The prevalence of frailty among patients with metabolic syndrome: a systematic review and meta-analysis.

Background: Growing evidence shows that metabolic syndrome and frailty are significantly associated. Screening and assessing frailty in patients with metabolic syndrome is important to help improve their clinical outcomes and quality of life. Therefore, understanding the prevalence of frailty in patients with metabolic syndrome is the first critical step, however, the prevalence reported in the literature varies widely.Aim: To pool the overall prevalence of frailty among patients with metabolic syndrome.Design: Systematic review and meta-analysis.Methods: The Cochrane Library, PubMed, Web of Science, Embase, APA PsycINFO, Scopus, CINAHL Complete, CNKI, Wan Fang, SinoMed, and VIP databases were searched from the inception to March 6, 2024. Statistical analysis was performed using STATA15 software. The prevalence was pooled using the random-effects model. The sources of heterogeneity were investigated by using meta-regression and subgroup analyses.Results: A total of 22 original studies published between 2007 and 2023 were included in this systematic review and meta-analysis, involving 19,921 metabolic syndrome patients. The prevalence of frailty and pre-frailty among patients with metabolic syndrome was 20% (95% CI: 16% to 25%, I2 = 99.44%) and 45% (95% CI: 36% to 53%, I2 = 99.20%). Subgroup analyses revealed differences in prevalence by frailty instruments, geographic regions, study settings, publication years, study quality, study design, and different components of metabolic syndrome.Conclusions: This systematic review and meta-analysis showed the high prevalence of frailty and pre-frailty in patients with metabolic syndrome. In the future, more high-quality longitudinal studies and exploration of other potential demographic characteristics that may influence frailty are needed to understand more information on frailty in patients with metabolic syndrome.

Microwave-assisted atmospheric alkaline leaching process and leaching kinetics of rare earth melt electrolysis slag.

This study focuses on the difficulty of converting fluorinated rare earth elements into hydroxylated rare earth elements in rare earth melt electrolysis slag (RMES) and proposes the use of a microwave-assisted atmospheric alkaline leaching method for the treatment of RMES. The leaching behavior of RMES under microwave-assisted atmospheric alkaline leaching was studied, and the optimal reaction conditions were determined. Under the conditions of a reaction temperature of 150 °C, initial NaOH concentration of 60 %, NaOH-to-slag mass ratio of 4:1, microwave power of 700 W, reaction time of 120 min, and stirring speed of 300 r/min, the conversion rate of fluorinated rare earths reached 99.17 %. The apparent rate equation of the microwave-assisted atmospheric alkaline leaching process was obtained by leaching kinetic analysis, and the apparent activation energy under this process was calculated to be 54.872 kJ/mol, which was 12.458 kJ/mol lower than that achieved when conventional heating was used for leaching (67.33 kJ/mol).

SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer.

The androgen receptor signaling inhibitor (ARSI) enzalutamide (Enz) has shown critical efficacy in the treatment of advanced prostate cancer (PCa). However, the development of drug resistance is a significant factor contributing to mortality in PCa patients. We aimed to explore the key mechanisms of Enz-resistance. Through analysis of GEO databases, we identified SLC4A4 as a novel driver in Enz resistance. Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-κB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. Hence, our results suggest that targeting SLC4A4 could be a promising therapeutic strategy for Enz resistance. STATEMENT OF SIGNIFICANCE: SLC4A4 is a novel driver of enzalutamide resistance.

Metabolomics unveil key pathways underlying the synergistic activities of aztreonam and avibactam against multidrug-resistant Escherichia coli.

PURPOSE: Aztreonam/avibactam is effective against serious infections caused by Gram-negative bacteria including Enterobacterales harboring metallo-ß-lactamases. While the utility of this combination has been established in vitro and in clinical trials, the purpose of this study is to enhance our understanding of the underlying mechanism responsible for their activities through metabolomic profiling of a multidrug-resistant Escherichia coli clinical isolate. METHODS: Metabolomic analyses of time-dependent changes in endogenous bacterial metabolites in a clinical isolate of a multidrug-resistant E. coli treated with aztreonam and avibactam were performed. E. coli metabolomes were compared at 15 min, 1 h and 24 h following treatments with either avibactam (4 mg/L), aztreonam (4 mg/L), or aztreonam (4 mg/L) + avibactam (4 mg/L). RESULTS: Drug treatment affected 326 metabolites with magnitude changes of at least 2-fold, most of which are involved primarily in peptidoglycan biosynthesis, nucleotide metabolism, and lipid metabolism. The feedstocks for peptidoglycan synthesis were depleted by aztreonam/avibactam combination; a significant downstream increase in nucleotide metabolites and a release of lipids were observed at the three timepoints. CONCLUSION: The findings indicate that the aztreonam/avibactam combination accelerates structural damage to the bacterial membrane structure and their actions were immediate and sustained compared to aztreonam or avibactam alone. By inhibiting the production of crucial cell wall precursors, the combination may have inflicted damages on bacterial DNA.

Small animal PET imaging with the 68Ga-labeled pH (low) insertion peptide-like peptide YJL-4 in a triple-negative breast cancer mouse model.

BACKGROUND: The aim of this study was to prepare a novel 68Ga-labeled pH (low) insertion peptide (pHLIP)-like peptide, YJL-4, and determine its value for the early diagnosis of triple-negative breast cancer (TNBC) via in vivo imaging of tumor-bearing nude mice. The novel peptide YJL-4 was designed using a template-assisted method and synthesized by solid-phase peptide synthesis. After modification with the chelator 1,4,7­triazacyclononane-N,N',N″-triacetic acid (NOTA), the peptide was labeled with 68Ga. Then, the biodistribution of 68Ga-YJL-4 in tumor-bearing nude mice was investigated, and the mice were imaged by small animal positron emission tomography (PET). RESULTS: The radiochemical yield and radiochemical purity of 68Ga-YJL-4 were 89.5 ± 0.16% and 97.95 ± 0.06%, respectively. The biodistribution of 68Ga-YJL-4 in tumors (5.94 ± 1.27% ID/g, 6.72 ± 1.69% ID/g and 4.54 ± 0.58% ID/g at 1, 2 and 4 h after injection, respectively) was significantly greater than that of the control peptide in tumors at the corresponding time points (P < 0.01). Of the measured off-target organs, 68Ga-YJL-4 was highly distributed in the liver and blood. The small animal PET imaging results were consistent with the biodistribution results. The tumors were visualized by PET at 2 and 4 h after the injection of 68Ga-YJL-4. No tumors were observed in the control group. CONCLUSIONS: The novel pHLIP family peptide YJL-4 can adopt an α-helical structure for easy insertion into the cell membrane in an acidic environment. 68Ga-YJL-4 was produced in high radiochemical yield with good stability and can target TNBC tissue. Moreover, the strong concentration of radioactive 68Ga-YJL-4 in the abdomen does not hinder the imaging of early TNBC.

CRISPR genome-wide screening identifies PAK1 as a critical driver of ARSI cross-resistance in prostate cancer progression.

Next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide (Enza) and darolutamide (Daro), are initially effective for the treatment of advanced prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). However, patients often relapse and develop cross-resistance, which consequently makes drug resistance an inevitable cause of CRPC-related mortality. By conducting a comprehensive analysis of GEO datasets, CRISPR genome-wide screening results, ATAC-seq data, and RNA-seq data, we systemically identified PAK1 as a significant contributor to ARSI cross-resistance due to the activation of the PAK1/RELA/hnRNPA1/AR-V7 axis. Inhibition of PAK1 followed by suppression of NF-κB pathways and AR-V7 expression effectively overcomes ARSI cross-resistance. Our findings indicate that PAK1 represents a promising therapeutic target gene for the treatment of ARSI cross-resistant PCa patients in the clinic. STATEMENT OF SIGNIFICANCE: PAK1 drives ARSI cross-resistance in prostate cancer progression.

Interventions based on salutogenesis for older adults: An integrative review.

AIMS: To synthesize the evidence of interventions based on salutogenesis for older adults. BACKGROUND: With the increasing tendency of global ageing and the progression of 'healthy ageing', salutogenesis has been adopted as a framework of health promotion for older adults. DESIGN: An integrative review following PRISMA guidelines. DATA SOURCES: Seven databases including PubMed, Cochrane Library, Web of Science, Embase, Scopus, PsycINFO and CINAHL Plus were systematically searched on 29 September 2022 and updated on 18 July 2023. RESULTS: Eighteen eligible studies were included in this review. Salutogenic-based interventions fell into three main categories: dialogue-based, health education courses based, and goal setting and achievement based. The intervention doses: length ranged from 4 weeks to 2 years, with most (n = 12) within 12 weeks; the duration of each session ranged from 30 to 150 min, with the majority (n = 7) within 1 h; the frequency ranged from five times weekly to three times in 10 months, and in six studies was once a week. Intervention providers were mostly multidisciplinary teams, while in four studies were nurses only. Most of the studies reported that salutogenic-based interventions could improve older adults' sense of coherence, quality of life, self-efficacy, self-management, meaning of life and mental health. CONCLUSIONS: This review synthesized the interventions based on salutogenesis for older adults, including salutogenesis application, intervention and its doses, intervention settings and providers, and intervention effects. Future research on the effectiveness of the intervention, the optimal dose of the intervention and the underlying mechanisms are still necessary to understand salutogenic-based interventions. NO PATIENT OR PUBLIC CONTRIBUTION: Not apply as it's a review paper. RELEVANCE TO CLINICAL PRACTICE: Salutogenic-based intervention is effective for older adults in different scenarios to improve their health outcomes. Nurses play a key role in salutogenic-based interventional programs and thus should be essential personnel as the intervention provider.

Simultaneous Determination of Levo-tetrahydropalmatine and Naltrexone in Rat Plasma by LC-MS/MS and its Application in a Pharmacokinetic Study.

BACKGROUND: Levo-tetrahydropalmatine and low-dose naltrexone are used in association with reducing cocaine-related cravings, but there are no analytical methods for the quantitative simultaneous analysis of this drug combination. OBJECTIVE: A highly selective and sensitive LC-MS/MS assay was developed and validated to simultaneously quantify l-THP and naltrexone. The analytical method for l-THP offers improved sensitivity compared to previously published methods. METHODS: The product ion transitions of l-THP and naltrexone were 357.0→193.0 and 342.2→324.1, respectively. Chromatographic separations were performed using a BEH-C18 column by an isocratic elution mode with acetonitrile and 0.1% formic acid in water containing 3 mM ammonium acetate. L-THP and naltrexone were extracted from rat plasma using a liquidliquid extraction method. RESULTS: For l-THP and naltrexone, the assay displayed good linear response over a concentration range of 0.5-1000 ng/mL and 0.25-500 ng/mL, respectively. The intra-day accuracy of the method for l-THP and naltrexone was 93.8-101% with a precision (%CV) of 2.43-8.15% and 93.4-108% with a precision of 3.47-8.22%. The inter-day accuracy for l-THP and naltrexone was 91.2-102% with a CV of 2.46-8.06% and 91.5-97.8% with a CV of 3.29-8.92%, respectively. CONCLUSION: The assay has been used for pharmacokinetic studies of l-THP and naltrexone in the rat.

Mechanism of inactivation of Aspergillus flavus spores by dielectric barrier discharge plasma.

Dielectric barrier discharge plasma (DBDP) displays strong against fungal spores, while its precise mechanism of spore inactivation remains inadequately understood. In this study, we applied morphological, in vivo and in vitro experiments, transcriptomics, and physicochemical detection to unveil the potential molecular pathways underlying the inactivation of Aspergillus flavus spores by DBDP. Our findings suggested that mycelium growth was inhibited as observed by SEM after 30 s treatment at 70 kV, meanwhile spore germination ceased and clustering occurred. It led to the release of cellular contents and subsequent spore demise by disrupting the integrity of spore membrane. Additionally, based on the transcriptomic data, we hypothesized that the induction of spore inactivation by DBDP might be associated with downregulation of genes related to cell membranes, organelles (mitochondria), oxidative phosphorylation, and the tricarboxylic acid cycle. Subsequently, we validated our transcriptomic findings by measuring the levels of relevant enzymes in metabolic pathways, such as superoxide dismutase, acetyl-CoA, total dehydrogenase, and ATP. These physicochemical indicators revealed that DBDP treatment resulted in mitochondrial dysfunction, redox imbalance, and inhibited energy metabolism pathways. These findings were consistent with the transcriptomic results. Hence, we concluded that DBDP accelerated spore rupture and death via ROS-mediated mitochondrial dysfunction, which does not depend on cell membranes.

Preparation of chitosan mesoporous membrane/halloysite composite for efficiently selective adsorption of Al(III) from rare earth ions solution through constructing pore structure on substrate.

The removal of impurity Al(III) from rare earth ion solution by selective adsorption method was one of the challenging tasks. Herein, calcination and acid dissolution treatment were used to construct the pore structure for the halloysite substrate (Hal-650-H) and provide conditions for the formation of the chitosan mesoporous membrane to prepare composite (Hal-H-2CS). The selective adsorption properties and mechanism of the Hal-H-2CS for Al(III) in the rare earth ion solution were studied. The results showed that the formation of mesoporous structures for chitosan provided abundant sites for the adsorption of Al(III). Hal-H-2CS showed remarkable selective adsorption properties for Al(III) in a wide pH range and the binary mixtures with high content of Al(III) or La(III). The maximum adsorption capacity of Al(III) was 106 mg/g, while the adsorption capacity of La(III) was only 1.41 mg/g at pH 4.0. In addition, the Hal-H-2CS exhibited excellent regeneration and structural stability. The remarkable selective properties of Hal-H-2CS was achieved by the synergistic effect between chitosan mesoporous membrane and Hal-650-H, the main adsorption sites were the OH, NH2, CONH2 of chitosan and the oxygen sites of the Hal-650-H. This work provides a new strategy for the design and preparation of outstanding selective adsorbent for Al(III).

The Promoting Mechanism of the Sterile Fermentation Filtrate of Serratia odorifera on Hypsizygus marmoreus by Means of Metabolomics Analysis.

Hypsizygus marmoreus has become one of the most popular edible mushrooms due to its high nutritional and economic value. Previous researchers found that Serratia odorifera could promote the growth of H. marmoreus by producing and secreting some of its inducers. However, the specific mechanism of action was still unclear. In this study, we found that the exogenous addition of sterile fermentation filtrate (HZSO-1), quorum sensing (QS) signaling molecules, 3-oxo-C6-HSL, cyclo(Pro-Leu), and cyclo(Tyr-Leu) could significantly promote the growth of H. marmoreus, increase the number of clamp junctions, and the diameter of mycelium (p < 0.05). In addition, non-targeted metabolomic analysis revealed that 706 metabolites were detected in the treated group. Of these, 307 metabolites were significantly different (p < 0.05). Compared with the control, 54 and 86 metabolites were significantly increased and decreased in the HZSO-1 group, respectively (p < 0.05). We speculate that the sterile fermentation filtrate of S. odorifera could mediate the carbohydrate and amino acid metabolism of H. marmoreus by influencing the pentose phosphate pathway (PPP) to increase the energy supply for the growth and development of the mycelium. The above results will further reveal the growth-promoting mechanism of S. odorifera on H. marmoreus.

Metabolomics reveals the mechanism of action of meropenem and amikacin combined in the treatment of Pseudomonas aeruginosa.

The treatment of Pseudomonas aeruginosa infection often involves the combined use of ß-lactam and aminoglycoside antibiotics. In this study, we employed metabolomic analysis to investigate the mechanism responsible for the synergistic activities of meropenem/amikacin combination therapy against multidrug-resistant P. aeruginosa strains harboring OXA-50 and PAO genes. Antibiotic concentrations for meropenem (2 mg/L) monotherapy, amikacin (16 mg/L) monotherapy, and meropenem/amikacin (2/16 mg/L) combination therapy were selected based on clinical breakpoint considerations. Metabolomic analysis revealed significant alterations in relevant metabolites involved in bacterial cell membrane and cell wall synthesis within 15 min of combined drug administration. These alterations encompassed various metabolic pathways, including fatty acid metabolism, peptidoglycan synthesis, and lipopolysaccharide metabolism. Furthermore, at 1 h and 4 h, the combination therapy exhibited significant interference with amino acid metabolism, nucleotide metabolism, and central carbon metabolism pathways, including the tricarboxylic acid cycle and pentose phosphate pathway. In contrast, the substances affected by single drug administration at 1 h and 4 h demonstrated a noticeable reduction. Meropenem/amikacin combination resulted in notable perturbations of metabolic pathways essential for survival of P. aeruginosa, whereas monotherapies had comparatively diminished impacts.

Comparative metabolomics reveal key pathways associated with the synergistic activities of aztreonam and clavulanate combination against multidrug-resistant Escherichia coli.

IMPORTANCE: Multidrug-resistant Escherichia coli is a major threat to the health care system and is associated with poor outcomes in infected patients. The combined use of antibiotics has become an important treatment method for multidrug-resistant bacteria. However, the mechanism for their synergism has yet to be explored.

Engineering pedicled vascularized bladder tissue for functional bladder defect repair.

An engineered bladder construct that mimics the structural and functional characteristics of native bladder is a promising therapeutic option for bladder substitution. We previously showed that pedicled vascularized smooth muscle tissue fabricated by grafting smooth muscle cell (SMC) sheets onto an axial capsule vascular bed had the potential for reliable bladder reconstruction. In this study, we investigated the feasibility of buccal mucosa graft (BMG) integration with the pedicled vascularized smooth muscle tissue to generate a full-layer pedicled vascularized bladder construct. BMG transplanted onto vascularized smooth muscle tissue showed good survival and developed into a pedicled vascularized bladder construct with full-layer structures, appropriate thickness, abundant vascularization, and effective barrier function. Then the full-thickness bladder defects were, respectively, reconstructed by pedicled capsule tissue (pedicled capsule group), nonpedicled vascularized bladder construct (nonpedicled construct group), and pedicled vascularized bladder construct (pedicled construct group). The picrosirius red (PSR) staining and immunohistochemistry results showed minimal fibrosis, maximal smooth muscle proportion, and high vascular density in the pedicled construct group. A continuous mucosal layer was observed only in the pedicled construct group. Moreover, morphological and functional studies revealed better bladder compliance and good ductility in the pedicled construct group. Overall, these results suggested that the BMG could be well integrated with vascularized smooth muscle tissue and generated a pedicled, fully vascularized, and structurally organized bladder construct, which facilitated structural remodeling and functional recovery and could become an alternative to bladder reconstruction.

A dual-responsive crimson fluorescent probe for real-time diagnosis of alcoholic acute liver injury.

The polarity and viscosity of the microenvironment are associated with the control of the onset and progression of pathological diseases, including inflammation, immuno-suppression and cancer. If appropriate treatment is neglected, alcoholic acute liver injury (AALI), the initial sign of alcoholic liver diseases, may transform into hepatic lesions. Therefore, it's crucial to create a particular probe to detect AALI swiftly and track its progression. Herein a polarity and viscosity dual-responsive crimson fluorescent probe (PPBI) was designed and developed, which can target mitochondria and lipid droplets. PPBI possesses aggregation-induced emission properties, good photostability and strong anti-interference ability against pH, metal ions, anions and biomolecules. This probe can distinguish cancer cells from normal ones using changes of green and red fluorescence, as well as identify changes in the cellular microenvironment associated with inflammatory and ferroptosis processes. In addition, changes in polarity and viscosity can be amplified by in vivo imaging in a mouse model to monitor alcohol-induced acute liver injury and to effectively detect the course of pharmacological intervention therapy. All the results suggest that PPBI could be a promising real-time fluorescence imaging tool for diagnosis and treatment of acute alcoholic liver injury.

Metabolomics revealed mechanism for the synergistic effect of sulbactam, polymyxin-B and amikacin combination against Acinetobacter baumannii.

Introduction: The emergence of multidrug-resistant (MDR) Acinetobacter baumannii prompts clinicians to consider treating these infections with polymyxin combination. Methods: Metabolomic analysis was applied to investigate the synergistic effects of polymyxin-B, amikacin and sulbactam combination therapy against MDR A. baumannii harboring OXA-23 and other drug resistant genes. The drug concentrations tested were based on their clinical breakpoints: polymyxin-B (2 mg/L), amikacin (16 mg/L), polymyxin-B/amikacin (2/16 mg/L), and polymyxin-B/amikacin/sulbactam (2/16/4 mg/L). Results: The triple antibiotic combination significantly disrupted levels of metabolites involved in cell outer membrane structure including fatty acids, glycerophospholipids, nucleotides, amino acids and peptides as early as 15 min after administration. Amikacin and polymyxin-B alone perturbed a large number of metabolites at 15 min and 1 h, respectively, but the changes in metabolites were short-lived lasting for less than 4 h. In contrast, the combination treatment disrupted a large amount of metabolites beyond 4 h. Compared to the double-combination, the addition of sulbactam to polymyxin-B/amikacin combination produce a greater disorder in A. baumannii metabolome that further confer susceptibility of bacteria to the antibiotics. Conclusion: The metabolomic analysis identified mechanisms responsible for the synergistic activities of polymyxin-B/amikacin/sulbactam against MDR A. baumannii.

Ipsilateral and contralateral patent processus vaginalis in pediatric patients with a unilateral nonpalpable testis.

This study aimed to investigate the incidence of patent processus vaginalis (PPV) in pediatric patients with a unilateral nonpalpable testis and explore the associated factors. From May 2014 to April 2017, 152 boys who were diagnosed with a unilateral nonpalpable testis and underwent laparoscopy in Shanghai Children's Hospital (Shanghai, China) were included in this study. The data were collected and reviewed, and the results were analyzed regarding the age at operation, side, development, and position of the nonpalpable testis. The mean age of the patients was 2.6 (standard deviation: 2.3) years. The testis was absent in 14 cases, nonviable in 81 cases, and viable in 57 cases. The incidence of PPV was 37.5% (57 of 152) on the ipsilateral side and 16.4% (25 of 152) on the contralateral side. The ipsilateral PPV was more prevalent when the nonpalpable testis occurred on the right side ( P < 0.01). Besides, patients with a viable testis had a greater incidence of ipsilateral PPV than those with a nonviable or absent testis ( P < 0.01). Moreover, this rate was the highest when the testis was in the abdominal cavity and the lowest when the testis was in the scrotum (both P < 0.01). However, the incidence of contralateral PPV was independent of all the factors. In conclusion, in children with a nonpalpable testis, the incidence of an ipsilateral PPV was significantly related to the side, development, and position of the testis, while it was independent of these factors on the contralateral side.

A real-world disproportionality analysis of apalutamide: data mining of the FDA adverse event reporting system.

Background: Apalutamide is a new drug class, which is approved to treat prostate cancer (PCa). The aim of our study was to assess the safety profiles of apalutamide in real-world through data mining of the United States Food and Drug Administration Adverse Event Reporting System (FAERS). Method: We included adverse event (AE) reports regarding apalutamide submitted to the FAERS from 2018 quarter 1 (2018Q1) to 2022 quarter 1 (2022Q1). Disproportionality analyses, including reporting odds ratio (ROR), were performed to identify the signals of AEs in patients receiving apalutamide. A signal was detected if the lower limit of the 95% confidence interval (CI) of ROR >1 and at least 3 AEs were reported. Results: The FAERS database documented 4,156 reports regarding apalutamide from 1 January 2018, to 31 March 2022. A total of 100 significant disproportionality preferred terms (PTs) were retained. Frequently observed AEs in patients receiving apalutamide included rash, fatigue, diarrhea, hot flush, fall, weight decreased, hypertension. The most significant system organ class (SOC) was "skin and subcutaneous tissue disorders", which mainly consisted of dermatological adverse events (dAEs). The additional AEs observed with the significantly signal contain lichenoid keratosis, increased eosinophil count, bacterial pneumonia, pulmonary tuberculosis, hydronephrosis. Conclusion: Our findings provide valuable evidence for apalutamide safety profile in the real-world, which could help clinicians and pharmacists to enhance their vigilance and improve the safety of apalutamide in clinical practice.

The role of frailty, social networks, and depression in self-neglect in an older Chinese population: A cross-sectional descriptive study.

OBJECTIVES: To identify the role of frailty, social networks, and depression in self-neglect in an older Chinese population. METHODS: The study was conducted in 521 older adults recruited from four community healthcare centers in a district in Beijing, China. Participants were investigated by a set of questionnaires. RESULTS: Frailty (ß=0.150, p=0.759) was not associated with self-neglect of older adults. Social isolation (ß=1.980, p<0.001) and depression (ß=3.606, p<0.001) were both factors associated with self-neglect in older adults. CONCLUSION: Management of depression and improvement of social networks of older adults should be incorporated into interventional strategies to effectively control self-neglect. Understanding self-neglect and its associated factors will ultimately contribute to the intervention development and well-being of older adults.

Physiologically-based pharmacokinetic modeling to inform dosing regimens and routes of administration of rifampicin and colistin combination against Acinetobacter baumannii.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to major antibiotics such as penicillin, cephalosporin, fluoroquinolone and aminoglycoside, and has become a significant nosocomial pathogen. The efficacy of rifampicin and colistin combination against CRAB could be dependent on the administration routes and drug concentrations at the site of infection. OBJECTIVE: The objective is to predict drug disposition in biological tissues. Treatment efficacy is extrapolated by assessing respective pharmacodynamic (PD) indices, as well as parameters associated with the emergence of resistance. METHODS: Physiologically-based pharmacokinetic models of rifampicin and colistin were utilized to predict tissue exposures. Dosing regimens and administration routes for combination therapy were evaluated in terms of in vitro antimicrobial susceptibility of A. baumannii associated with targeted PD indices and resistance parameters. RESULTS: Simulated exposures in blood, heart, lung, skin and brain were consistent with reported penetration rates. The results demonstrated that a combination of colistin and rifampicin using conventional intravenous (i.v.) doses could achieve effective exposures in the blood and skin. However, for lung infections, colistin by inhalation would be required due to low lung penetration from intravenous route. Inhaled colistin alone provided good PD coverage but this practice could encourage the emergence of additional resistance which may be overcome by a combination regimen that includes inhaled rifampicin. CONCLUSION: This in silico extrapolation provides valuable information on dosing regimens and routes of administration against CRAB infections in specific tissues. The PBPK modeling approach could be a non-invasive way to inform therapeutic benefits of combination antimicrobial therapy.