Pulmonary hypertension across the spectrum of left heart and lung disease.

AIMS: Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2-3), but this group is not well-characterized. METHODS AND RESULTS: Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2-3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2-3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2-3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2-3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2-3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.86), and patients with G2-3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38-0.86). CONCLUSIONS: Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2-3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02980887.

Ortho-Substituent Effects on Halogen Bond Geometry for N-Haloimide⋯2-Substituted Pyridine Complexes.

The nature of (imide)N-X⋯N(pyridine) halogen-bonded complexes formed by six N-haloimides and sixteen 2-substituted pyridines are studied using X-ray crystallography (68 crystal structures), Density Functional Theory (DFT) (86 complexation energies), and NMR spectroscopy (90 association constants). Strong halogen bond (XB) donors such as N-iodosuccinimide form only 1:1 haloimide:pyridine crystalline complexes, but even stronger N-iodosaccharin forms 1:1 haloimide:pyridine and three other distinct complexes. In 1:1 haloimide:pyridine crystalline complexes, the haloimide's N─X bond exhibits an unusual bond bending feature that is larger for stronger N-haloimides. DFT complexation energies (ΔEXB ) for iodoimide-pyridine complexes range from -44 to -99 kJ mol-1 , while for N-bromoimide-pyridine, they are between -31 and -77 kJ mol-1 . The ΔEXB of I⋯N XBs in 1:1 iodosaccharin:pyridine complexes are the largest of their kind, but they are substantially smaller than those in [bis(saccharinato)iodine(I)]pyridinium salts (-576 kJ mol-1 ), formed by N-iodosaccharin and pyridines. The NMR association constants and ΔEXB energies of 1:1 haloimide:pyridine complexes do not correlate as these complexes in solution are heavily influenced by secondary interactions, which DFT studies do not account for. Association constants follow the σ-hole strengths of N-haloimides, which agree with DFT and crystallography data. The haloimide:2-(N,N-dimethylamino)pyridine complex undergoes a halogenation reaction resulting in 5-iodo-2-dimethylaminopyridine.

N-X⋠⋠⋠O-N Halogen Bonds in Complexes of N-Haloimides and Pyridine-N-oxides: A Large Data Set Study.

N-X⋅⋅⋅- O-N+ halogen-bonded systems formed by 27 pyridine N-oxides (PyNOs) as halogen-bond (XB) acceptors and two N-halosuccinimides, two N-halophthalimides, and two N-halosaccharins as XB donors are studied in silico, in solution, and in the solid state. This large set of data (132 DFT optimized structures, 75 crystal structures, and 168 1 H NMR titrations) provides a unique view to structural and bonding properties. In the computational part, a simple electrostatic model (SiElMo) for predicting XB energies using only the properties of halogen donors and oxygen acceptors is developed. The SiElMo energies are in perfect accord with energies calculated from XB complexes optimized with two high-level DFT approaches. Data from in silico bond energies and single-crystal X-ray structures correlate; however, data from solution do not. The polydentate bonding characteristic of the PyNOs' oxygen atom in solution, as revealed by solid-state structures, is attributed to the lack of correlation between DFT/solid-state and solution data. XB strength is only slightly affected by the PyNO oxygen properties [(atomic charge (Q), ionization energy (Is,min ) and local negative minima (Vs,min )], as the σ-hole (Vs,max ) of the donor halogen is the key determinant leading to the sequence N-halosaccharin>N-halosuccinimide>N-halophthalimide on the XB strength.

Identification of ferroptosis-related genes in male mice with sepsis-induced acute lung injury based on transcriptome sequencing.

BACKGROUND: Sepsis can result in acute lung injury (ALI). Studies have shown that pharmacological inhibition of ferroptosis can treat ALI. However, the regulatory mechanisms of ferroptosis in sepsis-induced ALI remain unclear. METHODS: Transcriptome sequencing was performed on lung tissue samples from 10 sepsis-induced mouse models of ALI and 10 control mice. After quality control measures, clean data were used to screen for differentially expressed genes (DEGs) between the groups. The DEGs were then overlapped with ferroptosis-related genes (FRGs) to obtain ferroptosis-related DEGs (FR-DEGs). Subsequently, least absolute shrinkage and selection operator (Lasso) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) were used to obtain key genes. In addition, Ingenuity Pathway Analysis (IPA) was employed to explore the disease, function, and canonical pathways related to the key genes. Gene set enrichment analysis (GSEA) was used to investigate the functions of the key genes, and regulatory miRNAs of key genes were predicted using the NetworkAnalyst and StarBase databases. Finally, the expression of key genes was validated with the GSE165226 and GSE168796 datasets sourced from the Gene Expression Omnibus (GEO) database and using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Thirty-three FR-DEGs were identified between 1843 DEGs and 259 FRGs. Three key genes, Ncf2, Steap3, and Gclc, were identified based on diagnostic models established by the two machine learning methods. They are mainly involved in infection, immunity, and apoptosis, including lymphatic system cell migration and lymphocyte and T cell responses. Additionally, the GSEA suggested that Ncf2 and Steap3 were similarly enriched in mRNA processing, response to peptides, and leukocyte differentiation. Furthermore, a key gene-miRNA network including 2 key genes (Steap3 and Gclc) and 122 miRNAs, and a gene-miRNA network with 1 key gene (Steap3) and 3 miRNAs were constructed using NetworkAnalyst and StarBase, respectively. Both databases predicted that mmu-miR-15a-5p was the target miRNA of Steap3. Finally, Ncf2 expression was validated using both datasets and qRT-PCR, and Steap3 was validated using GSE165226 and qRT-PCR. CONCLUSIONS: This study identified two FR-DEGs (Ncf2 and Steap3) associated with sepsis-induced ALI via transcriptome analyses, as well as their functional and metabolic pathways.

Iron deficiency in pulmonary vascular disease: pathophysiological and clinical implications.

AIMS: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear. METHODS AND RESULTS: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide. CONCLUSION: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.

Process design and optimization on self-sustaining pyrolysis and carbonization of municipal sewage sludge.

Pyrolysis can realize the reduction and resource utilization of municipal sewage sludge (MSS). In this paper, a self-sustaining pyrolysis process is designed for municipal sewage sludge, and the process flow is simulated by Aspen plus software. By changing the initial moisture content of sludge, moisture content after drying, pyrolysis temperature and air supply in the incinerator, the possibility of achieving energy self-balance in the system is analysed. The simulation results show that by adjusting the parameters of the system, this process can realize the energy self-balance of sludge drying and pyrolysis treatment. Considering the system's energy loss, the dry basis calorific value of sludge should not be less than 10 MJ/kg. The higher the initial moisture content of sludge, the more external energy input the system needs. It is recommended to dehydrate sludge mechanically to about 60 % before entering the system. When the pyrolysis temperature is increased, the amount of oil and gas produced by sludge pyrolysis increases, and it is easier to achieve self-balance of system energy. But the higher the pyrolysis temperature, the greater the energy consumption required. In practice, it is suggested that the pyrolysis temperature is about 400 °C. The moisture content of dried sludge has little effect on the energy self-balance of the system, and it is recommended to be about 30 %. The air supply volume of the incinerator mainly affects the flue gas outlet temperature and flue gas volume, but has little effect on the energy balance of the system.

Submicron particle formation from co-firing of coal and municipal sewage sludge.

With the increasing production of municipal sewage sludge (MSS) in China every year, the co-firing of MSS and pulverized coal is getting more and more widely applied in large coal-fired power plants. The co-firing of MSS and pulverized coal will produce a large amount of particulate matter (PM) emissions, especially submicron particles. In this paper, the formation characteristics of submicron particles in the co-firing process of coal and MSS were studied in a drop tube furnace. The influence of the furnace temperature and the addition ratio of sludge on the particle size distribution and element composition of submicron particles in MSS, pulverized coal combustion and co-firing was mainly studied. The experimental results show that the furnace temperature has an influence on the formation of PM0.4. For sludge combustion, increasing the furnace temperature will promote the formation of PM0.4. The main reason is that increasing the furnace temperature promotes the gasification of Si, S, Fe, and P to form the precursor of PM0.4 or PM0.4. At same furnace temperature, the volume concentration and mass concentration of PM0.4 produced from pulverized coal combustion are less than that of sludge. Different from sludge combustion, co-firing of pulverized coal and sludge has a synergistic effect on eliminating PM0.4 formation. Increasing the addition ratio of sludge can decrease the volume concentration and mass concentration of PM0.4. This is because that aluminosilicates formed during co-firing promotes the scavenge Si, Ca, Fe, thereby reducing the precursors of PM0.4 and the mass yield of PM0.4. Increasing the furnace temperature in co-firing can inhibit the formation of PM0.4. When the furnace temperature is between 1100 °C and 1300 °C, increasing the furnace temperature will reduce the Fe content and increase the content of Si, Ca, Na, K, and P in PM0.4. However, the reduction of Fe and the increase of Si, Ca, Na, K, and P in PM0.4 offset each other, resulting in an insensitive relationship between the mass yield of PM0.4 and the furnace temperature.

Dual-band polarization-insensitive toroidal dipole quasi-bound states in the continuum in a permittivity-asymmetric all-dielectric meta-surface.

Ultra-high quality (Q) factor resonances derived from the bound states in the continuum (BICs) have drawn much attention in optics and photonics. Especially in meta-surfaces, they can enable ultrasensitive sensors, spectral filtering, and lasers because of their enhanced light-matter interactions and rare superiority of scalability. In this paper, we propose a permittivity-asymmetric all-dielectric meta-surface, comprising high-index cuboid tetramer clusters with symmetric structural parameters and configuring periodically on a glass substrate. Simulation results offer dual-band quasi-BICs with high Q values of 4447 and 11391, respectively. Multipolar decomposition in cartesian and electromagnetic distributions are engaged to analyze the physical mechanism of dual quasi-BIC modes, which reveals that they are both governed by magnetic quadrupole (MQ) and in-plane toroidal dipole (TD). The polarization-insensitive and scalable characteristics are also investigated. Additionally, we appraise the sensing performances of the proposed structure. As an example, our work supports an uncommon route to design dual-band polarization-insensitive TD quasi-BICs resonators and facilitates their applications in optic and photonics, such as low-threshold lasers and sensing.

Ligand exchange among iodine(I) complexes.

A detailed investigation of ligand exchange between iodine(I) ions in [N⋯I⋯N]+ halogen-bonded complexes is presented. Ligand exchange reactions were conducted to successfully confirm whether iodine(I) complex formation, via the classical [N⋯Ag⋯N]+ to [N⋯I⋯N]+ cation exchange reaction from their analogous Ag+ complexes, could be determined solely by using 1H NMR spectroscopy. In instances where the formation of the iodine(I) complex was unclear or in low yield by the traditional cation exchange reaction, a ligand exchange reaction was used to form the desired iodine(I) complexes in a quantitative manner. Mixing two homoleptic [N⋯I⋯N]+ iodine(I) complexes in 1 : 1 ratio was found to undergo a statistical ligand exchange, with 1H NMR studies showing that the preferred formation of the relative heteroleptic [N1⋯I⋯N2]+ complexes increases with greater differences in the Lewis basicities of two XB acceptors of the complexes involved.

Robust estimates of regional treatment effects in multiregional randomized clinical trials with semiparametric logistic model.

In multiregional randomized clinical trials (MRCTs), determining the regional treatment effect of a new treatment over an existing one is important to both the sponsor and related regulatory agencies. Also of particular interest is to test the null hypothesis that the treatment benefit is the same among all the regions. Existing methods are mainly for continuous endpoint and use parametric models, which are not robust. MRCTs are known for facing increased variation and heterogeneity and a robust model for its design and analysis would be desirable. We consider clinical trials with a binary primary endpoint and propose a robust semiparametric logistic model which has a known parametric and an unknown nonparametric component. The parametric component represents our prior knowledge about the model, and the nonparametric part reflects uncertainty. Compared to the classic logistic model for this problem, the proposed model has the following advantages: robust to model assumption, more flexible and accurate to model the relationship between the response and covariates, and possibly more accurate parameter estimates. The model parameters are estimated by profile maximum likelihood approach, and the null hypothesis of regional treatment difference being the same is tested by the profile likelihood ratio statistic. Asymptotic properties of the estimates are derived. Simulation studies are conducted to evaluate the performance of the proposed model, which demonstrated clear advantages over the classic logistic model. The method is then applied to analyzing a real MRCT.

Macrocyclic complexes based on [N⋯I⋯N]+ halogen bonds.

New 1-2 nm macrocyclic iodine(I) complexes prepared VIA a simple ligand exchange reaction manifest rigid 0.5-1 nm cavities that bind the hexafluorophosphate anion in the gas phase. The size of the cavities and the electrostatic interactions with the iodine(I) cations influence the anion binding properties of these macrocyclic complexes.

Light- and pH-regulated Water-soluble Pseudorotaxanes Comprising a Cucurbit[7]uril and a Flavylium-based Axle.

A linear double pyridinium-terminated thread comprising a central chalcone moiety is shown to provide two independent binding sites with similar affinity for cucurbit[7]uril (CB7) macrocycles in water as judged from NMR, UV-Visible and fluorescence spectroscopies. Association results in [2] and [3]pseudorotaxanes, which are both pH and photosensitive. Switching from the neutral chalcone to the cationic flavylium form upon irradiation at 365 nm under acidic conditions provided an enhanced CB7 association (K1:1 increases from 1.2×105  M-1 to 1.5×108  M-1 ), limiting spontaneous on-thread cucurbituril shuttling. This co-conformational change in the [2]pseudorotaxane is reversible in the dark with kobs =4.1×10-4  s-1 . Threading the flavylium moiety into CB7 leads to a dramatic increase in the fluorescence quantum yield, from 0.29 in the free axle to 0.97 in the [2]pseudorotaxane and 1.0 in the [3]pseudorotaxane.

Dihypoiodites stabilised by 4-ethylpyridine through O-I-N halogen bonds.

Four bis(O-I-N) compounds have been synthesised from various dihypoiodites and 4-ethylpyridine. The compounds were characterised in both the solution and solid states by NMR spectroscopy (1H, 15N), X-ray diffraction, and computational calculations.

Damming an electronic energy reservoir: ion-regulated electronic energy shuttling in a [2]rotaxane.

We demonstrate the first example of bidirectional reversible electronic energy transfer (REET) between the mechanically bonded components of a rotaxane. Our prototypical system was designed such that photoexcitation of a chromophore in the axle results in temporary storage of electronic energy in a quasi-isoenergetic "reservoir" chromophore in the macrocycle. Over time, the emissive state of the axle is repopulated from this reservoir, resulting in long-lived, delayed luminescence. Importantly, we show that cation binding in the cavity formed by the mechanical bond perturbs the axle chromophore energy levels, modulating the REET process, and ultimately providing a luminescence read-out of cation binding. Modulation of REET processes represents an unexplored mechanism in luminescent molecular sensor development.

Carbonyl Hypoiodites as Extremely Strong Halogen Bond Donors.

Neutral halogen-bonded O-I-N complexes were prepared from in situ formed carbonyl hypoiodites and aromatic organic bases. The carbonyl hypoiodites have a strongly polarized iodine atom with larger σ-holes than any known uncharged halogen bond donor. Modulating the Lewis basicity of the selected pyridine derivatives and carboxylates leads to halogen-bonded complexes where the classical O-I⋅⋅⋅N halogen bond transforms more into a halogen-bonded COO- ⋅⋅⋅I-N+ ion-pair (salt) with an asymmetric O-I-N moiety. X-ray analyses, NMR studies, and calculations reveal the halogen bonding geometries of the carbonyl hypoiodite-based O-I-N complexes, confirming that in the solid-state the iodine atom is much closer to the N-atom of the pyridine derivatives than its original position at the carboxylate O-atom.

Multiple Fano resonances excitation on all-dielectric nanohole arrays metasurfaces.

Both toroidal dipoles, electric dipoles and magnetic dipoles belong to one type of electromagnetic excitation. In this paper, we present an all-dielectric metasurface composed of an array of square nanoholes. It can simultaneously generate four resonance responses excited by TD, EQ and MD in the continuous near-infrared band. By introducing the in-plane symmetry breaking of the unit cell, asymmetric dielectric nanohole arrays are used to achieve two quasi-BIC resonance modes with high Q-factors excited by EQ and MD. The paper theoretically analyzes and demonstrates the relationship between structural asymmetry and the radiative Q-factor of two Fano resonances, that are governed by symmetry-protected BICs. And multipole decomposition and near-field analysis are performed to demonstrate the dominant role of various electromagnetic excitations in the four modes. The spectra response is also calculated for different incident polarization angles and medium refractive indices. The proposed metasurface is more feasible and practical compared to other complex nanostructures, which may open avenues for the development of applications such as biochemical sensing, optical switches and optical modulators, and provide a reference for the design of devices with polarization-independent properties.

Tuning Multiple Fano Resonances for On-Chip Sensors in a Plasmonic System.

This paper proposed a plasmonic resonator system, consisting of a metal-insulator-metal structure and two stubs, and a Fano resonance arose in its transmittance, which resulted from the coupling between the two stubs. On the basis of the proposed structure, a circle and a ring cavity are separately added above the stubs to create different coupled plasmonic structures, providing triple and quadruple Fano resonances, respectively. Additionally, by adjusting the geometric parameters of the system, multiple Fano Resonances obtained can be tuned. The proposed structure can be served as a high efficient refractive index sensor, yielding a sensitivity of 2000 nm/RIU and figure of merit (FOM) of 4.05 × 10 4 and performing better than most of the similar structures. It is believed that the proposed structure may support substantial applications for on-chip sensors, slow light and nonlinear devices in highly integrated photonic circuits.

Photochromic rotaxanes and pseudorotaxanes.

Among stimulus-responsive molecular ring-on-thread rotaxanes and pseudorotaxanes, variants incorporating photochromic sub-units are attracting considerable attention as their properties and structure can be remotely and precisely controlled, additionally without producing chemical waste. The focus herein is on photoswitching-driven assembly/disassembly and modulation of properties resulting from light-activated isomerization or changes in electronic properties.

[Epidemiological characteristics of imported malaria cases in Neijiang City, 2013].

OBJECTIVE: To understand the epidemiological characteristics of imported malaria cases in Neijiang City in 2013, so as to provide the references for malaria elimination in the city. METHODS: The epidemiological data of malaria cases were collected from the Parasitic Diseases Information Management System of Chinese Center for Disease Control and Prevention, and the data were analyzed with the descriptive epidemiological method. RESULTS: Totally 19 cases of imported malaria cases were reported in Neijiang City in 2013, which was increased by 375% comparing to that in 2012 (4 cases) , and all the cases were confirmed by the laboratory. Among these cases, 14 were (73.68%) falciparum malaria cases, 5 (26.32%) were vivax malaria cases; 13 cases (68.42%) were from African countries, and the other 6 (31.58%) were from Southeast Asia. These cases were distributed throughout each quater, which had no significant seasonality. All the cases were male aged from 20-49 years, and the majority of them (16 cases, 84.21%) were farmers and workers. CONCLUSIONS: The prevention and control situation of imported malaria is severe in Neijiang City. The capacity construction of malaria diagnosis and treatment of basic medical institutions as well as the health education and monitoring and management to floating population should be strengthened.

The removal process of 2,2-dichloroacetamide (DCAcAm), a new disinfection by-product, in drinking water treatment process and its toxicity on zebrafish.

The removal process of 2,2-dichloroacetamide (DCAcAm), a new disinfection by-product (DBP) in conventional drinking water treatment plant (C-DWTP) and advanced DWTP (ADWTP) was studied with newly maximum formation potential (MFP) process. It was demonstrated that the advanced treatment displayed greater removal efficiency towards DCAcAm formation potential (MFP) than the conventional treatment. The hydrophilic natural organic matter and natural organic matter with molecular weight <1 kDa or >10 kDa leaded to more DCAcAm formation, and the aromatic protein was inferred as one part of DCAcAm precursor. DCAcAm was found to cause delayed development and malformation to zebrafish embryos at embryonic growth stage. Compared with heart toxicity, it caused a significant neuron toxicity. It also could cause the acute DNA damage to adult zebrafish, which should be extremely cautioned.