Characteristics and risk factors for invasive fungal infection in hospitalized patients with acute-on-chronic hepatitis B liver failure: a retrospective cohort study from 2010 to 2023.

Background and aim: The global burden of invasive fungal infections (IFIs) is emerging in immunologic deficiency status from various disease. Patients with acute-on-chronic hepatitis B liver failure (ACHBLF) are prone to IFI and their conditions are commonly exacerbated by IFI. However, little is known about the characteristics and risk factors for IFI in hospitalized ACHBLF patients. Methods: A total of 243 hospitalized ACHBLF patients were retrospectively enrolled from January 2010 to July 2023. We performed restricted cubic spline analysis to determine the non-linear associations between independent variables and IFI. The risk factors for IFI were identified using logistic regression and the extreme gradient boosting (XGBoost) algorithm. The effect values of the risk factors were determined by the SHapley Additive exPlanations (SHAP) method. Results: There were 24 ACHBLF patients (9.84%) who developed IFI on average 17.5 (13.50, 23.00) days after admission. The serum creatinine level showed a non-linear association with the possibility of IFI. Multiple logistic regression revealed that length of hospitalization (OR = 1.05, 95% CI: 1.02-1.08, P = 0.002) and neutrophilic granulocyte percentage (OR = 1.04, 95% CI: 1.00-1.09, P = 0.042) were independent risk factors for IFI. The XGBoost algorithm showed that the use of antibiotics (SHAP value = 0.446), length of hospitalization (SHAP value = 0.406) and log (qHBV DNA) (SHAP value = 0.206) were the top three independent risk factors for IFI. Furthermore, interaction analysis revealed no multiplicative effects between the use of antibiotics and the use of glucocorticoids (P = 0.990). Conclusion: IFI is a rare complication that leads to high mortality in hospitalized ACHBLF patients, and a high neutrophilic granulocyte percentage and length of hospitalization are independent risk factors for the occurrence of IFI.

Carrageenan maintains the contractile phenotype of vascular smooth muscle cells by increasing macromolecular crowding in vitro.

BACKGROUND: The contractile phenotype of vascular smooth muscle cells (VSMCs) results in good diastolic and contractile capacities, and its altered function is the main pathophysiological basis for diseases such as hypertension. VSMCs exist as a synthetic phenotype in vitro, making it challenging to maintain a contractile phenotype for research. It is widely recognized that the common medium in vitro is significantly less crowded than in the in vivo environment. Additionally, VSMCs have a heightened sense for detecting changes in medium crowding. However, it is unclear whether macromolecular crowding (MMC) helps maintain the VSMCs contractile phenotype. PURPOSE: This study aimed to explore the phenotypic, behavioral and gene expression changes of VSMCs after increasing the crowding degree by adding carrageenan (CR). METHODS: The degree of medium crowding was examined by a dynamic light scattering assay; VSMCs survival and activity were examined by calcein/PI cell activity and toxicity and CCK-8 assays; VSMCs phenotypes and migration were examined by WB and wound healing assays; and gene expression was examined by transcriptomic analysis and RT-qPCR. RESULTS: Notably, 225 µg/mL CR significantly increased the crowding degree of the medium and did not affect cell survival. Simultaneously, CR significantly promoted the contraction phenotypic marker expression in VSMCs, shortened cell length, decreased cell proliferation, and inhibited cell migration. CR significantly altered gene expression in VSMCs. Specifically, 856 genes were upregulated and 1207 genes were downregulated. These alterations primarily affect the cellular ion channel transport, microtubule movement, respiratory metabolism, amino acid transport, and extracellular matrix synthesis. The upregulated genes were primarily involved in the cytoskeleton and contraction processes of VSMCs, whereas the downregulated genes were mainly involved in extracellular matrix synthesis. CONCLUSIONS: The in vitro study showed that VSMCs can maintain the contractile phenotype by sensing changes in the crowding of the culture environment, which can be maintained by adding CR.

Lysophosphatidic acid receptor 1 (LPA1) antagonists as potential migrastatics for triple negative breast cancer.

Metastasis is responsible for about 90% of cancer deaths. Anti-metastatic drugs, termed as migrastatics, offer a distinctive therapeutic approach to address cancer migration and invasion. However, therapeutic exploitation of metastasis-specific targets remains limited, and the effective prevention and suppression of metastatic cancer continue to be elusive. Lysophosphatidic acid receptor 1 (LPA1) is activated by an endogenous lipid molecule LPA, leading to a diverse array of cellular activities. Previous studies have shown that the LPA/LPA1 axis supports the progression of metastasis for many types of cancer. In this study, we report the synthesis and biological evaluation of fluorine-containing triazole derivatives as potent LPA1 antagonists, offering potential as migrastatic drugs for triple negative breast cancer (TNBC). In particular, compound 12f, the most potent and highly selective in this series with an IC50 value of 16.0 nM in the cAMP assay and 18.4 nM in the calcium mobilization assay, inhibited cell survival, migration, and invasion in the TNBC cell line. Interestingly, the compound did not induce apoptosis in TNBC cells and demonstrated no cytotoxic effects. These results highlight the potential of LPA1 as a migrastatic target. Consequently, the LPA1 antagonists developed in this study hold promise as potential migrastatic candidates for TNBC.

B1 inhomogeneity corrected CEST MRI based on direct saturation removed omega plot model at 5T.

PURPOSE: CEST can image macromolecules/compounds via detecting chemical exchange between labile protons and bulk water. B1 field inhomogeneity impairs CEST quantification. Conventional B1 inhomogeneity correction methods depend on interpolation algorithms, B1 choices, acquisition number or calibration curves, making reliable correction challenging. This study proposed a novel B1 inhomogeneity correction method based on a direct saturation (DS) removed omega plot model. METHODS: Four healthy volunteers underwent B1 field mapping and CEST imaging under four nominal B1 levels of 0.75, 1.0, 1.5, and 2.0 µT at 5T. DS was resolved using a multi-pool Lorentzian model and removed from respective Z spectrum. Residual spectral signals were used to construct the omega plot as a linear function of 1/ B 1 2 $$ {B}_1^2 $$ , from which corrected signals at nominal B1 levels were calculated. Routine asymmetry analysis was conducted to quantify amide proton transfer (APT) effect. Its distribution across white matter was compared before and after B1 inhomogeneity correction and also with the conventional interpolation approach. RESULTS: B1 inhomogeneity yielded conspicuous artifact on APT images. Such artifact was mitigated by the proposed method. Homogeneous APT maps were shown with SD consistently smaller than that before B1 inhomogeneity correction and the interpolation method. Moreover, B1 inhomogeneity correction from two and four CEST acquisitions yielded similar results, superior over the interpolation method that derived inconsistent APT contrasts among different B1 choices. CONCLUSION: The proposed method enables reliable B1 inhomogeneity correction from at least two CEST acquisitions, providing an effective way to improve quantitative CEST MRI.

NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

Multimodal approach utilising a weight management programme prior to bariatric surgery in patients with BMI ≥50 kg/m2: A propensity score matching retrospective cohort study.

We evaluated preoperative weight loss and days from initial consult to surgery in patients with BMI ≥50 kg/m2 who were and were not enrolled in medical weight management (MWM) prior to laparoscopic sleeve gastrectomy. We retrospectively identified patients with BMI ≥50 kg/m2 who had primary sleeve gastrectomy between 2014 and 2019 at two bariatric surgery centres in our healthcare system. Patients presenting after 2017 that received preoperative MWM (n = 28) were compared to a historical cohort of non-MWM patients (n = 118) presenting prior to programme initiation in 2017 on preoperative percent total body weight loss (%TBWL) and days from initial consult to surgery. A total of 151 patients (MWM, 33; non-MWM, 118) met inclusion criteria. BMI was significantly greater in MWM versus non-MWM (p = .018). After propensity score matching, median BMI at initial consult in non-MWM versus MWM no longer differed (p = .922) neither were differences observed on the basis of weight, age, sex, race or ethnicity. After PSM, MWM had significantly lower BMI at surgery (p = .018), lost significantly more weight from consult to surgery (p < .001) and achieved significantly greater median %TBWL from consult to surgery (p < .001). We noted no difference between groups on 6-month weight loss (p = .533). Days from initial consult to surgery did not differ between groups (p < .863). A preoperative MWM programme integrated into multimodal treatment for obesity in patients with a BMI ≥50 kg/m2 resulted in clinically significant weight loss without prolonging time to surgery.

The role of postoperative radiotherapy or chemoradiation in pT1-2N1M0 oral squamous cell carcinoma.

BACKGROUND: Postoperative radiotherapy (PORT) and concurrent chemoradiation (CCRT) are indicated for patients with advanced oral cancer. However, the benefits for pT1-2N1 disease without adverse pathological features are controversial. METHODS: This retrospective study using the Taiwan Cancer Registry database included patients with pT1-2N1 oral cancer from January 1, 2011, to December 31, 2017. Overall survival was analyzed in patients receiving surgery alone, PORT, or CCRT. RESULTS: Among the 862 patients, the five-year overall survival rate in patients receiving surgery alone, PORT, and CCRT was 62.2%, 58.7%, and 71.1% (P = 0.03), respectively. CCRT was associated with longer survival than PORT (P = 0.008). Survival in patients with pT2 disease was significantly higher with CCRT than PORT (P = 0.001), but no difference was observed in pT1 disease. CONCLUSION: CCRT demonstrated a favorable impact on survival outcomes in patients diagnosed with pT2N1 oral cancer when compared to PORT. However, no significant survival benefits were observed for patients with pT1 disease.

Five-year outcomes of revisional bariatric surgery: gastric band to sleeve gastrectomy or to Roux-en-Y gastric bypass.

BACKGROUND: Revisional bariatric surgery after an index adjustable gastric band (AGB) may be indicated to remedy weight relapse or band-related complications. We examined outcomes five years following revision from AGB to laparoscopic sleeve gastrectomy (AGB-LSG) or to Roux-en-Y gastric bypass (AGB-RYGB). METHODS: We conducted a retrospective review to identify patients (men and women, age 18-80) who underwent one revisional bariatric procedure with AGB as the index procedure at two medical centers in our healthcare system between January 2012 and February 2017. We only included patients with a pre-revision BMI > 30 kg/m2 for whom 5-year follow-up data were available. We compared 5-year weight loss and remission of comorbidities in patients undergoing AGB-LSG and AGB-RYGB conversion. RESULTS: A total of 114 patients met inclusion criteria (65 AGB-LSG, 49 AGB-RYGB). At 5-year post-revision, percent total weight loss (3.4% vs 19.9%; p < 0.001), percent excess weight loss (7.0% vs 50.8%; p < 0.001) and decrease in BMI (1.5 vs 8.8; p < 0.001) was greater in AGB-RYGB vs. AGB-LSG. No significant difference in remission or development of new comorbidities was observed. CONCLUSION: Conversion of AGB to RYGB is associated with superior intermediate-term weight loss compared to conversion of AGB to LSG. Future multicenter studies with larger sample sizes are necessary to further describe the intermediate-term outcomes of revisional bariatric surgery.

Tumor associated macrophages as key contributors and targets in current and future therapies for melanoma.

INTRODUCTION: Despite the success of immunotherapies for melanoma in recent years, there remains a significant proportion of patients who do not yet derive benefit from available treatments. Immunotherapies currently licensed for clinical use target the adaptive immune system, focussing on Tcell interactions and functions. However, the most prevalent immune cells within the tumor microenvironment (TME) of melanoma are macrophages, a diverse immune cell subset displaying high plasticity, to which no current therapies are yet directly targeted. Macrophages have been shown not only to activate the adaptive immune response, and enhance cancer cell killing, but, when influenced by factors within the TME of melanoma, these cells also promote melanoma tumorigenesis and metastasis. AREAS COVERED: We present a review of the most up-to-date literatureavailable on PubMed, focussing on studies from within the last 10 years. We also include data from ongoing and recent clinical trials targeting macrophages in melanoma listed on clinicaltrials.gov. EXPERT OPINION: Understanding the multifaceted role of macrophages in melanoma, including their interactions with immune and cancer cells, the influence of current therapies on macrophage phenotype and functions and how macrophages could be targeted with novel treatment approaches, are all critical for improving outcomes for patients with melanoma.

Coexisting Magnetism, Ferroelectric, and Ferrovalley Multiferroic in Stacking-Dependent Two-Dimensional Materials.

Two-dimensional (2D) multiferroic materials have widespread application prospects in facilitating the integration and miniaturization of nanodevices. However, the magnetic, ferroelectric, and ferrovalley properties in one 2D material are rarely coupled. Here, we propose a mechanism for manipulating magnetism, ferroelectric, and valley polarization by interlayer sliding in a 2D bilayer material. Monolayer GdI2 is a ferromagnetic semiconductor with a valley polarization of up to 155.5 meV. More interestingly, the magnetism and valley polarization of bilayer GdI2 can be strongly coupled by sliding ferroelectricity, making these tunable and reversible. In addition, we uncover the microscopic mechanism of the magnetic phase transition by a spin Hamiltonian and electron hopping between layers. Our findings offer a new direction for investigating 2D multiferroic devices with implications for next-generation electronic, valleytronic, and spintronic devices.

Objectively measured the impact of ambient air pollution on physical activity for older adults.

BACKGROUND: Air pollution poses a significant health risk to the human population, especially for vulnerable groups such as the elderly, potentially discouraging their engagement in physical activity. However, there is a lack of sufficient objective and longitudinal data in current research on how air pollution affects physical activity among older adults. With these gaps, we aimed to explore the relationship between air pollution and objective measurement-based physical activity among older adults by engaging in a longitudinal study design. METHODS: A total of 184 older adults were recruited from three cities with varying levels of air quality. Mean daily minutes of physical activity were measured with 7 consecutive days of accelerometer monitoring (ActiGraph GT3X-BT). Corresponding air pollution data including daily PM2.5 (µg/m3), PM10 (µg/m3) and air quality index (AQI) were sourced from the China National Environmental Monitoring Centre at monitor locations close to older adults' addresses. Associations between air quality and physical activity were estimated using a fixed effect model, adjusting for average daytime temperature, rain, age and weight. RESULTS: AQI and PM2.5 were observed to exhibit significant, inverse, and linear associations with mean daily walk steps, minutes of light physical activity (LPA), moderate physical activity (MPA) and moderate-to-vigorous physical activity (MVPA) in the single variable models. A one-level increase in AQI corresponded to a decline in 550.04 steps (95% [CI] = -858.97, -241.10; p < 0.001), 10.43 min (95% [CI] = -17.07, -3.79; p < 0.001), 4.03 min (95% [CI] = -7.48, -0.59; p < 0.001) and 4.16 min (95% [CI] = -7.77, -0.56; p < 0.001) in daily walking steps, LPA, MPA, and MVPA, respectively. A one-level increase in PM2.5 correlated with a decline in daily walk steps, LPA, MPA and MVPA by 361.85 steps (95% [CI] = -516.53, -207.16; p < 0.001), 8.97 min (95% [CI] = -12.28, -5.66; p < 0.001), 3.73 min (95% [CI] = -5.46, -2.01; p < 0.001,) and 3.79 min (95% [CI] = -5.59, -1.98; p < 0.001), respectively. However, PM10 displayed a significant negative association exclusively with LPA, with one-level increase in PM10 resulting in a 3.7-minute reduction in LPA (95% [CI] = -6.81, -0.59, p < 0.05). CONCLUSION: Air pollution demonstrates an inverse association with physical activity levels among older adults, potentially discouraging their engagement in physical activity. Different air quality indicators may exert varying impacts on physical activity. Future studies are warranted to enhance policy interventions aimed at reducing air pollution and promoting physical activity.

Surface CN bonds mediate photocatalytic CO2 reduction into efficient CH4 production in TiO2-decorated g-C3N4 nanosheets.

Graphitic carbon nitride (g-C3N4, CN) has garnered considerable attention in the field of photocatalysis due to its favorable band gap and high specific surface area. However, its primary practical limitation lies in the strong radiative recombination of lone pair (LP) electronic states, leading to limited efficiency in separating photogenerated carriers and subsequently diminishing photocatalytic performance. In this study, we devised and synthesized a heterojunction photocatalytic system comprising TiO2 nanosheets supported on modified g-C3N4 (MCN), designated as MCN/TiO2. The presence of CN functional groups on the tri-s-triazine nitrogen captures photogenerated electrons by modifying LP electronic states, resulting in a reduction in the fluorescence emission intensity of g-C3N4. Simultaneously, it forms chemical bonds with the supported TiO2 nanosheets, creating an efficient electron transfer pathway for the accumulation of photogenerated electrons at the active Ti sites. Experimentally, the MCN/TiO2 photocatalytic system exhibited optimal performance in CO2 reduction. The CH4 production rate reached 26.59 µmol g-1 h-1, surpassing that of TiO2 and CN/TiO2 by approximately 8 and 3 times, respectively. Furthermore, this photocatalytic system demonstrated exceptional photostability over five cycles, each lasting 4 h. This research offers a valuable approach for the efficient separation and transfer of photogenerated carriers in composite materials based on g-C3N4.

Macromolecular Crowding Enhances Matrix Protein Deposition in Tissue-Engineered Vascular Grafts.

Successful in vitro culture of small-diameter tissue-engineered vascular grafts (TEVGs) requires rapid deposition of biomacromolecules secreted by vascular smooth muscle cells in a polyglycolic acid mesh scaffold's three-dimensional (3D) porous environment. However, common media have lower crowding conditions than in vivo tissue fluids. In addition, during the early stages of construction, most of the biomolecules secreted by the cells into the medium are lost, which negatively affects the TEVG culture process. In this study, we propose the use of macromolecular crowding (MMC) to enhance medium crowding to improve the deposition and self-assembly efficiency of major biomolecules in the early stages of TEVG culture. The addition of carrageenan significantly increased the degree of MMC in the culture medium without affecting cell viability, proliferation, and metabolic activity. Protein analysis demonstrated that the deposition of collagen types I and III and fibronectin increased significantly in the cell layers of two-dimensional and 3D smooth muscle cell cultures after the addition of a MMC agent. Collagen type I in the culture medium decreased significantly compared with that in the medium without a MMC agent. Scanning electron microscopy demonstrated that MMC agents considerably enhanced the formation of matrix protein structures during the early stages of 3D culture. Hence, MMC modifies the crowding degree of the culture medium, resulting in the rapid formation of numerous matrix proteins and fiber structures. Impact Statement Small-diameter tissue-engineered vascular grafts (TEVGs) are one of the most promising means of treating cardiovascular diseases; however, the in vitro construction of TEVGs has some limitations, such as slow deposition of extracellular matrix (ECM), long culture period, and poor mechanical properties. We hypothesized that macromolecular crowding can increase the crowding of the culture medium to construct a more bionic microenvironment, which enhances ECM deposition in the medium to the cell layer and reduces collagen loss, accelerating and enhancing TEVG culture and construction in vitro.

Do all algae grow faster in environments replenished by reclaimed water? Examples of two effluents produced in Beijing.

Reclaimed water with nitrogen, phosphorus, and other contaminants may trigger algal blooms during its ecological utilization in replenishing rivers or lakes. However, the effect of reclaimed water on algal growth rates is not well understood. In this study, the growth potentials of algae in terms of Cyanophyta, Chlorophyta, and Bacillariophyta, as well as mixed algae in both regular culture medium and reclaimed water produced from treatment plants in Beijing with similar N and P concentrations, were compared to evaluate whether reclaimed water could facilitate algal growth. In addition, reclaimed water was also sterilized to verify the impact of bacteria's presence on algal growth. The results indicated that most algae grew faster in reclaimed water, among which the growth rate of Microcystis aeruginosa even increased by 5.5 fold. The growth of mixed algae in reclaimed water was not enhanced due to the strong adaptive ability of the community structure. Residual bacteria in the reclaimed water were found to be important contributors to algal growth. This work provided theoretical support for the safe and efficient utilization of reclaimed water.

Repositioning baloxavir marboxil as VISTA agonist that ameliorates experimental asthma.

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA), a novel negative checkpoint regulator, plays an essential role in allergic pulmonary inflammation in mice. Treatment with a VISTA agonistic antibody could significantly improve asthma symptoms. Thus, for allergic asthma treatment, VISTA targeting may be a compelling approach. In this study, we examined the functional mechanism of VISTA in allergic pulmonary inflammation and screened the FDA-approved drugs for VISTA agonists. By using mass cytometry (CyTOF), we found that VISTA deficiency primarily increased lung macrophage infiltration in the OVA-induced asthma model, accompanied by an increased proportion of M1 macrophages (CD11b+F4/80+CD86+) and a decreased proportion of M2 macrophages (CD11b+F4/80+CD206+). Further in vitro studies showed that VISTA deficiency promoted M1 polarization and inhibited M2 polarization of bone marrow-derived macrophages (BMDMs). Importantly, we discovered baloxavir marboxil (BXM) as a VISTA agonist by virtual screening of FDA-approved drugs. The surface plasmon resonance (SPR) assays revealed that BXM (KD = 1.07 µM) as well as its active form, baloxavir acid (BXA) (KD = 0.21 µM), could directly bind to VISTA with high affinity. Notably, treatment with BXM significantly ameliorated asthma symptoms, including less lung inflammation, mucus secretion, and the generation of Th2 cytokines (IL-5, IL-13, and IL-4), which were dramatically attenuated by anti-VISTA monoclonal antibody treatment. BXM administration also reduced the pulmonary infiltration of M1 macrophages and raised M2 macrophages. Collectively, our study indicates that VISTA regulates pulmonary inflammation in allergic asthma by regulating macrophage polarization and baloxavir marboxil, and an old drug might be a new treatment for allergic asthma through targeting VISTA.

Ixazomib-based frontline therapy followed by ixazomib maintenance in frail elderly newly diagnosed with multiple myeloma: a prospective multicenter study.

Background: Frail elderly patients with newly diagnosed multiple myeloma (NDMM) have inferior survival and less benefit from high-dose therapies. This prospective study aimed to investigate the efficacy, safety, and quality of life (QoL) of induction treatment of ixazomib/lenalidomide/dexamethasone (IRd) and ixazomib/pegylated liposomal doxorubicin/dexamethasone (IDd) followed by ixazomib/dexamethasone (Id) maintenance therapy in frail, elderly patients with NDMM. Methods: From July 2019 to December 2021, this non-randomized concurrent controlled clinical study enrolled 120 NDMM patients aged ≥65 years with frailty defined by the International Myeloma Working Group (IMWG) frailty score or Mayo geriatric scoring system. The enrolled patients received 6-8 cycles of IRd or IDd followed by Id maintenance therapy for a minimum of 2 years at the discretion of physicians based on patient's clinical characteristics (chiCTR1900024917). Findings: The median age was 71 years and 55% of the patients were males. The overall response rate (ORR) was 82% and 77%, complete response (CR) rate was 25% and 12% for IRd and IDd groups, respectively. The difference in ORR of the Idd group minus the IRd group was -5.36% (95% CI: -18.9% to 8.19%), indicating that the ORR of the IDd group was neither inferior nor non-inferior to the IRd group. After a median follow-up of 34.3 months, the median progression-free survival (PFS) was 21.6 and 13.9 months, OS was not reached and 29.2 months in IRd and IDd groups, respectively. 28 and 33 patients discontinued induction therapy, 20 and 19 discontinued maintenance therapy in IRd and IDd groups, respectively. Cumulative Grade 3 or higher hematological adverse events (AEs) occurred in 10 of the 60 patients (17%) and non-hematological AEs occurred in 15 of the 60 patients (25%) in the IRd group, while 13 of the 60 patients (22%) and 21 of the 60 patients (35%) in the IDd group. Patients were observed with clinically significant improvement in QoL when compared with that at baseline in both IRd and IDd groups by evaluation per cycle (P < 0.0001). Interpretation: The results demonstrated that compared with IRd regimen, IDd regimen showed no significant advantage, but the survival of the IDd group was shorter than that of the IRd group, indicating an all-oral outpatient triplet regimen with IRd, which has low toxicity and has improved QoL, could be the viable first-line treatment option for frail NDMM patients. Funding: The Young Elite Scientist sponsorship program by bast of Beijing Association for Science and Technology (No. BYESS2023116) and Beijing Medical Award Foundation (No. YXJL-2018-0539-0073).

The Role of Exercise in Statin-Associated Muscle Symptoms Outcomes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective: To provide a synthesis of randomized controlled trials (RCTs) investigating statin-associated muscle symptoms (SAMS) in adults who underwent exercise training intervention. Patients and Methods: We systematically searched 5 electronic databases for placebo-controlled RCTs through January 31, 2023. We included short-term and long-term exercise interventions that compared the efficacy and safety of exercise+statin vs exercise+placebo in healthy adults and reported SAMS preintervention and postintervention. Publication bias and methodological study quality assessments were performed. Results: Five of 454 potentially qualifying RCTs met the inclusion criteria, all short-term exercise RCTs. Participants were predominantly physically inactive young to middle-aged (M=37.2 y) men (57%), 252 (49%) who were on statin therapy, and 271 (53%) on placebo. Of the 3 RCTs providing qualitative SAMS results, 19 (9%) out of 220 participants reported SAMS on exercise+statin and 10 (4%) out of 234 reported SAMS on exercise+placebo. There was no difference between exercise+statin vs exercise+placebo for maximal oxygen consumption (d=-0.18; 95% CI, -0.37 to 0.00; P=.06) or creatine kinase after short-term exercise (d=0.59; 95% CI, -0.06 to 1.25; P=.08). Participants in the exercise+statin group reduced low-density lipoprotein cholesterol vs exercise+placebo (d=-1.84; 95% CI, -2.28 to -1.39; P<.001). Most of the RCTs exhibited low levels of risk of bias (k=4, 80%) and achieved moderate methodological study quality (75.0%±5.2%). Conclusion: Self-reported SAMs tended to be 5% greater after short-term exercise in statin users compared with placebo, although this difference did not achieve statistical significance. There remains an important need for placebo-controlled RCTs investigating the prevalence of statin-induced SAMS during exercise training.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Rescuing Nucleus Pulposus Cells from ROS Toxic Microenvironment via Mitochondria-Targeted Carbon Dot-Supported Prussian Blue to Alleviate Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is invariably accompanied by excessive accumulation of reactive oxygen species (ROS), resulting in progressive deterioration of mitochondrial function and senescence in nucleus pulposus cells (NPCs). Significantly, the main ROS production site in non-immune cells is mitochondria, suggesting mitochondria is a feasible therapeutic target to reverse IVDD. Triphenylphosphine (TPP), which is known as mitochondrial-tropic ligands, is utilized to modify carbon dot-supported Prussian blue (CD-PB) to scavenge superfluous intro-cellular ROS and maintain NPCs at normal redox levels. CD-PB-TPP can effectively escape from lysosomal phagocytosis, permitting efficient mitochondrial targeting. After strikingly lessening the ROS in mitochondria via exerting antioxidant enzyme-like activities, such as superoxide dismutase, and catalase, CD-PB-TPP rescues damaged mitochondrial function and NPCs from senescence, catabolism, and inflammatory reaction in vitro. Imaging evaluation and tissue morphology assessment in vivo suggest that disc height index, mean grey values of nucleus pulposus tissue, and histological morphology are significantly improved in the IVDD model after CD-PB-TPP is locally performed. In conclusion, this study demonstrates that ROS-induced mitochondrial dysfunction and senescence of NPCs leads to IVDD and the CD-PB-TPP possesses enormous potential to rescue this pathological process through efficient removal of ROS via targeting mitochondria, supplying a neoteric strategy for IVDD treatment.