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In São Paulo, Brazil, the first case of coronavirus disease 2019 (CoViD-19) was confirmed on 26 February, the first death due to CoViD-19 was registered on 16 March, and on 24 March, São Paulo implemented the isolation of persons in non-essential activities. A mathematical model was formulated based on non-linear ordinary differential equations considering young (60 years old or less) and elder (60 years old or more) subpopulations, aiming to describe the introduction and dissemination of the new coronavirus in São Paulo. This deterministic model used the data collected from São Paulo to estimate the model parameters, obtaining R0 = 6.8 for the basic reproduction number. The model also allowed to estimate that 50% of the population of São Paulo was in isolation, which permitted to describe the current epidemiological status. The goal of isolation implemented in São Paulo to control the rapid increase of the new coronavirus epidemic was partially succeeded, concluding that if isolation of at least 80% of the population had been implemented, the collapse in the health care system could be avoided. Nevertheless, the isolated persons must be released one day. Based on this model, we studied the potential epidemiological scenarios of release by varying the proportions of the release of young and elder persons. We also evaluated three different strategies of release: All isolated persons are released simultaneously, two and three releases divided in equal proportions. The better scenarios occurred when young persons are released, but maintaining elder persons isolated for a while. When compared with the epidemic without isolation, all strategies of release did not attain the goal of reducing substantially the number of hospitalisations due to severe CoViD-19. Hence, we concluded that the best decision must be postponing the beginning of the release.
Toxoplasma gondii infections are common in humans and animals worldwide. Domestic free-range chickens (Gallus domesticus) are excellent sentinels of environmental contamination with T. gondii oocysts because they feed on the ground. Chickens can be easily infected with T. gondii; however, clinical toxoplasmosis is rare in these hosts. Chickens are comparatively inexpensive and thus are good sentinel animals for T. gondii infections on the farms. Here, the authors reviewed prevalence, the persistence of infection, clinical disease, epidemiology and genetic diversity of T. gondii strains isolated from chickens worldwide for the past decade. Data on phenotypic and molecular characteristics of 794 viable T. gondii strains from chickens are discussed, including new data on T. gondii isolates from chickens in Brazil. This paper will be of interest to biologists, epidemiologists, veterinarians and parasitologists.
In this paper, the generation of relativistic electron mirrors (REM) and the reflection of an ultra-short laser off the mirrors are discussed, applying two-dimension particle-in-cell simulations. REMs with ultra-high acceleration and expanding velocity can be produced from a solid nanofoil illuminated normally by an ultra-intense femtosecond laser pulse with a sharp rising edge. Chirped attosecond pulse can be produced through the reflection of a counter-propagating probe laser off the accelerating REM. In the electron moving frame, the plasma frequency of the REM keeps decreasing due to its rapid expansion. The laser frequency, on the contrary, keeps increasing due to the acceleration of REM and the relativistic Doppler shift from the lab frame to the electron moving frame. Within an ultra-short time interval, the two frequencies will be equal in the electron moving frame, which leads to the resonance between laser and REM. The reflected radiation near this interval and corresponding spectra will be amplified due to the resonance. Through adjusting the arriving time of the probe laser, a certain part of the reflected field could be selectively amplified or depressed, leading to the selective adjustment of the corresponding spectra.
The aim of this study was to examine whether the presence of risk alleles of the norepinephrine transporter gene (SLC6A2) polymorphisms is associated with differences in regional cerebral blood flow (rCBF) measured by 99mTc-HMPAO single photon emission computerized tomography in a Korean sample of ADHD.
The present study included 24 children with ADHD (9.5±2.4 years), consisting of 20 boys and 4 girls, aged 6-16 years. We investigated the G1287A and -3081(A/T) polymorphisms of the SLC6A2. The rCBF was compared between the ADHD subjects with and without risk alleles at the G1287A polymorphism and at the -3081(A/T) polymorphism. Image analyses were performed with voxelwise t-statistics using SPM2.
1) The ADHD subjects with the A allele (risk allele) at the G1287A polymorphism showed reduced perfusion in the left middle frontal gyrus, left inferior parietal lobule, precuneus, right superior frontal gyrus, and right superior parietal lobule as compared with ADHD subjects without the A allele (p< 0.001).
2) The ADHD subjects with the A allele at the G1287A polymorphism showed increased perfusion in the right middle frontal gyrus, right middle temporal gyrus, right superior temporal gyrus, right fusiform gyrus, right precentral gyrus, and right anterior lobe of cerebellum as compared with ADHD subjects without the A allele (p< 0.001).
3) No significant perfusion differences were found between ADHD subjects with and without the T allele (risk allele) at the -3081(A/T) polymorphism.
Our findings suggest that the SLC6A2 G1287A polymorphism might exert differential effects on rCBF in children with ADHD.
Many family characteristics were reported to increase the risk of bipolar disorder (BPD). The development of BPD may be mediated through different pathways, involving diverse risk factor profiles. We evaluated the associations of family characteristics to build influential causal-pie models to estimate their contributions on the risk of developing BPD at the population level. We recruited 329 clinically diagnosed BPD patients and 202 healthy controls to collect information in parental psychopathology, parent-child relationship, and conflict within family. Other than logistic regression models, we applied causal-pie models to identify pathways involved with different family factors for BPD. The risk of BPD was significantly increased with parental depression, neurosis, anxiety, paternal substance use problems, and poor relationship with parents. Having a depressed mother further predicted early onset of BPD. Additionally, a greater risk for BPD was observed with higher numbers of paternal/maternal psychopathologies. Three significant risk profiles were identified for BPD, including paternal substance use problems (73.0%), maternal depression (17.6%), and through poor relationship with parents and conflict within the family (6.3%). Our findings demonstrate that different aspects of family characteristics elicit negative impacts on bipolar illness, which can be utilized to target specific factors to design and employ efficient intervention programs.
Menopausal syndrome has been reported to be a worldwide women's mental health problem. Aborigines in rural areas have poorer access to mental health services. Thus, it is important to evaluate such symptoms of female aborigines with different menopausal statuses and their association with depression.
The aim of the study is to evaluate the association between physiological menopausal symptoms and depression during different menopausal period among female Taiwanese aborigines.
A total of 672 Taiwanese aboriginal women, aged 40–60, were recruited in the interviewing study and classified as pre-, peri-, and postmenopausal according to menstrual bleeding patterns in the previous 12 months. Then, the postmenopausal symptoms, depression, self-perceived health, family support, and associated demographic variables were assessed by questionnaire based on the results of interviewing by research assistants.
The results revealed that perimenopausal statuses were associated with depression and women with a perimenopausal status had a higher prevalence of depression than those with a premenopausal status. A higher score on physiological postmenopausal symptoms was found to be significantly associated with depression. Furthermore, somatic symptoms were associated with depression for pre-, peri-, and postmenopausal statuses. Moreover, sexual dysfunction and vasomotor symptoms were associated with depression only in the premenopausal status and postmenopausal status, respectively.
Depression should be routinely evaluated for female Taiwanese aborigines consulting with physicians for menopause symptoms, especially for somatic symptoms. Furthermore, attention should be provided to premenopausal women with sexual dysfunction and postmenopausal women with vasomotor symptoms for depression.
Post-stroke depression (PSD) is the most common psychiatric complication facing stroke survivors and has been associated with increased distress, physical disability, poor rehabilitation, and suicidal ideation. However, the pathophysiological mechanisms underlying PSD remain unknown, and no objective laboratory-based test is available to aid PSD diagnosis or monitor progression.
Here, an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach was performed to identify differentially expressed proteins in plasma samples obtained from PSD, stroke, and healthy control subjects.
The significantly differentiated proteins were primarily involved in lipid metabolism and immunoregulation. Six proteins associated with these processes – apolipoprotein A-IV (ApoA-IV), apolipoprotein C-II (ApoC-II), C-reactive protein (CRP), gelsolin, haptoglobin, and leucine-rich alpha-2-glycoprotein (LRG) – were selected for Western blotting validation. ApoA-IV expression was significantly upregulated in PSD as compared to stroke subjects. ApoC-II, LRG, and CRP expression were significantly downregulated in both PSD and HC subjects relative to stroke subjects. Gelsolin and haptoglobin expression were significantly dysregulated across all three groups with the following expression profiles: gelsolin, healthy control > PSD > stroke subjects; haptoglobin, stroke > PSD > healthy control.
Early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of PSD. The combination of increased gelsolin levels accompanied by decreased haptoglobin levels shows promise as a plasma-based diagnostic biomarker panel for detecting increased PSD risk in post-stroke patients.
Cardiovascular disease (CVD) and depressive disorders are the most two harmful problems for human health in the 21st century. The relationships between the two diseases are complicated, yet the mechanisms are not clear so far. This study addressed this issue by clarifying shared and unique factors between metabolic syndrome (MS) and mild psychiatric disorder (MPD) using the 8-year follow-up Landseed cohort.
A total of 5712 community residents were followed-up and analyzed. The point prevalence rates of MS and MPD and their comorbidity rate were estimated by each wave. Three multiple logistic regression models, with each treating MS, MPD, and comorbid condition as dependent variable, were compared to identify the shared and unique factors. Variables specifically correlate with MS or MPD are defined as unique factors; whilst those correlated with both MS and MPD or with comorbid condition as shared factors.
The point prevalence rates of MS ranged 13.83-14.26%, MPD ranged 17.17-19.60%, and comorbidity rates 2.75-3.07% in three waves. Educational level and weekly exercise frequency are shared factors of MS and MPD. Moderate personal income is a unique protective factor for MS; and male and abstaining from alcohol use are unique protective factors for MPD.
A balanced life style is beneficial for both physical and psychological health. Specifically, there are no dose-response effects between weekly exercise frequency and MS or MPD. It is important for clinicians and health educators to educate community people to engage in exercise in a proper way to improve public health.
Alcohol consumption is a part of the aboriginal culture. It was found that is a predominant health problem in aboriginal community. There was little research describing whether gender differences in harmful drinking and adverse drinking consequence among aborigines. Thus, it is important to evaluate such differences in order to provide evidence for developing interventions in problem drinking.
The aim of the study is to examine the gender differences in the prevalence, correlates, and adverse drinking consequences among harmful alcohol users in Taiwanese aborigines.
A cross-sectional survey was conducted. 449 study participants, aged 18-60, were recruited into the study from community-dwelling aborigines in southern Taiwan. Alcohol Use Disorders Identification Test (AUDIT) was used to collect information regarding harmful alcohol drinking. Personal characteristics, related risk factors and adverse drinking consequences were assessed by questionnaire.
The result revealed that the prevalence of harmful drinking in male users was 71.6%, female users were 49.2%. The results showed that female harmful alcohol users were more likely to have poor mental health, 58% of them with suicidal ideation, 50% with depression, more inactive in religious practice, and unemployed. It was also found that more than half of the male harmful alcohol users have adverse drinking consequence, including accidental injury, quarreled with others, and unable to work.
Harmful drinking was a predominant health problem in aborigines. This finding suggested that depression and suicidal ideation should be routinely evaluated for female harmful alcohol users by the professional of primary care.
Serotonin transporter (SERT) and dopamine transporter (DAT) levels differ in patients with major depressive disorder (MDD) who are in a depressed state in comparison with healthy controls. In addition, a family history of depression is a potent risk factor for developing depression, and inherited vulnerability to serotonergic and dopaminergic dysfunction is suspected in this. The aim of this study was to examine the availabilities of midbrain SERT and striatal DAT in healthy subjects with and without a first-degree family history of MDD.
Eight healthy subjects with first-degree relatives with MDD and 16 sex- and age-matched healthy controls were recruited. The availabilities of SERT and DAT were approximated using SPECT, employing [123I] 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) and [99mTc] TRODAT-1 as the ligands, respectively. There are missing data for one participant with a first-degree family history of MDD from the ADAM study, due to a lack of the radio-ligand at the time of experiment.
SERT availability in the midbrain was significantly lower in subjects with a first-degree family history of MDD than in healthy subjects. However, DAT availability was no different between two groups.
The results with regard to the midbrain SERT level suggest the heritability of MDD.
Current available antidepressants exhibit low remission rate with a long response lag time. Growing evidence has demonstrated acute sub-anesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant effects. However, a long term use of ketamine tends to elicit its adverse reactions. The present study aimed to investigate the antidepressant-like effects of intermittent and consecutive administrations of ketamine on chronic unpredictable mild stress (CUMS) rats, and to determine whether ketamine can redeem the time lag for treatment response of classic antidepressants. The behavioral responses were assessed by the sucrose preference test, forced swimming test, and open field test. In the first stage of experiments, all the four treatment regimens of ketamine (10 mg/kg ip, once daily for 3 or 7 consecutive days, or once every 7 or 3 days, in a total 21 days) showed robust antidepressant-like effects, with no significant influence on locomotor activity and stereotype behavior in the CUMS rats. The intermittent administration regimens produced longer antidepressant-like effects than the consecutive administration regimens and the administration every 7 days presented similar antidepressant-like effects with less administration times compared with the administration every 3 days. In the second stage of experiments, the combination of ketamine (10 mg/kg ip, once every 7 days) and citalopram (20 mg/kg po, once daily) for 21 days caused more rapid and sustained antidepressant-like effects than citalopram administered alone. In summary, repeated sub-anesthestic doses of ketamine can redeem the time lag for the antidepressant-like effects of citalopram, suggesting the combination of ketamine and classic antidepressants is a promising regimen for depression with quick onset time and stable and lasting effects.
We aimed to investigate the heterogeneity of seasonal suicide patterns among multiple geographically, demographically and socioeconomically diverse populations.
Weekly time-series data of suicide counts for 354 communities in 12 countries during 1986–2016 were analysed. Two-stage analysis was performed. In the first stage, a generalised linear model, including cyclic splines, was used to estimate seasonal patterns of suicide for each community. In the second stage, the community-specific seasonal patterns were combined for each country using meta-regression. In addition, the community-specific seasonal patterns were regressed onto community-level socioeconomic, demographic and environmental indicators using meta-regression.
We observed seasonal patterns in suicide, with the counts peaking in spring and declining to a trough in winter in most of the countries. However, the shape of seasonal patterns varied among countries from bimodal to unimodal seasonality. The amplitude of seasonal patterns (i.e. the peak/trough relative risk) also varied from 1.47 (95% confidence interval [CI]: 1.33–1.62) to 1.05 (95% CI: 1.01–1.1) among 12 countries. The subgroup difference in the seasonal pattern also varied over countries. In some countries, larger amplitude was shown for females and for the elderly population (≥65 years of age) than for males and for younger people, respectively. The subperiod difference also varied; some countries showed increasing seasonality while others showed a decrease or little change. Finally, the amplitude was larger for communities with colder climates, higher proportions of elderly people and lower unemployment rates (p-values < 0.05).
Despite the common features of a spring peak and a winter trough, seasonal suicide patterns were largely heterogeneous in shape, amplitude, subgroup differences and temporal changes among different populations, as influenced by climate, demographic and socioeconomic conditions. Our findings may help elucidate the underlying mechanisms of seasonal suicide patterns and aid in improving the design of population-specific suicide prevention programmes based on these patterns.
The small intestine is an important digestive organ and plays a vital role in the life of a pig. We tested the hypothesis that the length of the small intestine is related to growth performance and intestinal functions of piglets. A total of 60 piglets (Duroc × Landrace × Yorkshire), weaned at day 21, were fed an identical diet during a 28-day trial. At the end of the study, all piglets were sacrificed, dissected and grouped according to small intestine lengths (SILs), either short small intestine (SSI), middle small intestine (MSI) or long small intestine (LSI), respectively. Positive relationships between SIL and BW, average daily gain (ADG), average daily feed intake (ADFI) and gain-to-feed ratios (G : F) were observed. Final BW, ADG, ADFI and G : F significantly increased (P < 0.05) in MSI and LSI piglets compared with SSI piglets. Short small intestine and MSI had greater jejunal mucosa sucrase and alkaline phosphatase activities (P < 0.05) than LSI piglets. The mRNA level of solute carrier family 2 member 2 (Slc2a2) in the jejunal mucosa of SSI piglets was the greatest. The MSI piglets had a greater (P < 0.05) ileal villus height than other piglets and greater (P < 0.05) villus height-to-crypt depth ratios than LSI piglets. However, the LSI piglets had a greater (P < 0.05) ileal crypt depth than SSI piglets. No significant differences in duodenal, jejunal, caecal and colonic morphologies were detected among the groups. Moreover, luminal acetate, propionate, butyrate and total short-chain fatty acid contents were greater (P < 0.05) in SSI and MSI piglets than those in LSI piglets. In addition, there was greater serum glucose concentration in MSI piglets than other piglets. Serum albumin concentration in SSI piglets was the lowest. In conclusion, these results indicate that SIL was significantly positively associated with growth performance, and in terms of intestinal morphology and mucosal digestive enzyme activity, the piglets with a medium length of small intestine have better digestion and absorption properties.
Adolescents have been largely neglected from tuberculosis control efforts. In low- to medium burden settings much of the tuberculosis burden in this age group occurs from school outbreaks. We report on a large tuberculosis outbreak in adolescents from a boarding high school in Jiangsu Province, China. From March to June 2018, a tuberculosis outbreak occurred in a boarding high school. We conducted an outbreak investigation involving clinical diagnostic tests and molecular analysis to determine the outbreak origin. Cases were detected through symptom screening, tuberculin skin testing (TST), chest radiography, sputum smear, solid sputum culture and GeneXpert MTB/RIF. Mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) genotyping and spoligotyping methods were performed on Mycobacterium tuberculosis (M. tuberculosis) isolates to identify the outbreak origin. A total of 845 students and 131 teachers/staff attended a TST screening for tuberculosis infection. The prevalence of elevated tuberculin reactions at ≥5, ≥10 and ≥15 mm was 12.19% (119/976), 6.35% (62/976) and 3.28% (32/976), respectively. Radiographic abnormalities were present in 5.73% (56 of 976) individuals, 40 students and 16 teachers/staff. Of these, 12 students were diagnosed with confirmed tuberculosis. In total, 14 students (two index cases and 12 confirmed cases) were diagnosed and reported in the tuberculosis outbreak, an attack rate of 1.7% (14/847) among students (two index cases and 845 screened students). Results from MIRU-VNTR typing and spoligotyping analyses demonstrated that three M. tuberculosis strains belong to the Beijing family with corresponding MIRU-VNTR alleles. This school-based tuberculosis outbreak among adolescents demonstrates that transmission among individuals in this age group is common and must be prioritised. It suggests that identifying and timely diagnosis of smear-positive cases, especially in the early phase of outbreaks, is the key to preventing further spread among close contacts.
In this study, the thermal deformation of a machine tool structure due to the heat generated during operation was analyzed, and embedded cooling channels were applied to exchange the heat generated during the operation to achieve thermal error suppression. Then, the finite volume method was used to simulate the effect of cooling oil temperature on thermal deformation, and the effect of thermal suppression was experimentally studied using a feed system combined with a cooler to improve the positioning accuracy of the machine tool. In this study, the supply oil temperature in the structural cooling channels was found to significantly affect the position accuracy of the moving table and moving carrier. If the supply oil temperature in the cooling channels is consistent with the operational ambient temperature, the position accuracy of the moving table in the Y direction and the moving carrier in the X and Z directions has the best performance under different feed rates. From the thermal suppression experiments of the embedded cooling channels, the positioning accuracy of the feed system can be improved by approximately 25.5 % during the dynamic feeding process. Furthermore, when the hydrostatic guideway is cooled and dynamic feeding is conducted, positioning accuracy can be improved by up to 47.8 %. The machining accuracy can be improved by approximately 60 % on average by using the embedded cooling channels in this study. Therefore, thermal suppression by the cooling channels in this study can not only effectively improve the positioning accuracy but also enhance machining accuracy, proving that the method is effective for enhancing machine tool accuracy.
Flow over aligned and staggered cube arrays is a classic model problem for rough-wall turbulent boundary layers. Earlier studies of this model problem mainly looked at rough surfaces with a moderate coverage density, i.e.
is the surface coverage density and is defined to be the ratio between the area occupied by the roughness and the total ground area. At lower surface coverage densities, i.e.
, it is conventionally thought that cubical roughness acts like isolated roughness elements; and that the single-cube drag coefficient, i.e.
is the drag force on one cubical roughness element,
is the fluid density,
is the height of the cube,
is the spatially and temporally averaged wind speed at the cube height, and
is the drag coefficient of an isolated cube. In this work, we conduct large-eddy simulations and direct numerical simulations of flow over wall-mounted cubes with very low surface coverage densities, i.e.
. The large-eddy simulations are at nominally infinite Reynolds numbers. The results challenge the conventional thinking, and we show that, at very low surface coverage densities, the single-cube drag coefficient may increase as a function of
. Our analysis suggests that this behaviour may be attributed to secondary turbulent flows. Secondary turbulent flows are often found above spanwise-heterogeneous roughness. Although the roughness considered in this work is nominally homogeneous, the secondary flows in our simulations are very similar to those observed above spanwise-heterogeneous surface roughness. These secondary vortices redistribute the fluid momentum in the outer layer, leading to high-momentum pathways above the wall-mounted cubes and low-momentum pathways at the two sides of the wall-mounted cubes. As a result, the spatially and temporally averaged wind speed at the cube height, i.e.
, is an underestimate of the incoming flow to the cubes, which in turn leads to a large drag coefficient
Some studies have shown that the excessive metabolic heat production is the primary cause for dead chicken embryos during late embryonic development. Increasing heat shock protein (HSP) expression and adjusting metabolism are important ways to maintain body homeostasis under heat stress. This study was conducted to investigate the effects of in ovo injection (IOI) of vitamin C (VC) at embryonic age 11th day (E11) on HSP and metabolic genes expression. A total of 320 breeder eggs were randomly divided into normal saline and VC injection groups. We detected plasma VC content and rectal temperature at chick’s age 1st day, and the mRNA levels of HSP and metabolic genes in embryonic livers at E14, 16 and 18, analysed the promoter methylation levels of differentially expressed genes and predicted transcription factors at the promoter regions. The results showed that IOI of VC significantly increased plasma VC content and decreased rectal temperature (P < 0.05). In ovo injection of VC significantly increased heat shock protein 60 (HSP60) and pyruvate dehydrogenase kinase 4 (PDK4) genes expression at E16 and PDK4 and secreted frizzled related protein 1 (SFRP1) at E18 (P < 0.05). At E16, IOI of VC significantly decreased the methylation levels of total CpG sites and −336 CpG site in HSP60 promoter and −1137 CpG site in PDK4 promoter (P < 0.05). Potential binding sites for nuclear factor-1 were found around −389 and −336 CpG sites in HSP60 promoter and potential binding site for specificity protein 1 was found around −1137 CpG site in PDK4 promoter. Our results suggested that IOI of VC increased HSP60, PDK4 and SFRP1 genes expression at E16 and 18, which may be associated with the demethylation in gene promoters. Whether IOI of VC could improve hatchability needs to be further verified by setting uninjection group.
We conducted active surveillance of acute respiratory viral infections (ARIs) among residents and healthcare personnel (HCP) at a long-term care facility during the 2015–2016 respiratory illness season. ARIs were observed among both HCP and patients, highlighting the importance of including HCP in surveillance programs.
Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a multi-systemic, heterogenous, life-threatening disease. Patisiran resulted in significant improvement in neuropathy and QoL at 18-months compared to placebo, and was generally well-tolerated in the Phase 3 APOLLO study. Methods: Multi-center, OLE study to evaluate the efficacy and safety of long-term patisiran dosing for ≤ 5 years in hATTR amyloidosis patients with polyneuropathy who have completed the APOLLO study (NCT02510261). Endpoints include safety, tolerability and long-term efficacy of patisiran. Measures of clinical benefit are the same endpoints used in APOLLO including changes in mNIS+7 composite neuropathy impairment score and QoL (Norfolk QoL-DN) Results: As of December 2017, 184 of 186 (99%) patients who completed APOLLO and 25 patients from the Ph 2 OLE study enrolled in the Global OLE study. Baseline data for 211(APOLLO/placebo, n=49; APOLLO/patisiran, n=137 and patisiran Ph 2 OLE, n=25) patients included: median age 61 years (26-84); 74% males; 46% V30M. Interim safety data and 12-month efficacy results will be presented. Conclusions: The global OLE study includes a diverse population of hATTR amyloidosis patients. Interim data will include the long-term safety and maintenance of effect in patients continuing on patisiran, as well as the impact of treatment with patisiran on patients previously treated with placebo.