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1.
Gerontology ; 2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38679016

ABSTRACT

Introduction There is inconsistent evidence on the associations between high-density lipoprotein cholesterol (HDL-C) and risk of sarcopenia. To determine the evidence existing between HDL-C and sarcopenia in Chinese middle-aged and older adults. Methods We used a panel study design of the China Health and Retirement Longitudinal Study (CHARLS), with 7,415 participants (mean age 57.5 years) from 2011, 2013, and 2015. HDL-C was measured by colormetric test of venous serum samples. Sarcopenia was defined as low muscle mass, plus low muscle strength, or low physical performance. Muscle mass was estimated by anthropometric measures. Muscle strength was measured by handgrip strength using dynamometer. Physical performance was measured by 5-time chair stand test, gait speed test, and short physical performance battery. Results With 961 (13.0%) sarcopenia cases, each 1-unit increase (1 SD = 15.4 mg/dL) of HDL-C levels was associated with 42% increased odds of incident sarcopenia [OR = 1.42, 95% confidence interval (CI) = 1.28 - 1.58] at 4 years follow up. Females with high HDL-C levels (HDL-C > 60 mg/dL) had a higher risk of sarcopenia [OR = 2.49, 95% CI = 1.76 - 3.52]. A J-shaped association between HDL-C and risk of sarcopenia in females. HDL-C was negatively associated with muscle mass [ = -0.23, 95% CI = -0.27 - -0.20] and hand grip strength [ = -0.05, 95% CI = -0.19 - 0.09]. Conclusion High HDL-C levels were associated with higher risk of sarcopenia among middle-aged and older Chinese adults, and appropriate control of its high levels informs the management of sarcopenia.

3.
BMC Nurs ; 22(1): 284, 2023 Aug 25.
Article in English | MEDLINE | ID: mdl-37626298

ABSTRACT

BACKGROUND: The curriculum humanistic competence of nursing teachers is important to cultivate the humanistic qualities of undergraduate nursing students. However, there are no evaluation tools for the curriculum humanistic competence of undergraduate nursing teachers in China. OBJECTIVE: To develop an index system to evaluate the curriculum humanistic competence of undergraduate nursing teachers. DESIGN: This research conducted a Delphi study. PARTICIPANTS: Semi-structured interviews were held with 19 experts, and Delphi rounds were conducted with 18 experts. SETTINGS: This study was conducted in 12 universities and 4 Grade A tertiary hospitals in China. METHODS: A literature review and semi-structured interviews were conducted to develop an initial framework. A two-round Delphi survey was employed to build the index system for undergraduate nursing teachers' curriculum humanistic competence. RESULTS: After two rounds of consultation, the index system included 5 first-level indicators, 11 second-level indicators and 41 third-level indicators. The Cr for two rounds of consultation were 0.929 and 0.923, and Kendall's W was 0.152(P<0.001). CONCLUSIONS: The index system for the evaluation of undergraduate nursing teachers' curriculum humanistic competence offers guidelines for undergraduate nursing teachers in China. It can be used in practice to develop high humanistic qualities in undergraduate nursing teachers.

5.
Nat Commun ; 14(1): 1904, 2023 04 05.
Article in English | MEDLINE | ID: mdl-37019928

ABSTRACT

Eribulin (Halaven) is the most structurally complex non-peptidic drug made by total synthesis and has challenged preconceptions of synthetic feasibility in drug discovery and development. However, despite decades of research, the synthesis and manufacture of eribulin remains a daunting task. Here, we report syntheses of the most complex fragment of eribulin (C14-C35) used in two distinct industrial routes to this important anticancer drug. Our convergent strategy relies on a doubly diastereoselective Corey-Chaykovsky reaction to affect the union of two tetrahydrofuran-containing subunits. Notably, this process relies exclusively on enantiomerically enriched α-chloroaldehydes as building blocks for constructing the three densely functionalized oxygen heterocycles found in the C14-C35 fragment and all associated stereocenters. Overall, eribulin can now be produced in a total of 52 steps, which is a significant reduction from that reported in both academic and industrial syntheses.


Subject(s)
Antineoplastic Agents , Furans , Ketones
6.
J Assoc Nurses AIDS Care ; 34(3): 292-306, 2023.
Article in English | MEDLINE | ID: mdl-37067998

ABSTRACT

ABSTRACT: Instruments evaluating HIV-related psychological distress (HRPD) in people living with HIV may lack sensitivity to capture patients' psychological burden. We developed a comprehensive scale measuring HRPD and evaluated its psychometric properties. A mixed-method study was conducted from July 2021 to April 2022; it involved a literature review, semistructured interviews ( n = 15), three rounds of panel discussions, two rounds of Delphi studies ( n = 20), a pilot test ( n = 20) to generate new scale items, and a cross-sectional survey ( n = 659) to evaluate the psychometric properties of the HIV-related psychological distress scale. The scale contains 22 items across 4 subscales (i.e., disease-related distress, treatment adherence distress, identity distress, and disclosure distress). The confirmatory factor analysis revealed high goodness of fit (χ 2 /df = 2.412, comparative fit index = 0.916, incremental fit index = 0.917, and Tucker‒Lewis index = 0.902), showing that the HIV-related psychological distress scale is a reliable (Cronbach's α = 0.871 overall) and valid scale for evaluating HRPD in China and can be used to dynamically evaluate and monitor HRPD levels during patient follow-up.


Subject(s)
HIV Infections , HIV , Humans , HIV Infections/psychology , Surveys and Questionnaires , Cross-Sectional Studies , Reproducibility of Results , China , Psychometrics/methods , Factor Analysis, Statistical
7.
Clin Nurs Res ; 32(1): 60-72, 2023 01.
Article in English | MEDLINE | ID: mdl-35259946

ABSTRACT

Psychological distress is a frequently reported outcome measure in HIV research. However, because of its poor conceptualization, many studies only partially capture it because they focus solely on depression or anxiety based on symptoms. This study undertook a concept analysis of HIV-related psychological distress (HRPD) using Walker and Avant's method. The findings include HRPD's (a) attributes, including changes to emotional status, symptom burden, HIV disclosure distress and HIV-related stigma; (b) antecedents, including HIV-related stressors, cognitive appraisal of stressors and difficulty coping with the disease or treatment; and (c) consequences, including poor health outcomes and posttraumatic growth. Lazarus and Folkman's theory and the conservation of resources theory were adapted to further understand HRPD. This article provides insight into HRPD and increases the awareness of how to screen and assess HRPD at an early stage. The findings indicate the need to develop specific and rigorous measures and to provide appropriate interventions.


Subject(s)
HIV Infections , Psychological Distress , Humans , Stress, Psychological/psychology , HIV , Anxiety , HIV Infections/complications , Adaptation, Psychological
8.
AIDS Care ; 35(2): 153-164, 2023 02.
Article in English | MEDLINE | ID: mdl-35642250

ABSTRACT

Although people living with HIV/AIDS (PLWHA) are known to be vulnerable to psychological distress (PD), little is known about the prevalence of PD among PLWHA. A systematic literature search of several databases was conducted from inception to August 2021 focusing on studies reporting on PD symptoms among PLWHA. The overall prevalence estimates were pooled using a random-effects meta-analysis. Differences according to study-level characteristics were examined using stratified meta-analysis. We pooled and analyzed data from 15 studies comprising 5593 PLWHA. The prevalence rate of PD among PLWHA was 43.7% (95% Confidence Interval: 29.9-57.5%). Subgroup analyses by gender, country, CD4 count, employment status and ever attended school found no statistically significant differences in the prevalence of PD. Heterogeneity in the prevalence of PD among PLWHA was partially explained by the assessment tool. Further large-scale studies of high quality are warranted to identify risk factors of PD in PLWHA in their respective socio-cultural contexts.


Subject(s)
Acquired Immunodeficiency Syndrome , HIV Infections , Humans , HIV Infections/epidemiology , HIV Infections/psychology , Acquired Immunodeficiency Syndrome/epidemiology , Prevalence , Risk Factors , CD4 Lymphocyte Count
9.
Aging Ment Health ; 26(4): 745-753, 2022 04.
Article in English | MEDLINE | ID: mdl-33818221

ABSTRACT

Objectives: This study aimed to examine (1) the feasibility of the study procedures (i.e. recruitment, retention, attendance, and assessment completion rates), and (2) the effects of horticultural therapy (HT) on apathy, cognitive ability, quality of life, and functional capacity.Methods: This was a parallel-group, match-paired, randomized controlled trial. Thirty-two participants were allocated to either the experimental or the control group. Data were collected at baseline (T0), immediately postintervention (T1), and 3 months postintervention (T2). The Apathy Evaluation Scale-informant version (AES-I); Mini-Mental State Examination (MMSE); Quality of Life in Alzheimer's disease (QoL-AD) scale; Barthel index (BI) were used to measure apathy, cognitive ability, quality of life, and functional capacity, respectively.Results: The recruitment, retention, attendance and assessment completion rates were 22.7%, 87.5%, 100% and 100%, respectively. The between-group differences in AES-I (p = 0.007) and MMSE (p = 0.034) scores were statistically significant at T1. In the experimental group, the AES-I (p = 0.001), MMSE (p = 0.010), and QoL-AD (p = 0.017) scores were significantly different over time. In the post hoc pair-wise analysis, the AES-I scores of the experimental group observed at T1 were significantly lower than that at T0 (p = 0.032). In the control group, the MMSE scores (p = 0.001) were significantly different over time.Conclusion: HT is feasible for residents with dementia and apathy. The HT program effectively reduced apathy and promoted cognitive function, but its effects on quality of life and functional capacity were not observed.


Subject(s)
Alzheimer Disease , Apathy , Dementia , Horticultural Therapy , Dementia/therapy , Humans , Nursing Homes , Pilot Projects , Quality of Life
10.
J Nurs Manag ; 30(7): 2107-2115, 2022 Oct.
Article in English | MEDLINE | ID: mdl-34798681

ABSTRACT

AIM: This study aimed to investigate the impact of self-efficacy on the relationship between organizational climate and humanistic practice ability (HPA) in Chinese nurses. BACKGROUND: To date, studies on the effect of organizational climate on nursing care have focused on care outcomes rather than care processes. Thus, this effect remains poorly understood. METHODS: A total of 757 participants were sampled from three tertiary hospitals in Guangdong Province from November to December 2019; subsequently, they completed a structured electronic questionnaire. A structural equation model was used to explore the impact of nursing organizational climate on nurses' HPA. RESULTS: A total of 688 valid questionnaires were collected. The nurses' average HPA score was 107.82 (SD 12.47). There was a positive correlation between organizational climate and HPA (r = .409, p < .05). Additionally, self-efficacy mediated this relationship (p < .01). CONCLUSIONS: This study provides new insights into nursing organizational climate, self-efficacy and nurses' HPA. IMPLICATIONS FOR NURSING MANAGEMENT: The significant mediating effect of self-efficacy suggests that managers should implement nurse professional development programmes using targeted strategies to foster greater self-efficacy, which could improve the quality of care and nurse-patient relationships.


Subject(s)
Nurses , Nursing Staff, Hospital , Humans , Self Efficacy , Surveys and Questionnaires , Nurse-Patient Relations , Organizational Culture , Job Satisfaction
11.
Geriatr Nurs ; 42(6): 1373-1378, 2021.
Article in English | MEDLINE | ID: mdl-34583236

ABSTRACT

The purpose of this study was to examine 1) the relationship between apathy and leisure activity participation in nursing home residents with Alzheimer disease (AD) and 2) the moderator effect of the severity of dementia on this relationship. Data were collected from 290 residents with AD using the Apathy Evaluation Scale-informant version (AES-I), Leisure Activities Questionnaire (LAQ), and Clinical Dementia Rating scale (CDR). The multiple linear regression model showed that leisure activity participation (ß=-0.452, p<0.001) was negatively associated with apathy, while the severity of dementia (ß=0.515, p<0.001) was positively associated with apathy. The severity of dementia moderated the effect of leisure activity participation on apathy (ß=-0.108, p=0.015). The results indicate that the effects of leisure activity participation on apathy diminish with the aggravation of AD. The severity of dementia should be considered when designing and delivering leisure activity interventions to manage apathy in nursing home residents with AD.


Subject(s)
Alzheimer Disease , Apathy , Cross-Sectional Studies , Humans , Leisure Activities , Nursing Homes
12.
Talanta ; 234: 122656, 2021 Nov 01.
Article in English | MEDLINE | ID: mdl-34364465

ABSTRACT

This work presents a new method of Cr speciation analysis based on micro sample pretreatment with a paper-based analytical device (PAD). By using electrokinetic separation and stacking on the PAD, Cr (VI) and Cr (III) can be separated and the recovered to achieve speciation analysis without have to be subjected to subtraction treatment. The separation and recovery properties of Cr (VI) and Cr (III) were characterized and optimized by UV-Vis spectrophotometry, with which the LOQ of 19.0 µg L-1 and 28.7 µg L-1, and the recoveries of 88-108% and 90-110%, were obtained for Cr (VI) and Cr (III), respectively. In addition, direct analysis of Cr (VI)/Cr (III) from an electroplating wastewater sample was also demonstrated with this method combined with atomic spectroscopy (GF-AAS and ICP-OES). This sample pretreatment method is fast, cheap and easy to be used. Combined with the high sensitivity and elemental selectivity of atomic spectroscopy and mass spectrometry, this PAD sample pretreatment method could be a compensation to their lack in speciation discrimination, and may play an important role in the speciation analysis of Cr.


Subject(s)
Chromium , Mass Spectrometry , Spectrum Analysis
13.
Talanta ; 210: 120635, 2020 Apr 01.
Article in English | MEDLINE | ID: mdl-31987178

ABSTRACT

In this work, a paper-based analytical device (PAD) for sensitive speciation detection of chromium (Cr) by smartphone camera was introduced. In anion electrokinetic stacking mode, Cr (VI) in the form of CrO42- was firstly enriched into a narrow band on a paper fluidic channel, and then the band was visualized by 1,5-diphenylcarbazide (DPC). Colorimetric detection of Cr (VI) was based on the gray intensity of stacking bands. Detection of Cr (III) was achieved by subtraction of the detection results of Cr (VI) before and after the sample was oxidized. Under optimized conditions, the detection limit of Cr (VI) and Cr (III) of 0.20 µM (~10.4 µg L-1) and 0.30 µM (~14.6 µg L-1) were achieved with a linear response in the range of 0.67-5.00 µM and 0.93-6.00 µM, respectively. The detection performance of PAD is close to that obtained by desktop spectrophotometry, thanks to the online stacking effect. Meanwhile, this PAD also exhibited a good selectivity over coexisting cations and anions, thanks to the charge selectivity of the stacking mode and the selective visualization reaction of DPC. Speciation detection of Cr from tap water, river water, surface water, and electroplating wastewater was demonstrated. This work shows the potential of PADs for on-site detection of Cr (VI) in environmental water samples.

14.
Insect Sci ; 27(2): 256-265, 2020 Apr.
Article in English | MEDLINE | ID: mdl-30047567

ABSTRACT

We tested the recent hypothesis that the "fly factor" phenomenon (food currently or previously fed on by flies attracts more flies than the same type of food kept inaccessible to flies) is mediated by bacterial symbionts deposited with feces or regurgitated by feeding flies. We allowed laboratory-reared black blow flies, Phormia regina (Meigen), to feed and defecate on bacterial Luria-Bertani medium solidified with agar, and isolated seven morphologically distinct bacterial colonies. We identified these using matrix-assisted laser desorption/ionization mass spectrometry and sequencing of the 16S rRNA gene. In two-choice laboratory experiments, traps baited with cultures of Proteus mirabilis Hauser, Morganella morganii subsp. sibonii Jensen, or Serratia marcescens Bizio, captured significantly more flies than corresponding control jars baited with tryptic soy agar only. A mixture of seven bacterial strains as a trap bait was more attractive to flies than a single bacterial isolate (M. m. sibonii). In a field experiment, traps baited with agar cultures of P. mirabilis and M. m. sibonii in combination captured significantly more flies than traps baited with either bacterial isolate alone or the agar control. As evident by gas chromatography-mass spectrometry, the odor profiles of bacterial isolates differ, which may explain the additive effect of bacteria to the attractiveness of bacterial trap baits. As "generalist bacteria," P. mirabilis and M. m. sibonii growing on animal protein (beef liver) or plant protein (tofu) are similarly effective in attracting flies. Bacteria-derived airborne semiochemicals appear to mediate foraging by flies and to inform their feeding and oviposition decisions.


Subject(s)
Diptera/microbiology , Animals , Appetitive Behavior , Feeding Behavior , Female , Male , Odorants/analysis , Symbiosis
15.
J Clin Nurs ; 29(3-4): 535-544, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31737968

ABSTRACT

AIMS AND OBJECTIVES: To explore the regulation role of work resources in male nurses' job burnout and job demands. BACKGROUND: Burnout syndrome affects a wide range of nurses. Although burnout and turnover rate have drawn many researchers' attention, little is known of work characteristics that may cause a high burnout and turnover rate in male nurses. DESIGN: A survey design was used. METHOD: A total of 366 male nurses in Guangzhou hospitals were included in this survey using the Burnout Scale (MBI-GS) and the Job demands Resources Scale. Data were processed by hierarchical regression analysis. (Followed the STROBE checklist) RESULTS: The male nurse's MBI score was (2.72 ± 1.02). Job demands affected the severity of male nurses' job burnout. Work resources are in a low level, especially at the social support, reward and skill diversity. The regression coefficients ß of job demands, work resources and interaction items of job demands and work resources were 0.277, 0.314 and -0.006, respectively, and both passed the significance test (p < .01).). The new explanatory quantity ΔR2 after introducing the interaction between job demands and working resources was also statistically significant (ΔR2  = 0.254, p < .01). CONCLUSION: Male nurses are at a mild level of job burnout, and work resources are in shortage. Work resources play a regulating role in job demands and burnout. RELEVANCE TO CLINICAL PRACTICE: The mild burnout may be a surface phenomenon or was a sign of trend of male nurses' intention to leave the job. Managers should pay attention to the emotional needs and mental health problems of male nurses' work environment.


Subject(s)
Burnout, Professional/psychology , Nurses, Male/psychology , Nursing Staff, Hospital/psychology , Adult , Burnout, Professional/diagnosis , Burnout, Professional/epidemiology , China , Cross-Sectional Studies , Humans , Male , Middle Aged , Nurses, Male/statistics & numerical data , Personnel Turnover , Social Support , Surveys and Questionnaires , Workload/psychology
16.
Sci Rep ; 9(1): 8038, 2019 May 24.
Article in English | MEDLINE | ID: mdl-31123298

ABSTRACT

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

17.
Sci Rep ; 9(1): 3908, 2019 03 07.
Article in English | MEDLINE | ID: mdl-30846726

ABSTRACT

Female mosquitoes exploit olfactory, CO2, visual, and thermal cues to locate vertebrate hosts. Male and female mosquitoes also consume floral nectar that provides essential energy for flight and survival. Heretofore, nectar-foraging mosquitoes were thought to be guided solely by floral odorants. Using common tansies, Tanacetum vulgare L., northern house mosquitoes, Culex pipiens L., and yellow fever mosquitoes, Aedes aegpyti (L.), we tested the hypothesis that the entire inflorescence Gestalt of olfactory, CO2 and visual cues is more attractive to mosquitoes than floral odorants alone. In laboratory experiments, we demonstrated that visual and olfactory inflorescence cues in combination attract more mosquitoes than olfactory cues alone. We established that tansies become net producers of CO2 after sunset, and that CO2 enhances the attractiveness of a floral blend comprising 20 synthetic odorants of tansy inflorescences. This blend included nine odorants found in human headspace. The "human-odorant-blend" attracted mosquitoes but was less effective than the entire 20-odorant floral blend. Our data support the hypothesis that the entire inflorescence Gestalt of olfactory, CO2 and visual cues is more attractive to mosquitoes than floral odorants alone. Overlapping cues between plants and vertebrates support the previously postulated concept that haematophagy of mosquitoes may have arisen from phytophagy.


Subject(s)
Cues , Culicidae , Feeding Behavior/physiology , Inflorescence , Olfactory Perception/physiology , Tanacetum , Visual Perception/physiology , Animals , Behavior, Animal/physiology , Female , Male , Odorants , Plant Nectar
18.
Environ Technol ; 40(20): 2684-2694, 2019 Aug.
Article in English | MEDLINE | ID: mdl-29513139

ABSTRACT

Municipal wastewater treatment plant (WWTP) effluent is increasingly used as reclaimed water and as water sources for downstream areas. Effluent dissolved organic nitrogen (DON) is considered to be the precursor to nitrogen disinfection by-products (N-DBPs). Here, we investigated DON removal by pre-ozonation-enhanced coagulation and found that (1) pre-ozonation significantly enhanced the removal of DON, dissolved organic carbon (DOC), and UV254 by coagulation. (2) pH had an important impact on the pre-ozonation-enhanced coagulation. At lower pH, the removal of DON, DOC, and UV254 is higher. (3) As ozone dosage increased, zeta potential gradually increased, while dissolved calcium concentrations declined and there was a strong correlation between zeta potential and dissolved calcium concentrations. (4) Small (<6 kDa) molecular weight DON was dominant in the effluent. Hydrophilic and hydrophobic DON accounted for 58.5% and 30.8% of the total, respectively. (5) Coagulation reduced overall DBP formation potentials to less than 20%. In contrast, overall DBP formation potentials increased after ozonation. However, pre-ozonation-enhanced coagulation not only removed 71% DON, but also reduced overall DBP formation potentials by more than 40%. (6) 3-DEEM spectra indicated that DBP formation potentials and DON concentrations were related to three main peaks, which corresponded to tryptophan-based proteins, aromatic proteins, and fulvic acids.


Subject(s)
Ozone , Water Pollutants, Chemical , Water Purification , Nitrogen , Wastewater
19.
J Chem Ecol ; 43(3): 215-224, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28130740

ABSTRACT

Urine of male house mice, Mus musculus, is known to have primer pheromone effects on the reproductive physiology of female mice. Urine-mediated releaser pheromone effects that trigger certain behavioral responses are much less understood, and no field studies have investigated whether urine deposits by male or female mice, or synthetic mouse pheromone, increase trap captures of mice. In field experiments, we baited traps with bedding soiled with urine and feces of caged female or male mice, and recorded captures of mice in these and in control traps containing clean bedding. Traps baited with female bedding preferentially captured adult males, whereas traps baited with male bedding preferentially captured juvenile and adult females, indicating the presence of male- and female-specific sex pheromones in soiled bedding. Analyses of headspace volatiles emanating from soiled bedding by gas chromatography/mass spectrometry revealed that 3,4-dehydro-exo-brevicomin (DEB) was seven times more prevalent in male bedding and that 2-sec-butyl-4,5-dihydrothiazole (DHT) was male-specific. In a follow-up field experiment, traps baited with DEB and DHT captured 4 times more female mice than corresponding control traps, thus indicating that DEB and DHT are sex attractant pheromone components of house mouse males. Our study provides impetus to identify the sex attractant pheromone of female mice, and to develop synthetic mouse pheromone as a lure to enhance the efficacy of trapping programs for mouse control.


Subject(s)
Behavior, Animal/drug effects , Biological Assay , Laboratories , Sex Attractants/pharmacology , Animals , Bedding and Linens , Female , Male , Mice , Odorants/analysis , Sex Attractants/chemistry
20.
J Org Chem ; 81(19): 8696-8709, 2016 10 07.
Article in English | MEDLINE | ID: mdl-27668321

ABSTRACT

An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η6-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated. Substrate scope investigations suggest that hydrogen-bonding interactions between the oxygen in the backbone of the ether-containing substrate and the [(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's. This insight led to a mechanistic proposal that predicts the observed absolute stereochemistry. Most importantly, this mechanistic insight allowed for the extension of this strategy to include N as an alternative hydrogen bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted piperazines is also demonstrated.

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