Selection of lubricant type and concentration for orodispersible tablets.

Lubricants are essential for most tablet formulations as they assist powder flow, prevent adhesion to tableting tools and facilitate tablet ejection. Magnesium stearate (MgSt) is an effective lubricant but may compromise tablet strength and disintegratability. In the design of orodispersible tablets, tablet strength and disintegratability are critical attributes of the dosage form. Hence, this study aimed to conduct an in-depth comparative study of MgSt with alternative lubricants, namely sodium lauryl sulphate (SLS), stearic acid (SA) and hydrogenated castor oil (HCO), for their effects on the tableting process as well as tablet properties. Powder blends were prepared with lactose, sodium starch glycolate or crospovidone as the disintegrant, and a lubricant at different concentrations. Angle of repose was determined for the mixtures. Comparative evaluation was carried out based on the ejection force, tensile strength, liquid penetration and disintegratability of the tablets produced. As the lubricant concentration increased, powder flow and tablet ejection improved. The lubrication efficiency generally decreased as follows: MgSt > HCO > SA > SLS. Despite its superior lubrication efficacy, MgSt is the only lubricant of four evaluated that reduced tablet tensile strength. Tablet disintegration time was strongly determined by tensile strength and liquid penetration, which were in turn affected by the lubricant type and concentration. All the above factors should be taken into consideration when deciding the type and concentration of lubricant for an orodispersible tablet formulation.

Correction: Nickel-catalyzed γ-alkylation of cyclopropyl ketones with unactivated primary alkyl chlorides: balancing reactivity and selectivity via halide exchange.

[This corrects the article DOI: 10.1039/D4RA02616K.].

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

Functional Outcomes after Abdominal Surgery in Older Adults - How concerned are we about this?

Amidst trends of a rapidly ageing population with better surgical outcomes for geriatric patients, it is imperative to consider outcome measures beyond mortality and morbidity rates. In fact, the preservation of one's postoperative function has been cited as a key priority for older adults and is a crucial determinant of postoperative independence and survival. This review aims to examine the prevalence of perioperative function reporting amongst older surgical patients undergoing elective major abdominal surgery for cancer. We systematically reviewed studies from inception to December 2023 for studies which focused on the outcomes of older surgical patients undergoing elective major abdominal surgery for cancer. Relevant citations were screened (title, abstract and full article review) based on the inclusion and exclusion criteria. 103 studies were included, of which only 31 studies consisting of 20885 participants reported perioperative function. While the nominal number of studies which report perioperative function has been on a steady rise since 2018, the proportion of studies which do so remains low. Postoperative function is three times less likely to be reported than preoperative function, suggesting that functional recovery is not sufficiently assessed. This suggests that there is still a poor uptake of functional recovery as an outcome measure amongst surgeons, and any increase in perioperative function reporting is likely due to the increased administration of frailty assessments. These findings should urge greater efforts in quantifying and enabling functional recovery to improve the clinical outcomes and quality of care for older surgical patients.

Nickel-catalyzed γ-alkylation of cyclopropyl ketones with unactivated primary alkyl chlorides: balancing reactivity and selectivity via halide exchange.

A novel method was developed for synthesizing γ-alkyl ketones via nickel-catalyzed cross-electrophile coupling of cyclopropyl ketones and non-activated primary alkyl chlorides. High reactivity and selectivity can be achieved with sodium iodide as a crucial cocatalyst that generates a low concentration of alkyl iodide via halide exchange, thus avoiding the formation of alkyl dimers. This reaction possessed excellent regioselectivity and high step economy circumventing in situ or pregenerated organometallics.

NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitate HBV-related acute-on-chronic liver failure-pyroptosis.

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

Dampened motivation in schizophrenia: evidence from a novel effort-based decision-making task in social scenarios.

Apathy represents a significant manifestation of negative symptoms within individuals diagnosed with schizophrenia (SCZ) and exerts a profound impact on their social relationships. However, the specific implications of this motivational deficit in social scenarios have yet to be fully elucidated. The present study aimed to examine effort-based decision-making in social scenarios and its relation to apathy symptoms in SCZ patients. We initially recruited a group of 50 healthy participants (16 males) to assess the validity of the paradigm. Subsequently, we recruited 45 individuals diagnosed with SCZ (24 males) and 49 demographically-matched healthy controls (HC, 25 males) for the main study. The Mock Job Interview Task was developed to measure effort-based decision-making in social scenarios. The proportion of hard-task choice and a range of subjective ratings were obtained to examine potential between-group differences. SCZ patients were less likely than HC to choose the hard task with strict interviewers, and this group difference was significant when the hard-task reward value was medium and high. More severe apathy symptoms were significantly correlated with an overall reduced likelihood of making a hard-task choice. When dividing the jobs into two categories based on the levels of social engagement needed, SCZ patients were less willing to expend effort to pursue a potential offer for jobs requiring higher social engagement. Our findings indicated impaired effort-based decision-making in SCZ can be generalized from the monetary/nonsocial to a more ecologically social dimension. Our findings affirm the critical role of aberrant effort allocation on negative symptoms, and may facilitate the development of targeted clinical interventions.

The network characteristics in schizophrenia with prominent negative symptoms: a multimodal fusion study.

Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.

Differences in vascular endothelial function and serum proteome between obese people with phlegm-dampness constitution and balanced constitution.

OBJECTIVE: To evaluate the extent of vascular endothelial dysfunction and preliminary identify serum protein biomarkers associated with obese individuals at risk for cardiovascular disease (CVD). METHODS: Fifteen obese volunteers with the phlegm-dampness constitution or balanced constitution were recruited for this study respectively. The clinical baseline data was collected, and the vascular endothelial function was evaluated using the EndoPATTM. Blood samples were collected for the serum proteome analysis. The differences in the serum protein expression levels between the two groups were detected and the protein interaction network analysis, correlation analysis, receiver operating characteristic (ROC) curve analysis, and random forest model investigation were conducted. RESULTS: There were no statistical differences found in the baseline data. For vascular endothelial function, the reactive hyperemia index (RHI) of the phlegm-dampness constitution obese group was significantly lower than that of the balanced constitution obese group (1.46 ± 0.30 vs 2.82 ± 0.78, P < 0.0001), indicating vascular endothelial dysfunction. There are 66 differentially expressed serum proteins between the two groups. apolipoprotein A2 (ApoA2), angiotensin-converting enzyme 2 (ACE-2), interleukin-33 (IL-33), and forkhead box P3 (FoxP3) showed significant differences and area under curve values of their ROC curves were greater than 0.7 and correlated significantly with RHI. CONCLUSION: Vascular endothelial dysfunction was present in the phlegm-dampness constitution obese group. Thus, alterations in the expression levels of key serum proteins, including ApoA2, ACE-2, IL-33, and FoxP3 could serve as potential biomarkers in the obese population at risk of CVD.

Range adaptive value representations in schizophrenia and major depression.

Anhedonia and amotivation are core symptoms of schizophrenia (SCZ) and major depressive disorder (MDD). Reward processing involves constructing and contrasting the representations for expected value (EV) and outcome value (OV) of a given stimulus, a phenomenon termed range adaptation. Impaired range adaptation can lead to anhedonia and amotivation. This study aimed to examine range adaptation in SCZ patients and MDD patients. Fifty SCZ, 46 MDD patients and 56 controls completed the Effort-based Pleasure Experience Task to measure EV and OV adaptation. SCZ and MDD patients showed altered range adaptation, albeit in different patterns. SCZ patients exhibited over-adaptation to OV and reduced adaptation to EV. By contrast, MDD patients exhibited diminished OV adaptation but intact EV adaptation. Both OV and EV adaptation were correlated with anhedonia and amotivation in SCZ and MDD. Taken together, our findings suggest that range adaptation is altered in both SCZ and MDD patients. Associations of OV and EV adaptation with anhedonia and amotivation were consistently found in SCZ and MDD patients. Impaired range adaptation in SCZ and MDD patients may be putative neural mechanisms and potential intervention targets for anhedonia and amotivation.

Streptomyces tamarix sp. nov.: antagonism against Alternaria gaisen producing streptochlorin, isolated from Tamarix root soil.

By the end of 2021, the pear yield in Xinjiang reached 1,795,900 tons, accounting for 1/9 of the country. Pear black spot, caused by Alternaria gaisen disease, has had a significant impact on the pear industry. A. gaisen can infect nearly all pear plants, resulting in black spots on the fruit that negatively affect both yield and quality. This study focused on the TRM76323 strain of Streptomyces, which was isolated from the soil of Tamarix chinensis in Xinjiang Province. Through a multiphase classification and identification method, the genetic classification status of the antagonistic strains was determined. The study also identified the antibacterial active components of streptochlorin using modern isolation and purification techniques. The antagonistic activity of Streptomyces against Alternaria was analyzed through in vitro and in vivo experiments. This research not only expanded the resource bank of antagonistic microorganisms in extreme environments in Xinjiang, but also identified active components that could contribute to the development of new drug lead compounds. Additionally, this study presents a novel approach for the prevention and control of pear black spot disease.

General limit to thermodynamic annealing performance.

Annealing has proven highly successful in finding minima in a cost landscape. Yet, depending on the landscape, systems often converge towards local minima rather than global ones. In this Letter, we analyze the conditions for which annealing is approximately successful in finite time. We connect annealing to stochastic thermodynamics to derive a general bound on the distance between the system state at the end of the annealing and the ground state of the landscape. This distance depends on the amount of state updates of the system and the accumulation of nonequilibrium energy, two protocol and energy landscape-dependent quantities which we show are in a trade-off relation. We describe how to bound the two quantities both analytically and physically. This offers a general approach to assess the performance of annealing from accessible parameters, both for simulated and physical implementations.

Bound on annealing performance from stochastic thermodynamics, with application to simulated annealing.

Annealing is the process of gradually lowering the temperature of a system to guide it towards its lowest energy states. In an accompanying paper [Y. Luo et al., Phys. Rev. E 108, L052105 (2023)10.1103/PhysRevE.108.L052105], we derived a general bound on annealing performance by connecting annealing with stochastic thermodynamics tools, including a speed limit on state transformation from entropy production. We here describe the derivation of the general bound in detail. In addition, we analyze the case of simulated annealing with Glauber dynamics in depth. We show how to bound the two case-specific quantities appearing in the bound, namely the activity, a measure of the number of microstate jumps, and the change in relative entropy between the state and the instantaneous thermal state, which is due to temperature variation. We exemplify the arguments by numerical simulations on the Sherrington-Kirkpatrick (SK) model of spin glasses.

Device-Independent Quantum Key Distribution Based on the Mermin-Peres Magic Square Game.

Device-independent quantum key distribution (DIQKD) is information-theoretically secure against adversaries who possess a scalable quantum computer and who have supplied malicious key-establishment systems; however, the DIQKD key rate is currently too low. Consequently, we devise a DIQKD scheme based on the quantum nonlocal Mermin-Peres magic square game: our scheme asymptotically delivers DIQKD against collective attacks, even with noise. Our scheme outperforms DIQKD using the Clauser-Horne-Shimony-Holt game with respect to the number of game rounds, albeit not number of entangled pairs, provided that both state visibility and detection efficiency are high enough.

Deubiquitination complex platform: A plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes.

Deubiquitinating enzymes (DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin‒proteasome degradation and are critical for regulating protein expression levels in vivo. Therefore, dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways. To data, extensive studies on the ubiquitin chain specificity of DUBs have been reported, but substrate protein recognition is still not clearly understood. As a breakthrough, the scaffolding role may be significant to substrate protein selectivity. From this perspective, we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity. Furthermore, we proposed a deubiquitination complex platform (DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples, which might fill the gaps in the understanding of DUB substrate specificity.

Adjuvant intra-arterial thrombolysis during mechanical thrombectomy is an effective means of improving outcomes for patients with large vessel occlusion stroke: A systematic review and meta-analysis.

OBJECTIVE: It is unknown whether adjunctive intra-arterial thrombolysis (IAT) during mechanical thrombectomy (MT) improves outcomes in patients with large vessel occlusion (LVO) stroke. This systematic review and meta-analysis aimed to compare the safety and efficacy of MT with and without IAT for the treatment of LVO stroke. METHODS: A systematic literature search of PubMed, Embase, and the Cochrane Library was conducted to identify studies that compared rates of 3-month functional independence (modified Rankin Scale score 0-2), successful revascularization, symptomatic intracranial hemorrhage, and 3-month mortality for MT+IAT and MT alone. Meta-analyses were performed using random effects models, and effect sizes were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). Heterogeneity was assessed with Cochran's Q test and I2 statistic. RESULTS: Twelve studies met eligibility criteria, comprising one randomized controlled trial and 11 observational cohort studies involving 2584 patients. Compared to MT alone, MT+IAT had a 43% higher odds of 3-month functional independence (OR 1.43, 95% CI 1.11-1.83; I2 =21%) and a 23% decrease in odds for 3-month mortality (OR 0.77, 95% CI 0.60-0.99; I2 =0%). There were no differences in successful revascularization (OR 1.39, 95% CI 0.89-2.17; I2 =57%) or symptomatic intracranial hemorrhage (OR 0.87, 95% CI 0.56-1.35; I2 =6%) between the two groups. CONCLUSIONS: The present study has demonstrated that, compared with MT alone, the use of adjunct IAT during MT in patients with LVO stroke resulted in better functional outcomes and lower mortality.

Application of UPLC-Triple TOF-MS/MS metabolomics strategy to reveal the dynamic changes of triterpenoid saponins during the decocting process of Asian ginseng and American ginseng.

Triterpenoid saponins are the main bioactive components contributed to the nutritional value of ginseng, and different process conditions will affect their content and quality. To study the holistic characterization and dynamic changes of triterpenoid saponins in Asian ginseng (ASG) and American ginseng (AMG) during soaking and decoction, a UPLC-Triple TOF-MS/MS-based metabolomics strategy was used to characterize and discover differential saponin markers. In total, 739 triterpenoid saponins (including 225 potential new saponins) were identified from ASG and AMG in untargeted metabolomics. Based on PCA and OPLS-DA, 51 and 48 saponin markers were screened from soaked and decocted ASG and AMG, respectively. Additionally, targeted metabolomics analysis and HCA of 22 ginsenoside markers suggested that decoction of ASG and AMG for 2 h to 4 h could significantly increase the contents of rare ginsenosides (G), such as G-Rg3, G-Rg5, G-F4. This study provides a scientific insight that high boiling combined with simmering enriches ASG and AMG extracts with rich rare ginsenosides that are more beneficial to human health.

Effective method for low-light image enhancement based on the JND and OCTM models.

Low-light images always suffer from dim overall brightness, low contrast, and low dynamic ranges, thus result in image degradation. In this paper, we propose an effective method for low-light image enhancement based on the just-noticeable-difference (JND) and the optimal contrast-tone mapping (OCTM) models. First, the guided filter decomposes the original images into base and detail images. After this filtering, detail images are processed based on the visual masking model to enhance details effectively. At the same time, the brightness of base images is adjusted based on the JND and OCTM models. Finally, we propose a new method to generate a sequence of artificial images to adjust the brightness of the output, which has a better performance in image detail preservation compared with other single-input algorithms. Experiments have demonstrated that the proposed method not only achieves low-light image enhancement, but also outperforms state-of-the-art methods qualitatively and quantitatively.

Betting against pandemics: Ethical implications of the "COVID Claimania" in Taiwan, 2020-2022.

Among measures tackling the impacts of the COVID-19 pandemic, the selling of private insurance policies covering individual infection is overlooked by the ethics literature. To record the "COVID Claimania" in Taiwan and to assess its ethical implications, we collected 38 policies from 10 insurers sold between January 2020 and May 2022 and found that their risk calculation of the COVID-19 prevalence ranged from 0.5% to 11.08%. In reality, the prevalence by the end of 2022 was 37% in Taiwan. Selling private insurance policies is ethically problematic in three ways. First, it represents the insurance industry's irresponsible risk-taking profit-seeking behaviors. Second, it would jeopardize the effectiveness of the disease-prevention measures by inducing uncontrollable moral hazards. Third, it would expose the insurance companies to unbearable financial risks and cause substantial negative external impacts. The government should intervene in the private insurance market in preparation for future public health emergencies.