While we report a median frequency of 40 tests per year (IQR 31

While we report a median frequency of 4.0 tests per year (IQR 3.1–5.3), provincial differences were noted [4.6 (IQR 3.4–6.0) in British Columbia, 3.7 (IQR 2.8–4.7) in Ontario, and 3.7 (IQR 2.9–4.5) in Quebec; P<0.0001]. These differences in testing rates may have influenced our findings. In terms of clinical significance, the click here benefits of more rapid suppression are still being explored. However, a recent re-analysis of two past clinical trials determined that the timing of initial suppression was not a reliable predictor of long-term suppression [19]. Exploration of the potential benefits of earlier suppression in additional cohorts with extended follow-up periods would

be beneficial. Careful selection of the antiretrovirals composing a HAART regimen is critical to patient tolerance and adherence. Our findings are consistent with those of other studies in demonstrating the importance of the initial

HAART regimen in the probability and rate of achieving virological suppression buy GSK2118436 [11,12,20]. As indicated here, individuals starting on ritonavir-boosted PI regimens or NNRTI regimens were more likely to achieve suppression than patients on unboosted PI regimens. This is probably related to side-effect profiles and convenience of dosing schedules. Our finding suggesting the superior virological efficacy of efavirenz compared with nevirapine is of interest, but should be interpreted cautiously. While this finding corresponds to the results of some other cohort studies comparing these two NNRTIs [11,21–23], it contrasts with the results of the 2NN randomized trial, in which no differences in virological Selleckchem RG7420 suppression were documented after 48 weeks of therapy [24]. Indeed, our “time to” analysis may have limited our ability to compare suppression between these antiretrovirals at a specific point later in follow-up, and it is possible that the differences ceased later on. The differences could also be a result of confounding, if patients thought to be less likely to adhere were prescribed nevirapine. For example, patients with depressive symptoms are often less able to tolerate efavirenz compared with nevirapine and may

be less adherent. Preferential prescription of nevirapine to these patients may at least partially explain our findings. However, as we lack data on treatment adherence and reasons behind initial prescriptions, this cannot be ascertained. Possible cohort biases (described later in this section) may also explain our findings. Importantly, on the basis of these data, we cannot draw any specific conclusions about the relative overall efficacies of these drugs as we did not compare the probabilities of subsequent virological failure, regimen switching, or adverse events in our analyses. Individuals with lower baseline viral load measurements and those with AIDS diagnoses at baseline were more likely to achieve virological suppression.

In this study, we attempted to investigate the potency of allicin

In this study, we attempted to investigate the potency of allicin against C. albicans, the predominant fungal species isolated from human infections. Allicin alone could exhibit antifungal activity, and when used in synergy with antimicrobial agents, it increased the efficacy of the therapeutic agents (Aala et al., 2010; Khodavandi et al., 2010). For example, combination of allicin

with amphotericin B and fluconazole has been demonstrated to have a significant synergistic effect in a mouse model of systemic candidiasis (An et al., 2009; Guo et al., 2010). Garlic and some of its derivatives destroy the Candida cell membrane integrity (Low JNK screening et al., 2008), inhibit growth (Lemar et al., 2002) and produce oxidative stress (Lemar et al., 2005) in C. albicans. Most of these abilities are related to an SH-modifying potential, because the activated disulfide bond of allicin has an effect on thiol-containing Gemcitabine compounds such as some proteins; however, the main targets of allicin on Candida are not well understood. It has been demonstrated that the antifungal activity

of allicin in vivo may be related to some secondary metabolites such as ajoene, diallyl trisulfide and diallyl disulfide, because the chemical structure of allicin is too unstable and converts to these secondary products immediately (Miron et al., 2004). Nonetheless, little is known about the potential in vivo activity of allicin against Candida. In this study, we used fluconazole as the standard anticandidal drug for comparison against allicin. The MICs of allicin Galeterone and fluconazole against C. albicans fell within the ranges 0.05–12 and 0.25–16 μg mL−1, respectively (Table 1), which is similar to findings from previous reports (Ankri & Mirelman, 1999; Khodavandi et al., 2010). All of the samples were sensitive to fluconazole and drug resistance was not seen. The time–kill study demonstrated a significant inhibition of Candida growth comparing untreated controls against those treated with allicin

and fluconazole, using inoculum sizes of 1 × 106 Candida cells mL−1 (P<0.05) and 1 × 104 Candida cells mL−1 (P<0.001) after 2- and 4-h incubation, respectively. This demonstrates that allicin decreased the growth of C. albicans almost as efficiently as fluconazole (P>0.05) for both inoculum sizes of Candida, demonstrating a comparable ability to inhibit the growth of the yeast cells (Fig. 1). The presence of pits on the cell surface and cellular collapse with high concentrations of allicin indicates that the cell membrane could be one of the targets of allicin in Candida (Lemar et al., 2002), whereas fluconazole in high concentrations can destroy the Candida cell entirely (Fig. 2).

People from the same village tend to resemble each other more tha

People from the same village tend to resemble each other more than people from different villages in terms of disease risk [33]. In addition, individuals in a household cluster are not usually ‘independent’ of each other. However, a significant design effect seems unlikely in a national survey including over

10 000 participants [34]. Another factor contributing to discrepancies between the local Manhiça and national surveys may lie in the age limits of the two surveys. Unlike the national survey, teenagers were not included in the current cross-sectional survey. HIV infection rates in teenagers are usually lower than in adults and including them in a survey could decrease the overall community

HIV prevalence estimate. As this was the first HIV population-based survey in the Manhiça INK 128 in vitro community, its acceptability was unknown and the survey was thus limited to adults. Future community studies in this and similar settings should include individuals younger than 18 and older than 47 years. ANC prevalence estimates generally provide useful information for monitoring HIV epidemic trends over time and have traditionally been used to estimate national rates [6]. The current findings show that, in this area, data derived from the ANC surveillance underestimate the HIV prevalence rates of women in the community, in all age groups but especially in the youngest group (18–27 years). These results are in agreement with AG-014699 nmr those of other studies [5, 35, 36]. The representativeness of participants and

nonresponse bias have been suggested as explanations for discrepancies between ANC and community estimates [3]. A plausible reason for Vitamin B12 the underestimation of the number of women infected with HIV in Manhiça based on the data from the ANC is the association of HIV infection and subfertility [37, 38]. HIV-infected women are generally less likely to become pregnant and would therefore be underrepresented at the ANC services [37]. It has been hypothesized that ‘hotspots’ for HIV infection may exist in small southern African communities [39]. For instance, migration [11] is known to be important in Manhiça District and could play an important role in local HIV transmission patterns [20]. Its location on the north–south highway and railway corridor between Maputo and Beira may also contribute to the particularly high HIV prevalence estimate found in the Manhiça area. In agreement with studies from Zambia and Cameroon [35, 40], HIV prevalence in the Manhiça community increased with age in both women and men. However, some population-based studies from South Africa have shown a decrease in HIV infection rates in the third decade of age [31, 41].

This observation is probably attributable to the impact of age in

This observation is probably attributable to the impact of age in all these risk indices and to the fact that HIV-infected patients are usually young. http://www.selleckchem.com/products/idasanutlin-rg-7388.html This finding also supports the conclusion that different tools to address the clinical status of this patient population need to be developed. CIMT together with inflammatory and oxidative biomarkers may be useful measurements for a more precise CVD risk assessment in these patients. Carotid ultrasonography is a noninvasive

diagnostic tool that provides a direct image of the arterial wall, and is strongly related to coronary atherosclerosis. Hence, CIMT is useful in making clinical decisions regarding implementation of therapy to prevent future adverse cardiovascular events. Also, the CIMT measurement enables the effect of treatments on atherosclerosis progression/regression to be evaluated in patient

Selleck GSK126 follow-up. Unfortunately, we have not measured CIMT in age- and gender-matched control subjects and we are therefore unable to present carotid thickness comparisons. However, a recent meta-analysis showed that CIMT in healthy populations is around 0.6–0.7 mm on average, similar to the values obtained in the present investigation in HIV-infected patients without atherosclerosis [16]. HIV-infected patients have a higher CVD risk, mainly because of lipid disturbances promoted by antiretroviral drugs, as well as the HIV infection itself. We found a higher rate of an abnormal fasting glucose, high blood pressure and lipodystrophy in the HIV-infected patients with atherosclerosis, reflecting insulin resistance associated with HIV infection and the antiretroviral from drugs used [33,34]. Paradoxically, a low BMI was associated with greater CIMT. A low BMI in HIV-infected patients is often attributable to the wasting syndrome and immune system depletion. Hence, the elevated inflammatory and oxidative activities that characterize this situation could, at least in part, explain this correlation. The results of the present

study suggest that the chronic oxidative and inflammatory status related to HIV infection may explain the discrepancy we observed between the presence of subclinical atherosclerosis and the FRS. Indeed, plasma MCP-1 concentrations were significantly increased in patients with subclinical atherosclerosis and low CVD risk estimated by the FRS and, in the multivariate analysis, both serum oxLDL and MCP-1 concentrations were associated with the presence of atherosclerosis. This finding is of particular note as these biochemical parameters can be measured relatively easily in order to improve the ability to identify at-risk individuals. In addition, the relationship between these markers and vascular lesions suggests that anti-inflammatory and antioxidant treatments could assist in the management of CVD risk in these patients. However, a caveat is that the OR for the association between these parameters and the presence of atherosclerosis was relatively small.

In HIV-1-uninfected women, the data regarding the effect of scree

In HIV-1-uninfected women, the data regarding the effect of screening for and treating BV find more on premature delivery are conflicting. As outlined above, in HIV-positive pregnant women there

are additional considerations regarding the potential effect of genital infections on MTCT of HIV-1, but these data are largely from the pre-cART era. In the setting of full virological suppression on cART it is unclear to what extent, if any, the presence of any genital infection will contribute to HIV MTCT. Newly diagnosed HIV-positive pregnant women should be screened for sexually transmitted infections as per the routine management of newly diagnosed patients [48]. For pregnant HIV-1-positive women already engaged in HIV care, in the absence of randomized controlled trials but for the reasons outlined above, the Writing Group suggests screening for genital tract infections including evidence of BV. This should be done as early as possible in pregnancy and

consideration should be given to repeating this PF-02341066 datasheet at around 28 weeks. Syphilis serology should be performed on both occasions. In addition, any infection detected should be treated according to the BASHH guidelines (www.bashh.org/guidelines), followed by a test of cure. Partner notification should take place where indicated, to avoid re-infection. With regard to cervical cytology, HIV-positive pregnant women should be managed as per the Guidelines for the NHS Cervical Screening Programme 2010 [49]. Routine cytology should be deferred until after the delivery, but if follow-up cytology or colposcopy is advised because of a previously abnormal result, then this should be undertaken. GBA3 4.2.1 Newly diagnosed HIV-positive pregnant women do not require any additional baseline investigations compared with non-pregnant HIV-positive women other than those routinely performed in the general antenatal clinic. Grading: 1D 4.2.2 HIV resistance testing should be performed prior to initiation of treatment (as per BHIVA guidelines for the

treatment of HIV-1 positive adults with antiretroviral therapy 2012; www.bhiva.org/PublishedandApproved.aspx), except for late-presenting women. Post short-course treatment a further resistance test is recommended to ensure that mutations are not missed with reversion during the off-treatment period. Grading: 1D In the case of late-presenting women, cART, based on epidemiological assessment of resistance, should be initiated without delay and modified once the resistance test is available. 4.2.3 In women who either conceive on cART or who do not require cART for their own health there should be a minimum of one CD4 cell count at baseline and one at delivery. Grading: 2D 4.2.4 In women who commence cART in pregnancy a viral load should be performed 2–4 weeks after commencing cART, at least once every trimester, at 36 weeks and at delivery.

For this, 10-mL samples were harvested, centrifuged, microfiltere

For this, 10-mL samples were harvested, centrifuged, microfiltered (0.45-μm pore size), and then concentrated by ultrafiltration using 15-mL ultracentrifuge filter devices with a cut-off of 10 kDa (Comitini et al., 2004b). The trials were carried out in duplicate. After fermentation, the main undesired compounds learn more produced by D. bruxellensis, as acetic acid (volatile acidity) and 4-ethyl phenol, were determined. The volatile acidity was determined by steam distillation following the procedures of the European Community (EC, 2000), and

4-ethyl phenol concentrations (vinyl phenols) were measured according to the protocol described by Chatonnet et al. (2006), using a GC-flame ionization detector. An anova was applied to the experimental data. The values of means were analysed using the software superanova

version 1.1 for Mac OS 9.1. The significant differences were determined by Duncan tests and the results were considered significant if the associated P value was <0.01. Our previous studies have shown that Kwkt production is enhanced by the presence of yeast extract and organic nitrogen compounds in the growth medium (data not shown). However, to avoid high-molecular-mass compounds in the supernatant and to facilitate the purification of Kwkt, we used SSM in the present study as a new substrate for K. wickerhamii growth and Kwkt production. As expected, the use of SSM resulted in a limited amount of total protein and a reduced killer

activity in comparison Crizotinib G protein-coupled receptor kinase with a richer media (Comitini et al., 2004a). Ultrafiltration procedures provided a concentration of 153-fold that from the culture broth, with a preliminary partial purification Kwkt (Table 1). Purified Kwkt was obtained after the DEAE-Sepharose Fast-Flow anion-exchange step. The 7-mL (75 mM) NaCl fraction from the elution contained the Kwkt killer activity, and the purification of the Kwkt protein was increased to 5005-fold, with a recovery of 4.2% (Table 1). Figure 1, lane (1), shows the purified profile of Kwkt with silver staining following SDS-PAGE, with an apparent molecular mass of 72 kDa, as eluted from the anion-exchange chromatography and reconcentrated 20-fold after a second step of ultrafiltration. Treatment of the purified Kwkt protein with endoglycosidase H did not show any reduction in the molecular mass of purified Kwkt [Fig. 1b, lanes (3), (4); positive control, lanes (1), (2)], demonstrating that Kwkt is a protein without a glycosyl portion. As previously shown using partially purified Kwkt (Comitini et al., 2004a) over the duration of the must microfermentations, the biomass evolution of S. cerevisiae selected wine strain (EC1118) showed typical kinetics and did not appear to be influenced by the presence of either the D. bruxellensis or the Kwkt (data not shown).

Thirteen DDBs were isolated from every enrichment culture using t

Thirteen DDBs were isolated from every enrichment culture using the R2A agar

or 100-fold-diluted NA plates. Gram staining revealed that nine strains were Gram-positive and four were Gram-negative. The bacterial 16S rRNA genes were analysed and the results are summarized in Table 1. Phylogenetic analysis was performed by constructing neighbour-joining trees. As shown in Fig. 2a, the Gram-positive strains (SS1, SS2, SS3, SS4, LS1, LS2, YMN1, YUL1, PFS1) were closely related to the genus Nocardioides in the family Nocardioidaceae, forming four clusters. Levels of 16S rRNA gene sequence similarity ranged from 92% to 100%. The Gram-negative strains (SS5, RS1, NKK1, NKJ1) were closely related to the genus Devosia in the family Hyphomicrobiaceae, forming two clusters, and their 16S rRNA gene sequence similarities ranged from 95% to 100%. AZD1208 purchase The initial DON degradation rates using the washed cells of the strains preincubated AZD1152-HQPA research buy with DMM, 1/3LB and 1/3R2A were examined (Table 1). All of the strains preincubated with DMM showed DON-degrading activities, and degraded 100 μg mL−1 of DON

to below the detection limit (0.5 μg mL−1) after the 24 h of incubation. Among the strains, SS5 and RS1 showed high rates of DON degradation, which were more than three times those of the other strains. Although strains NKK1 and NKJ1 were closely related to strains SS5 and RS1, the degradation rates were lower. Strains SS5, RS1 and NKJ1 expressed DON-degrading activities regardless of the preincubation media used. Preincubation with 1/3LB enhanced the DON-degrading activities of strains SS5 and RS1, but repressed that of NKK1. These results provided insight into the diversity of DON-degradation phenotypes within closely related strains. Meanwhile,

all of the Gram-positive strains exhibited high DON-degrading activities by preincubation with DMM, although they exhibited Erastin very low activities by preincubation with 1/3R2A or 1/3LB. That the buffer with autoclaved cells did not decrease the concentration of DON and that the buffer filtrates during DON degradation also did not (data not shown) indicate that the decrease of DON is attributed to the enzymatic reactions catalysed in the living cells. Figure 3a and b show the time course of DON degradation, and HPLC elution profiles of DON and its metabolites in washed cells of representative strains LS1, SS5 and these autoclaved strains. The profiles of the two strains showed at least three peaks in addition to the DON peak (6.5 min); one peak corresponded to the peak in the authentic standards of 3-epi-DON (4.5 min), indicating that both strains produced 3-epi-DON. The HPLC elution profiles also revealed unidentified peaks at 3.0 and 6.9 min in the RS1 sample, and at 1.6 and 4.8 min in the LS1 sample. These peaks were not detected when DDBs were autoclaved or were incubated without DON (Fig. 3c), indicating that these peaks were the products derived from DON.

Little is known about patient perception of paediatric oral medic

Little is known about patient perception of paediatric oral medicine services offered in relation to these conditions. The concept of a diary is increasingly recognised as a valuable way to capture patient events and perspective in healthcare research.

This article provides the background to the use of solicited diaries as a method of accessing the perspective of children and young people and describes a service evaluation that aimed to explore the experiences of young people with chronic oral ulcers attending the paediatric oral medicine clinic in a UK Dental Hospital. Chronic oral ulcers were found to significantly impact on a variety of physical and psychosocial aspects of young find more people’s lives. Overall, feedback regarding the specialist service was positive but suggestions were Selleck Panobinostat made for

improvements. This article reviews the use of the solicited diary within healthcare research. It also illustrates the value of the diary in exploration of children and young people’s perspective on their chronic oral mucosal disease. In addition, a need for further research in this area has been highlighted. “
“International Journal of Paediatric Dentistry 2012; 22: 363–368 Background.  Effective caries control and management requires identification of susceptible children for timely intervention. Streptococcus mutans (S. mutans) is an important biomarker of caries risk. Aim.  This study aimed to comparatively evaluate the validities of a novel immunoassay and a conventional culture-based assay in detecting salivary S. mutans in a paediatric cohort. Methods.  190 children aged 3–4 years were recruited. The abundance of S. mutans in their saliva samples was analysed with three assay systems viz. a conventional culture-based assay (Dentocult SM), a novel immunoassay system (Saliva-Check MUTANS) based on monoclonal antibody technology and a Taqman

real-time PCR assay taken as a gold standard. Results.  The novel immunoassay accurately differentiated saliva samples with high (≥5 × 105 CFU/mL) and low (<5 × 105 CFU/mL) S. mutans levels. The sensitivity/specificity was 97.6%/90.6%. The conventional culture-based assay reached a reasonably high sensitivity/specificity (92.8%/81.3%) in identifying Olopatadine children with moderate (≥104 CFU/mL) S. mutans level. Its sensitivity/ specificity in selecting children with high (≥105 CFU/mL) and very high (>106 CFU/mL) S. mutans levels were not sufficient (78.7%/79.8% and 25.8%/91.8%, respectively). Conclusion.  The monoclonal antibody-based immunoassay accurately and rapidly determines S. mutans abundance in saliva and could be useful for chairside assessment of children’s caries risk. “
“Childhood obesity, dental caries, and periodontal disease are major public health problems due to their adverse impact on the growth and development of children. To examine the association between nutritional status, oral health, and lifestyle habits among schoolchildren in Serbia.

We determined that in this data set missingness may be categorize

We determined that in this data set missingness may be categorized as MAR, as the probability of the missing value is likely to be independent of the value itself but dependent on the values of other variables in the data set. We assessed the potential effect of missing

selleck inhibitor data on our effect estimates, by using a multiple imputation method with five imputed data sets [23–25]. Similar to the complete case analysis, a binomial regression model with a Poisson distribution and a robust error variance was run on the imputed data sets. Intercooled stata (version 9.0; Stata Corporation, College Station, TX, USA) was used for all analyses. The multiple imputation was conducted using Stata’s ice program [26]. Between 1996 and 2006, 738 treatment-naïve persons initiated HAART. One-third (n=224) of patients initiated and received HAART by participating in 13 different HIV treatment trials. Nine trials were sponsored by the ACTG and four by pharmaceutical

companies (Table 1). The mean age of patients was 38.5 years (SD 9.0 years), 31% were women, 62% were Black, 28% were White, 6.8% were Hispanic and almost 2% were Native American (Table 2). More than a third (37.4%) of subjects had no insurance; one-quarter (25.6%) had public insurance (Medicaid and/or Medicare). At baseline, 26% of subjects had an AIDS diagnosis, the median CD4 cell count was 157 cells/μL [interquartile range (IQR) 40–345 cells/μL] and the mean viral load was 4.7 log10 (SD 1.0) HIV-1 RNA copies/mL. One-half of subjects initiated HAART within 5 months of receiving a diagnosis of HIV infection. The median distance buy LY294002 travelled one way to receive care at the UNC ID clinic was 47 miles (IQR 27–71 miles). The major risk factor for HIV acquisition was heterosexual intercourse (54.1%) with only 13% of subjects reporting IDU as a risk factor. Trial participation rates for MSM, heterosexual men and women were respectively 36.5, 29.6 and 24.3%, and these rates differed significantly (P=0.02). In bivariable analysis, compared with MSM, heterosexual men [prevalence

ratio (PR) 0.81, 95% confidence interval (CI) 0.63, Chloroambucil 1.04] and women (PR 0.67, 95% CI 0.50, 0.88) were less likely to enrol in HIV treatment trials. After adjustment, heterosexual men were slightly less likely (PR 0.79, 95% CI 0.57, 1.11) and women were no less likely (PR 0.97, 95% CI 0.68, 1.39) to enter these trials than MSM (Table 3). To evaluate which variables were responsible for the substantial change in the adjusted prevalence ratio comparing women with MSM, we eliminated variables one at a time from the multivariable model and found that insurance status and months from HIV diagnosis to HAART initiation accounted for most of the change. Without adjusting for months from HIV diagnosis to HAART initiation, women were 14% less likely to participate in trials (PR 0.86, 95% CI 0.62, 1.18).

We determined that in this data set missingness may be categorize

We determined that in this data set missingness may be categorized as MAR, as the probability of the missing value is likely to be independent of the value itself but dependent on the values of other variables in the data set. We assessed the potential effect of missing

Epacadostat chemical structure data on our effect estimates, by using a multiple imputation method with five imputed data sets [23–25]. Similar to the complete case analysis, a binomial regression model with a Poisson distribution and a robust error variance was run on the imputed data sets. Intercooled stata (version 9.0; Stata Corporation, College Station, TX, USA) was used for all analyses. The multiple imputation was conducted using Stata’s ice program [26]. Between 1996 and 2006, 738 treatment-naïve persons initiated HAART. One-third (n=224) of patients initiated and received HAART by participating in 13 different HIV treatment trials. Nine trials were sponsored by the ACTG and four by pharmaceutical

companies (Table 1). The mean age of patients was 38.5 years (SD 9.0 years), 31% were women, 62% were Black, 28% were White, 6.8% were Hispanic and almost 2% were Native American (Table 2). More than a third (37.4%) of subjects had no insurance; one-quarter (25.6%) had public insurance (Medicaid and/or Medicare). At baseline, 26% of subjects had an AIDS diagnosis, the median CD4 cell count was 157 cells/μL [interquartile range (IQR) 40–345 cells/μL] and the mean viral load was 4.7 log10 (SD 1.0) HIV-1 RNA copies/mL. One-half of subjects initiated HAART within 5 months of receiving a diagnosis of HIV infection. The median distance Selleckchem Pexidartinib travelled one way to receive care at the UNC ID clinic was 47 miles (IQR 27–71 miles). The major risk factor for HIV acquisition was heterosexual intercourse (54.1%) with only 13% of subjects reporting IDU as a risk factor. Trial participation rates for MSM, heterosexual men and women were respectively 36.5, 29.6 and 24.3%, and these rates differed significantly (P=0.02). In bivariable analysis, compared with MSM, heterosexual men [prevalence

ratio (PR) 0.81, 95% confidence interval (CI) 0.63, Interleukin-2 receptor 1.04] and women (PR 0.67, 95% CI 0.50, 0.88) were less likely to enrol in HIV treatment trials. After adjustment, heterosexual men were slightly less likely (PR 0.79, 95% CI 0.57, 1.11) and women were no less likely (PR 0.97, 95% CI 0.68, 1.39) to enter these trials than MSM (Table 3). To evaluate which variables were responsible for the substantial change in the adjusted prevalence ratio comparing women with MSM, we eliminated variables one at a time from the multivariable model and found that insurance status and months from HIV diagnosis to HAART initiation accounted for most of the change. Without adjusting for months from HIV diagnosis to HAART initiation, women were 14% less likely to participate in trials (PR 0.86, 95% CI 0.62, 1.18).