[Mechanism of traditional Chinese medicine in treating ulcerative colitis-related colorectal cancer by regulating NF-κB-related signaling pathways: a review].

Ulcerative colitis is a chronic, recurrent, and nonspecific intestinal inflammatory disease, which is difficult to cure and has the risk of deterioration into related tumors. Long-term chronic inflammatory stimulation can increase the risk of cancerization. With the signaling pathway as a key link in the regulation of tumor microenvironments, nuclear factor-kappa B(NF-κB) is an important regulator of intestinal inflammation. It can also be co-regulated as downstream factors of other signaling pathways, such as TLR4, MAPK, STAT, PI3K, and so on. At present, a large number of animal experiments have proved that traditional Chinese medicine(TCM) can reduce inflammation by interfering with NF-κB-related signaling pathways, improve intestinal inflammation, and inhibit the progression of inflammation to tumors. This article reviewed the relationship between NF-κB-related signaling pathways and the intervention mechanism of TCM, so as to provide a reference for the clinical treatment of ulcerative colitis and the optimization of related cancer prevention strategies.

Improving rice eating and cooking quality by enhancing endogenous expression of a nitrogen-dependent floral regulator.

Improving rice eating and cooking quality (ECQ) is one of the primary tasks in rice production to meet the rising demands of consumers. However, improving grain ECQ without compromising yield faces a great challenge under varied nitrogen (N) supplies. Here, we report the approach to upgrade rice ECQ by native promoter-controlled high expression of a key N-dependent floral and circadian clock regulator Nhd1. The amplification of endogenous Nhd1 abundance alters rice heading date but does not affect the entire length of growth duration, N use efficiency and grain yield under both low and sufficient N conditions. Enhanced expression of Nhd1 reduces amylose content, pasting temperature and protein content while increasing gel consistence in grains. Metabolome and transcriptome analyses revealed that increased expression of Nhd1 mainly regulates the metabolism of carbohydrates and amino acids in the grain filling stage. Moreover, expression level of Nhd1 shows a positive relationship with grain ECQ in some local main cultivars. Thus, intensifying endogenous abundance of Nhd1 is a promising strategy to upgrade grain ECQ in rice production.

Evolution and Genetic Diversity of the Retroviral Envelope in Anamniotes.

Retroviruses are widely distributed in all vertebrates, as are their endogenous forms, endogenous retroviruses (ERV), which serve as "fossil" evidence to trace the ancient origins and history of virus-host interactions over millions of years. The retroviral envelope (Env) plays a significant role in host range determination, but major information on their genetic diversification and evolution in anamniotes is lacking. Here, by incorporating multiple-round in silico similarity search and phylogenomic analysis, more than 30,000 copies of ERV lineages with gamma-type Env (GTE), covalently associated Env, were discovered by searching against all fish and amphibian genomes and transcriptomic assemblies, but no beta-type Env (BTE), noncovalently associated Env, was found. Furthermore, a nine-type classification system of anamniote GTE was proposed by combining phylogenetic and domain/motif analyses. The elastic genomic organization and overall phylogenetic incongruence between anamniotic Env and its neighboring polymerase (Pol) implied that early retroviral diversification in anamniotic vertebrates was facilitated by frequent recombination. At last, host cellular opioid growth factor receptor (OGFr) gene capturing by anamniotic ERVs with GTE was reported for the first time. Overall, our findings overturn traditional Pol genotyping and reveal a complex evolutionary history of anamniotic retroviruses inferred by Env evolution. IMPORTANCE Although the retroviral envelope (Env) protein in amniotes has been well studied, its evolutionary history in anamniotic vertebrates is ambiguous. By analyzing more than 30,000 copies of ERV lineages with gamma-type Env (GTE) in anamniotes, several important evolutionary features were identified. First, GTE was found to be widely distributed among different amphibians and fish. Second, nine types of GTE were discovered and defined, revealing their great genetic diversity. Third, the incongruence between the Env and Pol phylogenies suggested that frequent recombination shaped the early evolution of anamniote retroviruses. Fourth, an ancient horizontal gene transfer event was discovered from anamniotes to ERVs with GTE. These findings reveal a complex evolution pattern for retroviral Env in anamniotes.

Knock out of amino acid transporter gene OsLHT1 accelerates leaf senescence and enhances resistance to rice blast fungus.

Plant amino acid transporters regulate not only long-distance transport and reallocation of nitrogen (N) from source to sink organs, but also the amount of amino acids in leaves hijacked by invading pathogens. However, the function of amino acid transporters in plant defense responses to pathogen infection remains unknown. In this study, we found that the rice amino acid transporter gene OsLHT1 was expressed in leaves and up-regulated by maturation, N starvation, and inoculation of the blast fungus Magnaporthe oryzae. Knock out of OsLHT1 resulted in development stage- and N supply-dependent premature senescence of leaves at the vegetative growth stage. In comparison with the wild type, Oslht1 mutant lines showed sustained rusty red spots on fully mature leaf blades irrespective of N supply levels. Notably, no relationship between the severity of leaf rusty red spots and concentration of total N or amino acids was found in Oslht1 mutants at different developmental stages. Disruption of OsLHT1 altered transport and metabolism of amino acids and biosynthesis of flavones and flavonoids, enhanced expression of jasmonic acid- and salicylic acid-related defense genes, production of jasmonic acid and salicylic acid, and accumulation of reactive oxygen species. OsLHT1 inactivation dramatically prevented the leaf invasion by M. oryzae, a hemi-biotrophic ascomycete fungus. Overall, these results establish a link connecting the activity of an amino acid transporter with leaf metabolism and defense against rice blast fungus.

Unraveling the Strong Fluorescence Enhancement of HPBI Molecules by ZIF-8 Colloidal Suspensions via Adsorption Analysis.

Enhancing the fluorescence of organic dye by colloidal particles is one of the most promising routes to optimize fluorescence detection. However, in addition to metallic particles, which serve as the most frequently used particles and have been found to employ the plasmonic resonance to provide strong fluorescence enhancement, neither new types of colloidal particles nor new fluorescence mechanisms have been intensively explored in recent years. In this work, strongly enhanced fluorescence was observed when 2-(2-hydroxyphenyl)-1H-benzimidazole (HPBI) molecules were simply mixed with zeolitic imidazolate framework-8 (ZIF-8) colloidal suspensions. Moreover, the enhancement factor ΔI = IHPBI+ZIF-8/IHPBI does not increase accordingly with the increasing amount of HPBI. To find out how the strong fluorescence was triggered and affected by the amount of HPBI, multiple techniques were applied to analyze the adsorption behavior. By combining analytical ultracentrifugation with first-principles calculations, we proposed that HPBI molecules were adsorbed onto the surface of ZIF-8 particles coordinatively and electrostatically, depending on the concentration of HPBI molecules. The coordinative adsorption would result in a new kind of fluorescence emitter. The new fluorescence emitters tend to distribute on the outer surface of ZIF-8 particles periodically. The distance between each fluorescence emitter is fixed and much smaller than the wavelength of the excitation light. Thus, it can be concluded that collective spontaneous emission might be triggered.

Association of Dietary Approaches to Stop Hypertension (DASH) diet with self-reported sleep-disordered breathing (SDB): a cross-sectional study from China.

Adherence to the Dietary Approaches to Stop Hypertension (DASH) diet has been associated with sleep quality. However, its relationship with sleep-disordered breathing (SDB) remains unknown. This study aimed to explore the association between the DASH diet and SDB using data from a community-based survey among adults in Suzhou, Eastern China. We conducted a cross-sectional analysis of the Suzhou Food Consumption and Health Survey in 2018-2020. Dietary intake was measured by a validated FFQ. The association between the DASH diet and SDB was estimated by multivariable logistic regression analysis. In addition, subgroup analysis and sensitivity analysis were performed to reinforce our findings. A total of 3939 participants were included in the final analysis. Participants in the upper quintile of the DASH score consumed more fruits, vegetables, nuts and legumes, whole grains, and dairy products, and less Na, red/processed meats, and sweetened beverages. The OR for the highest compared with the lowest quintile of the DASH score was 0·68 (95 % CI 0·52, 0·88; Pfor trend = 0·004) for SDB after multivariable adjustment. Of the eight DASH components, vegetables, nuts and legumes, and dairy products were inversely associated with SDB. The associations were similar in subgroups by age, sex, BMI, smoking, alcohol drinking, hypertension, diabetes and hyperlipidaemia. Adherence to the DASH diet was independently associated with decreased odds of self-reported SDB. Our novel results expand previous findings on diet and sleep and suggest the possibility of improving SDB by enhancing diet quality.

Comorbidities are associated with self-reported sleep-disordered breathing and insomnia: a cross-sectional study from China.

PURPOSE: We aimed to examine the associations of comorbidities with self-reported sleep-disordered breathing (SDB) and insomnia among Chinese adults. METHODS: The study used data from a community-based cross-sectional survey performed in China in 2018-2020. Multivariable logistic regression models were used to analyze the associations of 12 comorbidities with SDB and insomnia. RESULTS: A total of 4329 Han Chinese adults aged ≥ 18 years were enrolled. Of these, 1970 (45.5%) were male, with a median age of 48 years (interquartile range: 34-59). Compared with the participants without any conditions, adjusted ORs for SDB and insomnia for those with ≥ 4 comorbidities were 2.33 (95% CI: 1.58, 3.43, P-trend < 0.001) and 3.89 (95% CI: 2.69, 5.64, P-trend < 0.001), respectively. Seven comorbidities (hypertension, hyperlipidemia, coronary heart disease (CHD), bone and joint disease, neck or lumbar disease, chronic digestive diseases, and chronic urological disease) were positively associated with both SDB and insomnia. Cancer and chronic obstructive pulmonary disease (COPD) were also independently associated with insomnia. Of all comorbidities, cancer was most strongly associated with insomnia (OR = 3.16; 95% CI: 1.78, 5.63; P < 0.001), and CHD was most strongly associated with SDB (OR = 1.77; 95% CI: 1.19, 2.64; P < 0.001). CONCLUSIONS: The findings showed that adults with an increasing number of comorbidities had higher odds for SDB and insomnia, which were independent of sociodemographic and lifestyle factors.

Prospective prescription review system correlated with more rational PPI medication use, better clinical outcomes and reduced PPI costs: experience from a retrospective cohort study.

INTRODUCTION: Proton pump inhibitor (PPI) abuse poses an overwhelming threat to the allocation of medical resources and places a heavy burden on global medical expenses. In this study, we put forward our prospective prescription review system and evaluated the effects of this system on clinical outcomes, rational medication use and costs related to PPIs. METHODS: A retrospective cohort study was conducted in which the included patients were divided into a preintervention group (2019.10-2020.09) and a postintervention group (2020.10-2021.09). To reduce the bias of patients' baseline characteristics, the propensity score matching (PSM) method was employed. The primary endpoints were the incidence of stress ulcers (SUs), the improvement and cure rates of gastrointestinal haemorrhage, the defined daily dose (DDD), the drug utilization index (DUI) and the DDD/100 patient-days. The secondary endpoints included the types of unreasonable medication orders for PPIs, the PPI utilization rate and PPI costs. RESULTS: A total of 53,870 patients were included to evaluate the secondary endpoints, and 46,922 patients were paired by PSM and assessed to evaluate the primary endpoints. The number of PPIs used and PPI costs were significantly lower in the postintervention group than in the preintervention group (P < 0.001). The rationality evaluation results showed that the frequency of PPI use and the number of drug interactions were significantly higher in the preintervention group than in the postintervention group (P < 0.01). The proportion of patients taking oral PPIs was significantly increased in the postintervention group (29.30% vs. 34.56%, p < 0.01). For the utilization of PPIs both for prevention and treatment, the DUI and DDD/100 patient-days were substantially decreased in the postintervention group (P < 0.001 and P < 0.05, respectively). The incidence of SUs in the postintervention group was 44.95%, and that in the preintervention group was 51.93% (p < 0.05). CONCLUSION: The implementation of the prospective prescription review system on rational PPI use correlated with reduced PPI costs, more rational PPI medication use and better clinical outcomes, and this system is worthy of long-term implementation for further improvement of rational drug use.

Family resilience of patients requiring long-term care: A meta-synthesis of qualitative studies.

BACKGROUND: Long-term care of patients with chronic illnesses is an important global public health issue, compromising the well-being of family members and the family functioning. Previous studies have examined the interactive experiences and processes of various systems in the families coping with long-term care stress; however, these studies have not been systematically reviewed and integrated. AIMS: This review aimed to synthesise the existing qualitative evidence on the experiences and processes of family resilience operate in families providing long-term care for patients with chronic illnesses and to provide suggestions for the development of interventions in future studies. MATERIALS & METHODS: We searched databases including PubMed, CINAHL, EMBASE, Web of Science, ProQuest and CNKI from their inception to March 2022. We used the JBI Critical Appraisal Tool for qualitative studies to evaluate the quality of the included studies was evaluated according to. We followed The Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) statement. The results were integrated using the thematic and content analysis method. RESULTS: Fourteen studies from eight countries covering 11 diseases reported on the experiences and coping processes of long-term care families. Based on McCubbin's Resiliency Model of Family Stress, Adjustment and Adaptation (FAAR), five analytical themes were synthesised: stressors (risk factors), family belief system, internal family coping strategies, external support and resilient adaptation indicators; the relationships between themes and subthemes were illustrated. DISCUSSION: This review synthesized qualitative evidence on the experiences and processes of family resilience operate in families providing long-term care. The results of this study found that the cognition and belief of family members regarding dilemmas have a two-way effect and act on the adaptation process of family members. In family adaptation, spirituality, hope, internal and external support are extremely important. In 14 studies, caregivers were from different countries with intercultural differences, but due to less reports on this content, it is difficult to compare the differences or impact that culture or ethnicity may have. CONCLUSIONS: Family resilience plays an important role in coping with stressors associated with the long-term care of a loved one through family belief systems, internal support systems and external support systems. The development of family resilience-based interventions for long-term care families should consider the family as a whole and further construct a multidisciplinary, multilevel and multi-type social support network to enhance family resilience.

Short report: COVID-19 related knowledge, anxiety, and attitude towards the back-to-school arrangement among college students in China: a cross-sectional study.

The coronavirus disease 2019 (COVID-19) pandemic has been assumed to affect mental health of college students. The present cross-sectional study was conducted to examine levels of knowledge and anxiety about COVID-19, as well as attitude towards the back-to-school arrangement among college students in China in May 2020. A total of 716 students (312 males, 404 females) were included. Only 38.1% of the participants showed good knowledge about COVID-19. Moderate and severe anxiety was observed among 7.6% of the students. There were 15.6% of the participants opposing the back-to-school arrangement. Female students had more risk of having anxiety symptoms and negative attitude towards the back-to-school arrangement (p < 0.05). In addition, the level of anxiety was positively associated with the negative attitude towards the back-to-school arrangement (r = 0.11, p < 0.05). We therefore suggest that health education and psychological interventions should be given to college students, especially females and those without health-related backgrounds during the COVID-19 pandemic.

Multiple Infiltration and Cross-Species Transmission of Foamy Viruses across the Paleozoic to the Cenozoic Era.

Foamy viruses (FVs) are complex retroviruses that can infect humans and other animals. In this study, by integrating transcriptomic and genomic data, we discovered 412 FVs from 6 lineages in amphibians, which significantly increased the known set of FVs in amphibians. Among these lineages, salamander FVs maintained a coevolutionary pattern with their hosts that could be dated back to the Paleozoic era, while in contrast, frog FVs were much more likely acquired from cross-species (class-level) transmission in the Cenozoic era. In addition, we found that three distinct FV lineages had integrated into the genome of a salamander. Unexpectedly, we identified a lineage of endogenous FVs in caecilians that expressed all complete major genes, demonstrating the potential existence of an exogenous form of FV outside of mammals. Our discovery of rare phenomena in amphibian FVs has significantly increased our understanding of the macroevolution of the complex retrovirus. IMPORTANCE Foamy viruses (FVs) represent, more so than other viruses, the best model of coevolution between a virus and a host. This study represents the largest investigation so far of amphibian FVs and reveals 412 FVs of 6 distinct lineages from three major orders of amphibians. Besides a coevolutionary pattern, cross-species and repeated infections were also observed during the evolution of amphibian FVs. Remarkably, expressed FVs including a potential exogenous form were discovered, suggesting that active FVs might be underestimated in nature. These findings revealed that the multiple origins and complex evolution of amphibian FVs started from the Paleozoic era.

Emergency hospitalizations for adverse drug events in China: Clinical pharmacists' approach to assessment and categorization.

PURPOSE: Little is known about emergency hospitalizations owing to adverse drug events (ADEs) in Chinese populations. The aim of this study was to identify the types and characteristics of ADEs as well as estimate the length of hospital stay and ADE-related costs in a hospital emergency setting in China. METHODS: This prospective study was conducted in the emergency department of our hospital from April 1, 2017 to December 31, 2019. ADEs of patients admitted to the emergency department were collected by a clinical pharmacist during daily pharmacy rounds. RESULTS: Of 4020 cases admitted to the emergency department, 198 emergency ADE-related hospitalizations (4.93%) were noted, which were classified into certain (n = 0, 0%), probable (n = 122, 61.6%), and possible (n = 76, 38.4%). The ADE was serious in 93.9% of the 198 cases. Ten cases were fatal, and two cases were life-threatening. More than 80% of the emergency ADE-related hospitalization cases were of patients over 60 years. The pharmacological agents implicated in the hospitalizations were oral antiplatelet agents (20.7%), oral hypoglycemic agents (16.7%), insulin (11.1%), and antihypertensive agents (9.1%). The average length of ADE-related hospital stay was 10 (7.0-14.0) days. ADE-related costs ranged from $1684.68 to $4531.35 for each hospitalization. The length of ADE-related hospital stay and associated costs were statistically significant. Most ADEs (n = 146, 73.7%) were preventable. CONCLUSIONS: Most emergency ADE-related hospitalizations in older adults resulted from lack of medication monitoring or inappropriate medication. Improved management of medicines by clinical pharmacists has the potential to reduce ADE-related hospitalizations in older adults in China.

Prevalence and Clinical Significance of Portal Vein Thrombosis in Patients With Cirrhosis and Acute Decompensation.

BACKGROUND & AIMS: Portal vein thrombosis (PVT) is a common and serious complication in patients with cirrhosis. However, little is known about PVT in patients with cirrhosis and acute decompensation (AD). We investigated the prevalence and clinical significance of PVT in nonmalignant patients with cirrhosis and AD. METHODS: We performed a retrospective study of 2 cohorts of patients with acute exacerbation of chronic liver disease who participated in the Chinese AcuTe on CHronic LIver FailurE study, established by the Chinese Chronic Liver Failure Consortium, from January 2015 through December 2016 (n = 2600 patients) and July 2018 through January 2019 (n = 1370 patients). We analyzed data on the prevalence, clinical manifestations, and risk factors of PVT from 2826 patients with cirrhosis, with and without AD. RESULTS: The prevalence of PVT in patients with cirrhosis and AD was 9.36%, which was significantly higher than in patients with cirrhosis without AD (5.24%) (P = .04). Among patients with cirrhosis and AD, 63.37% developed PVT recently (the first detected PVT with no indication of chronic PVT). Compared with patients without PVT, a significantly higher proportion of patients with PVT had variceal bleeding (47.33% vs 19.63%; P < .001) and patients with PVT had a significantly higher median serum level of D-dimer (2.07 vs 1.25; P < .001). Splenectomy and endoscopic sclerotherapy were independent risk factors for PVT in patients with cirrhosis and AD. The 1-year mortality rate did not differ significantly between patients with vs without PVT. CONCLUSIONS: In an analysis of data from 2826 patients with cirrhosis, a significantly higher proportion of those with AD had PVT than those without AD. PVT was associated with increased variceal bleeding, which would increase the risk for AD. Strategies are needed to prevent PVT in patients with cirrhosis, through regular screening, to reduce portal hypertension. ClinicalTrials.gov no: NCT02457637 and NCT03641872.

In Situ Metal-Assisted Ligand Modification Induces Mn4 Cluster-to-Cluster Transformation: A Crystallography, Mass Spectrometry, and DFT Study.

Dehydration of (S,S)-1,2-bis(1H-benzo[d]imidazol-2-yl)ethane-1,2-diol (H4 L) to (Z)-1,2-bis(1H-benzo[d]imidazol-2-yl)ethenol) (H3 L') was found to be metal-assisted, occurs under solvothermal conditions (H2 O/CH3 OH), and leads to [MnII 4 (H3 L)4 Cl2 ]Cl2 ⋅5 H2 O⋅5 CH3 OH (Mn4 L4 ) and [MnII 4 (H2 L')6 (µ3 -OH)]Cl⋅4 CH3 OH⋅H2 O (Mn4 L'6 ), respectively. Their structures were determined by single-crystal XRD. Extensive ESI-MS studies on solutions and solids of the reaction led to the proposal consisting of an initial stepwise assembly of Mn4 L4 from the reactants via [MnL] and [Mn2 L2 ] below 80 °C, and then disassembly to [MnL] and [MnL2 ] followed by ligand modification before reassembly to Mn4 L'6 via [MnL'], [MnL'2 ], and [Mn2 L'3 ] with increasing solvothermal temperature up to 140 °C. Identification of intermediates [Mn4 Lx L'6-x ] (x=5, 4, 3, 2, 1) in the process further suggested an assembly/disassembly/in situ reaction/reassembly transformation mechanism. These results not only reveal that multiple phase transformations are possible even though they were not realized in the crystalline state, but also help to better understand the complex transformation process between coordination clusters during "black-box" reactions.

Clinical efficacy and safety of polymyxins based versus non-polymyxins based therapies in the infections caused by carbapenem-resistant Acinetobacter baumannii: a systematic review and meta-analysis.

BACKGROUND: The prevalence of infections due to carbapenem-resistant Acinetobacter baumannii (CRAB) is on the rise worldwide. Polymyxins are considered as last-resort drugs for CRAB infections, but there is still controversy regarding the efficacy and safety of polymyxins based therapies in CRAB infections. The present systematic review was designed to compare the efficacy and safety of polymyxins based therapies versus non-polymyxins based therapies in CRAB infections. METHODS: We performed a systematic literature search in PubMed, Embase, CINAHL, Cochrane Library, and clinicaltrials.gov to identify eligible studies reporting the clinical outcomes of patients with CRAB infections. The meta-analysis employed a random-effects model to estimate the odds ratio (OR) and standardized mean difference (SMD) with 95% confidence interval (CI). The primary outcome was 1-month mortality for any cause. We also examined clinical response, microbiological response, length of stay in hospital, and adverse events. RESULTS: Eleven eligible studies were analyzed (1052 patients in total), including 2 randomized clinical trials. Serious risk of bias was found in 8 out of the 11 studies. There was no statistically significant difference between polymyxins based therapies and non-polymyxins based therapies in 1-month mortality for any cause (OR, 0.95; 95% CI, 0.59 to 1.53), microbiological response (OR, 3.83; 95% CI, 0.90 to 16.29) and length of stay in hospital (SMD, 0.24; 95% CI, - 0.08 to 0.56). The pooled OR of clinical response indicated a significant difference in favor of polymyxin based therapies (OR, 1.99; 95% CI, 1.31 to 3.03). The pooled OR of adverse events showed that non-polymyxins based therapies were associated with fewer adverse events (OR, 4.32; 95% CI, 1.39 to 13.48). CONCLUSION: The performance of polymyxins based therapies was better than non-polymyxin based therapies in clinical response rate and similar to non-polymyxin based therapies in terms of 1-month mortality and microbiological response in treating CRAB infections. Due to the limitations of our study, we cannot draw a firm conclusion on the optimal treatment of CRAB infections, but polymyxins would be a relatively effective treatment for CRAB infections. Adequate and well-designed large scale randomized controlled trials are required to clarify the relative efficacy of polymyxins based and non-polymyxins based therapies.

Elevated Prevalence of Azole-Resistant Aspergillus fumigatus in Urban versus Rural Environments in the United Kingdom.

Azole resistance in the opportunistic pathogen Aspergillus fumigatus is increasing, dominated primarily by the following two environmentally associated resistance alleles: TR34/L98H and TR46/Y121F/T289A. By sampling soils across the South of England, we assess the prevalence of azole-resistant A. fumigatus (ARAf) in samples collected in both urban and rural locations. We characterize the susceptibility profiles of the resistant isolates to three medical azoles, identify the underlying genetic basis of resistance, and investigate their genetic relationships. ARAf was detected in 6.7% of the soil samples, with a higher prevalence in urban (13.8%) than rural (1.1%) locations. Twenty isolates were confirmed to exhibit clinical breakpoints for resistance to at least one of three medical azoles, with 18 isolates exhibiting resistance to itraconazole, 6 to voriconazole, and 2 showing elevated minimum inhibitory concentrations to posaconazole. Thirteen of the resistant isolates harbored the TR34/L98H resistance allele, and six isolates carried the TR46/Y121F/T289A allele. The 20 azole-resistant isolates were spread across five csp1 genetic subtypes, t01, t02, t04B, t09, and t18 with t02 being the predominant subtype. Our study demonstrates that ARAf can be easily isolated in the South of England, especially in urban city centers, which appear to play an important role in the epidemiology of environmentally linked drug-resistant A. fumigatus.

Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery.

Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.).

Phosphorothioate-modified CpG oligodeoxynucleotide (CpG ODN) induces apoptosis of human hepatocellular carcinoma cells independent of TLR9.

Toll-like receptors (TLRs) expressed on cancer cells are closely associated with tumor development. In this study, we investigated the biological functions of the TLR9 ligand, CpG oligodeoxynucleotide (CpG ODN), on TLR9 expressed in the cytoplasm of hepatocellular carcinoma (HCC) cells. In vitro, human HCC cell lines were transfected with phosphorothioate-modified oligodeoxynucleotides TLR9 agonist OND M362 and its negative control ODN M362 ctrl, which inhibited the proliferation of HCC cells by inducing apoptosis without altering the cell cycle. Interestingly, ODN M362 and ODN M362 Ctrl displayed a similar proapoptotic effect on HCC, possibly related to phosphorothioate modification of the structure of CpG ODN. Although both of them resulted in the upregulation of the TLR9 receptor, their effect on HCC apoptosis was independent of TLR9. They also upregulated inflammatory cytokines, but did not activate the NF-κB signaling pathway. Finally, the activities of ODN M362 and ODN M362 Ctrl were demonstrated in nude mice inoculated with HCC cells. These findings suggest that the phosphorothioate-modified TLR9 agonist ODN M362, and its control, elicit antitumor activity in HCC cells and may serve as a novel therapeutic target for HCC therapy.

Loneliness, Living Alone, and Risk of Cardiovascular Disease Among Older Adults in China.

BACKGROUND: Older adults are prone to live alone and feel lonely. The main objective of this study was to assess the associations of loneliness and living alone with cardiovascular disease (CVD) among community-dwelling older individuals in China. METHODS: We conducted a longitudinal analysis on 3 661 participants aged older than 65 years from the latest 2014 and 2018 waves of the Chinese Longitudinal Healthy Longevity Survey. Cox proportional hazards models were used to assess the associations of loneliness and living alone with CVD risk, with adjustment for confounding factors. RESULTS: A total of 616 incident CVD cases were identified during follow-up. Participants who reported feeling lonely experienced a 28% increased risk of developing CVD after adjustment for sociodemographic characteristics, lifestyle factors, and baseline health status (adjusted hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 1.01-1.62; ptrend = .046). In contrast, no significant association was observed between living alone and CVD risk. Subgroup analyses showed that among those individuals who lived alone, often feeling lonely doubled the risk of CVD compared to never being lonely (HR: 2.17, 95% CI: 1.20-3.93; ptrend = .007). CONCLUSIONS: Loneliness was an independent risk factor for CVD among Chinese older adults. Our findings underscore the importance of addressing loneliness in the prevention of CVD among older individuals, especially those who live alone.

Impact of Hydrogen Voiding in Chip-to-Chip Electroless All-Copper Interconnections.

Three-dimensional (3D) integration has become a leading approach in chip packaging. The interconnection density and reliability of micro-bumps in chip stacking are often threatened by high bonding temperatures. The method of building chip-to-chip interconnections by electroless deposition of metal has its distinct merit, while the interfacial defect issue, especially that related to voiding during the merging of opposite sides, remains largely unsolved. In this study, to trace the influencing factors in the voiding, the growth characteristics of the electroless all-copper interconnections were examined by carrying out deposition experiments in a microfluidic channel device. The results show that when the gap between the opposite copper bumps to be electrolessly merged is as low as 10 µm, significant voids appear at the inflow side and the top of the copper bumps because the hydrogen cannot be expelled in time. A finite-element flow model of the plating solution between the chips was established, which showed that the flow rate of the plating solution around the copper bumps was much higher than in the merging gap, causing an uneven supply of reactants. Based on these findings, we proposed two potential solutions, one is to improve the flow mode of the plating solution, and the other is to add the reaction inhibitor, 2,2'-bipyridine. Finally, the combination of these two approaches successfully achieved an improved merging quality of the copper joints.