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Study 2: experimental test of placebo acceptability and framing effects in the context of antibiotic overprescribing
A nationally representative UK sample was recruited to increase the generalisability of our qualitative findings and experimentally test acceptability and efficacy ratings for different placebo treatments to substitute unnecessary antibiotic use in primary care. Additionally, we compared two framing contexts, while als...
PMC10510165
Hypotheses
chronic illness, anxiety
CHRONIC ILLNESS
Our quantitative hypotheses were based on previous research findings and included the following:Qualitative hypothesis: Existing perceptions of placebos will vary with regard to the underlying level of knowledge and personal attitudes. However, a common theme will be a perceived need for deception to ensure placebo eff...
PMC10510165
Methods
PMC10510165
Participants
Following an a priori power calculation with an estimated a power of 0.99 and an α error probability of 0.01 to detect a medium effect size
PMC10510165
Design
chronic illness, anxiety
CHRONIC ILLNESS
We employed a 2 × 5 between-within subjects design and measured three dependent variables. This included (1) the general acceptability of a treatment offered in a hypothetical patient scenario (measured on a 5-point Likert scale ranging from “highly unacceptable” to “highly acceptable”), (2) the personal acceptability ...
PMC10510165
Materials and procedure
Study completion took approximately 10 min. The mean completion times were 13:34 min for Study 1 and 11:05 min for Study 2. Participants completed the study in their own time and could decide for themselves how much time to spend on each section. All materials can be accessed in Additional File
PMC10510165
Data analysis
All data were rigorously vetted prior to the analyses. We excluded participants who met one or more of the following criteria: (1) identical responses to all three qualitative questions, (2) study completion in less than 5 min (which may indicate a lack of engagement with the study contents) or more than 60 min (which ...
PMC10510165
Qualitative analyses
The free-text responses to the survey were examined using content analysis—a systematic method for uncovering patterns and themes within qualitative data [
PMC10510165
Quantitative analyses
anxiety
REGRESSION
Before conducting any ANCOVAs or ANOVAs, assumptions were tested for each DV by checking for significant outliers, producing QQ plots and running Shapiro–Wilk tests (to check normality assumptions), running Mauchly’s test of sphericity, conducting Levene’s tests for homogeneity of variance and running a Box’s M test to...
PMC10510165
Results
PMC10510165
Content analysis of qualitative answers
An overview of content codes and associated frequencies is provided in Additional File The participants identified positive psychological effects and the utility of placebos in monitoring medication efficacy as major advantages. In addition, respondents also highlighted the absence of side effects associated with place...
PMC10510165
Effects of framing and treatment conditions on dependent variables
Three 2 × 5 mixed ANOVAs were conducted to test for effects of the framing group (placebo vs. sugar pill) and the treatment condition (blinded + pure placebo vs. open-label + pure placebo vs. open-label + impure placebo vs. antibiotic treatment vs. no treatment) on general acceptability, personal acceptability and expe...
PMC10510165
Effects of demographic variables and medical history on dependent variables
Additional 2 × 5 mixed ANOVAs were conducted to test for effects of the binary variables pertaining to demographic information and medical history and the treatment conditions on general acceptability, personal acceptability and expected effectiveness of the treatment. Only significant results will be presented below. ...
PMC10510165
Age
Age showed significant interactions with treatment conditions across all three DVs. For general acceptability (
PMC10510165
Sex
Sex showed significant interactions with treatment conditions across all three DVs. For general acceptability (
PMC10510165
Antibiotics taken
Whether or not participants had taken antibiotics in the past 12 months had significant interaction effects with treatment conditions across all three DVs. Participants who had recently taken antibiotics, rated the antibiotics treatment option as more generally acceptable (
PMC10510165
Chronic illness and immunocompromised conditions
chronic illness
CHRONIC ILLNESS
An underlying chronic illness or immunocompromised condition was found to have significant main effects on general treatment acceptability (
PMC10510165
Effects of individual differences on dependent variables.
Additional 2 × 5 mixed ANOVAs were conducted to test for effects of the binary variables pertaining to individual differences and the treatment conditions on general acceptability, personal acceptability and expected effectiveness of the treatment. Again, only significant results will be presented below.
PMC10510165
Health anxiety
anxiety
Health anxiety produced significant interaction effects with the treatment condition for general acceptability (
PMC10510165
Health literacy
Health literacy was found to have a significant interaction effect with the treatment condition on general acceptability (
PMC10510165
Health risk-taking
Health-related risk-taking has a significant interaction effect with the treatment condition on personal acceptability (
PMC10510165
Brief discussion
respiratory infections, anxiety
RESPIRATORY INFECTIONS, CHRONIC ILLNESSES
Study 2 provides the first comprehensive evidence of the general acceptability of clinical placebo use by the UK general population. Our nationally representative online study confirmed beliefs in efficacy and general support for the use of open-label impure placebos to replace unnecessary antibiotic treatments for res...
PMC10510165
Study 3: experimental test of placebo acceptability across different contexts of primary care prescribing
depression, lower back pain, chronic back pain, pain
RESPIRATORY INFECTIONS
Study 3 aimed to extend the previous quantitative study by comparing placebo attitudes across a wider range of clinical scenarios. In addition to the initial scenario of respiratory infections, we included vignettes involving less severe depression and lower back pain, where participants had to rate the acceptability a...
PMC10510165
Hypotheses
infection, depression, back pain, pain
INFECTION
Our quantitative hypotheses were based on the findings from Study 1 and Study 2. The hypotheses reported and tested here deviate slightly from our pre-registration. We had planned to test, again, for the effects of demographic variables, medical history and individual differences variables on placebo attitudes. However...
PMC10510165
Methods
PMC10510165
Participants
Following an a priori power calculation with an estimated a power of 0.99 and an α error probability of 0.01 to detect a medium effect size
PMC10510165
Design
depression, lower back pain, pain
DISEASE, RESPIRATORY INFECTION
We employed a 3 × 5 between-within subjects design and measured the same three dependent variables as in Study 2. Participants were randomly assigned to one of three between-subjects groups, which differed in the disease context of the patient scenario. Group 1 were presented with the same scenario of a respiratory inf...
PMC10510165
Materials and procedure
depression, chronic back pain, infections
RESPIRATORY INFECTION, INFECTIONS
Materials and procedure were almost identical to Study 2. The main difference pertained to the use of clinical scenarios. Instead of a single focus on infections, we included three alternative patient scenarios describing either a respiratory infection, a case of less severe depression or a case of chronic back pain (s...
PMC10510165
Data Analysis
The same quality screening criteria were applied as in Study 2. Variables were computed the same way as in Study 2. Again, assumptions of normality and sphericity were violated for our ANOVAs, which is why we will report Greenhouse–Geisser adjustments throughout.
PMC10510165
Results
PMC10510165
Effects of scenario group and treatment conditions on dependent variables
Three 3 × 5 mixed ANOVAs were conducted to test for effects of the scenario group (infection/antibiotics vs. depression/antidepressants vs. back pain/pain killers) and the treatment condition (blinded + pure placebo vs. open-label + pure placebo vs. open-label + impure placebo vs. antibiotic treatment vs. no treatment)...
PMC10510165
Brief discussion
respiratory infections, respiratory infection, pain, infection, depression
RESPIRATORY INFECTIONS, INFECTION, RESPIRATORY INFECTION, HEAT
Study 3 extended our previous focus group study and online experiment through the comparison of different prescribing contexts and their respective effects on public attitudes around placebos. We replicated our previous findings on the acceptability of different placebo types for replacing unnecessary antibiotic treatm...
PMC10510165
General discussion
respiratory infections, infection, chronic illness, anxiety
RESPIRATORY INFECTIONS, INFECTION, CHRONIC ILLNESS, DISEASE
Our three-part, mixed methods study provides the first comprehensive evidence for the public acceptability of clinical placebos. It thereby indicates support for a novel, behavioural approach to reduce overtreatment in primary care. Our qualitative and quantitative results both highlight particular potential for the us...
PMC10510165
Implications for clinical practice and policy
infections
INFECTIONS
Our findings have important implications for clinical practice, because they suggest an acceptable behavioural approach towards reducing overtreatment in UK primary care. It appears that replacing unnecessary medication with open-label impure placebos could be supported by the general UK population—particularly in the ...
PMC10510165
Importance of shared decision-making
Our findings point to the likely importance of shared decision-making approaches when trialling clinical placebo use. A key theme emerging from our focus groups was the prerequisite of a trusting doctor-patient relationship, which is unlikely to emerge without building a rapport during a process of shared decision-maki...
PMC10510165
Communication about placebos
When communicating about placebos, language is likely to play an important role. Both Studies 1 and 2 demonstrated public sensitivity to terminology. Our focus groups highlighted negative public associations with the term “impure”, which may affect acceptability of impure placebos. Instead, it may be favourable to desc...
PMC10510165
Provision of decision aids
infection
INFECTION, AIDS
To support the process of shared decision-making, the use of decision aids is likely going to be crucial. Both our PPI engagement activities and our focus group research highlighted the potential barrier of short appointment times for explaining the rationale behind placebo use and the scientific evidence around its ef...
PMC10510165
Practical considerations
When designing trials of clinical placebo use, several practical considerations will need to be accounted for. This includes specific contexts for placebo use, the mitigation of adverse consequences and administrative challenges.
PMC10510165
Contexts of clinical placebo use
depression, infections, chronic pain, anxiety
CHRONIC PAIN, INFECTIONS
Our initial focus group results demonstrated that participants were most supportive of placebo use for non-serious illnesses and in the context of mental health treatments (e.g. anxiety and depression). Study 3 confirmed that placebo use for less severe depression was rated more acceptable and effective than for chroni...
PMC10510165
Mitigation of adverse consequences
INFECTIONS TOE
Our focus groups raised a number of potential adverse consequences of clinical placebo use. These might include patients considering themselves treated through placebos and consequently taking less precaution about spreading their infections to others or failing to seek further help if symptoms worsen. An additional co...
PMC10510165
Administrative challenges
A final practical consideration is administrative challenges including the question about prescription charges for placebos. Our focus groups appeared divided on this point and future trials may need to collect further, context-specific data on public attitudes towards prescription charges.
PMC10510165
Study limitations
When interpreting our research findings, a number of theoretical and practical study limitations need to be considered.
PMC10510165
Defining placebos
pain
Previous research has highlighted the difficulties of defining what constitutes a placebo. Especially the category of “impure placebos” is not without contention, because of ambiguous terminology and inconsistent use in the past literature [The present study used a broad definition of impure placebos and adopted a prag...
PMC10510165
Use of hypothetical patient vignettes
A more practical research limitation pertained to the use of hypothetical patient scenarios across all three studies reported in this article. We asked participants to consider a fictitious patient case rather than assessing decisionmaking in real-life medical contexts. This methodological approach has many advantages ...
PMC10510165
Attitude measurement
A final limitation is the use of Likert-type rating scales to measure attitudes around general acceptability, personal acceptability and predicted effectiveness of different treatment types. Attitudes are inherently difficult to quantify and opinions lack absolute values. While the use of Likert-type scales is common p...
PMC10510165
Conclusions
Clinical placebo use could be a publicly acceptable approach for combatting overprescribing in primary care. Acceptability appears to be highest for the use of open-label impure placebos for cases where overtreatment is likely to result in both personal side effects and negative consequences for wider society (e.g. ant...
PMC10510165
Acknowledgements
Sarah Tonkin-Crine
WRIGHT
The authors gratefully acknowledge comments by Dr Haroon Ahmed, Dr Miroslav Sirota, Dr Sarah Tonkin-Crine and Prof David Wright, which informed the research design and interpretation of findings.
PMC10510165
Authors’ contributions
EMK: conceptualisation, data collection, data analysis, writing—original draft, writing—review and editing. TE: data analysis, writing—original draft, writing—review and editing. EY: conceptualisation, data collection. SS: conceptualisation, writing—review and editing. ST: conceptualisation, writing—review and editing.
PMC10510165
Funding
This research was funded by an internal grant at the University of Leicester from the Wellcome Trust Institutional Strategic Support Fund (204801/Z/16/Z).
PMC10510165
Availability of data and materials
OSF
The quantitative datasets generated during the current studies, study materials and study preregistration forms are available in the Open Science Framework (OSF) with the identifier
PMC10510165
Declarations
PMC10510165
Ethics approval and consent to participate
All studies received ethical approval from the Institutional Review Board of the University of Leicester (reference numbers for Studies 1, 2 and 3 respectively: 37530-emk12-ls:psychology&visionsciences; 37978-eieo1-ls:psychology&visionsciences; 39206-emk12-ls:psychology&visionsciences). Participants gave informed conse...
PMC10510165
Consent for publication
Consent for publication was obtained from all participants across the three studies reported in the manuscript. This included consent to publish anonymised quotations from qualitative research.
PMC10510165
Competing interests
The authors declare that they have no competing interests.
PMC10510165
References
PMC10510165
Objective
miscarriages
MISCARRIAGES, MISCARRIAGE, COMPLICATIONS
The complications associated with miscarriages have surfaced as a major concern in maintaining women’s physical and mental health. The present study evaluated the efficacy of three medication regimes for the complete expulsion of retained intrauterine tissues in patients who underwent a miscarriage.
PMC10557307
Methods
coagulative blood disorders
DISEASES, MISCARRIAGE
In this randomized clinical trial, 90 patients participated with their gestational age below 12 weeks, each having undergone a recent miscarriage. After being screened for underlying diseases and coagulative blood disorders, they were randomly allocated into three groups. For the first group, labeled as the control gro...
PMC10557307
Results
abortion, bleeding, RPOC, pain
BLEEDING
The mean age of participants and gestational age were 29.76 ± 5.53 years and 8.23 ± 2.29 weeks, respectively. There was no significant difference between the three treatment groups regarding the amount of bleeding after the abortion(P = 0.627). Regarding pain severity, the group that received Misoprostol plus Methylerg...
PMC10557307
Conclusion
pain
The effectiveness of the drugs in the two drug groups combined with oxytocin and methylergometrine is higher than the misoprostol group alone. An outpatient approach was deemed more satisfactory against surgical maneuvers and hospitalizations by patients since family support influenced their pain coping mechanism.
PMC10557307
Trial registration
The trial was registered in the Iranian registry of clinical trials on 04/10/2019. (
PMC10557307
Keywords
PMC10557307
Introduction
bleeding, death, infertility, infection, RPOC, abortion, intrauterine tissue retention, muscle contractions
BLEEDING, POSTPARTUM HEMORRHAGE, COAGULATION DISORDERS, INTRAUTERINE ADHESION, RETAINED PRODUCTS OF CONCEPTION, INFECTION, MISCARRIAGE, COMPLICATIONS
Globally, the complications succeeding a spontaneous or unsafe abortion have been recognized as an impediment to women’s general well-being [The prevalent long-term complications of intrauterine tissue retention include infertility, bleeding, intrauterine adhesion, coagulation disorders, infection, and death, which are...
PMC10557307
Main text
PMC10557307
Methods and materials
PMC10557307
Study design
bleeding, miscarriage, spotting, pain
ADVERSE EVENTS, BLEEDING, MISCARRIAGE, SECONDARY
This clinical trial was performed on 90 patients referred to the gynecology and obstetrics clinic affiliated with Jahrom University of Medical Sciences with miscarriage and a gestational age below 12 weeks from March to July 2020.The sample size was calculated according to Paris et al. [After taking a comprehensive his...
PMC10557307
Participants
vaginal bleeding, pelvic infection, seizure, asthma, glaucoma, RPOC, sepsis, hypersensitivity
VAGINAL BLEEDING, PELVIC INFECTION, HEPATIC DISORDERS, ASTHMA, INCOMPLETE ABORTION, GLAUCOMA, THROMBOEMBOLISM, SEPSIS, HYPERTENSION, HYPERSENSITIVITY
The eligibility criteria assigned for the patients to enter the study were as follows: gestational period below 12 weeks as confirmed by sonography & Last Menstrual Period (LMP); spontaneous and/or incomplete abortion diagnosed by sonography; and vaginal bleeding history in the current pregnancy that encouraged patient...
PMC10557307
Randomization and blindness
BLIND
Random allocation was done using Random Allocation Software as a random division with the nine-way random block method by an epidemiologist who was not involved in the study. Using the lottery, the letters A, B, and C will be considered symbols of one of the three intervention groups. In the next step, each of the nine...
PMC10557307
Intervention
ADVERSE EVENTS, COMPLICATIONS
A thorough and organized history was obtained from the patients who met the criteria to participate in the study. Additionally, they received a particular informed consent form to acquaint them with the research objectives and were categorized into three groups regarding gestational age. The first group of patients was...
PMC10557307
Data Collection
intrauterine death, bleeding, RPOC, pain
BLEEDING, DISEASES
A demographic questionnaire used to gather information about age, sex, weight, blood pressure, existing underlying diseases, and the gestational age of the patients was given to the patients to fill in. Also, sonographic studies were employed to confirm intrauterine death.After a 3-day outpatient intervention, the pati...
PMC10557307
Statistical analysis
Data analysis was done using Stata software version 14. At first, the Kolmogorov-Smirnov test was used to check the normality of the data. The descriptive statistics section reported the results as mean, standard deviation, frequency, and percentage. The analytical statistics section used one-way ANOVA, Chi-square, and...
PMC10557307
Results
PMC10557307
Population characteristics
In this study, among the 110 eligible patients, 90 patients were evaluated and randomly allocated into three distinctive groups, each consisting of 30 participants. The first, second, and third groups received a dose of misoprostol, misoprostol plus methylergometrine, and misoprostol plus oxytocin, respectively, and we...
PMC10557307
Comparison of therapeutic effects
bleeding, PCOS, pain, RPOC, abortion
BLEEDING, STILL, DRUG SIDE EFFECTS, RETAINED PRODUCTS OF CONCEPTION, POLYCYSTIC OVARY SYNDROME, RETAINED PRODUCTS OF CONCEPTION
There was no significant difference between the three treatment groups regarding the amount of bleeding after the abortion(P = 0.627). Still, in the Misoprostol + Methylergometrine group, 80% of the patients were in the mild bleeding group. In contrast, in the two groups of Misoprostol + Oxytocin and Misoprostol alone,...
PMC10557307
Discussion
bleeding, fetus abortion, pain, RPOC, abortion, RPOC expulsion
BLEEDING, POSTPARTUM HEMORRHAGE, UTERINE CERVIX, CONTRACTION, UTERUS, FETAL DEATH, INCOMPLETE ABORTION, COMPLICATIONS
The result of this study confirms an improved efficacy of the medical therapy of misoprostol, either combined with oxytocin or with methylergonovine, in successful expulsion of the RPOC. Although treatment by misoprostol alone (83.3%) has not resulted in remarkable statistical significance, greater therapeutic efficacy...
PMC10557307
Limitations
bleeding
BLEEDING
Our study had several limitations. First, Short-term follow-up and small sample size were among the barriers that limited the present study. Second, in this study, to evaluate bleeding, only the severity of bleeding was considered, and the volume of bleeding and the average number of days during which there is bleeding...
PMC10557307
Acknowledgements
The authors are grateful to all the participants in this study. Also, We would like to express our sincere gratitude to the Clinical Research Development Unit of Peymanieh Hospital, affiliated with Jahrom University of Medical Sciences, for providing suitable environmental facilities and research requirements.
PMC10557307
Authors’ contributions
HT
AR and ZZ considered and planned the study. AR and VR were responsible for the literature search and screening. ZZ and HT were responsible for data collection. VR participated in the statistical analysis. AR, HT, and ZZ contributed to data interpretation. AR and ZZ drafted the manuscript, and VR critically revised the ...
PMC10557307
Funding
This study was done with the financial support of Jahrom University of Medical Sciences. The funding agency had no role in the study design, collection, analysis, and interpretation of data and manuscript writing.
PMC10557307
Data Availability
The datasets generated and analyzed during the current research are not publicly available as individual privacy could be compromised, but are available from the corresponding author on reasonable request.
PMC10557307
Declarations
PMC10557307
Ethics approval
Written informed consent was obtained from the patients in our study. The purpose of this research was completely explained to the patient, and assured that the researcher would keep their information confidential. The protocol of this study was approved by the ethical committee of Jahrom University of Medical Sciences...
PMC10557307
Consent for publication
Not applicable.
PMC10557307
Competing interests
The authors declare that they have no competing interests.
PMC10557307
Abbreviations
RPOC
World Health Organization, RPOC:retained products of conceptionLast Menstrual PeriodIntrauterine device, VAS:Visual Analogue Scale system
PMC10557307
References
PMC10557307
Abbreviations:
Long-chain PUFA (LC-PUFA) are transferred from the mother to the fetus during pregnancy to meet the fetal needs for development; maternal LC-PUFA supply is crucial since the synthesis of LC-PUFA by the fetus and placenta is very lowPrevious evidence has indicated that consumption of fish oil which is rich in Interestin...
PMC10751948
Materials and methods
PMC10751948
Study design and participants
LATE PREGNANCY, SECONDARY
This single centre double-blind, placebo-controlled randomised trial Flow diagram of the study.For this secondary analysis of the main trial, blood samples were obtained at two study visits, early and late pregnancy (mean 13·8 (
PMC10751948
Clinical parameters
EARLY PREGNANCY
Weight was obtained from welfare women clinic records and was self-reported. Height was measured with a wall stadiometer at the first visit. Pre-pregnancy BMI (kg/mGDM was diagnosed at 24–28 gestational weeks on the basis of a 2 h 75 g oral glucose tolerance test if one or more values were: 0 h ≥ 5·3, 1 h ≥ 10·0 and 2 ...
PMC10751948
Dietary intervention
LATE PREGNANCY
Women consumed two fish oil capsules and one probiotic capsule (or matched placebos) daily from early pregnancy/first study visit until 6 months postpartum; herein, we include data from the intervention from early until late pregnancy. The fish oil capsules (Incromega E1070, Croda Europe Ltd) contained 2·4 g of
PMC10751948
Fatty acid analyses
BLOOD
Blood samples were obtained from the antecubital vein of the mother in the morning after at least 9 h fasting and were then separated into aliquots and frozen in −80°C. The fatty acid composition of four serum lipid fractions (PC, CE, TAG and NEFA) was determined by GC (Agilent Technologies). Samples were batch-analyse...
PMC10751948
Low-grade inflammation
Serum hsCRP was analysed using an automated colorimetric immunoassay on a Dade Behring Dimension RXL autoanalyzer (Siemens Healthcare) in a certified laboratory (TYKSLAB, the Hospital District of Southwest Finland). The lower limit of detection was 0·1 mg/l. The data are expressed as mg/l. A high-throughput proton NMR ...
PMC10751948
Statistics
LATE PREGNANCY, EARLY PREGNANCY
Natural log-transformation was performed for fatty acid variables with skewness > 1. Z-scores were calculated for all fatty acid variables. The effect of the intervention on the fatty acids was determined in late pregnancy: one-way ANOVA followed by Tukey’s post hoc test or Welch ANOVA followed by Tamhane’s T2 post hoc...
PMC10751948
Results
PMC10751948
Baseline characteristics of the pregnant women
Obese
OBESE, GESTATIONAL DIABETES MELLITUS
Clinical characteristics and diet intake of the women are presented in The baseline characteristics and dietary intake of all pregnant women and according to the intervention groups(Mean values and standard deviations; inter-quartile ranges; numbers and percentages)GDM, gestational diabetes mellitus.The statistical si...
PMC10751948
Change in
pregnancy-induced
The pregnancy-induced changes in With respect to
PMC10751948
Impact of the dietary intervention with fish oil and/or probiotics on serum fatty acid composition in the four lipid fractions
LATE PREGNANCY
The dietary intervention had an impact on the total (Mean values and standard deviations)The following variables were natural log-transformed: 18:3One-way ANOVA followed by Tukey’s post hoc test.Welch ANOVA followed by Tamhane’s T’2 post hoc test.Significantly different from probiotics Significantly different from pl...
PMC10751948
The
EARLY PREGNANCY
Out of all forty-eight (a) The heatmap describing the Pearson correlation coefficients between early pregnancy serum hsCRP and GlycA and In early pregnancy, positive correlations with GlycA were observed for ALA (18:3In late pregnancy, GlycA correlated positively with eicosatetraenoic acid (ETA, 20:4
PMC10751948
The
GDM
GDM, REGRESSION
Regarding the association between the (a)–(d) The association of Out of all The fatty acids related to the onset of GDM in the univariate logistic regression analyses (
PMC10751948
Discussion
hypertriacylglycerolaemia, inflammation, GDM
GDM, INFLAMMATION
We demonstrate that fish oil and the combination of fish oil and probiotics had an impact on the sFA profile in pregnant women with overweight and obesity whilst against our expectations probiotics did not when the four intervention groups were compared. However, when women receiving probiotics were compared against wo...
PMC10751948