Decreasing Case Fatality Rates for Patients With Cirrhosis Infected With SARS-CoV-2: A National COVID Cohort Collaborative Study.

BACKGROUND & AIMS: The virulence and severity of SARS-CoV-2 infections have decreased over time in the general population due to vaccinations and improved antiviral treatments. Whether a similar trend has occurred in patients with cirrhosis is unclear. We used the National COVID Cohort Collaborative (N3C) to describe the outcomes over time. METHODS: We utilized the N3C level 3 data set with uncensored dates to identify all patients with chronic liver disease (CLD) with and without cirrhosis who had SARS-CoV-2 infection as of November 2023. We described the observed 30-day case fatality rate (CFR) by month of infection. We used adjusted survival analyses to calculate relative hazard of death by month of infection compared with infection at the onset of the COVID-19 pandemic. RESULTS: We identified 117,811 total patients with CLD infected with SARS-CoV-2 between March 2020 and November 2023: 27,428 (23%) with cirrhosis and 90,383 (77%) without cirrhosis. The observed 30-day CFRs during the entire study period were 1.1% (1016) for patients with CLD without cirrhosis and 6.3% (1732) with cirrhosis. Observed 30-day CFRs by month of infection varied throughout the pandemic and showed a sustained downward trend since 2022. Compared with infection in Quarter 2 of 2020 (at the beginning of the pandemic), the adjusted hazards of death at 30 days for infection in Quarter 3 of 2023 were 0.20 (95% confidence interval [CI], 0.08-0.50) for patients with CLD without cirrhosis and 0.35 (95% CI, 0.18-0.69) for patients with CLD with cirrhosis. CONCLUSIONS: In this N3C study, we found that the observed 30-day CFR decreased progressively for patients with CLD both with and without cirrhosis, consistent with broader trends seen in the general population.

Zn-facilitated surface reconstruction of Ni-MOF for an enhanced oxygen evolution reaction.

Facilitating the surface reconstruction of pre-catalysts has been considered an effective strategy for constructing low-cost and highly efficient OER electrocatalysts. Metal doping is a feasible way to activate the surface reconstruction, thus enhancing the OER performance. Herein, we report a facile hydrothermal method to synthesize a series of Zn-doped Ni-MOF on nickel foam (NiZn-MOF/NF) as promising pre-catalysts toward the oxygen evolution reaction (OER). The Zn leaching of NiZn-MOF/NF can promote the surface self-reconstruction of NiZn-MOF/NF into oxygen-vacancy-rich NiOOH after electrochemical activation. Benefiting from the optimized electronic structure, abundant defects, more accessible active sites, and enhanced electrical conductivity, the reconstructed metal oxyhydroxide hybrids exhibit better electrocatalytic activity than the catalysts transformed from Ni-MOF/NF without Zn doping. The optimized NiZn-MOF/NF-OH as an OER catalyst has an overpotential of 336 mV at 100 mA cm-2, and a Tafel slope of 65.9 mV dec-1, as well as stability over 12 h. This work reveals that Zn cation-doping/leaching induces the surface reconstruction of pre-catalysts for enhanced oxygen catalytic activity, which provides a new approach for the development of advanced electrocatalysts.

Synthesis of N-Aryl-4-trifluoromethylthiazol-2-amines via Insertion/Annulation of Trifluoromethylimidoyl Sulfoxonium Ylides with Sodium Thiocyanate.

An efficient p-TsOH-mediated insertion of sodium thiocyanate into trifluoromethylimidoyl sulfoxonium ylides has been reported, affording annulated N-aryl-4-trifluoromethylthiazol-2-amines in 42-84% yields in a one-pot manner. This protocol encompasses a variety of trifluoromethylimidoyl sulfoxonium ylides with thiocyanate serving as the source of the "S-C═N" moiety of the thiazole ring. The versatile transformations of the resulting pharmacologically important N-aryl-4-trifluoromethylthiazol-2-amines were also demonstrated.

Common definitions and variables are needed for the United States to join the conversation on acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a variably defined syndrome characterized by acute decompensation of cirrhosis with organ failures. At least 13 different definitions and diagnostic criteria for ACLF have been proposed, and there is increasing recognition that patients with ACLF may face disadvantages in the current United States liver allocation system. There is a need, therefore, for more standardized data collection and consensus to improve study design and outcome assessment in ACLF. In this article, we discuss the current landscape of transplantation for patients with ACLF, strategies to optimize organ utility, and data opportunities based on emerging technologies to facilitate improved data collection.

Insufficient Plasma Melatonin and Its Association With Neuropsychiatric Impairments in Patients With T2DM.

Purpose: Type 2 diabetes mellitus (T2DM) is associated with multiple neuropsychiatric impairments, including cognitive dysfunction, and melatonin (MLT) plays a crucial role in maintaining normal neuropsychiatric functions. This study is aimed at investigating the change in plasma MLT levels and its association with neuropsychiatric impairments in T2DM patients. Methods: One hundred twenty-six T2DM patients were recruited, and their demographics and clinical data were collected. Apart from the plasma glycated hemoglobin (HbA1c) levels and other routine metabolic indicators, the plasma concentrations of MLT, C-reactive protein (CRP), Interleukin 6 (IL-6), soluble myeloid triggered receptor 1 (sTREM 1), and receptor 2 (sTREM 2) were measured. Moreover, the executive function and depressive tendency were evaluated via the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and the Epidemiological Research Center Depression Scale (CES-D), respectively. Result: Compared with the low HbA1c group, the T2DM patients in the high HbA1c group presented lower plasma MLT levels but higher plasma concentrations of inflammatory biomarker levels, together with higher scores in the BRIEF-A and CES-D scales. Moreover, results of the Pearson correlation test showed that the plasma MLT levels were negatively correlated with the BRIEF-A and CES-D scores, as well as plasma concentrations of HbA1c and inflammatory indications, indicating that MLT may mediate their neuroinflammation and neuropsychiatric impairments. Furthermore, the ROC curve results indicated that plasma MLT levels have a predictive effect on executive impairment and depressive status in T2DM patients. Conclusion: MLT levels decreased in patients with T2DM and were associated with neuropsychiatric impairments and inflammatory status, and MLT might be developed as a therapeutic agent and predictive indicator for T2DM-associated executive impairment and depression status.

Solvent-Controlled Enantiodivergent Construction of P(V)-Stereogenic Molecules via Palladium-Catalyzed Annulation of Prochiral N-Aryl Phosphonamides with Aromatic Iodides.

In this work, we describe an efficient and modular method for enantiodivergent accessing P(V)-stereogenic molecules by utilizing the catalytic atroposelective Catellani-type C-H arylation/desymmetric intramolecular N-arylation cascade reaction. The enantioselectivity of this protocol was proved to be tuned by the polarity of the solvent, thus providing a wide range of both chiral P(V)-stereogenic enantiomers in moderate to good yields with good to excellent enantiomeric excesses. Noteworthy is that the strategy developed herein represents an unprecedented example of solvent-dictated inversion of the enantioselectivity of P(V)-stereogenic compounds.

Recent advances in the synthesis of trifluoromethyl-containing heterocyclic compounds via trifluoromethyl building blocks.

Trifluoromethylated heterocyclic compounds have played an increasingly significant role in pharmaceuticals, agrochemicals, and materials. This is because the introduction of trifluoromethyl could enhance the lipophilicity, metabolic stability, and pharmacokinetic properties of heterocyclic drug molecules. Therefore, the synthesis of trifluoromethylated heterocyclics has become a major subject of research. The construction of trifluoromethylated heterocyclics via the annulation of trifluoromethyl building blocks with suitable partners has been proved to be a powerful strategy. In this review, we systematically summarize and discuss recent advances in the preparation of trifluoromethyl-containing heterocyclics via trifluoromethyl building block strategies over the period from 2019 to the present.

Risk factors for severe outcomes of coronavirus disease 2019 through the waves of the pandemic: Comparing patients with and without solid organ transplantation.

BACKGROUND: While coronavirus disease 2019 (COVID-19) is no longer a public health emergency, certain patients remain at risk of severe outcomes. To better understand changing risk profiles, we studied the risk factors for patients with and without solid organ transplantation (SOT) through the various waves of the pandemic. METHODS: Using the National COVID Cohort Collaborative we studied a cohort of adult patients testing positive for COVID-19 between January 1, 2020, and May 2, 2022. We separated the data into waves of COVID-19 as defined by the Centers for Disease Control. In our primary outcome, we used multivariable survival analysis to look at various risk factors for hospitalization in those with and without SOT. RESULTS: A total of 3,570,032 patients were captured. We found an overall risk attenuation of adverse COVID-19-associated outcomes over time. In both non-SOT and SOT populations, diabetes, chronic kidney disease, and congestive heart failure were risk factors for hospitalization. For SOT specifically, longer time periods between transplant and COVID-19 were protective and age was a risk factor. Notably, asthma was not a risk factor for major adverse renal cardiovascular events, hospitalization, or mortality in either group. CONCLUSIONS: Our study provides a longitudinal view of the risks associated with adverse COVID-related outcomes amongst SOT and non-SOT patients, and how these risk factors evolved over time. Our work will help inform providers and policymakers to better target high-risk patients.

Dibutyl phthalate released by solitary female locusts mediates sexual communication at low density.

Sex pheromones play a crucial role in mate location and reproductive success. Insects face challenges in finding mates in low-density environments. The population dynamics of locusts vary greatly, ranging from solitary individuals to high-density swarms, leading to multiple-trait divergence between solitary and gregarious phases. However, differences in sexual communication between solitary and gregarious locusts have not been sufficiently explored. Herein, we found that solitary locusts but not gregarious ones heavily rely on a single compound, dibutyl phthalate (DBP), for sexual communication. DBP is abundantly released by solitary female locusts and elicits strong attraction of male solitary and gregarious locusts. Solitary adult males display much higher electrophysiological responses to DBP than adult females. Additionally, LmigOr13 was identified as the DBP-specific odorant receptor expressed in neurons housed in basiconic sensilla. Male LmigOr13-/- mutants generated by CRISPR/Cas9 have low electrophysiological responses and behavioral attraction to DBP in both laboratory and field cage experiments. Notably, the attractiveness of DBP to male locusts becomes more evident at lower population densities imposed by controlling the cage size. This finding sheds light on the utilization of a sex pheromone to promote reproductive success in extremely low-density conditions and provides important insights into alternative approaches for population monitoring of locusts.

Bumblebees attend to both the properties of the string and the target in string-pulling tasks, but prioritize the features of the string.

Previous studies have demonstrated that associative learning and experience play important roles in the string-pulling of bumblebees (Bombus terrestris). However, the features of the target (artificial flower with sugar reward) and the string that bees learn in such tasks remain unknown. This study aimed to explore the specific aspects of the string-flower arrangement that bumblebees learn and how they prioritize these features. We show that bumblebees trained with string-pulling are sensitive to the flower stimuli; they exhibit a preference for pulling strings connected to flowers over strings that are not attached to a target. Additionally, they chose to pull strings attached to flowers of the same color and shape as experienced during training. The string feature also plays a crucial role for bumblebees when the flower features are identical. Furthermore, bees prioritized the features of the strings rather than the flowers when both cues were in conflict. Our results show that bumblebees solve string-pulling tasks by acquiring knowledge about the characteristics of both targets and strings, and contribute to a deeper understanding of the cognitive processes employed by bees when tackling non-natural skills.

Differential toxic and antiepileptic features of Vigabatrin raceme and its enantiomers.

BACKGROUND: The study aimed to investigate the potential pharmacological and toxicological differences between Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. The researchers focused on the toxic effects and antiepileptic activity of these compounds in a rat model. METHODS: The epileptic rat model was established by intraperitoneal injection of kainic acid, and the antiepileptic activity of VGB, S-VGB, and VGB was observed, focusing on the improvements in seizure latency, seizure frequency and sensory, motor, learning and memory deficits in epileptic rats, as well as the hippocampal expression of key molecular associated with synaptic plasticity and the Wnt/ß-catenin/GSK 3ß signaling pathway. The acute toxic test was carried out and the LD50 was calculated, and tretinal damages in epileptic rats were also evaluated. RESULT: The results showed that S-VGB exhibited stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. These findings suggest that S-VGB and VGB may modulate neuronal damage, glial cell activation, and synaptic plasticity related to epilepsy through the Wnt/ß-catenin/GSK 3ß signaling pathway. The study provides valuable insights into the potential differential effects of VGB enantiomers, highlighting the potential of S-VGB as an antiepileptic drug with reduced side effects. CONCLUSION: S-VGB has the highest antiepileptic effect and lowest toxicity compared to VGB and R-VGB.

The pyrexia channel remodels egg-laying of Liriomyza huidobrensis in response to temperature change.

BACKGROUND: The pea leafminer, Liriomyza huidobrensis, is one of the most important insect pests on vegetables and ornamentals. The survival and egg-laying behavior of leafminers are markedly affected by the environment temperature. However, the mechanisms underlying the relationship between egg-laying and temperature are still largely unknown. RESULTS: Here, we find that leafminers have evolved an adaptive strategy to overcome the stress from high or low temperature by regulating oviposition-punching plasticity. We further show that this oviposition-punching plasticity is mediated by the expression of pyx in the ovipositor when subjected to disadvantageous temperature. Specifically, down-regulation of pyx expression in leafminers under low temperature stress led to a significant decrease in the swing numbers of ovipositor and puncture area of the egg spot, and consequently the lower amount of egg-laying compared to leafminers at ambient temperature. Conversely, activation of pyx expression under high temperature stress increased the swing numbers and puncture area, still resulting in a reduction of egg-laying amount. CONCLUSION: Thereby, leafminers are able to coordinate pyx channel expression level and accordingly depress the oviposition. Our study uncovers a molecular mechanism underlying the adaptive strategy in insects that can avoid disadvantageous temperature for reproducing offspring. © 2024 Society of Chemical Industry.

[Effect of Naotaifang on microglial polarization and glial scar following cerebral ischemia reperfusion injury].

This study aims to investigate the effect of Naotaifang(NTF) on the proteins associated with microglial polarization and glial scar in the rat model of cerebral ischemia reperfusion injury(CIRI). The CIRI model was established by middle cerebral artery occlusion/reperfusion. The 48 successfully modeled rats were randomized into model 7 d, model 14 d, NTF 7 d, and NTF 14 d groups(n=12). In addition, 12 SD rats were selected as the sham group. The NTF group was administrated with NTF suspension at 27 g·kg~(-1)·d~(-1) by gavage, and the sham, model 7 d, and model 14 d groups were administrated with the same volume of normal saline every day by gavage for 7 and 14 days, respectively. After the intervention, Longa score was evaluated. The infarct volume was measured by 2,3,5-triphenyl-2H-tetrazolium chloride(TTC) staining. Morris water maze and open field tests were carried out to evaluate the spatial learning, memory, cognitive function, and anxiety degree of rats. Hematoxylin-eosin(HE) staining was employed to observe the morphological structure and damage of the brain tissue. The immunofluorescence assay was employed to measure the expression of glial fibrillary acidic protein(GFAP) and glial scar. Western blot was employed to determine the protein levels of GFAP, neurocan, phosphacan, CD206, arginase-1(Arg-1), interleukin(IL)-1ß, IL-6, and IL-4. Compared with the sham, model 7 d and model 14 d groups showed cerebral infarction of different degrees, severe pathological injury of cerebral cortex and hippocampus, neurological impairment, reduced spatial learning and memory, cognitive dysfunction, severe anxiety, astrocyte hyperplasia, thickening penumbra glial scar, and up-regulated protein levels of IL-1ß, IL-6, GFAP, neurocan, phosphacan, CD206, and Arg-1(P<0.01). Compared with the model group, NTF 7 d and NTF 14 d groups improved spatial learning, memory, and cognitive function, reduced anxiety, improved nerve function, reduced cerebral infarction volume, reduced astrocyte hyperplasia, thinned penumbra glial scar, down-regulated the protein levels of GFAP, neurocan, phosphacan, IL-6, and IL-1ß, and up-regulated the protein levels of IL-4, CD206, and Arg-1(P<0.05 or P<0.01). NTF exerts a neuroprotective effect on CIRI by inducing the M2 polarization of microglia, inhibiting inflammatory response, and reducing the formation of glial scar.

Development of a liver disease-specific large language model chat interface using retrieval-augmented generation.

BACKGROUND AND AIMS: Large language models (LLMs) have significant capabilities in clinical information processing tasks. Commercially available LLMs, however, are not optimized for clinical uses and are prone to generating hallucinatory information. Retrieval-augmented generation (RAG) is an enterprise architecture that allows the embedding of customized data into LLMs. This approach "specializes" the LLMs and is thought to reduce hallucinations. APPROACH AND RESULTS: We developed "LiVersa," a liver disease-specific LLM, by using our institution's protected health information-complaint text embedding and LLM platform, "Versa." We conducted RAG on 30 publicly available American Association for the Study of Liver Diseases guidance documents to be incorporated into LiVersa. We evaluated LiVersa's performance by conducting 2 rounds of testing. First, we compared LiVersa's outputs versus those of trainees from a previously published knowledge assessment. LiVersa answered all 10 questions correctly. Second, we asked 15 hepatologists to evaluate the outputs of 10 hepatology topic questions generated by LiVersa, OpenAI's ChatGPT 4, and Meta's Large Language Model Meta AI 2. LiVersa's outputs were more accurate but were rated less comprehensive and safe compared to those of ChatGPT 4. RESULTS: We evaluated LiVersa's performance by conducting 2 rounds of testing. First, we compared LiVersa's outputs versus those of trainees from a previously published knowledge assessment. LiVersa answered all 10 questions correctly. Second, we asked 15 hepatologists to evaluate the outputs of 10 hepatology topic questions generated by LiVersa, OpenAI's ChatGPT 4, and Meta's Large Language Model Meta AI 2. LiVersa's outputs were more accurate but were rated less comprehensive and safe compared to those of ChatGPT 4. CONCLUSIONS: In this demonstration, we built disease-specific and protected health information-compliant LLMs using RAG. While LiVersa demonstrated higher accuracy in answering questions related to hepatology, there were some deficiencies due to limitations set by the number of documents used for RAG. LiVersa will likely require further refinement before potential live deployment. The LiVersa prototype, however, is a proof of concept for utilizing RAG to customize LLMs for clinical use cases.

The association between mean arterial pressure and acute kidney injury reversal among patients with decompensated cirrhosis.

BACKGROUND AND AIMS: This study informs how mean arterial pressure (MAP) impacts acute kidney injury (AKI) recovery among all patients hospitalized with cirrhosis, regardless of etiology. APPROACH AND RESULTS: We identified incident AKI episodes among subjects in our cohort of patients with decompensated cirrhosis. AKI was defined as a ≥50% increase in creatinine from an outpatient baseline (≥7 days prior) that required hospitalization. Linear mixed effects models were completed to determine the impact between AKI recovery, MAP, and time. To determine the impact of MAP on AKI reversal, we completed time-dependent Cox regression models with time beginning at the time of peak creatinine and ending at death, discharge, or AKI reversal, among those hospitalized with AKI and those with persistent AKI (≥48 h) We identified 702 hospitalized patients with cirrhosis with AKI. We found those with AKI reversal had, on average, higher MAP (2.1 mm Hg, p <0.05) and a greater increase in MAP over time (0.1 mm Hg per hour, p <0.001). Among all 702 hospitalized patients with AKI and adjusted for confounders, each 5 mm Hg increase in MAP was associated with 1.07× the hazard of AKI reversal ( p <0.01). Similarly, among those with persistent AKI after adjusting for confounders, each 5 mm Hg increase in MAP was associated with a 1.19× greater likelihood of AKI reversal ( p <0.001). DISCUSSION: Our data demonstrate that MAP significantly increases the likelihood of AKI recovery regardless of severity or injury or AKI phenotype. We believe these data highlight the importance of MAP as a clinical tool to promote kidney function recovery among patients with cirrhosis hospitalized with AKI.

Outpatient mean arterial pressure: A potentially modifiable risk for acute kidney injury and death among patients with cirrhosis.

Mean arterial blood pressure (MAP), which decreases as portal hypertension progresses, may be a modifiable risk factor among patients with cirrhosis. We included adults enrolled in the Functional Assessment in Liver Transplantation study. We completed latent class trajectory analyses to define MAP trajectories. We completed time-dependent Cox-regression analyses to test the association between outpatient MAP and 3 cirrhosis-related outcomes: (1) stage 2 acute kidney injury (AKI), defined as a ≥200% increase in serum creatinine from baseline; (2) a 5-point increase in the MELD-Na score, defined as the incidence of increase from initial MELD-Na; (3) waitlist mortality, defined as death on the waitlist. For each outcome, we defined MAP cut points by determining the maximally selected Log-rank statistic after univariable Cox-regression analyses. Among the 1786 patients included in this analysis, our latent class trajectory analyses identified 3 specific outpatient MAP trajectories: "stable-low," "stable-high," and "increasing-to-decreasing." However, >80% of patients were in a "stable-low" trajectory. We found in adjusted analyses that outpatient MAP was associated with each of our outcomes: Stage 2 AKI (adjusted hazard ratio 0.88 per 10 mm Hg increase in MAP [95% CI: 0.79-0.99]); 5-point increase in MELD-Na (adjusted hazard ratio: 0.91 [95% CI: 0.86-0.96]; waitlist mortality (adjusted hazard ratio: 0.89 [95% CI: 0.81-0.96]). For each outcome, we found that an outpatient MAP of 82 mm Hg was most associated with outcomes ( p <0.05 for all). Our study informs the association between outpatient MAP and cirrhosis-related outcomes. These findings, coupled with the identification of specific thresholds, lay the foundation for the trial of targeted outpatient MAP modulation in patients with cirrhosis.

Global and Regional Burden and Trend of Neoplasms Attributable to Alcohol Consumption in the Past 3 Decades.

OBJECTIVES: To provide valuable insights for targeted cancer screening among high-risk patients, we analyzed the global and regional burden of neoplasms resulting from alcohol consumption between 1990 and 2019. METHODS: The information used in this study was collected from the Global Burden of Disease 2019 dataset. Initially, the database was used to extract details of mortality rates, disability-adjusted life years (DALYs), and the number of individuals affected by alcohol-related neoplasms (ARNs). Subsequently, the data were compared by cancer type, sex, age, region, and sociodemographic index. Furthermore, the study involved the calculation and comparison of estimated annual percentage changes in age-standardized DALYs rates (ASDRs) and mortality rates. RESULTS: The impact of alcohol on the burden of cancer varied by type of cancer, sex, age, and geographical location. Notably, males exhibited significantly higher ASDRs compared with females. Specifically, in 2019, alcohol emerged as the primary contributor to the number of DALYs associated with esophageal cancer, followed by liver cancer and colorectal cancer in men. Patients aged 50+ years exhibited a heightened rate of DALYs associated with ARNs. From 1990 to 2019, ASDRs among individuals with ARNs did not exhibit a decline in low-middle and low sociodemographic index regions. CONCLUSIONS: Alcohol consumption represents a significant risk factor for the burden of cancer, particularly within the realm of digestive system malignancies. Consequently, targeted cancer screening efforts should be directed toward the population that engages in alcohol drinking, with a particular focus on men aged 50 years and older, residing in economically disadvantaged areas.

3D Temperature-Controlled Interchangeable Pattern for Size-Selective Nanoparticle Capture.

Patterned surfaces with distinct regularity and structured arrangements have attracted great interest due to their extensive promising applications. Although colloidal patterning has conventionally been used to create such surfaces, herein, we introduce a novel 3D patterned poly(N-isopropylacrylamide) (PNIPAM) surface, synthesized by using a combination of colloidal templating and surface-initiated photoinduced electron transfer-reversible addition-fragmentation chain transfer (SI-PET-RAFT) polymerization. In order to investigate the temperature-driven 3D morphological variations at a lower critical solution temperature (LCST) of ∼32 °C, multifaceted characterization techniques were employed. Atomic force microscopy confirmed the morphological transformations at 20 and 40 °C, while water contact angle measurements, upon heating, revealed distinct trends, offering insights into the correlation between surface wettability and topography adaptations. Moreover, quartz crystal microbalance with dissipation monitoring and electrochemical measurements were employed to detect the topographical adjustments of the unique hollow capsule structure within the LCST. Tests using different sizes of PSNPs shed light on the size-selective capture-release potential of the patterned PNIPAM, accentuating its biomimetic open-close behavior. Notably, our approach negates the necessity for expensive proteins, harnessing temperature adjustments to facilitate the noninvasive and efficient reversible capture and release of nanostructures. This advancement hopes to pave the way for future innovative cellular analysis platforms.