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ABSTRACT Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-β-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-β-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.

Abstract Background Nonsecretory multiple myeloma (NSMM) is a rare type of multiple myeloma (MM). Few studies have described the clinical features and outcomes of NSMM in novel agents. Additionally, the prognostic characteristics have remained controversial in recent years. Purpose To investigate the clinical and prognostic features of NSMM and explore the prognostic value of involved free light chain (FLC) levels in NSMM patients in the Chinese population. Methods We retrospectively enrolled 176 newly diagnosed NSMM cases between January 2005 and December 2021 from 19 clinical centers in China. The control group was selected using a 1:4 propensity score matching technique of newly diagnosed secretory MM, with age, sex and diagnosis time as the matching variables. Results The median age of NSMM patients was 60 years, and 22.6% of patients were classified as ISS stage 3. The ORR of the NSMM patients was 87.4%, and the CR was 65.8%. Compared to the matched secretory MM patients, more NSMM patients achieved CR after first-line treatment (65.8% vs. 36%, p = 0.000). The ORR of first-line treatment was not significantly different between NSMM and secretory MM (89.45% vs. 84.7%, p = 0.196). The first-line PFS was 27.5 m and 23 m (p = 0.063), and the median OS was 81 m and 70 months (p = 0.401). However, for CR-achieved NSMM and CR-not-achieved NSMM patients, the median PFS was 37 m vs. 16 m (p = 0.021), while the median OS showed no difference (107 m vs. 87 m, p = 0.290). In multivariate analysis, the significant factors for PFS were age ≥ 65 and ISS-3. ISS-3 was the only independent prognostic factor of OS. The iFLC ≥ 50 mg/L group had a high ORR of 97.3%, and the median PFS and OS were 48 m and NR, respectively. Compared to the matched secretory MM, the iFLC ≥ 50 mg/L group also showed more CR and longer OS (NR vs. 70 m, p = 0.006) and PFS (48 m vs. 23 m, p = 0.003). Conclusions Our results revealed that Chinese NSMM patients are younger and have a higher CR but not superior survival. The subgroup of NSMM patients with iFLC ≥ 50 mg/L had better outcomes than secretory MM.

Abstract Recent studies have identified DNA replication stress as an important feature of advanced prostate cancer (PCa). The identification of biomarkers for DNA replication stress could therefore facilitate risk stratification and help inform treatment options for PCa. Here, we designed a robust machine learning-based framework to comprehensively explore the impact of DNA replication stress on prognosis and treatment in 5 PCa bulk transcriptomic cohorts with a total of 905 patients. Bootstrap resampling-based univariate Cox regression and Boruta algorithm were applied to select a subset of DNA replication stress genes that were more clinically relevant. Next, we benchmarked 7 survival-related machine-learning algorithms for PCa recurrence using nested cross-validation. Multi-omic and drug sensitivity data were also utilized to characterize PCa with various DNA replication stress. We found that the hyperparameter-tuned eXtreme Gradient Boosting model outperformed other tuned models and was therefore used to establish a robust replication stress signature (RSS). RSS demonstrated superior performance over most clinical features and other PCa signatures in predicting PCa recurrence across cohorts. Lower RSS was characterized by enriched metabolism pathways, high androgen activity, and a favorable prognosis. In contrast, higher RSS was significantly associated with TP53, RB1, and PTEN deletion, exhibited increased proliferation and DNA replication stress, and was more immune-suppressive with a higher chance of immunotherapy response. In silico screening identified 13 potential targets (e.g. TOP2A, CDK9, and RRM2) from 2249 druggable targets, and 2 therapeutic agents (irinotecan and topotecan) for RSS-high patients. Additionally, RSS-high patients were more responsive to taxane-based chemotherapy and Poly (ADP-ribose) polymerase inhibitors, whereas RSS-low patients were more sensitive to androgen deprivation therapy. In conclusion, a robust machine-learning framework was used to reveal the great potential of RSS for personalized risk stratification and therapeutic implications in PCa.

Abstract It is challenging to match the mutual interactions between implant and host because the biomaterials usually cannot actively adjust their performance to the changing microenvironment. Surface potential is one of the critical factors affecting the bioactivity of biomaterials, but it is difficult to be directly controlled in vivo. Magnetic stimulation has attracted much attention due to its deep penetrability, good reliability, and convenient operability. Here, titanium dioxide (TiO2) nanotubes and Terfenol‐D/P(VDF‐TrFE) composite film are prepared by anodic oxidation and solution casting methods on opposite sides of a titanium sheet, respectively. Terfenol‐D magnetostrictive microparticles deform under a magnetic field, generating surface potential on the P(VDF‐TrFE) piezoelectric matrix through magneto‐electric coupling. Correspondingly, equal opposite charges are induced on the surface of TiO2 nanotubes. Stem cells cultured on TiO2 nanotubes show that cell adhesion, proliferation, and differentiation abilities can be regulated by magnetic strength, which correlates with the absorption of charged proteins. Therefore, a cascade coupling of magnetic, mechanical, electric, biochemical, and cellular effects is established. This work demonstrates the feasibility of regulating the bioactivity of biomaterials in vivo through a magnetic field.

Inflammasome molecules make up a family of receptors that typically function to initiate a proinflammatory response upon infection by microbial pathogens. Dysregulation of inflammasome activity has been linked to unwanted chronic inflammation, which has also been implicated in certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and related animal models. Classical inflammasome activation-dependent events have intrinsic and extrinsic effects on both innate and adaptive immune effectors, as well as resident cells in the target tissue, which all can contribute to an autoimmune response. Recently, inflammasome molecules have also been found to regulate the differentiation and function of immune effector cells independent of classical inflammasome-activated inflammation. These alternative functions for inflammasome molecules shape the nature of the adaptive immune response, that in turn can either promote or suppress the progression of autoimmunity. In this review we will summarize the roles of inflammasome molecules in regulating self-tolerance and the development of autoimmunity.

Background: Cardiovascular implantable electronic devices (CIED) are more and more widely used in the clinical treatment of cardiovascular diseases. However, CIED implantation may also result in a variety of physical, psychological, and social problems among patients. To help patients adapt to life after CIED implantation, it is important to know patients’ needs from their perspectives. Explore the needs of CIED patients from their perspectives to guide healthcare providers to improve their quality of life. Methods: PubMed, Web of Science, Embase, the Cochrane Library, CNKI, the VIP database, the Wanfang database, and the China Biomedical Literature database were searched for qualitative studies on the experience of patients with CIED dating from January 2000 to August 2022. The quality of each article was evaluated according to the 2016 edition of the Joanna Briggs Institute Evidence-Based Health Care Center Qualitative Research Quality Evaluation Criteria and an integrative meta-synthesis was undertaken. Results: A total of 18 documents were included, and 111 categories were extracted. Analysis of the data resulted in the identification of 3 themes and 12 subthemes. The first theme, Equipment Symbiosis, included “Mixed feelings about the device as part of the body”, “Mixed feelings about the patient’s role”, and “Mixed feelings about an electrical stimulus”. The second theme, External Support, included “Husband and wife relationship damaged”, “Eager to participate, unwilling to be overprotected”, “Want to return to work but are forced to leave”, and “Information supply and demand mismatch”. The third theme, Self-coping, included “How to face a doctor”, “How to deal with activity restrictions”, “How to face yourself”, “How to face the future”, and “How to face death”. Conclusions: Healthcare providers need to accelerate technological innovation and clinical adoption of CIED. Additionally, healthcare providers need to establish a diverse support system led by medical staff, with family members, peers, and society working together, and improve CIEDs remote monitoring to help patients improve their quality of life.

Purpose: Increasing evidence has elucidated the significance of lipid metabolism in predicting therapeutic efficacy. Obviously, a systematic analysis of lipid metabolism characterizations of gastric cancer (GC) needs to be reported.Experimental design: Based on two proposed computational algorithms (TCGA-STAD and GSE84437), the lipid metabolism characterization of 367 GC patients and its systematic relationship with genomic characteristics, clinicopathologic features, and clinical outcomes of GC were analyzed in our study. Differentially expressed genes (DEGs) were identified based on the lipid metabolism cluster. At the same time, we applied single-factor Cox regression and random forest to screen signature genes to construct a prognostic model, namely, the lipid metabolism score (LMscore). Next, we deeply explored the predictive value of the LMscore for GC. To verify the specific changes in lipid metabolism, a total of 90 serum, 30 tumor, and non-tumor adjacent tissues from GC patients, were included for pseudotargeted metabolomics analysis via SCIEX triple quad 5500 LC-MS/MS system.Results: Five lipid metabolism signature genes were identified from a total of 3,104 DEGs. The LMscore could be a prognosticator for survival in different clinicopathological GC cohorts. As well, the LMscore was identified as a predictive biomarker for responses to immunotherapy and chemotherapeutic drugs. Additionally, significant changes in sphingolipid metabolism and sphingolipid molecules were discovered in cancer tissue from GC patients by pseudotargeted metabolomics.Conclusion: In conclusion, multivariate analysis revealed that the LMscore was an independent prognostic biomarker of patient survival and therapeutic responses in GC. Depicting a comprehensive landscape of the characteristics of lipid metabolism may help to provide insights into the pathogenesis of GC, interpret the responses of gastric tumors to therapies, and achieve a better outcome in the treatment of GC. In addition, significant alterations of sphingolipid metabolism and increased levels of sphingolipids, in particular, sphingosine (d16:1) and ceramide, were discovered in GC tissue by lipidome pseudotargeted metabolomics, and most of the sphingolipid molecules have the potential to be diagnostic biomarkers for GC.

To solve the problem of fatigue failure in fillet welds of traction rod brackets on locomotive bogies of a given model, the cause for failure and the improvement method were studied. The results show that when there is maximum clearance at weld roots, maximum incomplete fusion of sidewalls, maximum incomplete fusion at weld roots, and maximum pores allowable in the ISO 5817 standard, the stress amplitude separately increases by 70~97%, 53~55%, 40~46%, and 19~34%. Despite this, when various types of defects of the maximum size are present in the weld alone, the static and fatigue strengths of fillet welds with a throat depth of 6 mm on the traction rod bracket can still meet the requirements in the UIC615-4 standard. In practical fillet welds, defects including clearance at weld roots, incomplete fusion, and pores are very likely to occur at the same time, which may induce fatigue failure in fillet welds of traction rod brackets within the original design life. According to the size of the frame and the traction rod brackets, a strengthening scheme for increasing the throat depth of fillet welds of traction rod brackets to 8 mm was designed. Calculation results of the strengthening scheme show that for new structures subjected to overall post-weld stress-relief thermal treatments, the maximum stress amplitude decreases by 5~29% when increasing the throat depth of fillet welds from 6 to 8 mm. For structures in service with the throat depth of fillet welds increased from 6 to 8 mm through repair welding, peak residual stress at the weld root after repair welding can reach 383 MPa. Because overall stress-relief thermal treatments cannot be performed on repair-welded structures, the fatigue strength of repair-welded fillet welds cannot meet the requirements of UIC615-4; therefore, local stress-relief treatments have to be performed in the welded zone. The results are of guiding significance for the treatment of locomotives in service and performance improvement of new locomotives and suggest that the current standard is relatively conservative.

Immunotherapies are needed in the clinic that effectively suppress β cell autoimmunity and reestablish long-term self-tolerance in type 1 diabetes. We previously demonstrated that nondepleting anti-CD4 (αCD4) and αCD8α antibodies establish rapid and indefinite remission in recent-onset diabetic NOD mice. Diabetes reversal by coreceptor therapy (CoRT) is induced by suppression of pathogenic effector T cells (Teffs) and the selective egress of T cells from the pancreatic lymph nodes and islets that remain free of infiltration in the long term. Here, we defined CoRT-induced events regulating early Teff function and pancreatic residency, and long-term tolerance. TCR-driven gene expression controlling autoreactive Teff expansion and proinflammatory activity was suppressed by CoRT, and islet T cell egress was dependent on sphingosine-1 phosphate. In both murine and human T cells, CoRT upregulated the Foxo1 transcriptional axis, which in turn was required for suppression and efficient pancreatic egress of Teffs. Interestingly, long-term tolerance induced in late-preclinical NOD mice was marked by reseeding of the pancreas by a reduced CD8+ Teff pool exhibiting an exhausted phenotype. Notably, PD-1 blockade, which rescues exhausted Teffs, resulted in diabetes onset in protected animals. These findings demonstrate that CoRT has distinct intrinsic effects on Teffs that impact events early in induction and later in maintenance of self-tolerance.

Type 1 diabetes (T1D) is widely considered to be a T cell driven autoimmune disease resulting in reduced insulin production due to dysfunction/destruction of pancreatic β cells. Currently, there continues to be a need for immunotherapies that selectively reestablish persistent β cell-specific self-tolerance for the prevention and remission of T1D in the clinic. The utilization of monoclonal antibodies (mAb) is one strategy to target specific immune cell populations inducing autoimmune-driven pathology. Several mAb have proven to be clinically safe and exhibit varying degrees of efficacy in modulating autoimmunity, including T1D. Traditionally, mAb therapies have been used to deplete a targeted cell population regardless of antigenic specificity. However, this treatment strategy can prove detrimental resulting in the loss of acquired protective immunity. Nondepleting mAb have also been applied to modulate the function of immune effector cells. Recent studies have begun to define novel mechanisms associated with mAb-based immunotherapy that alter the function of targeted effector cell pools. These results suggest short course mAb therapies may have persistent effects for regaining and maintaining self-tolerance. Furthermore, the flexibility to manipulate mAb properties permits the development of novel strategies to target multiple antigens and/or deliver therapeutic drugs by a single mAb molecule. Here, we discuss current and potential future therapeutic mAb treatment strategies for T1D, and T cell-mediated autoimmunity.

The sea surface roughness parameterization and the universal stability function are key components of the evaporation duct prediction model based on the Monin–Obukhov similarity theory. They determine the model's performance, which in turn affects the efficiency and accuracy of electromagnetic applications at sea. In this study, we collected layered meteorological and hydrological observation data and preprocessed them to obtain near-surface reference modified refractivity profiles. We then optimized the sea surface roughness parameterization and the universal stability function using particle swarm optimization and simulated annealing algorithms. The results show that the particle swarm optimization algorithm outperforms the simulated annealing algorithm. Compared to the original model, the particle swarm optimization algorithm improved the prediction accuracy of the model by 5.09% under stable conditions and by 9.97% under unstable conditions, demonstrating the feasibility of the proposed method for optimizing the evaporation duct prediction model. Subsequently, we compared the electromagnetic wave propagation path losses under two different evaporation duct heights and modified refractivity profile states, confirming that the modified refractivity profile is more suitable as the accuracy criterion for the evaporation duct prediction model. [ABSTRACT FROM AUTHOR]

Cardiac telerehabilitation is a method that uses digital technologies to deliver cardiac rehabilitation from a distance. It has been shown to have benefits to improve patients’ disease outcomes and quality of life, and further reduce readmission and adverse cardiac events. The outbreak of the coronavirus pandemic has brought considerable new challenges to cardiac rehabilitation, which foster cardiac telerehabilitation to be broadly applied. This transformation is associated with some difficulties that urgently need some innovations to search for the right path. Artificial intelligence, which has a high level of data mining and interpretation, may provide a potential solution. This review evaluates the current application and limitations of artificial intelligence in cardiac telerehabilitation and offers prospects.

Abstract Background As a disease of hematopoietic stem cell, chronic myeloid leukemia (CML) possesses unique biological and clinical features. However, the biologic mechanism underlying its development remains poorly understood. Thus, the objective of the present study is to discuss the effect of cytidine deaminase (CDA) gene silencing on the apoptosis and proliferation of CML K562 cells. Methods CDA mRNA expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzymatic activity of CDA was measured by a nuclide liquid scintillation method. RT-qPCR and Western blot analysis were used to detect CDA mRNA and protein expression. Cell proliferation, apoptosis and cell cycle were measured by CCK-8 assay and flow cytometry. The expression of proteins relevant to cell proliferation, apoptosis and cell cycle was measured by Western blot analysis. Tumor xenografts were implanted in nude mice to verify the effect of CDA silencing on tumor growth in vivo. Results CML and AL patients showed increased mRNA expression and enzymatic activity of CDA. Compared with the blank group, the mRNA and protein expression of CDA in the shRNA-1 and shRNA-2 groups decreased significantly. As a result, the proliferation of K562 cells was inhibited after CDA silencing and the cells were mainly arrested in S and G2 phases, while the apoptosis rate of these cells was increased. In addition, CDA gene silencing in K562 cells led to down-regulated p-ERK1/2, t-AKT, p-AKT and BCL-2 expression and up-regulated expression of P21, Bax, cleaved caspase-3/total caspase-3 and cleaved PARP/total PARP. Finally, CDA gene silencing inhibited tumor growth. Conclusion Our study demonstrated that CDA gene silencing could inhibit CML cell proliferation and induce cell apoptosis. Therefore, CDA gene silencing may become an effective target for the treatment of leukemia.

The frequent occurrences of cyberbullying on social platforms have sparked a great deal of social conflict, and bystander intervention plays a crucial role in preventing the escalation of cyberbullying. This research examines the impact of victim self-disclosure on bystander intervention in cyberbullying through two experimental studies. The studies collected data from March to July of 2022, utilizing a convenience sampling approach to recruit university students as experiment participants. Study 1 recruited 247 valid participants, while Study 2 recruited 522 eligible participants. The results of Study 1 indicate that the perceptible dimensions (frequency, privacy, and valence) of victim self-disclosure impact bystander intervention. Specifically, in a low privacy context, positive self-disclosure increases bystander intervention, while negative self-disclosure does the opposite. The results of Study 2 suggest that the valence of self-disclosure affects bystander intervention through the mediation of victim blaming, with interpersonal distance moderating the impact of victim self-disclosure valence on the extent of victim blaming. This moderated mediation model clarifies the psychological process by which the valence of victim self-disclosure affects bystander intervention. The findings of this study contribute to the understanding of the social psychological process behind bystander intervention, providing a scientific basis and pathway for reducing cyberbullying and fostering a harmonious online environment. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptor 1 (FGFR1) has been reported in gastric cancer to be a prognostic factor. However, miR-497-targeted FGFR1 has not been explored in the carcinogenesis of gastric cancer. The present study intended to revalidate the prognostic significance of FGFR1 in patients with gastric cancer, and the mechanism of miR-497-regulated FGFR1 was investigated in gastric cancer cell proliferation and apoptosis. The messenger RNA (mRNA) and protein levels were assayed by RT-qPCR and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Cell proliferation was analyzed by CCK-8 assay. Annexin V-FITC/PI staining was used to evaluate the apoptosis in AGS and SGC-7901 cells. FGFR1 was frequently up-regulated in gastric cancer tissues and associated with poor overall survival in patients with gastric cancer. Interestingly, FGFR1 loss-of-function resulted in a significant growth inhibition and apoptosis in AGS and SGC-7901 cells. In addition, we found that miR-497 was inhibited in gastric cancer tissues and cell lines, while overexpression of miR-497 could suppress proliferation and induce apoptosis in AGS and SGC-7901 cells. Importantly, bioinformatics analysis and experimental data suggested that FGFR1 was a direct target of miR-497, which could inhibit FGFR1 expression when transfected with miR-497 mimics. Furthermore, we found that overexpression of FGFR1 reversed the growth inhibition and apoptosis of miR-497 mimics in AGS and SGC-7901 cells. These findings suggested that overexpression of miR-497 inhibited proliferation and induced apoptosis in gastric cancer through the suppression of FGFR1.

Type 1 diabetes (T1D) is an autoimmune disease that is generally considered to be T cell-driven. Accordingly, most strategies of immunotherapy for T1D prevention and treatment in the clinic have targeted the T cell compartment. To date, however, immunotherapy has had only limited clinical success. Although certain immunotherapies have promoted a protective effect, efficacy is often short-term and acquired immunity may be impacted. This has led to the consideration of combining different approaches with the goal of achieving a synergistic therapeutic response. In this review, we will discuss the status of various T1D therapeutic strategies tested in the clinic, as well as possible combinatorial approaches to restore β cell tolerance.

The COVID-19 pandemic has brought enormous challenges to both employees and organizations all over the world. Previous studies have found high turnover rates among prison officers since the outbreak of COVID-19. This cross-sectional study aimed to investigate the mediating role of job burnout between job demands and turnover intention, as well as the moderating role of the perceived efficacy in overcoming COVID-19 in Chinese prison officers. In total, 1316 prison officers were recruited to complete an online questionnaire between May 2022 and June 2022 (during the COVID-19 pandemic). The bootstrapping approach was used to assess the moderated mediation model in this study. The results showed that prison officers' job demands were positively associated with their turnover intention. Job burnout mediated the relationship between job demands and turnover intention. Perceived efficacy in overcoming COVID-19 moderated the effect of job burnout on turnover intention. Based on these results, suggestions were provided to reduce the high turnover rate of prison officers in public health events like the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

To solve the problem of fatigue failure in fillet welds of traction rod brackets on locomotive bogies of a given model, the cause for failure and the improvement method were studied. The results show that when there is maximum clearance at weld roots, maximum incomplete fusion of sidewalls, maximum incomplete fusion at weld roots, and maximum pores allowable in the ISO 5817 standard, the stress amplitude separately increases by 70~97%, 53~55%, 40~46%, and 19~34%. Despite this, when various types of defects of the maximum size are present in the weld alone, the static and fatigue strengths of fillet welds with a throat depth of 6 mm on the traction rod bracket can still meet the requirements in the UIC615-4 standard. In practical fillet welds, defects including clearance at weld roots, incomplete fusion, and pores are very likely to occur at the same time, which may induce fatigue failure in fillet welds of traction rod brackets within the original design life. According to the size of the frame and the traction rod brackets, a strengthening scheme for increasing the throat depth of fillet welds of traction rod brackets to 8 mm was designed. Calculation results of the strengthening scheme show that for new structures subjected to overall post-weld stress-relief thermal treatments, the maximum stress amplitude decreases by 5~29% when increasing the throat depth of fillet welds from 6 to 8 mm. For structures in service with the throat depth of fillet welds increased from 6 to 8 mm through repair welding, peak residual stress at the weld root after repair welding can reach 383 MPa. Because overall stress-relief thermal treatments cannot be performed on repair-welded structures, the fatigue strength of repair-welded fillet welds cannot meet the requirements of UIC615-4; therefore, local stress-relief treatments have to be performed in the welded zone. The results are of guiding significance for the treatment of locomotives in service and performance improvement of new locomotives and suggest that the current standard is relatively conservative. [ABSTRACT FROM AUTHOR]