Treatment of obstructive sleep apnea with a simple CPAP device.

PURPOSE: CPAP is the "gold standard" treatment for obstructive sleep apnea (OSA). Current CPAP models have developed additional functions including automatic CPAP and pressure relief. However, CPAP adherence has not improved over the last three decades. Many patients in low-income countries cannot afford these CPAP devices. A novel simple CPAP device with a fixed pressure without pressure controller was developed. METHODS: Manual CPAP pressure titration was performed in 127 patients with OSA. Six patients with a titration pressure higher than 11 cmH2O and 14 patients who could not tolerate CPAP were excluded, leaving 107 participating in the following 2 studies. In study one, 54 of 107 patients were treated by both conventional fixed CPAP and simple CPAP in random order. In the second study, another 53 patients were treated by both autoCPAP in automatic function and simple CPAP in random order. Simple CPAP was fixed at 10 cmH2O, 8 cmH2O, and 6 cmH2O for patients whose titration pressure was between 9-10, 7-8, and ≤ 6 cmH2O, respectively. Conventional fixed CPAP device was set exactly the same as manual titration pressure. RESULTS: All patients whose manual titration pressure ≤ 10 cmH2O were effectively treated by simple CPAP (AHI 40.7 ± 2.3 events/h before vs 2.5 ± 0.3 events/h after, p < 0.001). Patients expressed similar preferences for simple CPAP, autoCPAP, and conventional fixed CPAP (p > 0.05). CONCLUSIONS: We conclude that a novel simple CPAP is an alternative treatment for most patients with OSA, which may widen access to CPAP therapy in the developing countries because of its low cost.

Graphene oxide links alterations of anti-viral signaling pathways with lipid metabolism via suppressing TLR3 in vascular smooth muscle cells.

Vascular smooth muscle cells (VSMCs), the main cells constructing blood vessels, are important in the regulation of the pathophysiology of vascular systems; however, relatively few studies have investigated the influence of nanomaterials (NMs) on VSMCs. In this study, we found that the interaction between graphene oxide and human VSMCs led to the cytotoxicity and morphological changes of cells. Because transcriptomic data suggested that graphene oxide decreased anti-viral signaling pathways via decreasing Toll-like receptor 3 (TLR3), we further verified that graphene oxide decreased interferon induced protein with tetratricopeptide repeats 1 (IFIT1) and the radical S-adenosyl methionine domain containing 2 (RSAD2), and TLR3-downstream genes involved in anti-viral responses. Due to the involvement of RSAD2 in lipid dysfunction, we also verified that graphene oxide disrupted lipid homeostasis and increased adipose triglyceride lipase (ATGL). Adding TLR3 agonist polyinosinic:polycytidylic acid (Poly IC) partially increased TLR3-downstream protein interleukin-8 (IL-8) and some lipid classes, particularly lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), in graphene oxide-exposed VSMCs. In mice receiving repeated intravenous injection of graphene oxide, significantly decreased TLR3, IFIT1 and RSAD2 but increased ATGL proteins were observed in aortas. We conclude that graphene oxide altered anti-viral signaling pathways and lipid metabolism via decreasing TLR3 in VSMCs.

An Urchin-Shaped Copper-Based Metalloporphyrin Nanosystem as a Sonosensitizer for Sonodynamic Therapy.

Sonodynamic therapy (SDT), as a novel cancer therapy strategy, might be a promising approach due to the depth-penetration property in tissue. Sonosensitizers are the key element for efficient SDT. However, the development of sonosensitizers with strong sonosensitization efficacy is still a significant challenge. Herein, an urchin-shaped copper-based metalloporphyrin liposome nanosystem (FA-L-CuPP) is constructed and identified as an excellent sonosensitizer. Under ultrasound (US) irradiation, FA-L-CuPP can be highly excited to generate several reactive oxygen species (ROS), such as singlet oxygen (1O2) and free radicals (⋅OH). The molecular orbital distribution calculations reveal that a strong intramolecular charge transfer might occur in the CuPP complex under US irradiation, which could afford enough energy to the surrounding O2 and H2O to concert 1O2, O2- and ⋅OH. Working as "ammunitions", the largely produced ROS can kill 4T1 tumor cells, effectively inhibiting tumor growth. This work provides an urchin-shaped nanosonosensitizer based on a copper complex, which might provide an idea to design a novel sonosensitizer for noninvasive and precise SDT antitumor applications.

IL-12 nanochaperone-engineered CAR T cell for robust tumor-immunotherapy.

Although chimeric antigen receptor T (CAR T) cell immunotherapy has demonstrated remarkable success in clinical, therapeutic effects are still limited in solid tumor due to lack of activated T cell infiltration in immunosuppression of tumor microenvironment. Herein, we develop IL-12 nanostimulant-engineered CAR T cell (INS-CAR T) biohybrids for boosting antitumor immunity of CAR T cells via immunofeedback. As stimulating nanochaperone, IL-12-loaded human serum albumin (HSA) nanoparticles are effectively conjugated onto CAR T cells via bioorthogonal chemistry without influencing their antitumor capabilities. IL-12 is responsively released from INS-CAR T biohybrids in presence of the increased thiol groups on cell-surface triggered by tumor antigens. In return, released IL-12 obviously promotes the secretion of CCL5, CCL2 and CXCL10, which further selectively recruits and expands CD8+ CAR T cells in tumors. Ultimately, the immune-enhancing effects of IL-12 nanochaperone significantly boost CAR T cell antitumor capabilities, dramatically eliminated solid tumor and minimized unwanted side effects. Hence, immunofeedback INS-CAR T biohybrids, which include INS that serves as an intelligent 'nanochaperone', could provide a powerful tool for efficient and safe antitumor immunotherapy.

Highly efficient removal of Cr(VI) by hexapod-like pyrite nanosheet clusters.

Pyrite nanomaterials show an excellent performance in remediating Cr(VI) contaminated wastewater. However, the high surface reactivity makes them easy to agglomerate to reduce their removal efficiency for Cr(VI). In this study, a novel hexapod-like pyrite nanosheet clusters material was successfully synthesized via a facile hydrothermal method with the assistance of fluorides. The products were pyrite microspherulites without fluoride ion. The hexapod-like pyrite nanosheet clusters had dramatically higher Cr(VI) removal efficiencies than microspherulites due to more dissolved Fe(II) and S(-II) into the suspension released for nanosheet clusters should be responsible for the enhanced removal rate of Cr(VI). The XPS analysis revealed that the rapid adsorption on the surface of pyrite nanosheet clusters followed by reduction of Cr(VI) to Cr(III) by FeS2 and subsequent precipitation of Cr(III) hydroxides/oxyhydroxides are responsible for the high removal capacity of Cr(VI). The hexapod-like pyrite nanosheet clusters material had high stability and longevity, and did not aggregate during the Cr(VI) removal process. The removal efficiency of Cr(VI) was still 100% after 5 cycles. Our study shows that the hexapod-like pyrite nanosheet clusters material could be acted as a recyclable and promising mineral material with high activity, stability, feasibility for remediating Cr(VI) contaminated environment.

Transcriptomic-based toxicological investigations of graphene oxide with modest cytotoxicity to human umbilical vein endothelial cells: changes of Toll-like receptor signaling pathways.

The wide uses of graphene oxide (GO) lead to the contact of GO with vascular systems, so it is necessary to investigate the toxicological effects of GO to endothelial cells. Recently, we reported that GO of small lateral size (<500 nm) was relatively biocompatible to human umbilical vein endothelial cells (HUVECs), but recent studies by using omics-techniques revealed that nanomaterials (NMs) even without acute cytotoxicity might induce other toxicological effects. This study investigated the effects of GO on HUVECs based on RNA-sequencing and bioinformatics analysis. Even after exposure to 100 µg/ml GO, the cellular viability of HUVECs was higher than 70%. Furthermore, 25 µg/ml GO was internalized but did not induce ultrastructural changes or intracellular superoxide. These results combined indicated GO's relatively high biocompatibility. However, by analyzing the most significantly altered Gene Ontology terms and Kyoto Encyclopedia of Gene and Genomes pathways, we found that 25 µg/ml GO altered pathways related to immune systems' functions and the responses to virus. We further verified that GO exposure significantly decreased Toll-like receptor 3 and interleukin 8 proteins, indicating an immune suppressive effect. However, THP-1 monocyte adhesion was induced by GO with or without the presence of inflammatory stimulus lipopolysaccharide. We concluded that GO might inhibit the immune responses to virus in endothelial cells at least partially mediated by the inhibition of TLR3. Our results also highlighted a need to investigate the toxicological effects of NMs even without acute cytotoxicity by omics-based techniques.

Identifying bronchoconstriction from the ratio of diaphragm EMG to tidal volume.

BACKGROUND: A fall of ≥ 20 % in forced expiratory volume in the first second (FEV1) with a cumulative dose of histamine ≤ 7.8 µmol is considered to indicate bronchial hyperactivity, but no method exists for patients who cannot perform spirometry properly. Here we hypothesized that increases in respiratory central output measured by chest wall electromyography of the diaphragm (EMGdi-c) expressed as a function of tidal volume (EMGdi-c/VT) would have discriminative power to detect a 'positive' challenge test. METHODS: In a physiological study EMGdi was recorded from esophageal electrode (EMGdi-e) in 16 asthma patients and 16 healthy subjects during a histamine challenge test. In a second study, EMGdi from chest wall surface electrodes (EMGdi-c) was measured during a histamine challenge in 44 asthma patients and 51 healthy subjects. VT was recorded from a digital flowmeter during both studies. RESULTS: With histamine challenge test the change in EMGdi-e/VT in patients with asthma was significantly higher than that in healthy subjects (104.2 % ± 48.6 % vs 0.03 % ± 17.1 %, p < 0.001). Similarly there was a significant difference in the change of EMGdi-c/VT between patients with asthma and healthy subjects (90.5 % ± 75.5 % vs 2.4 % ± 21.7 %, p < 0.001). At the optimal cut-off point (29 % increase in EMGdi-c/VT), the area under the ROC curve (AUC) for detection of a positive test was 0.91 (p < 0.001) with sensitivity 86 % and specificity 92 %. CONCLUSIONS: We conclude that EMGdi-c/VT may be used as an alternative for the assessment of bronchial hypersensitivity and airway reversibility to differentiate patients with asthma from healthy subjects.

Nanoengineered CAR-T Biohybrids for Solid Tumor Immunotherapy with Microenvironment Photothermal-Remodeling Strategy.

Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable clinical success in eradicating hematologic malignancies. However, hostile microenvironment in solid tumors severely prevents CAR-T cells migrating, infiltrating, and killing. Herein, a nanoengineered CAR-T strategy is reported for enhancing solid tumor therapy through bioorthogonal conjugation with a nano-photosensitizer (indocyanine green nanoparticles, INPs) as a microenvironment modulator. INPs engineered CAR-T biohybrids (CT-INPs) not only retain the original activities and functions of CAR-T cells, but it is further armed with fluorescent tracing and microenvironment remodeling abilities. Irradiated with laser, CT-INPs demonstrate that mild photothermal intervention destroys the extracellular matrix, expanded blood vessels, loosened compact tissue, and stimulated chemokine secretion without damping CAR-T cell activities. Those regulations induce an immune-favorable tumor microenvironment for recruitment and infiltration of CT-INPs. CT-INPs triggered photothermal effects collapse the physical and immunological barriers of solid tumor, and robustly boosted CAR-T immunotherapy. Therefore, CAR-T biohybrids provide reliable treatment strategy for solid tumor immunotherapy via microenvironment reconstruction.

Click CAR-T cell engineering for robustly boosting cell immunotherapy in blood and subcutaneous xenograft tumor.

The adoptive transfer of chimeric antigen receptor-T (CAR-T) cells has shown remarkable clinical responses in hematologic malignancies. However, unsatisfactory curative results and side effects for tumor treatment are still unsolved problems. Herein we develop a click CAR-T cell engineering strategy via cell glycometabolic labeling for robustly boosting their antitumor effects and safety in vivo. Briefly, paired chemical groups (N3/BCN) are separately incorporated into CAR-T cell and tumor via nondestructive intrinsic glycometabolism of exogenous Ac4GalNAz and Ac4ManNBCN, serving as an artificial ligand-receptor. Functional groups anchored on cell surface strengthen the interaction of CAR-T cell and tumor via bioorthogonal click chemistry, further enhancing specific recognition, migration and selective antitumor effects of CAR-T cells. In vivo, click CAR-T cell completely removes lymphoma cells and minimizes off-target toxicity via selective and efficient bioorthogonal targeting in blood cancer. Surprisingly, compared to unlabeled cells, artificial bioorthogonal targeting significantly promotes the accumulation, deep penetration and homing of CAR-T cells into tumor tissues, ultimately improving its curative effect for solid tumor. Click CAR-T cell engineering robustly boosts selective recognition and antitumor capabilities of CAR T cells in vitro and in vivo, thereby holding a great potential for effective clinical cell immunotherapy with avoiding adverse events in patients.

Transcriptomic analysis suggested the involvement of impaired lipid droplet biogenesis in graphene oxide-induced cytotoxicity in human umbilical vein endothelial cells.

Previous studies revealed that direct contact with graphene oxide (GO) induced cytotoxic effects, but the importance of involvement of metabolic pathways, in particular lipid metabolism pathways, might be overlooked. In this study, human umbilical vein endothelial cells (HUVECs) were exposed to GO with large size (denoted as GO-L) or small size (denoted as GO-S), and transcriptomics were used to understand the mechanisms of cytotoxicity of GO at systemic levels. It was shown that GO-L more significantly induced cytotoxicity compared with GO-S. Transcriptomic analysis revealed that compared with GO-S, GO-L had larger impact on gene ontology terms related with mitochondrial function as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related with cell death and growth. But GO-S showed greater influence on KEGG pathways related with lipid metabolism. Both types of GO showed minimal impact on oxidative stress but increased de novo lipogenesis protein fatty acid synthase (FASN). However, only GO-S significantly promoted acyl-CoA synthetase 3 (ACSL3), a key enzyme responsible for esterification of free fatty acids and lipid droplet biogenesis. Not surprisingly, GO-L but not GO-S impaired lipid droplet biogenesis, and increasing lipid levels by oleic acid or α-linolenic acid reduced the cytotoxicity of GO-L to HUVECs. Combined, the results from this study suggested that impaired lipid droplet biogenesis was involved in GO-induced cytotoxicity in HUVECs, and inducing lipid droplet biogenesis could prevent the cytotoxicity of GO.

Graphene oxide size-dependently altered lipid profiles in THP-1 macrophages.

Previous studies focused on biocompatibility of graphene oxide (GO) to macrophages, but the impact of GO on lipid profiles in macrophages was less investigated. Herein, we investigated the interactions between THP-1 macrophages and GO of different sizes (GO of size 500-5000 nm, denoted as GO-L; GO of size < 500 nm, denoted as GO-S). We found that after 24 h exposure, the internalization of GO appeared to be minimal, whereas up to 50 µg/mL of GO-L but not GO-S reduced lipid accumulation, accompanying with a significantly reduced release of soluble monocyte chemoattractant protein-1 (MCP-1) but not interleukin-6 (IL-6). Moreover, lipidomic data showed that GO-L decreased the levels of 17 lipid classes, whereas GO-S only decreased the levels of 5 lipid classes. For comparison, 50 µg/mL carbon black (CB) significantly increased lipid accumulation with considerable particle internalization. GO-reduced lipid accumulation was not related with increase of reactive oxygen species (ROS) or induction of autophagy, and modulation of autophagy by chemicals showed no significant effect to alter the effects of GO-L on lipid accumulation. However, exposure to GO reduced the mRNA and protein levels of key components in peroxisome proliferators-activated receptor (PPAR) signaling pathway, a pathway that is related with lipid droplet biogenesis, and the modulation of PPARγ by chemicals altered the effects of GO-L on lipid accumulation. In conclusion, our results suggested that GO size-dependently altered lipid profiles in THP-1 macrophages that might be related with PPAR signaling pathway.

Multi-walled carbon nanotubes (MWCNTs) transformed THP-1 macrophages into foam cells: Impact of pulmonary surfactant component dipalmitoylphosphatidylcholine.

Pulmonary surfactant or its components can function as barriers toward nanomaterials (NMs) entering pulmonary systems. However, since pulmonary surfactant mainly consists of lipids, it may be necessary to investigate the effects of co-exposure to NMs and pulmonary surfactant or its components on lipid metabolism and related signaling pathways. Recently we found that multi-walled carbon nanotubes (MWCNTs) transformed THP-1 macrophages into lipid-laden foam cells via ER stress pathway. Here this study further investigated the impact of pulmonary surfactant component dipalmitoylphosphatidylcholine (DPPC) on this process. Up to 64 µg/mL hydroxylated or carboxylated MWCNTs induced lipid accumulation and IL-6 release in THP-1 macrophages, accompanying with increased oxidative stress and p-chop proteins (biomarker for ER stress). Incubation with 100 µg/mL DPPC led to MWCNT surface coating but did not significantly alter MWCNT internalization, lipid burden or IL-6 release. However, lipidomics indicated that DPPC altered lipid profliles in MWCNT-exposed cells. DPPC also led to a higher level of de novo lipogenesis regulator FASN in cells exposed to hydroxylated MWCNTs, as well as a higher level of p-chop and scavenger receptor MSR1 in cells exposed to carboxylated MWCNTs. Combined, DPPC did not significantly affect MWCNT-induced lipid accumulation but altered lipid components and ER stress in macrophages.

Absence of dynamic hyperinflation during exhaustive exercise in severe COPD reflects submaximal IC maneuvers rather than a nonhyperinflator phenotype.

Approximately 20% of chronic obstructive pulmonary disease (COPD) patients have been considered to have a "nonhyperinflator phenotype." However, this judgment depends on patients making a fully maximal inspiratory capacity (IC) maneuver at rest, since the IC during exercise is compared with this baseline measurement. We hypothesized that IC maneuvers at rest are sometimes submaximal and tested this hypothesis by measuring IC and associated neural respiratory drive at rest and during inhalation of CO2 and exercise in patients with COPD. Twenty-six COPD patients [age 66 ± 6 yr, mean forced expiratory volume in 1 s (FEV1) 40 ± 11% predicted] and 39 healthy subjects (age 39 ± 14 yr, FEV1 98 ± 12% predicted) were studied. IC and the diaphragm electromyogram (EMGdi) associated with it (EMGdi-IC) and forced inspiratory vital capacity (FIVC) and its corresponding EMGdi (EMGdi-FIVC) were measured during inhalation of 8% CO2 (8% CO2-92% O2) and room air. Incremental exhaustive cycle ergometer exercise was also performed in both patients with COPD and healthy subjects. IC, EMGdi-IC, FIVC, and EMGdi-FIVC during breathing 8% CO2 were significantly greater than those during breathing room air in both patients with COPD and healthy subjects (all P < 0.001). EMGdi-IC in patients with COPD constantly increased during exercise from 145 ± 40 µV at rest to 185 ± 52 µV at the end of exercise but change in IC was variable. Neural respiratory drive and its relevant IC increased during hypercapnia. Exercise-related hypercapnia in patients with COPD raises neural respiratory drives, which compensate for IC reduction, leading to underestimation of dynamic hyperinflation measured by IC at rest breathing room air.NEW & NOTEWORTHY Inspiratory capacity measured during hypercapnia is higher than that during eucapnia. Thus total lung capacity is not always be achieved by a standard inspiratory capacity maneuver, leading to risk of underestimation of dynamic hyperinflation in patients with severe chronic obstructive pulmonary disease after exhaustive exercise.

Bioorthogonal Metabolic Labeling Utilizing Protein Biosynthesis for Dynamic Visualization of Nonenveloped Enterovirus 71 Infection.

Bioorthogonal metabolic labeling through the endogenous cellular metabolic pathways (e.g., phospholipid and sugar) is a promising approach for effectively labeling live viruses. However, it remains a big challenge to label nonenveloped viruses due to lack of host-derived envelopes. Herein, a novel bioorthogonal labeling strategy is developed utilizing protein synthesis pathway to label and trace nonenveloped viruses. The results show that l-azidohomoalanine (Aha), an azido derivative of methionine, is more effective than azido sugars to introduce azido motifs into viral capsid proteins by substituting methionine residues during viral protein biosynthesis and assembly. The azide-modified EV71 (N3-EV71) particles are then effectively labeled with dibenzocyclooctyl (DBCO)-functionalized fluorescence probes through an in situ bioorthogonal reaction with well-preserved viral infectivity. Dual-labeled imaging clearly clarifies that EV71 virions primarily bind to scavenger receptors and are internalized through clathrin-mediated endocytosis. The viral particles are then transported into early and late endosomes where viral RNA is released in a low-pH dependent manner at about 70 min postinfection. These results first reveal viral trafficking and uncoating mechanisms, which may shed light on the pathogenesis of EV71 infection and contribute to antiviral drug discovery.

Pharmacological and toxicological aspects of carbon nanotubes (CNTs) to vascular system: A review.

Carbon nanotubes (CNTs) are novel carbon based nanomaterials (NMs) that could be used in many areas ranging from electronics to biotechnology. The present review summarized pharmacological and toxicological aspects of CNTs to vascular systems, because the vascular systems are important targets for CNTs during manufacturing process, daily contact and biomedical uses. Functionalized CNTs could be used as novel nanoplateforms to regulate angiogenesis for cancer therapy, as well as nanocarriers to cross blood brain barrier (BBB), one of the major obstacles to prevent the entering of therapeutic substances into brains. However, it has also been shown that inhalational or intravenous contact with CNTs might induce adverse vascular effects, such as progression of atherosclerotic plaque, vasomotor dysfunction, and changes of blood pressure and/or heart rate in laboratory animals, although currently there are only limited reports obtained from CNT-exposed human beings and the results are inconclusive. The mechanisms associated with the vascular toxicity of CNTs remain poorly understood, and it appears that multiple signaling pathways are likely to be involved. The toxicity of CNTs to vascular systems might be reduced by controlling the physicochemical properties of CNTs, particularly lengths, diameters and surface chemistry. At present, the beneficial and adverse effects of CNTs to vascular systems are still largely unknown and require further extensive studies.

Photocatalytic and Ferric Ion Sensing Properties of a New Three-Dimensional Metal-Organic Framework Based on Cuboctahedral Secondary Building Units.

A new three-dimensional microporous metal-organic framework based on Zn(II) clusters with the formula {[Zn7(NDC)5.5(µ4-OH)3]·7DMF} n (1) (H2NDC = 1,4-naphthalenedicarboxylic acid) had been synthesized and characterized. The MOF 1 displays an uncommon bsn topology, which is based on a unique heptanuclear Zn7(OH)3(CO2)11 cluster as a secondary building unit. The MOF had been employed as a photocatalyst for the photodegradation of model organic dyes rhodamine B and methyl violet in light. The results of photocatalytic experiments showed that 1 can successfully be employed as the photocatalyst for the benign decomposition of these dyes. A mechanism for the photcatalysis exhibited by 1 had been proposed using the results of density of states (DOS) and partial DOS calculations. The fluorescence properties of the MOF have been investigated, which revealed that 1 could be exploited as the luminescent sensor to recognize Fe3+ ions with perceptible quenching (K sv = 6.55 × 104 M-1) and a limit of detection of 1.16 ppm.

Correlation between TLR2, TLR3, TLR4, and TLR9 polymorphisms and susceptibility to and prognosis of severe hepatitis among the newborns.

BACKGROUND: This study was aimed to explore how toll-like receptor 2 (TLR2), TLR3, TLR4 and TLR9 influenced the risk and prognosis of severe hepatitis among the Chinese newborns. METHODS: Altogether 135 newborns diagnosed with severe hepatitis and 140 healthy newborns were included in this study. Totally 12 single nucleotide polymorphisms (SNPs) within TLR2, TLR3, TLR4, and TLR9 were chosen and genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the logistic regression. The univariate and multivariate analyses were used to analyze independent factors for prognosis of severe hepatitis among the Chinese newborns. RESULTS: The SNPs within TLR2 [ie, rs1898830 (A>G) and rs3804100 (T>C)], TLR3 [ie, rs1879026 (G>T)], TLR4 [ie, rs2149356 (T>G)], and TLR9 [ie, rs187084 (T>C), rs352139 (A>G), and rs352140 (C>T)] were significantly associated with modified risk of neonatal severe hepatitis (all P<.05). Furthermore, rs1898830, rs1879026, rs187084 and rs352139 were also demonstrated to modulate the prognosis [ie, aspartate aminotransferase (AST)/alanine transaminase (ALT)>1.5] of newborns with severe hepatitis (all P<.05). Interestingly, the haplotype A-C-G-G-C-A-T were associated with higher susceptibility to neonatal severe hepatitis, and the newborns carrying haplotype A-C-G-G-C-A-T appeared to be correlated with more favorable prognosis (all P<.05). CONCLUSIONS: Certain SNPs and haplotypes within TLR2, TLR3, TLR4, and TLR9 can be considered as the potentially treatment targets for neonatal severe hepatitis.