Pattern-Matched Polymer Ligpands Toward Near-Perfect Synergistic Passivation for High-Performance and Stable Br/Cl Mixed Perovskite Light-Emitting Diodes.

Mixed Br/Cl perovskite nanocrystals (PeNCs) exhibit bright pure-blue emission benefiting for fulfilling the Rec. 2100 standard. However, phase segregation remains a significant challenge that severely affects the stability and emission spectrum of perovskite light-emitting diodes (PeLEDs). Here, we demonstrate the optimization of the spacing between polydentate functional groups of polymer ligands to match the surface pattern of CsPbBr1.8Cl1.2 PeNCs, resulting in effective synergistic passivation effect and significant improvements in PeLED performances. The block and alternating copolymers with different inter-functional group spacing are facilely synthesized as ligands for PeNCs. Surprisingly, block copolymers with a higher functional group density do not match PeNCs, while alternating copolymers enable efficient PeNCs with the high photoluminescence intensity, low non-radiative recombination rate and high exciton binding energy. Density functional theory calculations clearly confirm the almost perfect match between alternating copolymers and PeNCs. Finally, pure-blue PeLEDs are achieved with the emission at 467 nm and Commission Internationale de l'Eclairage (CIE) coordinates of (0.131, 0.071), high external quantum efficiency (9.1%) and record spectral and operational stabilities (~ 80 mins) in mixed-halide PeLEDs. Overall, this study contributes to designing the polymer ligands and promoting the development of high-performance and stable pure-color PeLEDs towards display applications.

Tri-system integration in metal-oxide nanocomposites via in-situ solution-processed method for ultrathin flexible transparent electrodes.

For stable operation of ultrathin flexible transparent electrodes (uFTEs), it is critical to implement effective risk management during concurrent multi-loading operation of electrical bias and mechanical folding cycles in high-humidity environments. Despite extensive efforts in preparing solution-processed uFTEs with cost-effective and high-throughput means, achieving in-situ nano-adhesion in heterogeneous metal-oxide nanocomposites remains challenging. In this work, we observed by serendipity liquid-like behaviour of transparent metal-oxide-semiconductor zinc oxide nanoparticles (ZnONPs) onto silver nanowires (AgNWs) developed by in-situ solution processed method (iSPM). This enabled us to address the long-standing issue of vulnerability in the nanocomposite caused by the interface of dissimilar materials between AgNWs and ZnONPs, resulting in a remarkably improved multi-loading operation. Importantly, substrate-integrated uFTEs constituted of the metal-oxide nanocomposite electrode semi-embedded in the polymer matrix of greatly thin <0.5 µm thickness is successfully demonstrated with the smooth surface topography, promoted by the tri-system integration including (i) AgNW-AgNW, (ii) ZnONP-ZnONP, and (iii) AgNW-ZnONP systems. Our finding unveils the complex interfacial dynamics associated with the heterogeneous interface system between AgNWs and ZnONPs and holds great promise in understanding the in-situ nano-adhesion process and increasing the design flexibility of next generation solution-processed uFTEs.

Two-Stage Dynamic Transformation from δ- to α-CsPbI3.

The phase transformation from δ- to α-CsPbI3has garnered extensive research interest. However, detailed understanding of this structural transformation at atomistic scale remains elusive. Here, we reported the full atomistic molecular dynamics simulation of this important phase transformation using an enhanced sampling method, Metadynamics (MetaD). Particularly, two-stage of dynamic transformation related to [PbI3]- chains' motions was observed, namely, the intrachain rearrangement followed by interchain connection. Moreover, the dynamic motion of Cs+ cations plays an important role in facilitating the interchain connection kinetically. The insights reported in this work will provide valuable guidance for further advancing the understanding of phase transformation of CsPbI3.

Clinical manifestations and early effectiveness of methimazole in patients with graves' hyperthyroidism-related severe hepatic dysfunction.

BACKGROUND: Graves' hyperthyroidism (GH) is often accompanied by mild to moderate liver injury, but severe hepatic dysfunction (SHD) is relatively rare. Whether patients with GH-related SHD can be treated with methimazole (MMI) remains controversial. This study aimed to determine the clinical characteristics and to evaluate the role of low-dose MMI for such patients. METHODS: 33 patients with GH-related SHD were selected for this retrospective study in the Fifth Medical Center of Chinese PLA General Hospital from January 2017 to July 2022. The clinical manifestations, therapeutic responses, and effectiveness of MMI were evaluated. RESULTS: Systemic jaundice (100.0%), yellow urine (100.0%), fatigue (87.9%), and goiter (66.7%) were the main symptoms. Total bilirubin (TBIL) had no linear correlation with free triiodothyronine (FT3) (r = -0.023, p = .899), free thyroxine (FT4) (r = 0.111, p = .540), T3 (r = -0.144, p = .425), and T4 (r = 0.037, p = .837). On the 14th day after admission, FT3, FT4, T3, T4, TBIL, direct bilirubin (DBIL), alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), and international normalized ratio (INR) decreased compared with the baseline (p < .05). The decrease rates of FT3, FT4, T3, T4, TBIL, and DBIL in the MMI group were higher than those in the non-MMI group (p < .05). The improvement rate of the MMI group (77.8%) was higher than that of the non-MMI group (9.5%, p = .001). MMI treatment is an independent predictor affecting the early improvement of patients (OR = 0.022, p = .010). CONCLUSIONS: The main clinical manifestations of patients with GH-related SHD were symptoms related to liver disease. Low-dose MMI was safe and effective for them.

Traversing the nucleation-growth landscape through heterogeneous random walks.

The nucleation-growth process is a crucial component of crystallization. While previous theoretical models have focused on nucleation events and postnucleation growth, such as the classical nucleation theory and Lifshitz-Slyozov-Wagner model, recent advancements in experiments and simulations have highlighted the inability of classical models to explain the transient dynamics during the early development of nanocrystals. To address these shortcomings, we present a model that describes the nucleation-growth dynamics of individual nanocrystals as a series of reversible chain reactions, with the free energy landscape extended to include activation-adsorption-relaxation reaction pathways. By using the Monte Carlo method based on the transition state theory, we simulate the crystallization dynamics. We derive a Fokker-Planck formalism from the master equation to describe the nucleation-growth process as a heterogeneous random walk on the extended free energy landscape with activated states. Our results reveal the transient quasiequilibrium of the prenucleation stage before nucleation starts, and we identify a postnucleation crossover regime where the dynamic growth exponents asymptotically converge towards classical limits. Additionally, we generalize the power laws to address the dimension and scale effects for the growth of large crystals.

Prehospital physiological parameters related illness severity scores can accurately discriminate the severe/critical state in adult patients with COVID-19.

BACKGROUND: Whether the National Early Warning Score 2 (NEWS2) can effectively discriminate the severe/critical state of patients with coronavirus disease 2019 (COVID-19) at the prehospital stage remains unknown. We aimed to assess the performance of NEWS2 in rapidly discriminating severe/critical COVID-19 and its relationship with prehospital medical services. METHODS: Six illness severity scores of 414 patients were calculated at the prehospital stage. Receiver operating characteristic curves were generated to explore the ability of these scores to discriminate severe/critical patients from mild/moderate patients. A logistic regression analysis was conducted to evaluate independent predictors associated with severe/critical state. RESULTS: The age, numbers of comorbidities, prehospital care workload, consumption of medical human resources, and illness severity scores of severe/critical patients were higher than those of mild/moderate patients (p < 0.05). When NEWS2 scores >2, the sensitivity, specificity, positive predictive value, and negative predictive value were 93.5%, 90.7%, 74.1%, and 98.0%, respectively. The C-statistic of NEWS2 (0.963) was higher than that of quick Sequential Organ Failure Assessment (0.680, p < 0.001), CRB-65 (0.879, p < 0.001), Rapid Acute Physiology Score (0.692, p < 0.001), and Rapid Emergency Medicine Score (0.879, p < 0.001). NEWS2 was positively correlated with the numbers of prehospital treatment measures (r = 0.732, p < 0.001), numbers of medical staff (r = 0.615, p < 0.001), and total transport time (r = 0.595, p < 0.001). Age ≥65 years (OR = 5.43, p = 0.016), hypertension (OR = 5.39, p < 0.001), active malignancy (OR = 5.94, p = 0.005), and NEWS2 scores >2 (OR = 124.88, p < 0.001) were independent predictors to discriminate severe/critical patients. Oxygen saturation (SpO2) (OR =1.87, p < 0.001) was the unique independent predictor to discriminate false positive patients from true positive patients. CONCLUSIONS: Prehospital NEWS2 can accurately and rapidly discriminate severe/critical COVID-19 during the Omicron variant wave. High levels of NEWS2 indicate an increase in prehospital care workload and consumption of medical human resources.

Incorporating Domain Knowledge and Structure-Based Descriptors for Machine Learning: A Case Study of Pd-Catalyzed Sonogashira Reactions.

Machine learning has revolutionized information processing for large datasets across various fields. However, its limited interpretability poses a significant challenge when applied to chemistry. In this study, we developed a set of simple molecular representations to capture the structural information of ligands in palladium-catalyzed Sonogashira coupling reactions of aryl bromides. Drawing inspiration from human understanding of catalytic cycles, we used a graph neural network to extract structural details of the phosphine ligand, a major contributor to the overall activation energy. We combined these simple molecular representations with an electronic descriptor of aryl bromide as inputs for a fully connected neural network unit. The results allowed us to predict rate constants and gain mechanistic insights into the rate-limiting oxidative addition process using a relatively small dataset. This study highlights the importance of incorporating domain knowledge in machine learning and presents an alternative approach to data analysis.

Two cases reports: Severe liver injury caused by 1,2,3-trichloropropane poisoning.

Background: 1,2,3-trichloropropane (TCP) poisoning can induce liver damage in humans and animals, but reports of severe liver injury and its histology are rare. We presented two cases of 1,2,3-TCP inhalation poisoning resulting in severe liver injury confirmed by exposure history, toxicology, biochemical index and pathology. Case description: Two young male presented acute poisoning process with mild to moderate early symptoms, and developed severe jaundice and coagulation dysfunction after exposure to 1,2,3-TCP. The total bilirubin (TBIL) in case 1 and case 2 reached the peak value of 635.8 µmol/L and 437.1 µmol/L on the 25th and 22nd days, respectively. Their liver enzymes and international normalized ratio increased rapidly to peak and fell back, and TBIL remained at a high level. 1,2,3-TCP was detected in their blood, and their liver histology indicated severe necrosis of hepatocytes, infiltration of massive inflammatory cells, and cholestasis. They all finally recovered after a long time of treatment. Conclusion: The two cases in this study demonstrate that 1,2,3-TCP inhalation poisoning without any protective measures can induce severe liver injury in humans.

Topology induced crossover between Langevin, subdiffusion, and Brownian diffusion regimes in supercooled water.

Despite extensive studies of supercooled water, it remains challenging to understand its peculiar dynamic anomalous properties. In this work, we integrated full atomistic simulations of supercooled water over the temperature range of room temperature to 200 K using a quantum-mechanics-based polarizable force field with the dressed dynamics method that couples fast collision events and slow reorganization dynamics of hydrogen-bond networks. Our analysis unveils the salient multiscale features in the transient relaxation dynamics of supercooled water. A classical Langevin behavior dominates at fast timescales, while long-time relaxations unveil two different activation barriers in two temperature regions: below and above 230 K. The modulation of the entropy spectrum by temperature is elucidated in terms of a three-state model underlined by the complexity of the water dynamics associated with a topological transition of a strong hydrogen-bond network. This state-dependent network topology is quantitatively characterized by power-law exponents of inverse network connectivity from 200 to 298 K. This work provides valuable guidance for further studies on the transient relaxation dynamics of supercooled water.

Bridging ribosomal synthesis to cell growth through the lens of kinetics.

Understanding prokaryotic cell growth requires a multiscale modeling framework from the kinetics perspective. The detailed kinetics pathway of ribosomes exhibits features beyond the scope of the classical Hopfield kinetics model. The complexity of the molecular responses to various nutrient conditions poses additional challenge to elucidate the cell growth. Herein, a kinetics framework is developed to bridge ribosomal synthesis to cell growth. For the ribosomal synthesis kinetics, the competitive binding between cognate and near-cognate tRNAs for ribosomes can be modulated by Mg2+. This results in distinct patterns of the speed - accuracy relation comprising "trade-off" and "competition" regimes. Furthermore, the cell growth rate is optimized by varying the characteristics of ribosomal synthesis through cellular responses to different nutrient conditions. In this scenario, cellular responses to nutrient conditions manifest by two quadratic scaling relations: one for nutrient flux versus cell mass, the other for ribosomal number versus growth rate. Both are in quantitative agreement with experimental measurements.

A Lower HCC Incidence in Chronic HBV-Infected Patients Recovered from Acute-on-Chronic Liver Failure: A Prospective Cohort Study.

Background: Activation of chronic hepatitis B virus (HBV) infection is an important cause of acute-on-chronic liver failure (ACLF). However, the effect of HBV-ACLF episode on hepatocellular carcinoma (HCC) occurrence remains largely unknown. Methods: A total of 769 HBV-ACLF patients and 2114 HBV-related chronic liver disease (HBV-CLD) patients diagnosed between August 1998 and December 2011 were enrolled in this prospective cohort study. Of the HBV-CLD patients, 380 received lifetime antiviral treatment with nucleos(t)ide analogues. Propensity score matching was applied to reduce baseline differences between HBV-ACLF and HBV-CLD cohorts. Results: The survival rate of HBV-ACLF patients was 53.6%, 50.3%, 47.8%, and 46.2% at 90-day, 1-year, 5-year, and 10-year, respectively. The cumulative incidence of HCC was lower in HBV-ACLF cohort with 369 eligible patients survived for >90 days than in HBV-CLD cohort with the 380 patients (5.77/1,000 vs. 9.78/1,000 person-years, p = 0.0497). HBV-ACLF episode decreased HCC risk regardless of liver cirrhosis, and in patients without family history of HCC. Multivariate Cox analyses indicated that male, increasing age, liver cirrhosis, and platelet count (≤100 × 109/L) increased, whereas HBV-ACLF episode decreased, HCC risk independently. In the propensity score-matched cohorts, HBV-ACLF episode reduced HCC incidence (10.20/1,000 vs. 4.66/1,000 person-years, p = 0.0326). The area under curve of nomogram was 0.812 for 3-year HCC probability. Conclusions: HBV-ACLF episode decreases HCC occurrence in chronic HBV patients. Older age and liver cirrhosis independently increased HCC occurrence. A nomogram-enrolled episode of ACLF reliably predicts the occurrence of HCC.

A Tale of Water Molecules in the Ribosomal Peptidyl Transferase Reaction.

The peptidyl transferase center (PTC) in the large subunit of the ribosome plays a critical role in protein synthesis by catalyzing the formation of peptide bonds with an astounding speed of about 15 to 20 peptide bonds per second. The ribosome coordinates the nucleophilic attack and deprotonation in the rate-limiting step at the PTC. However, the details of peptide bond formation within the ribosome, particularly the precise role of the two water molecules in the PTC, remain unclear. Here, we propose a novel stepwise "proton shuttle" mechanism which corroborates all the reported experimental measurements so far. In this mechanism, a water molecule close to A76 of peptidyl-tRNA 2'- and 3'-O stabilizes the transition state. The other one adjacent to the carbonyl oxygen of peptidyl-tRNA actively participates in the proton shuttle, playing the catalytic role of ribosome-catalyzed peptide bond formation.

A review on recent advances in the electrochemical reduction of CO2 to CO with nano-electrocatalysts.

The electrochemical reduction (ECR) of CO2 is a powerful strategy to reduce the world's carbon footprint by converting CO2 to useful products such as CH3OH and CO. Recent techno-economic analysis has found that for the electro-conversion of CO2 to be adapted for practical use, the main products formed from this reaction need to be low-order, such as CO. This review summarizes recent progress in the ECR of CO2 to CO on nano-electrocatalysts (noble, non-noble metals and carbon nanomaterials) and provides the limitations and challenges that each electrocatalyst faces. It discusses the mechanism behind the performance of the electrocatalysts and offers the potential future prospects of the ECR process.

Reversibility of acute-on-chronic liver failure syndrome in hepatitis B virus-infected patients with and without prior decompensation.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome associated with high short-term mortality and reversibility. This study aimed to compare the characteristics of survival and reversibility in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) patients with and without previous decompensation. Overall, 1044 patients who fulfilled the acute hepatic insult criteria of the APASL-ACLF Research Consortium (AARC) definition were enrolled from a prospectively established cohort of HBV-related liver failure patients. These patients were divided into the AARC ACLF group and the non-AARC ACLF group according to prior decompensation. Mortality, reversibility of ACLF syndrome, and predicted factors associated with reversibility were evaluated. Liver transplantation-free mortality of the AARC ACLF group was significantly lower than that of the non-AARC ACLF group (28 days: 28.2% vs. 40.3%, p = .012; 90 days: 41.7% vs. 65.4%, p < .001). The 5-year cumulative reversal rates of ACLF syndrome were 88.0% (374/425) and 66.0% (31/47) in the AARC and non-AARC ACLF groups, respectively, (p = .039). Following reversibility of ACLF syndrome, 340/374 (90.9%) and 21/31 (67.7%) patients in the AARC and non-AARC ACLF groups, respectively, maintained a stable status within 5 years. Although prior decompensation indicated poor reversibility of ACLF syndrome, HBV-infected patients with prior decompensation who fulfilled the acute hepatic insult criteria of the AARC definition showed favourable reversibility and maintained a stable status after receiving nucleoside analogues. The AARC ACLF definition identified HBV-ACLF as a distinct syndrome with good reversibility. HBV-infected patients with prior decompensation could be included in the AARC ACLF management.

Granulocyte Colony-Stimulating Factor Accelerates the Recovery of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure by Promoting M2-Like Transition of Monocytes.

Background and Aim: Acute-on-chronic liver failure (ACLF) has a high mortality rate. The role of granulocyte colony-stimulating factor (G-CSF) in ACLF remains controversial. Monocytes/macrophages are core immune cells, which are involved in the initiation and progression of liver failure; however, the effect of G-CSF on monocytes/macrophages is unclear. The study aimed to verify the clinical efficacy of G-CSF and explore the effect of it on monocytes in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) paitents. Methods: We performed a large randomized controlled clinical trial for the treatment of HBV-ACLF using G-CSF. A total of 111 patients with HBV-ACLF were prospectively randomized into the G-CSF group (5 µg/kg G-CSF every day for 6 days, then every other day until day 18) or the control group (standard therapy). All participants were followed up for at least 180 days. The relationship between monocyte count and mortality risk was analyzed. The effect of G-CSF on the phenotype and function of monocytes from patients with HBV-ACLF was evaluated using flow cytometry in vivo and in vitro experiments. Results: The survival probability of the G-CSF group at 180 days was higher than that of the control group (72.2% vs. 53.8%, P = 0.0142). In the G-CSF-treated group, the monocyte counts on days 0 and 7 were independently associated with an evaluated mortality risk in the fully adjusted model (Model 3) [at day 0: hazard ratio (HR) 95% confidence interval (CI): 15.48 (3.60, 66.66), P = 0.0002; at day 7: HR (95% CI): 1.10 (0.50, 2.43), P=0.8080]. Further analysis showed that after treatment with G-CSF in HBV-ACLF patients, the expression of M1-like markers (HLA-DR and CD86) in monocytes decreased (HLA-DR: P = 0.0148; CD86: P = 0.0764). The expression of MerTK (M2-like marker) increased (P = 0.0002). The secretion of TNF-α, IL-6, and IL-10 from monocytes decreased without lipopolysaccharide (LPS) stimulation (TNF-α: P < 0.0001; IL-6: P= 0.0025; IL-10: P = 0.0004) or with LPS stimulation (TNF-α: P = 0.0439; P = 0.0611; IL-10: P = 0.0099). Similar effects were observed in vitro experiments. Conclusion: G-CSF therapy confers a survival benefit to patients with HBV-ACLF. G-CSF can promote the anti-inflammatory/pro-restorative phenotype (M2-like) transition of monocytes, which may contribute to the recovery of ACLF.Clinical Trial Registration Number: ClinicalTrials.gov, identifier (NCT02331745).

Mechanisms of Efficient Desalination by a Two-Dimensional Porous Nanosheet Prepared via Bottom-Up Assembly of Cucurbit[6]urils.

Many researchers have examined the desalination performance of various kinds of two-dimensional (2D) porous nanosheets prepared by top-down approaches such as forming pores on the plain based on molecular dynamics (MD) simulations. In contrast, it is rare to find MD simulations addressing the desalination performance of a 2D porous nanosheet prepared by bottom-up approaches. We investigated the desalination performance of a 2D porous nanosheet prepared by the assembly of cucurbit[6]uril (CB[6]) via MD simulation. The model 2D CB[6] nanosheet features CB[6] with the carbonyl-fringed portals of 3.9 Å and the interstitial space filled with hydrophobic linkers and dangling side chains. Our MD simulation demonstrated that the 2D porous CB[6] nanosheet possesses a 70 to 140 times higher water permeance than commercial reverse osmosis membranes while effectively preventing salt passage. The extremely high water permeance and perfect salt rejection stem from not only CB[6]'s nature (hydrophilicity, negative charge, and the right dimension for size exclusion) but also the hydrophobic and tightly filled interstitial space. We also double-checked that the extremely high water permeance was attributable to only CB[6]'s nature, not water leakage, by contrasting it with a 2D nanosheet comprising CB[6]-spermine complexes. Lastly, this paper provides a discussion on a better cucurbituril homologue to prepare a next-generation desalination membrane possessing great potential to such an extent to surpass the 2D porous CB[6] nanosheet based on quantum mechanics calculations.

1-Chloronaphthalene-Induced Donor/Acceptor Vertical Distribution and Carrier Dynamics Changes in Nonfullerene Organic Solar Cells and the Governed Mechanism.

Electron donors and acceptors in organic solar cells (OSCs) shall strike a favorable vertical phase separation that acceptors and donors have sufficient contact and gradient accumulation near the cathodes and anodes, respectively. Random mixing of donors/acceptors at surface will result in charge accumulation and severe recombination for low carrier-mobility organic materials. However, it is challenging to tune the vertical distribution in bulk-heterojunction films as they are usually made from a well-mixed donor/acceptor solution. Here, for the first time, it presents with solid evidence that the commonly used 1-chloronaphthalene (CN) additive can tune the donor/acceptor vertical distribution and establish the mechanism. Different from the previous understanding that ascribed the efficiency enhancement brought by CN to the improved molecular stacking/crystallization, it is revealed that the induced vertical distribution is the dominant factor leading to the significantly increased performance. Importantly, the vertical distribution tunability is effective in various hot nonfullerene OSC systems and creates more channels for the collection of dissociated carriers at corresponding organic/electrode interfaces, which contributes the high efficiency of 18.29%. This study of the material vertical distribution and its correlation with molecular stacking offers methods for additives selection and provides insights for the understanding and construction of high-performance OSCs.

Invasive Pulmonary Aspergillosis in Acute-on-Chronic Liver Failure Patients: Short-Term Outcomes and Antifungal Options.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) patients are susceptible to invasive fungal infections. We evaluated the prognosis and antifungal options in ACLF patients with invasive pulmonary aspergillosis (IPA). METHODS: ACLF patients with IPA from 15 hospitals were retrospectively screened from 2011 to 2018, and 383 ACLF patients without lung infections were included from a prospective cohort (NCT02457637). Demographic, laboratory, clinical data, and 28-day outcomes were documented in the two cohorts. RESULTS: ACLF patients with probable IPA (n = 145) had greater 28-day mortality (33.6% vs. 15.7%, p < 0.001) than those without (n = 383). The respiratory failure-associated 28-day mortality was greater in ACLF patients with IPA than in those without before (17.1% vs. 0.3%, p < 0.001) and after (16.0% vs. 0.0%, p < 0.001) propensity score matching in 116 pairs. IPA patients with lung injury had greater 28-day all-cause mortality (66.5% vs. 24.2%, p < 0.001) and IPA-associated mortality (45.8% vs. 8.1%, p < 0.001) than patients without lung injury (PaO2/FiO2 ≥ 400 mmHg). Antifungal therapy was prescribed to 139 of 145 patients, and 102 patients were treated with voriconazole alone (n = 59) or sequential/combined therapy (n = 43) with varying loading doses (100-800 mg) and daily maintenance doses (0-800 mg). A proposed optimal voriconazole regimen (loading dose, 200 mg twice daily; daily maintenance dose, 100 mg) achieved comparable short-term survival and optimal trough drug concentrations (1-5 µg/mL) on therapeutic drug monitoring in 26 patients. CONCLUSION: Presence of IPA increases the short-term mortality of ACLF patients mainly due to respiratory failure. An optimal voriconazole regimen is needed for such critical patients.

Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry.

BACKGROUND AND AIMS: Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with possession of human leukocyte antigen (HLA) class I (A*01, B*08) and class II (DRB1*03, -04, -07, or -13) alleles, depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. APPROACH AND RESULTS: We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*04, which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15) was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD: DRB1*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups. CONCLUSIONS: Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.