentiate primary VF from secondary asphyxia-associated VF may allow tailoring of therapies to improve cardiac arrest outcomes. Therefore, the primary goal of this investigation was to develop a novel technique utilizing wavelet synchrosqueezed transform (WSST) and decision-tree classifier that was specifically adapted to discriminate between these two incidents of VF. Methods Secondary analytical investigation of electrocardiography (ECG) data obtained from swine models of either primary VF (n = 18) or secondary asphyxia-associated VF (7 min of asphyxia prior to VF induction; n = 12). In the primary analysis, WSST technique was applied to the first 35 s of the VF ECG signal to identify the most differentiating characteristics of the signal for use as features to develop a machine learning algorithm to classify the arrest as either primary VF vs. secondary asphyxia-associated VF. The performance of this new interactive Machine Learning algorithm with Wavelet Energy features of ECG (MLWAVE) was assessed using both classification accuracy and area under the receiver operating characteristic curve (AUCROC). To evaluate the validity of the new technique, the amplitude spectrum area (AMSA)-based technique, a well-established defibrillation classification method, was also applied to the same ECG signals. The classification accuracy and AUCROC were then compared between the two techniques. Results For the primary analysis evaluating the first 35 s of the VF waveform, the MLWAVE technique classified the type of VF with high accuracy (28/28 [100%], AUCROC: 1.00). The MLWAVE technique performed better than the AMSA technique across all comparisons, but given the small sample sizes, differences were not statistically significant (accuracy: 100% vs. 85.7%; p = 0.24; AUCROC: 1.00 vs. 0.82; p = 0.24). Conclusion This analytical investigation illustrates the advantages of the MLWAVE signal processing method which was associated with 100% accuracy in classifying the type of VF waveform: primary vs. asphyxia-associated. Such classification could lead to personalized tailoring of resuscitation (e.g., immediate defibrillation vs. continued CPR and treatment of reversible cardiac arrest causes before defibrillation) to improve outcomes for cardiac arrest.

Background: Orotracheal intubation of infants using direct laryngoscopy can be challenging. We aimed to investigate whether video laryngoscopy with a standard blade done by anaesthesia clinicians improves the first-attempt success rate of orotracheal intubation and reduces the risk of complications when compared with direct laryngoscopy. We hypothesised that the first-attempt success rate would be higher with video laryngoscopy than with direct laryngoscopy. Methods: In this multicentre, parallel group, randomised controlled trial, we recruited infants without difficult airways abnormalities requiring orotracheal intubation in operating theatres at four quaternary children's hospitals in the USA and one in Australia. We randomly assigned patients (1:1) to video laryngoscopy or direct laryngoscopy using random permuted blocks of size 2, 4, and 6, and stratified by site and clinician role. Guardians were masked to group assignment. The primary outcome was the proportion of infants with a successful first attempt at orotracheal intubation. Analysis (modified intention-to-treat [mITT] and per-protocol) used a generalised estimating equation model to account for clustering of patients treated by the same clinician and institution, and adjusted for gestational age, American Society of Anesthesiologists physical status, weight, clinician role, and institution. The trial is registered at ClinicalTrials.gov, NCT03396432. Findings: Between June 4, 2018, and Aug 19, 2019, 564 infants were randomly assigned: 282 (50%) to video laryngoscopy and 282 (50%) to direct laryngoscopy. The mean age of infants was 5·5 months (SD 3·3). 274 infants in the video laryngoscopy group and 278 infants in the direct laryngoscopy group were included in the mITT analysis. In the video laryngoscopy group, 254 (93%) infants were successfully intubated on the first attempt compared with 244 (88%) in the direct laryngoscopy group (adjusted absolute risk difference 5·5% [95% CI 0·7 to 10·3]; p=0·024). Severe complications occurred in four (2%) infants in the video laryngoscopy group compared with 15 (5%) in the direct laryngoscopy group (–3·7% [–6·5 to –0·9]; p=0·0087). Fewer oesophageal intubations occurred in the video laryngoscopy group (n=1 [

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease caused by ADA2 gene mutation that is characterized by three phenotype domains: vasculopathy and inflammation, hematological abnormality, and immunodeficiency. Most patients are pediatric patients; adult-onset patients are only occasionally reported. To describe a Chinese case of adult-onset DADA2 in a Chinese patient and explore the genotype and phenotype characteristics of adult-onset DADA2. We examined the clinical, serological, and genetic features of a Chinese adult-onset DADA2 patient. English literature on DADA2 was reviewed. The clinical and genetic characteristics of different age and mutation subgroups were compared. A Chinese Han male presented with recurrent fever, rash, immunodeficiency, and significant vascular events since the age of 25 years. Serum ADA2 activity was diminished, and genotyping revealed a unique compound heterozygous mutation of exon2-10del/exon7del in the ADA2 gene leading to complete exon 7 deletion. Treatment with a TNFα inhibitor achieved disease control. A total of 269 cases carrying 102 mutations were analyzed through a literature review. Adult-onset patients had few symptoms in all three clinical domains; vasculopathy and inflammation were the major symptoms. Patients with null mutations had early disease onset and more frequent hematological abnormalities and immunodeficiency. Patients in all subgroups responded well to TNFα inhibitors. We reported the first Chinese adult-onset DADA2 patient, with a unique mutation. Screening for and differentiation of DADA2 are recommended for patients of all ages, as they might become symptomatic later in life and treatment strategies differ from those of traditional vasculitis. Key Points • We report a novel compound heterozygous deletion mutations of exons 2-10 and exon 7, leading to complete loss of exon 7 in the ADA2 gene. • Adult-onset DADA2 patients had high similarity to systemic vasculitis. • Null mutations contribute to earlier disease onset and more aggressive disease. • We suggest screening for DADA2 in patients with significant central vasculitis, hematological abnormality and immunodeficiency.

Background Spatially resolved gene expression has emerged as a crucial technique to understand complex multicellular interactions within the tumor and its microenvironment. Interrogation of complex cellular interactions within the tumor microenvironment (TME) requires a multi-omics approach where multiple RNA and protein targets can be visualized within the same tumor sample and be feasible in FFPE sample types. Simultaneous detection of RNA and protein can reveal cellular sources of secreted proteins, identify specific cell types, and visualize the spatial organization of cells within the tissue. Examination of RNA by in situ hybridization (ISH) and protein by immunohistochemistry (IHC) or immunofluorescence (IF) are widely used and accepted techniques for the detection of biomarkers in tumor samples. Given the similarities in workflow, co-detection of RNA and protein by combining ISH and IHC/IF in a single assay can be a powerful multi-omics solution for interrogating the complex tumor and its microenvironment. Methods In this report we combined the single cell, single molecule RNA ISH technology known as RNAscope with IHC/IF to simultaneously detect RNA and protein in the same FFPE tumor section using both chromogenic and fluorescence detection methods. Results We demonstrate co-localization of target mRNA and the corresponding protein in human cancer samples, visualize infiltration of immune cells into the TME, characterize the activation state of immune cells in the TME, identify single cell gene expression within cellular boundaries demarcated by IHC/IF, examine cell type-specific expression of multiple immune checkpoint markers, and distinguish endogenous T cells from activated CAR+ T cells. Overall, we show that co-detection of RNA by the RNAscope ISH assay and protein by the IHC/IF assay in the same FFPE section is a feasible methodology. The combined RNAscope ISH-IHC/IF workflow is a powerful technique that can be used to study gene expression signatures at the RNA and protein level with spatial and single cell resolution. Conclusions By leveraging the strength of the similar workflows of RNAscope ISH and IHC/IF assays, this methodology combines transcriptomics and proteomics in the same tissue section, providing a multi-omics approach for characterizing complex tissues and revealing cell type specific gene expression with spatial and single cell resolution.

Background The ability of T cells to mediate anti-tumor immunity has been harnessed to develop successful immunotherapies in recent years. Although direct presentation of tumor antigens by tumor cells plays an important role in the effector function of cytotoxic T lymphocytes (CTLs), cross-presentation by professional antigen presenting cells such as dendritic cells (DCs) is vital for priming naive CD8+ T cells and developing a sustainable cytotoxic response. Natural killer (NK) cells within the tumor microenvironment (TME) recruit a specific population of DCs called conventional type 1 DCs (cDC1s) into the TME by secreting chemokines such as CCL5 and XCL1. However, these cells are very low in abundance and are characterized by the expression of numerous markers, making their detection in the tissue context challenging. Methods Therefore, to interrogate the presence of cDC1 and NK cells in the TME and reveal their spatial relationship we utilized the highly sensitive and specific RNAscope Multiplex Fluorescence in situ hybridization (ISH) assay. Probes for XCR1, THBD, CLEC9A, and CCR5 were used to identify cDC1 cells within 4 cervical cancer tumors. These tumors were then assessed for the presence of NK cells by using specific marker probes such as CD56 and NCR1 and chemokines XCL1 and CCL5. Finally, CTLs were visualized to determine if there is a correlation between the presence of cDC1 and NK cells and CTL infiltration within the cervical cancer tumors. Results Our results revealed a strong correlation between the presence of NK cells, cDC1 cells, and CTLs within 3 out of 4 cervical cancer samples. The NK cells showed expression of the chemokines XCL1 and CCL5, which are the ligands for XCR1 and CCR5 respectively, suggesting that the XCR1+/CCR5+ cDC1 cells may have been potentially recruited by these NK cells. Regions high in cDC1 and NK cells also showed significantly higher levels of CTL recruitment, as indicated by the presence of CD8+/IFNG+ T cells. Conversely, 1 of the 4 cervical cancer samples demonstrated relatively lower levels of NK cells which correlated with lower cDC1 cells and in turn lower CTL infiltration. Conclusions In conclusion, by utilizing the RNAscope Multiplex ISH assay we were able to identify and visualize the spatial relationship between NK cells, CTLs, and cDC1 cells, a rare subset of DC cells that excel at presenting tumor antigens to T cells. Using this technology, it is possible to spatially interrogate the TME and detect specialized immune cells when assessing response to immunotherapies.

Manual wheelchair users experience numerous invisible barriers while navigating cities, often reporting how stressful journeys are. This stress affects a wheelchair user’s quality of life. To alleviate such psychological burden, we propose a novel intervention strategy with a respiratory biofeedback interface which is designed to help users feel relaxed in urban navigation. We conducted a study in a real-world setting to explore its potential to provide real-time psychological support. From qualitative and quantitative analysis, we report on the strengths and weaknesses of the approach.

The fuzzy particle swarm optimization (FPSO-RRB- algorithm is used to solve the logistics transportation time optimization problem, a three-dimensional particle coding method based on receiving point, particle position sequence and particle position rounding operation is proposed, the results are compared with those of fuzzy particle swarm optimization algorithm. The experimental results show that the fuzzy particle swarm optimization algorithm can effectively optimize the logistics transportation time.

Aerosol acidity governs several key processes in aerosol physics and chemistry, thus affecting aerosol mass and composition, and ultimately the climate and human health. Previous studies have reported the aerosol pH separately in China and the United States, implying a different aerosol acidity between these two countries. However, underlying mechanisms responsible for the pH difference are not fully understood, limited by the scarcity of simultaneous measurements of aerosol composition and gas species, especially in China. Here we conduct a comprehensive assessment of the aerosol acidity in China and the United States, using extended ground-level measurements and regional chemical transport model simulations. We show aerosol in China is significantly less acidic than that in the United States, with pH values 1–2 units higher. Based on a multivariable Taylor Series method and a series of sensitivity tests, we identify several major factors leading to the pH difference. Compared to the United States, aerosols in China are generally in total ammonia (TNH3 = NH4+ + NH3) rich conditions where particle phase ammonium (NH4+) concentrations are adequate enough to nearly neutralize major acidic inorganic anions such as sulfate, nitrate, and chloride, leading to a higher aerosol pH. Higher relative availability of the stronger acidic component, sulfate, compared with the weaker acidic component, total nitrate (TNO3 = NO3− + HNO3), also contributes to the lower aerosol pH in the United States. As a response to higher aerosol pH, the higher nitrate to sulfate molar ratios in China indicates a nitrate-rich condition, further leading to higher aerosol water uptake which will continually promote nitrate aerosol formation. Considering the historical emissions trends, the difference in aerosol acidity between these two countries is expected to continue as SO2 and NOx emissions are further controlled. The differences in aerosol acidity highlight in the present study imply potential differences in formation mechanisms, physicochemical properties, and toxicity of aerosol particles between China and the United States.