The corresponding rates among those who received counseling

The corresponding rates among those who received counseling selleck Idelalisib were 17% and 21%. The treatment effect was statistically significant in both groups (p < .05 among African Americans; p < .001 among non-Hispanic Whites). The trend toward lower quitting rates among African Americans in both treatment groups was not significant. In the 7-month follow-up of smokers from the two states and district who enrolled in counseling during 2006�C2007, there were no significant differences between African Americans and non-Hispanic Whites in reported 30-day point prevalence of abstinence from smoking among respondents: 24% versus 27% in Texas, 29% versus 27% in Louisiana, and 23% versus 23% in DC. Among African Americans in all three locations, there were no significant differences in reported abstinence as a function of gender; 30%�C36% of the African Americans were male.

Further analyses examined satisfaction with the service. The mean satisfaction levels among African Americans on a 4-point scale were 3.5 in Texas, 3.3 in Louisiana, and 3.3 in DC. Corresponding means among non-Hispanic Whites were 3.4, 3.3, and 3.2. None of the differences between locations or groups were significant. Discussion In examining disparities in smoking cessation outcomes from 1990 to 2000 between Whites and African Americans, King et al. (2004) found lower cessation rates for African Americans. The current data do not show a difference and should be distinguished in important respects. King et al. looked at data from National Health Interview Surveys across all modalities of cessation assistance available at that time.

From 1990 to 2000, only a few states offered quitline services, so quitlines did not substantially contribute to the findings of King et al. The current data are based on quitline data collected after 2000. Quitlines provide individually tailored cessation assistance, which may contribute to the equivalence of cessation rates across groups in the current data. This paper presents empirical data from Texas, Louisiana, and DC that demonstrate that telephone counseling for smoking cessation is as effective for African Americans as it is for non-Hispanic Whites. Finding similar patterns of results for effectiveness, utilization, and satisfaction across all three areas studied strengthens the generalizability of those findings. Data from a randomized trial were included to show that the equivalence of effectiveness was found in a randomized sample as well as among self-selected empirical populations, further strengthening confidence in that finding. Governmental health agencies in Texas, Louisiana, and DC recruited high Brefeldin_A proportions of African American smokers to the quitlines.

Figure Figure11 shows the incidence rates

.. Figure Figure11 shows the incidence rates things of significant anemia and significant Hb decline in the overall cohort according to the three significantly independent factors. Specifically, SNP rs1127354 had an overwhelming impact on the anemic events. In 431 patients with major genotype CC, significant anemia and significant Hb decline developed in 81 (19%) and 168 (39%) patients, respectively. In contrast, none (0%) and three (2%) of 130 patients with minor genotype CA/AA showed each anemic event, respectively, as described above. Positive predictive values of SNP rs1127354 alone for the likelihood of significant anemia and significant Hb decline were 14.3% and 39.1%, respectively. Negative predictive values were 100% and 97.7%, respectively. Values of predictive accuracy were 35.7% and 53.

5%, respectively. Figure Figure22 depicts time-course changes in qualitative Hb decline from baseline according to SNP rs1127354 genotypes. The SNP genotype significantly influenced Hb decline at week 2 as well as week 4 (P = 5.437 �� 10-9). Figure 2 Hemoglobin decline from baseline at week 2 and 4 of treatment according to the inosine triphosphatase single nucleotide polymorphism rs1127354 genotypes. Bars within boxes denote the median value of hemoglobin (Hb) decline from baseline. The boxes and … Contribution of Hb decline at week 2 of treatment Hb decline from baseline at week 2 of treatment, an on-treatment factor, significantly influenced significant Hb decline (P = 1.96 �� 10-33). An ROC curve was depicted to identify an optimal cut-off point for prediction of significant Hb decline by using Hb decline at week 2 (Figure (Figure3).

3). The AUC was 0.913 (95%CI: 0.885-0.941, P = 4.08 �� 10-43). The maximal value of Youden��s index was 0.713. The sensitivity and false-positive rate were 0.844 and 0.131, respectively. The optimal cut-off point of Hb decline at week 2 was 1.45 g/dL. Figure 3 Receiver operating characteristic curves generated with every cut-off point of predicted probability of significant hemoglobin decline (> 3.0 g/dL at week 4 of treatment) corresponding to each hemoglobin decline from baseline at week 2 of treatment. … When this variable, together with baseline variables, was incorporated into multiple logistic regression analysis to generate a statistic model for predicting significant Hb decline, the re-performed analysis using the derivation group data identified four significantly independent variables: Hb decline at week 2 [P = 3.

29 Brefeldin_A �� 10-17, OR = 7.54 (g/dL), 95%CI: 4.71-12.05], GFR [P = 2.16 �� 10-4, OR = 0.962 (mL/min/1.73 m2), 95%CI: 0.942-0.982], rs1127354 (P = 5.75 �� 10-4, OR = 10.94, 95%CI: 2.80-42.71), baseline Hb [P = 7.86 �� 10-4, OR = 1.50 (g/dL), 95%CI: 1.18-1.90]. The model was expressed as: S = -8.285 – 2.020 �� Hb decline at week 2 -0.039 �� GFR + 2.

Importantly, the high virus load leads to functional inactivation

Importantly, the high virus load leads to functional inactivation of CD4+ T cells. selleck Sorafenib The functional inactivation of CD4+ T cells is most likely a result of continued triggering by high viral load in combination with other parameters such as inflammatory cytokines, and expression of inhibitory receptors or pro-apoptotic molecules [14]. This is a relevant limitation of the CD8+ T cell-depletion experiments, and therefore a role of CD4+ T cells in the induction of immunopathology during LCMV-infection cannot be excluded. Here, we studied the role of CD4+ T cells in the destruction of splenic architecture and hepatic damage during LCMV infection. To restore CD4+ T cell function, CD8-depleted BL/6 mice were adoptively transferred with LCMV-immune CD4+ T cells or LCMV-GP61-specific T cell receptor transgenic (SMARTA [15]) CD4+ T cells.

We found that functional CD4+ T cells selectively destroy the splenic marginal zone, reduce protective LCMV-neutralizing antibodies and exert liver cell damage. Therefore, our results define an important role of CD4+ T cells in the induction of immunopathology in spleen and liver after LCMV infection. Results Adoptive transfer of LCMV-specific CD4+ T cells to CD8+ T cell-depleted mice rescues CD4+ T cell function in LCMV infection BL/6 mice clear LCMV-WE doses of up to 106 pfu within two weeks after infection below the detection limit of conventional plaque forming assays [16]. Control of LCMV is primarily mediated by cytotoxic CD8+ T cells and depletion of CD8+ T cells leads to high viremia until antibodies are mounted approximately 40 days after infection [13].

To analyze the function of LCMV-specific CD4+ T cells in the absence of CD8+ T cells and high viremia, BL/6 mice were depleted of CD8+ T cells by monoclonal antibody and infected with LCMV. As shown previously [13], CD8+ T cell depletion resulted in a drastic reduction of the relative and absolute number of LCMV-specific CD4+ T cells producing IFN�� and TNF�� on day 8 and 11 after infection (Fig. 1A,B). For example on day 11, the mean percentage of CD4+ T cell producing IFN�� after restimulation with GP61 decreased significantly from 0.63% to 0.05% and the mean absolute number of IFN��-producing CD4+ T cells dropped significantly from 0.65��105 to 0.085��105. Figure 1 Model to study LCMV-specific CD4+ T cell responses in the absence of CD8+ T cells.

In order to obtain functional LCMV-specific CD4+ T cells in CD8-depleted BL/6 mice, the following experiment was performed: First, Batimastat na?ve BL/6 mice were depleted of CD8+ T cells by monoclonal antibody. On the same day, splenocytes of LCMV-infected BL/6 mice (17 days post infection) were harvested, purified for CD4+ T cells by MACS and adoptively transferred i.v. to these na?ve CD8-depleted BL/6 mice. Each mouse received 1.5��107 purified CD4+ T cells, which contained about 2.

9 mL/min and 8 3 mL/min, respectively, in the monotherapy

9 mL/min and 8.3 mL/min, respectively, in the monotherapy selleck chem group; and 7.4 mL/min and 6.2 mL/min, respectively, in the intensification group (P<0.01 for all comparisons). Figure 4 shows week 52 GFR changes (MDRD) stratified by baseline GFR. No significant GFR decline was noted in patients with low baseline GFR, although numbers were small. Figure 4 Week 52 glomerular filtration rate (MDRD) changes, by baseline rate and treatment (efficacy population). Discussion In providing a framework for the conditional intensification of monotherapy, the Roadmap [16] provides a rational approach to improve long-term outcomes, while minimizing the risk of drug resistance due to continued sub-optimal monotherapy or adverse events associated with unnecessary combination treatment.

Under the Roadmap, nucleosides with a low genetic barrier to resistance (e.g. lamivudine) are intensified with a non-cross-resistant second agent if any HBV replication is still measurable at Week 24. Although telbivudine is more potent than lamivudine with less on-treatment resistance [5],[15], it is closest to lamivudine in terms of the features informing Roadmap decisions; and intensification was applied to any patient with detectable Week 24 viremia. The requirement for a non-cross-resistant second agent predicates the use of adefovir or tenofovir [6], with tenofovir the better choice due to greater potency [10]. Over half the patients achieved undetectable Week 24 viremia on telbivudine alone, and, following tenofovir intensification of the remaining 45%, the overall proportion of undetectable HBV DNA was greater than 90% at Week 52.

The additional reduction in HBV DNA seen following tenofovir intensification of viremic patients is presumably due to additive antiviral activity. There was no in-study comparator to estimate the treatment effect of tenofovir intensification over continued telbivudine monotherapy in viremic patients. Nor was tenofovir monotherapy investigated, or the effect of switching viremic patients to tenofovir as opposed to adding it to telbivudine. However, historical data suggest that intensification would have significantly improved Week 52 outcomes over what would have been seen had telbivudine monotherapy been continued. In GLOBE [15] a broadly similar rate of undetectable viremia at Week 24 (45%) was seen in HBeAg+ telbivudine patients to that seen here (55%), but with a substantially lower rate of undetectable DNA at Week 52 (60%).

GLOBE also showed lower rates of undetectable HBV DNA, ALT normalization and HBeAg seroconversion at Week 52, and higher rates of drug resistance at Week 48, for patients with detectable Week 24 viremia [15], although the design of these analyses precludes cross-study Carfilzomib comparison. Similar results were observed in a study of telbivudine versus lamivudine in over 300 Chinese patients [22].

Despite this, there is reluctance to regulate cigarette smoking i

Despite this, there is reluctance to regulate cigarette smoking in certain areas such as private homes selleck EPZ-5676 and cars (Mills, White, Pierce, & Messer, 2011; Semple et al., 2012). For children, parental smoking remains the major determinant of ETS exposure, with maternal smoking having been reported to play a more important role than paternal smoking (Jarvis et al., 1985). Understanding the strength of association between parental smoking and child ETS exposure will inform the development of future tobacco control policies. The majority of studies of the association between parental smoking and ETS exposure in children have focused on children at an age when active smoking is a possibility (i.e., early adolescence onwards; Heron, Hickman, Macleod, & Munafo, 2011; Sims et al., 2010).

This raises the potential problem of misclassification in such studies, where child reports of active smoking may be particularly inaccurate (Dolcini, Adler, Lee, & Bauman, 2003). Unfortunately, using cotinine levels to validate smoking status in children and young adolescents can be imprecise, when light, irregular smoking is common (Benowitz, 1996). Therefore, in order to more accurately assess the association between parental smoking and child ETS exposure, data on children collected at an age before active smoking is common are required. By comparing estimates at two ages, where active smoking is and is not likely, respectively, we can make indirect comparisons to assess the extent to which we have adequately adjusted for potential biases in measurement.

The use of cotinine as an assessment for ETS exposure, which is the primary metabolite of nicotine, can further improve the precision of these comparisons. Earlier studies may have underestimated the health consequences of ETS exposure through the use of self-report measures of exposure given that adults are likely to underreport their active smoking in the presence of children (Jefferis et al., 2010; Whincup et al., 2004). In this study, we sought to explore the association between maternal smoking behavior and child cotinine levels within nonsmokers, adjusting for other potential confounders. We also investigated the association child smoking has on cotinine levels of all participants. We used data from a birth cohort study based in the United Kingdom, where cotinine levels in the child were assessed when the child was aged 7 and 15 years.

This allowed a comparison of the impact of maternal smoking behavior on child cotinine levels at an age when child smoking was unlikely (7 years) and at an age where it was more likely (15 years). METHODS Avon Longitudinal Study of Parents and Children The sample for this study was drawn from the Avon Longitudinal Study of Parents and Children Anacetrapib (ALSPAC) (Boyd et al., 2012), an on-going population-based cohort study in the South-West of England. Recruitment to ALSPAC began in 1990�C1992.

Quantitative concentrations of varenicline (ng/ml) were returned;

Quantitative concentrations of varenicline (ng/ml) were returned; with the Lower Limit of Quantitation for the analyses established at 1.00 ng/ml. Data Analysis Time selleck chem inhibitor to first smoking occasion following the lapse exposure was analyzed using a Cox regression survival model and end of study group abstinence rates were compared using a Chi-squared test. Measures of abstinence (continuous days of abstinence, percentage of abstinent participants, number of negative COT samples, and hours of abstinence) were based on COT-validated self-report and were analyzed using Fisher��s exact test (only p values are reported). All variables with multiple time points were analyzed using repeated measures regressions with an autoregressive (a) covariance structure in SAS PROC Mixed.

Pairwise comparisons between placebo and varenicline groups were conducted using planned comparison t tests at individual time points. A Cox regression survival model was used to assess the effects of possible moderators for abstinence duration following the lapse exposure (gender, race, education, FTND, CO and COT measures, cigarettes per day, and years of regular smoking). For the CPT, three missing values were interpolated as the median of that participant��s data at the lower and higher surrounding prices. The median number of cigarettes purchased across participants in each group was determined for each of the two time points (study Days 1 and 7), resulting in four median datasets. For each median dataset, values less than1 and all but the first (lowest price) instance of 1 within a set were eliminated because in logarithmic coordinates zero is undefined and small median values of 0.

5 and 1 provide little resolution. These four datasets were fit with nonlinear regression to the exponential equation by Hursh and Silberberg (2008): logQ=logQ0+k(e?��Q0C?1). The independent variable C represents cost (price per cigarette), the dependent variable Q represents consumption (cigarettes purchased at a particular GSK-3 price), and e is a constant known as Euler��s number. Scaling parameter k indicates the range of logQ and was set to 2 in this study because it was the lowest integer with an antilog (100) that covered the range of cigarettes purchased. Free parameters are Q0 (demand intensity) and �� (demand elasticity). Statistical comparisons among the four median datasets (pre and postinduction for both groups) were performed with an extra sum-of-squares F test using GraphPad Prism? v. 5.

ADM smokers who are both price sensitive and see PCPs on a regula

ADM smokers who are both price sensitive and see PCPs on a regular basis may have been induced to quit smoking. Additional studies using more recent data will be needed to confirm that individuals with ADM disorders are still likely to quit smoking after receiving smoking afatinib mechanism of action cessation counseling by PCPs. Our measures of smoking status were obtained by self-report which is not as accurate as biological markers such as cotinine (Burling & Burling, 2003; Perez-Stable, Benowitz, & Marin, 1995). However, prior studies have shown that self-report is a reasonable measure of smoking behavior when compared with biologic markers (Patrick et al., 1994). Since the HCC2 survey did not ask amount of cigarette consumption, we cannot ascertain whether individuals reduced their cigarette use.

However, complete cessation is a reasonable outcome since even low levels of smoking engender health risks (Pechacek & Babb, 2004). Our measure of smoking cessation intervention only measures receipt of a discussion on quitting smoking and should not be considered equivalent to receipt of a full smoking cessation intervention such as the 5 A��s (Fiore et al., 2008) or even ��Ask, Advise, Refer�� (Schroeder, 2005). However, it is encouraging to see a positive association with smoking cessation even with this lower level of intervention. Although our measure of psychosis is a lifetime and not a past year measure as the other ADM measures, neither this did result in a high proportion of individuals with psychosis in our study sample nor did this group strongly influence our findings.

Our inclusion of binge drinking and substance use in our definition of ADM disorder includes some individuals who have episodes of heavy drinking or who use drugs illicitly but without any evidence of experiencing problems resulting from such use, which defines a disorder. Unfortunately, the limits of the survey do not allow us to differentiate between individuals with these problems who do or do not have problems from such use. Future studies are needed to more definitively evaluate effects among individuals with these alcohol and substance use disorders. Our measure of binge drinking does not match the current definitions of binge drinking (five or more drinks for men, four or more drinks for women), as its threshold is at a higher level of drinks (six or more drinks regardless of gender). As a result, our measure includes those who drink more on a given Brefeldin_A occasion but may miss individuals who would currently be considered binge drinkers. Additional studies with data based on the current definition of binge drinking may be helpful in determining whether the relationship also exists for these additional binge drinkers not identified in our data.

Because three different restriction digestions were utilized, mul

Because three different restriction digestions were utilized, multiple selleckbio RAMs might represent the same gene/uncharacterized region. The following criteria needed to be met in order for a gene/uncharacterized genomic region identified from a PB-induced RAM to be viewed as being in common between the studies: (1) the RAM must have been cloned in both the B6C3F1 (2 and/or 4 weeks PB) and CAR WT (precancerous and/or tumor) mice, and (2) the unique RAMs in the B6C3F1 and CAR WT mice must have aligned to the same region of the genome. Hypermethylated RAMs (significant increases, Student’s t-test, p < 0.05) and newly methylated RAMs are considered to be increases in methylation, whereas hypomethylated RAMs (both 100% decreases, and those which are significant, Student's t-test, p < 0.

05) are considered to be decreases. Genes and uncharacterized genomic regions, identified from identical, unique PB-induced RAMs that formed in both CAR WT (precancerous liver and/or liver tumor) and B6C3F1 (2 and/or 4 weeks treated), are listed in Table 3 and Supplemental Table S3, respectively. TABLE 3 Genes Identified from Identical, Unique PB-induced RAMs that Formed in both CAR WT (Precancerous Liver and/or Liver Tumor) and B6C3F1 (2- and/or 4-Week Treated) Mice. Cloning and sequencing revealed two observations regarding criterion number 2 (above). First, following digestion with the same methylation-sensitive restriction enzyme, PCR products occasionally formed which (1) represented distinct RAMs that differed by more than 2 bp in multiple groups (B6C3F1, 2 and/or 4 weeks, and CAR WT, precancerous liver and/or liver tumor) and (2) aligned to the same region of the genome.

Second, following digestion with the same methylation-sensitive restriction enzyme, PCR products occasionally formed which (1) represented distinct RAMs that were within GSK-3 2 bp of one another (e.g., unique RAMs at 315 and 317 bp) in multiple groups (B6C3F1, 2 and/or 4 weeks, and CAR WT, precancerous liver and/or liver tumor) and (2) aligned to the same region of the genome. Thus, for a particular restriction digestion, unique RAMs in the B6C3F1 and CAR WT mice that were within 2 bp of one another or more than 2 bp apart, which were represented by PCR products that aligned to the same region of the genome, were considered to be one RAM. This is evident in Table 3 and Supplemental Table S3. The following is an example of situation number 1, above. A PCR product, representing a 464-bp RAM that was identified after RsaI/MspI digestion and AP-PCR, was cloned in the B6C3F1 mice at 4 weeks, and aligned to Bcat2 (Table 3).

, 2009; Torikaiu, Uwano, Nakamori, Tarora, & Takahashi, 2005) Mc

, 2009; Torikaiu, Uwano, Nakamori, Tarora, & Takahashi, 2005). McGrath, Brown, Meruva, and Chan (2009) showed that hydroquinone, catechol, and methyl derivatives of catechol are produced in highest amounts selleckchem Dorsomorphin at tobacco pyrolysis temperatures ��350��C due to their limited thermal stability at higher temperatures. Formation of other phenols such as cresols, phenol, and resorcinol is favored between 350 and 600 ��C. Hence, temperature is considered an essential factor for the formation and the decomposition of many toxins like phenolic compounds in the smoke. The temperature at which the tobacco is heated inside the head of the waterpipe reaches up to 450 ��C (Shihadeh 2003; Shihadeh & Saleh, 2005), whereas the burning temperatures of cigarette tobacco can reach up to 950 ��C (Cz��g��ny et al.

, 2009). Therefore, high levels of phenols and their derivatives are expected in the waterpipe smoke because the smoke is generated at optimal temperatures for phenols production. Many analytic techniques were developed to determine phenols in cigarette smoke (Moldoveanu & Kiser, 2007). The most common techniques are high-performance liquid chromatography (HPLC) with ultra violet or fluorescence detection and capillary gas chromatography with mass spectrometry (GC-MS) (Moldoveanu & Kiser, 2007). In this study, the identification and quantification of phenolic compounds and their derivatives in the particle phase of the mainstream waterpipe smoke was realized using GC-MS selected ion current profile (GC-MS-SICP) chromatogram method after sample derivatization.

EXPERIMENTAL Chemicals A standard mixture of seven phenols (phenol, o-cresol, m-cresol, p-cresol, catechol, resorcinol, and hydroquinone) and a mixture of two deuterated phenols (phenol-d6 and 4-methylphenol- d8) at 1000 ��g/ml each were purchased from Absolute Anacetrapib Standards. Polystyrene divinylbenzene (PS-DVB) SPE cartridges (CHROMABOND?; EASY 200mg, 3ml) were purchased from Sorbent Technology. The derivatizing reagent, bis (trimethylsilyl)-trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) and HPLC-grade solvents of methanol, dichlomethane, and ethylacetate were purchased from Sigma-Aldrich. Smoke Generation and Collection Mainstream waterpipe smoke was generated and collected in accordance with the Beirut method (Katurji, Daher, Sheheitli, Saleh, & Shihadeh, 2010; Shihadeh & Saleh, 2005) using Nakhla Double Apple (Egypt) waterpipe tobacco preparation and Three Kings (Holland) charcoal. During each machine smoking session, the smoke exiting the waterpipe mouthpiece was split into four parallel branches and each stream drawn through a 47-mm glass fiber filter pad (47mm, Pall Gelman Type A/E). As in Shihadeh et al.

ZDF rats have a constellation of metabolic abnormalities, and TZD

ZDF rats have a constellation of metabolic abnormalities, and TZD treatment may improve renal acidification and NHE3 function by acting on mechanisms independent of renal lipid content. We used FFA-incubated OKP cells to investigate the effect of intracellular lipid reduction in the absence of other potential confounding factors. MEK162 OKP cells avidly take up FFA carried on albumin from the culture medium and store them predominantly as triglycerides in intracellular lipid droplets (46). OKP cells also appear to be rather susceptible to lipotoxicity. While a high dose of FFA (1.5 mM) causes irreversible cellular damage by promoting apoptosis, a low dose of FFA (0.75 mM), with no significant effect on apoptosis or baseline NHE3 activity, is sufficient to abolish the insulin stimulation of NHE3 function (6).

We examined the reversibility of this phenomenon in lipid-loaded OKP cells maintained in a nutrient-poor medium to promote lipid catabolism, mitochondrial beta-oxidation of intracellular FFA, and hence recovery from lipotoxicity. Compared with cells studied immediately after lipid loading (Fig. 4A), intracellular lipid droplets were markedly reduced in cells allowed to recover for 36 h (Fig. 4B) and the regulation of NHE3 by insulin was partly restored (Fig. 4C). Cells maintained in nutrient-poor medium continued to reduce their intracellular lipid stores and remained viable in culture for up to 6 days, but NHE3 activity and insulin response gradually decreased with prolonged serum and nutrient deprivation in both vehicle- and FFA-incubated cells (not shown).

These cell culture artifacts seen with prolonged serum starvation make these later time points unsuitable for the study of NHE3 regulation. Fig. 4. Recovery of insulin-stimulated NHE3 activity in opossum kidney (OKP) cells after intracellular lipid reduction. OKP cells were incubated with 0.75 mM nonesterified fatty acids (FFA) or vehicle (albumin) for 12 h, with or without incubation with FFA-free … Effect of rosiglitazone on NHE3 activity in OKP cells. Our findings in lean control rats do not support a direct effect of TZD on urinary acidification in the absence of renal steatosis (Fig. 2). However, the presence of intracellular lipid deposits may alter the transcriptional and metabolic makeup of the proximal tubule, and it is theoretically possible that TZD may have a direct effect on urinary acidification in the altered environment of the steatotic kidney.

This effect, if Anacetrapib present, would not be related to the reduction of steatosis but rather to TZD, which would drastically alter the interpretation of our data. To examine this possibility, we incubated control and lipid-loaded OKP cells with different concentrations of rosiglitazone for 24 h. Rosiglitazone treatment had no effect on intracellular lipid content in OKP cells, as estimated by Oil Red O staining (not shown).