Chronic kidney disease and cognitive performance: NHANES 2011-2014.

PURPOSE: Previous studies suggest an association between chronic kidney disease (CKD) and cognitive impairment. The purpose of this study was to explore the association between the diverse stages of CKD and the cognitive performance of elderly American adults. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 were used. Multivariate adjusted logistic regression, subgroup analysis, and the restricted cubic spline model were used to assess the associations of CKD stage and estimated glomerular filtration rate (eGFR) with cognitive performance. The measures used to evaluate cognitive function included the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, the Animal Fluency test, and the Digit Symbol Substitution test (DSST). RESULTS: This study included 2234 participants aged ≥ 60 years. According to the fully adjusted model, stages 3-5 CKD were significantly associated with the CERAD test score (OR = 0.70, 95% CI [0.51, 0.97], p = 0.033), the Animal Fluency test score (OR = 0.64, 95% CI [0.48, 0.85], p = 0.005), and the DSST score (OR = 0.60, 95% CI [0.41, 0.88], p = 0.013). In addition, the incidence of poor cognitive function increased with decreasing eGFR, especially for individuals with low and moderate eGFRs. Both the DSST score (p nonlinearity < 0.0001) and the Animal Fluency test score (p nonlinearity = 0.0001) had nonlinear dose-response relationships with the eGFR. However, a linear relationship was shown between the eGFR and CERAD test score (p nonlinearity = 0.073). CONCLUSIONS: CKD, especially stages3-5 CKD, was significantly associated with poor cognitive performance in terms of executive function, learning, processing speed, concentration, and working memory ability. All adults with CKD should be screened for cognitive impairment.

Synergistic Activity and Mechanism of Sanguinarine with Polymyxin B against Gram-Negative Bacterial Infections.

Compounds that potentiate the activity of clinically available antibiotics provide a complementary solution, except for developing novel antibiotics for the rapid emergence of multidrug-resistant Gram-negative bacteria (GNB). We sought to identify compounds potentiating polymyxin B (PMB), a traditional drug that has been revived as the last line for treating life-threatening GNB infections, thus reducing its nephrotoxicity and heterogeneous resistance in clinical use. In this study, we found a natural product, sanguinarine (SA), which potentiated the efficacy of PMB against GNB infections. The synergistic effect of SA with PMB was evaluated using a checkerboard assay and time-kill curves in vivo and the murine peritonitis model induced by Escherichia coli in female CD-1 mice in vivo. SA assisted PMB in accelerating the reduction in bacterial loads both in vitro and in vivo, improving the inflammatory responses and survival rate of infected animals. The subsequent detection of the intracellular ATP levels, membrane potential, and membrane integrity indicated that SA enhanced the bacterial-membrane-breaking capacity of PMB. A metabolomic analysis showed that the inhibition of energy metabolism, interference with nucleic acid biosynthesis, and the blocking of L-Ara4N-related PMB resistance may also contribute to the synergistic effect. This study is the first to reveal the synergistic activity and mechanism of SA with PMB, which highlights further insights into anti-GNB drug development.

Efficacy and safety of compassionate use for rare diseases: a scoping review from 1991 to 2022.

BACKGROUND: Compassionate use is a system that provides patients with expedited access to drugs which has not yet been approved, but currently in clinical trials. The investigational drugs have been authorized for compassionate use in cases involving patients suffered from life-threatening diseases and with no alternative treatments. For instance, patients afflicted with highly heterogeneous rare diseases are eligible for treatment assistance through the compassionate use program. This study aims to investigate the characteristics of compassionate use in the context of rare diseases, evaluate the efficacy and safety of compassionate use for rare diseases, and analyze the marketing approval of investigational drugs. METHODS: The case reports/case series of compassionate use were collected by conducting searches on Embase, PubMed, Web of Science, CNKI and SinoMed, spanning from January 1991 to December 2022. Subsequently, two independent reviewers evaluated these reports. Case reports/case series that met the inclusion criteria and exclusion criteria were enrolled. Information extracted from these reports and series included patients' basic information, the investigational drug's name, its indication, adverse events, treatment outcomes, and other relevant data. RESULTS: A total of forty-six studies were included, encompassing 2079 patients with an average age of 38.1 years. Thirty-nine different drugs were involved in 46 studies. Furthermore, neoplasms emerged as the most common therapeutic area for compassionate use in rare disease management (23/46, 50.0%). Regarding the treatment efficacy, four studies reported successful disease resolution, while 35 studies observed symptom improvement among patients. Conversely, four studies documented no significant effects on patients' diseases. Moreover, one study reported worsened results following compassionate use, while the efficacy was not described in 2 studies. Adverse events were reported in 31 studies (67.4%) because of the compassionate use, while no adverse events occurred in 13 studies (28.3%). In other 2 studies, there was no description about whether treatment-emergent adverse events (TEAEs) were happened. 136 patients (6.5%) had Grade 5 adverse events (death), of which 19 deaths (0.9%) were considered to be related to compassionate use. Furthermore, the investigational drugs in 33 studies (33/46, 71.7%) received new drug approval at the end of January 31, 2023.The time lag from the start of the compassionate use to the formal approval of the investigational drug was 790.5 (IQR 359-2199.3) days. We found that in 11 studies, encompassing 9 different drugs, some compassionate use indications had not received regulatory authorities at the end of January 31, 2023. CONCLUSION: The current status of compassionate use for rare diseases was clarified systematically in this study. Compassionate use of investigational drug is a significant treatment option for rare disease. In general, compassionate use appears to demonstrate favorable efficacy in the context of rare diseases, with a significant proportion of compassionate use drugs subsequently receiving marketing approval. However, the safety of drugs for compassionate use cannot be fully evaluated due to the safety data were not covered in some enrolled studies. Therefore, the establishment of an adverse event reporting system specific to compassionate use is warranted.

Ceftazidime-Avibactam for Carbapenem-Resistant Gram-Negative Bacteria Infections: A Real-World Experience in the ICU.

Purpose: Ceftazidime-avibactam (C-A) is a treatment option for carbapenem-resistant gram-negative bacterial (CR-GNB) infections, but little is known regarding its suitability for the intensive care unit (ICU). The current study aimed to analyze use of C-A for critically ill patients, determine independent predictors of clinical outcome and mortality and explore routine dosages for patients in continuous renal replacement therapy (CRRT). Patients and Methods: A single-center, retrospective and observational study was conducted in critically ill patients receiving different C-A-based therapies for CR-GNB infections in a tertiary teaching hospital in Beijing, China. Demographic data, severity of infection, clinical outcomes and mortality were assessed. The primary and secondary outcome of this study was 90-day all-cause mortality and 14-day clinical response, respectively. Results: A total of 43 patients with CR-GNB infection were enrolled, including 14 (32.6%) patients received C-A monotherapy. C-A monotherapy and combination with other agents did not affect 14-day clinical response or 90-day survival. All-cause mortality at 90-days was 39.5% (17/43). Multivariate Cox analysis showed that concomitant with bloodstream infection was independent risk factors for 90-day mortality and that the time to initiation of C-A and Acute Physiology and Chronic Health Evaluation (APACHE) score was independent predictors of 14-day clinical response. Five CRRT patients who received high-dose C-A therapy (>3.75 g/d) had prolonged survival compared with 5 who received low-dose C-A (<3.75 g/d, p = 0.03). Conclusion: C-A was an effective therapy for severe CR-GNB infections and clinical response correlated with the time of C-A initiation. A dosage >3.75g/d C-A was associated with prolonged survival of CRRT patients. Randomized controlled trials or multicenter studies are needed to confirm these findings.

Erratum to "Identification of anti-Mycobacterium tuberculosis agents targeting the interaction of bacterial division proteins FtsZ and SepFe" [Acta Pharmaceutica Sinica B 13 (2023) 2056-2070].

[This corrects the article DOI: 10.1016/j.apsb.2023.01.022.].

Clinical outcomes and safety of intravenous polymyxin B-based treatment in critically ill patients with carbapenem-resistant Acinetobacter baumannii nosocomial pneumonia.

OBJECTIVES: Polymyxin B (PMB)-based therapy is one of the most important treatments for patients with nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal PMB-based combination regimen has not been well documented. METHODS: In this retrospective study, 111 critically ill patients in the intensive care unit with CRAB nosocomial pneumonia who received intravenous PMB-based therapy between 1 January 2018 and 1 June 2022 were included. The primary outcome was all-cause mortality within 28 days. Cox proportional hazards regression was used to explore risk factors for mortality in the enrolled patients treated with PMB-based regimens and the three most frequent combination regimens. RESULTS: PMB + sulbactam (SB) regimen was significantly associated with a decreased risk of mortality (aHR = 0.10, 95% CI 0.03-0.39; P = 0.001). The proportion of low-dose PMB in PMB + SB regimen (79.2%) was higher than in PMB + carbapenem (61.9%) or tigecycline (50.0%) regimens. In contrast, PMB + carbapenem regimen significantly increased mortality (aHR = 3.27, 95% CI 1.47-7.27; P = 0.004). Although the proportion of high-dose PMB in PMB + tigecycline (17.9%) was higher than in the other two regimens, mortality remained highest (42.9%) and serum creatinine increased significantly. CONCLUSIONS: PMB in combination with SB may be a promising treatment option for patients with CRAB-induced nosocomial pneumonia, as mortality was significantly reduced with low-dose PMB and no increased risk of nephrotoxicity was observed.

Association between bilirubin levels and risk of stroke: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the association between bilirubin levels and stroke risk. DESIGN: Systematic review and meta-analysis, reported in accordance with Meta-analysis Of Observational Studies in Epidemiology guidelines. DATA SOURCES: The PubMed, Embase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure Databases were searched from inception up to 27 February 2022. ELIGIBILITY CRITERIA: Cohort studies assessing the dose-response relationship between bilirubin levels and risk of stroke were eligible for inclusion. There were no language restrictions. DATA EXTRACTION AND SYNTHESIS: All data from eligible studies were collected and assessed by two independent investigators. We generated pooled relative risks (RRs) with 95% CIs. We used a restricted cubic spline model for the dose-response analyses. Subsequent subgroup analyses were conducted according to stroke outcomes, follow-up duration, geographical area and size of the cohort. RESULTS: Nine articles including results from 11 cohort studies with 7835 cases of stroke and 263 596 participants met the inclusion criteria. The summarised RR of stroke comparing the highest and lowest bilirubin level was 0.85 (95% CI 0.72 to 0.99). The dose-response analysis indicated that a 15 µmol/L increment of bilirubin level was associated with an 18% lower risk of stroke (RR=0.82, 95% CI 0.67 to 0.99). For ischaemic stroke, the RR was 0.76 (95% CI 0.58 to 0.99). Significant publication bias was not detected. CONCLUSIONS: Elevated bilirubin levels were associated with a decreased risk of stroke among adults. PROSPERO REGISTRATION NUMBER: CRD42017071497.

Identification of anti-Mycobacterium tuberculosis agents targeting the interaction of bacterial division proteins FtsZ and SepFe.

Tuberculosis (TB) is one of the deadly diseases caused by Mycobacterium tuberculosis (Mtb), which presents a significant public health challenge. Treatment of TB relies on the combination of several anti-TB drugs to create shorter and safer regimens. Therefore, new anti-TB agents working by different mechanisms are urgently needed. FtsZ, a tubulin-like protein with GTPase activity, forms a dynamic Z-ring in cell division. Most of FtsZ inhibitors are designed to inhibit GTPase activity. In Mtb, the function of Z-ring is modulated by SepF, a FtsZ binding protein. The FtsZ/SepF interaction is essential for FtsZ bundling and localization at the site of division. Here, we established a yeast two-hybrid based screening system to identify inhibitors of FtsZ/SepF interaction in M. tuberculosis. Using this system, we found compound T0349 showing strong anti-Mtb activity but with low toxicity to other bacteria strains and mice. Moreover, we have demonstrated that T0349 binds specifically to SepF to block FtsZ/SepF interaction by GST pull-down, fluorescence polarization (FP), surface plasmon resonance (SPR) and CRISPRi knockdown assays. Furthermore, T0349 can inhibit bacterial cell division by inducing filamentation and abnormal septum. Our data demonstrated that FtsZ/SepF interaction is a promising anti-TB drug target for identifying agents with novel mechanisms.

Identification of Potent Zika Virus NS5 RNA-Dependent RNA Polymerase Inhibitors Combining Virtual Screening and Biological Assays.

The Zika virus (ZIKV) epidemic poses a significant threat to human health globally. Thus, there is an urgent need for developing effective anti-ZIKV agents. ZIKV non-structural protein 5 RNA-dependent RNA polymerase (RdRp), a viral enzyme for viral replication, has been considered an attractive drug target. In this work, we screened an anti-infection compound library and a natural product library by virtual screening to identify potential candidates targeting RdRp. Then, five selected candidates were further applied for RdRp enzymatic analysis, cytotoxicity, and binding examination by SPR. Finally, posaconazole (POS) was confirmed to effectively inhibit both RdRp activity with an IC50 of 4.29 µM and the ZIKV replication with an EC50 of 0.59 µM. Moreover, POS was shown to reduce RdRp activity by binding with the key amino acid D666 through molecular docking and site-directed mutation analysis. For the first time, our work found that POS could inhibit ZIKV replication with a stronger inhibitory activity than chloroquine. This work also demonstrated fast anti-ZIKV screening for inhibitors of RdRp and provided POS as a potential anti-ZIKV agent.

Association between loneliness and dementia risk: A systematic review and meta-analysis of cohort studies.

Loneliness has been reported to be associated with an increased risk of dementia; however, the extent of this relationship remains controversial. This study aimed to assess the strength of the relationship between loneliness and dementia using a meta-analysis approach. PubMed, EMBASE, and China National Knowledge Internet databases were systematically searched for potentially included studies from inception up to 17 February 2022. A meta-analysis was performed using a random-effects model to assess pooled relative risks (RRs) and 95% confidence intervals (CIs). A literature search identified 16 cohort studies (published in 15 articles), among which 4,625 dementia cases and 62,345 individuals were selected for further meta-analysis. Loneliness was associated with an increased risk of Alzheimer's disease (AD) (RR: 1.72, 95% CI: 1.32-2.23; P < 0.001) and dementia (RR: 1.23, 95% CI: 1.16-1.31; P < 0.00001). However, no significant association between loneliness and risk of mild cognitive impairment (MCI) (RR: 1.34, 95% CI: 0.97-1.87; P = 0.080) or vascular dementia (VaD) (RR: 1.01, 95% CI: 0.51-1.99; P = 0.973) was observed. Results revealed that loneliness might increase the risk of Alzheimer's disease and dementia. Early interventions that limit loneliness may reduce risk of dementia and Alzheimer's disease.

Evaluating the national system for rare diseases in China from the point of drug access: progress and challenges.

BACKGROUND: There are about 7000 rare diseases worldwide, of which only 5% of the diseases can be treated with medicines, showing that it's important to improve patient access to orphan drugs. Recently, China has actively worked to set up a national system for rare diseases to improve the diagnosis and treatment capabilities and ensure the accessibility of drugs. However, the benefits of the system have yet not to be measured. This study aimed to provide an overview of orphan drug access based on the Compendium of China's First List of Rare Diseases and National Network to Collaborate on Diagnosis and Treatment of Rare Diseases, expecting to map a blueprint for orphan drug access in China. METHODS: Framework of China's national system for rare diseases was summarized. We surveyed the availability and affordability of 79 approved orphan drugs based on the Compendium of China's First List of Rare Diseases in 30 leading provincial institutions from 2017 to 2020. The availability was measured annually at 3 levels (market, hospital and drug), and affordability was reflected by comparing costs of daily defined dose with per capita income of urban and rural residents, with the National Basic Medical Insurance considered. RESULTS: The market availability of orphan drugs in China showed an upward trend. As of 2020, the median hospital-level availability was 41.1% (increased by 1.5 times), highly available drugs increased by 16.5%. There were 64/74 orphan drugs that were affordable to rural/urban residents with the National Basic Medical Insurance considered (an increase of 14.1%), and the urban-rural gap of affordability ratio was narrowed (down by 6.0%). Comprehensive analysis showed the proportions of drugs with better availability and affordability in urban and rural areas by 2020 were 39.4% and 32.3%, respectively, which had increased but were still at a low level. CONCLUSIONS: China's national system for rare diseases has made great progress in orphan drug access, indicating that it's been functioning under the joint reformation of medical treatment, medical insurance and medicines supply. The list of rare diseases will be updated and collaboration in networks will be enhanced to further improve the system.

Calpain Inhibitor Calpeptin Improves Alzheimer's Disease-Like Cognitive Impairments and Pathologies in a Diabetes Mellitus Rat Model.

Diabetes mellitus (DM) has been considered an accelerator of Alzheimer's disease (AD), but the cellular and molecular mechanisms underlying this effect are not fully understood. Here, we attempted to determine the role and regulatory mechanism of calpain in the AD-like cognitive decline and pathological changes in rats caused by DM. In the initial stages, our results verified that DM model rats showed cognitive impairment, as well as a loss of neurons, decreased pericyte marker (PDGFR-ß and α-SMA), and calpain-2 expression and amyloid-ß (Aß) deposition in the hippocampal tissues. In high glucose-induced primary pericytes, the cell apoptotic rate was increased, and cell proliferation was inhibited in a time-dependent manner. The protein level of calpain-2 was also upregulated by HG induction, but the level of calpain-1 did not change with HG treatment, which was also observed in DM model rats. Subsequently, some DM model rats were administered calpeptin, an inhibitor of calpain. Our data revealed that calpeptin treatment significantly suppressed calpain-1 and calpain-2 expression in the hippocampal tissues and effectively improved the cognitive impairments of DM model rats. Neuronal loss, Aß accumulation, pericyte loss, inflammation, and oxidative stress injury in the hippocampal tissues of DM model rats were also partly rescued by calpeptin administration. Our work demonstrated that the calpain inhibitor calpeptin could alleviate DM-induced AD-like cognitive impairments and pathological changes in rats, and this effect may be associated with pericytes. Calpeptin may become a promising drug to treat the AD-like complications of DM.

Screening and Identification of a Novel Anti-tuberculosis Compound That Targets Deoxyuridine 5'-Triphosphate Nucleotidohydrolase.

Tuberculosis (TB) is still a threat to humans worldwide. The rise of drug-resistant TB strains has escalated the need for developing effective anti-TB agents. Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is essential for thymidylate biosynthesis to maintain the DNA integrity. In Mycobacterium tuberculosis, dUTPase provides the sole source for thymidylate biosynthesis, which also has the specific five-residue loop and the binding pockets absent in human dUTPase. Therefore, dUTPase has been regarded as a promising anti-TB drug target. Herein, we used a luminescence-based dUTPase assay to search for the inhibitors target M. tuberculosis dUTPase (Mt-dUTPase) and identified compound F0414 as a potent Mt-dUTPase inhibitor with an IC50 of 0.80 ± 0.09 µM. F0414 exhibited anti-TB activity with low cytotoxicity. Molecular docking model and site-directed mutation experiments revealed that P79 was the key residue in the interaction of Mt-dUTPase and F0414. Moreover, F0414 was shown to have stronger binding with Mt-dUTPase than with Mt-P79A-dUTPase by surface plasmon resonance (SPR) detection. Interestingly, F0414 exhibited insensitivity and weak directly binding on human dUTPase compared with that on Mt-dUTPase. All the results highlight that F0414 is the first compound reported to have anti-TB activity by inhibiting Mt-dUTPase, which indicates the potential application in anti-TB therapy.

Autophagic Flux Detection: Significance and Methods Involved.

Macroautophagy is an important biological process in eukaryotic cells by which longevity proteins, misfolded proteins, and damaged organelles are degraded. The autophagy process consists of three key steps: (1) the formation of autophagosomes; (2) the fusion of the autophagosomes with lysosomes; and (3) the degradation of the contents of autolysosomes. If any of the three steps is impaired, autophagy will not be able to complete its biological function. Dysfunctional or blocked autophagy is closely involved in the pathogenesis of a variety of diseases. The accurate determination of the autophagy activity in vivo and in vitro has become a challenge in the field of autophagy research. At present, the most widely used detection method to determine autophagy activity in mammalian cells is to quantify LC3B in the cells by Western blot, or to observe the formation and changes of autophagosomes and autolysosomes by immunofluorescence and electron microscopy. However, ignoring the dynamic characteristics of autophagy and only evaluating the number of autophagosomes or the presence of LC3B cannot completely reflect the activation or a blockage of the autophagy system, and objectively analyze its real role in the occurrence and development of a disease. For example, the accumulation of autophagosomes and autolysosomes can occur through an increase in substrate to be degraded after the activation of autophagy, or it may be caused by the partial obstruction or blockage of autophagy. In this chapter, new and familiar ways to detect the autophagic flux are methodically summarized to provide researchers with a multi-angled viewpoint.

14-kDa phosphohistidine phosphatase is a potential therapeutic target for liver fibrosis.

Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-shPhpt1 administration significantly attenuates CCl4-induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration, and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis.NEW & NOTEWORTHY PHP14 inhibition via adeno-associated virus (AAV)-mediated gene silencing could potently attenuate carbon tetrachloride (CCl4)-induced liver fibrosis. PHP14 could regulate the migration of macrophages to the site of injury in vivo. PHP14 knockdown in vivo influenced the environment of fibrogenesis and relevant signaling pathways, subsequently affecting myofibroblast activation.