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BNP PARIBAS WTA FINALS SINGAPORE
Kallang, Singapore
THE MODERATOR: Questions, please.
Q. What do you think about round robin or groups? Who are the toughest opponent for you?
ANGELIQUE KERBER: I think every opponent is tough here. I mean, doesn't matter against who you play. You have to play your best tennis starting already from the first match. That's why we are here, the best top eight players.
Yeah, you have to be ready from the beginning. So I'm really looking forward to playing, yeah, I think three different matches.
Q. Talk a little bit about the mentality, as well, for playing a round robin. Because obviously if you do lose, it's not the end of your campaign. But that can also affect you mentally, as well. Just talk a little bit about how you found it in the past and what you have learned.
ANGELIQUE KERBER: Yeah, I think it is completely different to the normal tournaments, of course. But I think that I'm also, yeah, having a lot of experience about this. I mean, you can win one match and you can be still playing the semis.
So you have to be focusing on every single point and game and set, because it can be important at the end of the groups. But I think it's great to have something different, because you know you are here, you play a minimum of three matches. You have three really tough matches to go for it.
And also, mentally, you know it's the last tournament. So you are trying to pushing yourself until the limits, taking all the energy that's left for every single match. Yeah, for me, it was of course the goal when I start the year to being here.
Q. From our side, it came as a surprise to read that you weren't working with Wim anymore. Can you explain what happened there and why...
ANGELIQUE KERBER: I was waiting for this question, actually. It's not the first; it's the third one (smiling).
Yeah, you know, yeah, we decide, like we decide to not working together anymore. We were like different views for the next steps. So that's, yeah, why I decide to, yeah, to split.
Q. Not that we were supposed to talk about 2017 anymore, but do you remember 12 months ago?
ANGELIQUE KERBER: Yes.
Q. Where your head was at? You certainly weren't here. I think you were preparing for Zhuhai, I guess. Where was your mind at that moment?
ANGELIQUE KERBER: Last year?
Q. 12 months ago, yeah.
ANGELIQUE KERBER: You know, I think last year it was like more to dealing with everything to taking all the experience with me to learning about myself, my game, the motivation. So a lot of things around the tennis court.
I think without, like I said all the time, without 2017 and without 2016, I wouldn't be here the same person and the same player like I am right now.
So it helps me also to growing the last few, 12, 24 months, and yeah, staying now here, like being and playing again in the WTA Finals.
Q. But do you remember 12 months ago this time last year? Were you annoyed you weren't in Singapore or were you focused on something else? Where were you at this time mentally last year?
ANGELIQUE KERBER: You know, of course I was watching Singapore a little bit, and I was preparing actually for Zhuhai last year this time. And I told myself, Okay, I hope that this year will finish as soon as possible so that I can start the new year with a new goal and trying to improving myself, taking all the experience that I had from 2017 to 2018.
Of course when I start, it was, yeah, to being here and not, yeah, in Zhuhai, to be honest.
Q. I had a follow-up from the coaching thing. What do you think then are the next steps for you for the next season that you really want to get going?
ANGELIQUE KERBER: You know, this I will think about it after Singapore. I mean, what will be the next steps, it is -- yeah, I will sit down with my team after this week, because now I will just really focusing on this tournament. I'm here with my team which is helping me, as well, over the last years. So I'm not alone here. This is important for me really to playing as good as I can, especially after this year where I won my third Grand Slam and trying to enjoying also last time Singapore.
Q. How different is the WTA Finals compared to a Grand Slam? When you're preparing for the US Open or Wimbledon, you're probably just alone or with your team or with your coach. But here you're spending a lot of time with the top eight, going to parties, taking selfies, managing the selfie stick. What is all that like for you?
ANGELIQUE KERBER: It is nice. I mean, I like it, because we are doing a lot of things together here, like yesterday, and it is a little bit more relaxed because we know we will play against each other three matches. We know how it works here.
You know, everybody who is here deserved it, and they played really consistent, great 2018. So I think that everybody is really proud and happy to staying here, playing here. Yeah, I think it's just a little bit more relaxed than during the tournaments.
Q. Did you know you were going to have to be the one to take the selfie? How did you manage that?
ANGELIQUE KERBER: I did it once like two years ago. It was quite a little bit windy there, so I was trying to managing good. It's a nice picture, so it's good.
Q. Just in terms of with Wim, the agreement to not continue, how much of that had to do with the disagreement of how he viewed your game or what you guys wanted to work on on the court next year? Or was it something completely unrelated to that?
ANGELIQUE KERBER: You know, thanks to Wim over the year we had great success together, and, you know, it's just like, yeah, we were talking a lot. You know, when you decide also like to not working anymore, so it's -- that was also the reason then if you know it why I decide to split before this tournament.
But of course I'm thankful to him. I mean, there were some details, but I don't want to go too deep or too deep into the details, but yeah, I think that was the decision from me and everybody who knows I take the decision like this so I was thinking a little bit like that.
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Frontiers in Endocrinology
Neuroendocrine Science
This article is part of the Research Topic
Diagnosis and Treatment of Primary Aldosteronism: from Clinical Origin to Translational Research View all 16 Articles
Vin-Cent Wu
National Taiwan University, Taiwan
Shao-Yu Yang
National Taiwan University Hospital, Taiwan
Leay Kiaw Er
Taipei Tzu Chi Hospital, Taiwan
Cortisol Cosecretion in Primary Aldosteronism
ACTH Stimulation Test for the Diagnosis of Primary Aldosteronism
Biases in Epidemiological Studies Related to Primary Aldosteronism
SYSTEMATIC REVIEW article
Front. Endocrinol., 16 March 2021 | https://doi.org/10.3389/fendo.2021.645488
Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies
Kosuke Inoue1,2, Takumi Kitamoto2,3, Yuya Tsurutani2, Jun Saito2, Masao Omura2 and Tetsuo Nishikawa2*
1Department of Epidemiology, University of California, Los Angeles (UCLA) Fielding School of Public Health, Los Angeles, CA, United States
2Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama, Japan
3Division of Endocrinology, Department of Medicine, Columbia University, New York, NY, United States
The hypothalamus-pituitary-adrenal (HPA) axis plays an important role in primary aldosteronism. Aldosterone biosynthesis is regulated not only by angiotensin II in the renin-angiotensin-aldosterone system, but also by adrenocorticotropic hormone (ACTH), one of the key components of the HPA axis. Although previous studies have reported cortisol cosecretion in primary aldosteronism, particularly aldosterone-producing adenoma (APA), the clinical relevance of such aldosterone and cortisol cosecretion from APA and hypertension or other metabolic disorders has not been fully established. Several somatic mutations including KCNJ5 and CACNA1D are known to induce autonomous production of aldosterone in APA, and the aldosterone responsiveness to ACTH may vary according to each mutation. The ACTH stimulation test has been reported to be a useful tool to distinguish the subtypes of primary aldosteronism (e.g., unilateral vs bilateral) in some studies, but it has not been commonly applied in clinical practice due to limited evidence. Given the recent advancement of imaging, omics research, and computational approach, it is important to summarize the most updated evidence to disentangle the potential impact of cortisol excess in primary aldosteronism and whether the ACTH stimulation test needs to be considered during the diagnostic process of primary aldosteronism. In this article, we conducted a systematic review of epidemiological studies about (i) cortisol cosecretion in primary aldosteronism and (ii) the ACTH stimulation test for the diagnosis of primary aldosteronism (including subtype diagnosis). Then, we discussed potential biases (e.g., confounding bias, overadjustment, information bias, selection bias, and sampling bias) in the previous studies and introduced some advanced epidemiological/statistical methods to minimize these limitations. A better understanding of biases and epidemiological perspective on this topic would allow us to produce further robust evidence and balanced discussion about the causal mechanisms involving the HPA axis and clinical usefulness of the ACTH stimulation test among patients with primary aldosteronism.
Primary aldosteronism (PA) is one of the common causes of secondary hypertension, increasing the risk of cardiovascular disease (CVD) and renal events (1–4). Since the first report of a patient with adrenal adenoma concurrently producing aldosterone and cortisol (5), cortisol cosecretion in PA has received substantial attention, particularly because it may cause severe complications due to cortisol excess in addition to aldosterone excess. A recent study using a mass spectrometry-based analysis in Europe showed that cortisol cosecretion in PA was associated with adverse metabolic risk factors (6), indicating the role of glucocorticoid on an increased risk of metabolic disorders among patients with PA (7–11). Moreover, while the actual prevalence of this phenotype is not clear, some studies have suggested a relatively high prevalence of PA with hypercortisolism than expected (6, 10–15). Therefore, it is imperative to understand the current state of knowledge about cortisol cosecretion in PA, and consider whether the evaluation of cortisol excess needs be recommended in general PA screening or not.
Although the hypothalamus-pituitary-adrenal (HPA) axis plays an important role in regulating aldosterone biosynthesis, the clinical usefulness of ACTH stimulation test during the management of PA, particularly for PA subtype diagnosis (e.g., aldosterone-producing adenoma [APA] vs. bilateral aldosterone hyperplasia [BAH]), has been unclear. In general, ACTH is known to stimulate both cortisol and aldosterone secretion acutely and transiently through binding to melanocortin type 2 receptor (MC2R) (16). Previous studies have shown the high performance of classifying subtype of PA based on plasma aldosterone concentrations during ACTH stimulation test under 1-mg dexamethasone suppression test (DST) (17, 18). Other studies have also reported a larger decrease in aldosterone levels following dexamethasone suppression of HPA axis among APA than BAH (19) or among KCNJ5-mutated APAs than KCNJ5 wild-type APAs (20), indicating the regulating role of endogenous ACTH on aldosterone secretion among patients with PA. Because lateralization of hyperaldosteronism is crucial to determine the target treatment (i.e., adrenalectomy or medication therapy) (21), there has been a great interest in the clinical benefit of conducting ACTH stimulation test during the PA confirmation process before AVS—a gold standard but more invasive and challenging procedure for PA subtype diagnosis.
Over the last several decades, observational studies have played a key role in PA research. Because exposure or treatment is not randomized in observational studies, we always need to be careful about confounding bias, a bias due to unmeasured common causes of exposure and outcomes (22). This is also the case in the "big data" analysis or machine learning-based approach because they do not guarantee the adjustment of a sufficient set of confounders and could rather introduce precisely wrong conclusion due to small variance of the estimates under the presence of bias. Moreover, both observational studies and randomized controlled trials suffer from other sources of bias including information bias (e.g., measurement error of hormone levels, self-report of history of hypertension and medications) (23) and selection bias (e.g., loss to follow-up, selection of study sample based on both exposure and outcome assessment) (24). Limited generalizability due to sampling bias is another issue of previous PA-related studies because most of the studies have been conducted at single-center and/or specific cohorts.
This review has two goals. First, we will provide updated summaries of epidemiological studies about cortisol cosecretion in primary aldosteronism and the clinical usefulness of the ACTH stimulation test to diagnose primary aldosteronism and/or its subtypes. Then, we will explain possible biases (e.g., confounding bias, overadjustment, information bias, selection bias, and sampling bias) in these epidemiological studies and some methods to minimize such limitations in future PA-related studies. Recognizing these biases and applying the advanced epidemiological methods would help us to build a further balanced and profound discussion on this topic—cortisol cosecretion and clinical usefulness of the ACTH stimulation test in PA.
Recently, there is increasing literature regarding cortisol cosecretion in PA and its impact on CVD risk factors (6, 25, 26). We conducted literature searches between January 2000 and November 2020 using the electronic databases MEDLINE and EMBASE for cohort studies investigating the cortisol cosecretion in primary aldosteronism. The following search terms were applied: ("cortisol" OR "cortisolemia" OR "Cushing") AND ("primary aldosteronism" OR "aldosterone-producing adenoma"). We extracted the following information: first author name, publication year, region of study, populations, exposures/comparators, outcomes, and study design. We restricted studies to those with a sample size ≥10 (to avoid case reports) and written in English. Flow of studies through review and summary of the identified 16 studies are shown in Figure 1A and Table 1 (6, 10–15, 27–35).
Figure 1 Flow of studies through review for (A) cortisol cosecretion and (B) clinical usefulness of ACTH stimulation test in primary aldosteronism.
Table 1 Summary of epidemiological studies about cortisol cosecretion in primary aldosteronism (PA).
Previous studies have shown a relatively high prevalence of subclinical Cushing's syndrome or subclinical hypercortisolemia among patients with PA although the definition of hypercortisolemia differs across studies and countries (Table 1). In 2009, Piaditis et al. reported 12.1% of patients with adrenal incidentalomas had PA with hypercortisolemia (36). Since then, several studies from the Asian cohort have reported a 5%–27% prevalence of subclinical hypercortisolemia among patients with PA or APA (11–15). A recent multicenter cohort study in Germany showed even 77.6% of subclinical hypercortisolemia among 161 patients with PA (10). While the difference in clinical characteristics between PA patients with and without hypercortisolemia is still not clear (mainly due to the small sample size in each previous study) and may vary by geographical area and definitions, most of these studies showed larger tumor size among PA patients with subclinical hypercortisolemia than those without.
In 2014, monoclonal antibodies against human CYP11B1 and CYP11B2 were developed and their expression was reported in APAs, indicating the cortisol synthesis in such adrenal tumors (37, 38). This finding was supported by a small cohort study reporting a significant decrease in serum cortisol levels during 1 mg DST after the resection of APAs (29) and a large mass spectrometry-based analysis showing higher excretion of cortisol and total glucocorticoid metabolites in the PA group compared with the healthy control group (6). Moreover, a previous case series showed that the majority of APAs with subclinical hypercortisolemia was composed mainly of ZF-like cells (39). Given that ZF comprise larger cells that synthesize glucocorticoids compared with ZG that synthesize aldosterone (40), such histopathological feature may be related to the large tumor size in APAs with subclinical hypercortisolemia, that requires further investigation.
Recent studies also have reported health outcomes related to autonomous cortisol secretion in APAs. The above-mentioned mass spectrometry-based analysis also found the correlation between glucocorticoid output and several metabolic markers including body mass index, waist circumference, insulin resistance, high-density lipoprotein, and diastolic blood pressure (6). Tang et al. showed higher proportions of cardiovascular complications, glucose intolerance/diabetes, and osteopenia/osteoporosis among patients with APAs and cortisol producing adenoma (CPA) than patients with pure APAs (14). Adolf et al. scrutinized the possible impact of cortisol excess on cardiac remodeling among PA patients (30). Across patients in the German Conn's registry, they found the association of total glucocorticoid excretion with the decrease in LVMI a year after the initiation of PA treatment (30). The association between subclinical hypercortisolemia and impaired glucose metabolism in patients with PA was also reported by other cohort studies (10, 11). These results support the adverse effect of glucocorticoid excess on health through the activation of not only glucocorticoid receptor but also mineralocorticoid receptor (MR) through the impaired conversion of cortisol to its MR-inactive cortisone (41). Another study using the same German registry showed significant increases in anti-TPO levels after adrenalectomy in unilateral PA patients with cortisol cosecretion but the trend was not found in unilateral PA patients without cortisol cosecretion and bilateral PA patients receiving mineralocorticoid antagonist therapy (34). Their findings generate the hypothesis that cortisol cosecretion among unilateral PA may exhibit the immunosuppressive effect. Given these findings, it would be important to evaluate the cortisol cosecretion among PA patients in routine clinical practice. To produce robust evidence, more research is warranted to clarify whether the adverse health outcomes of APAs with subclinical hypercortisolemia differ between those with and without CPA.
The possible influence of mild cortisol excess in PA on the interpretation of AVS has been suggested in prior literature. In general, cannulation success is evaluated by selectivity index (the ratio of cortisol concentration for each adrenal vein and inferior vena cava [IVC]), and the lateralization is evaluated by lateralization index (the aldosterone to cortisol ratio on the dominant side with excess aldosterone secretion over aldosterone to cortisol ratio on the non-dominant side) and contralateral suppression index (the aldosterone to cortisol ratio on the non-dominant side over aldosterone to cortisol ratio in IVC) (21). Based on the findings from AVS in patients with CPA, but without PA, Goupil et al, suggested that autonomous unilateral cortisol hypersecretion could confound the accuracy of AVS by affecting the aldosterone/cortisol ratio in the adrenal vein (i.e., selectivity index, lateralization index, and contralateral suppression index), leading to misdiagnosis and suboptimal management (42). However, a recent single-center study focusing on PA with mildly elevated cortisol levels (mean serum cortisol levels during the 1-mg DST = 3.3 μg/dl) showed that the rates of cannulation success or lateralization did not differ between PA patients with mild cortisol excess and those without cortisol excess during AVS with ACTH stimulation (blood sample was obtained 1 h after the stimulation) (35). A multi-center cohort study on this topic would help us to validate their findings and further understand which AVS parameters are useful for the management of PA with cortisol cosecretion.
Lastly, some studies have investigated the genetic mutation of APA with cortisol cosecretion. A recent study based on a Taiwanese database showed that the presence of KCNJ5 mutations was significantly lower among APA patients with subclinical hypercortisolemia than those without (15). Their immunohistochemistry analysis revealed the lower CYP11B1 expression among KCNJ5 mutated APAs, which generally display a ZF-like phenotype (43). Although the underlying mechanism is unclear, enhanced 18-oxocortisol synthesis in KCNJ5 mutated APAs may contribute to the findings of the lower cortisol levels in the mutated APAs than KCNJ5 wild-type APAs. They also found that patients with subclinical hypercortisolemia and KCNJ5 wild-type APAs exhibited the lowest complete clinical success rate (36.8%) after adrenalectomy (43), highlighting the importance of detecting these phenotypes for the management of APAs (15). Genetic and epigenetic analysis in a Japanese single-center study showed that APA with hypercortisolemia was not associated with the prevalence of KCNJ5 mutations but associated with lower DNA methylation rate of the CYP11B1 promoter than APA without hypercortisolemia (32). However, this study was based on only 16 APAs and the causal relationship between DNA methylation and the regulation of gene expression is still unclear. Given that some somatic mutations, such as CTNNB1 and PRKACA (44, 45), have also been reported in both APAs and CPAs, future research about these mutations and cortisol cosecretion among PA patients would be warranted.
Aldosterone production from the adrenal glomerulosa is regulated by ACTH as well as potassium, angiotensin II, and serotonin (46). Previous biological studies showed that acute ACTH administration increases plasma aldosterone through binding to MC2R (47), suggesting that ACTH may play a role in inappropriate hypersecretion of aldosterone in some PAs (16). A previous study showed aldosterone responsiveness to even very low dose ACTH (i.e., 0.003 IU), followed by a treadmill test (48). Since the first report of the ACTH stimulation test for patients with PA in 1978 (5), several epidemiological studies have investigated whether the ACTH stimulation test is useful to diagnose PA or its subtype. We conducted literature searches between January 2000 and November 2020 using the electronic databases MEDLINE and EMBASE for cohort studies investigating the cortisol cosecretion in primary aldosteronism. The following search terms were applied: ("ACTH" OR "adrenocorticotropic hormone" OR "corticotropin") AND ("primary aldosteronism" OR "aldosterone-producing adenoma"). We extracted the following information: first author name, publication year, region of study, populations, exposures/comparators, outcomes, and study design. We restricted studies to those with a sample size ≥10 (to avoid case reports) and written in English. Flow of studies through review and summary of the identified 9 studies are shown in Figure 1B and Table 2 (17–19, 49–54).
Table 2 Summary of epidemiological studies about ACTH stimulation test for the definite and the subtype diagnosis of primary aldosteronism (PA).
In 1995, Stowasser et al. reported higher plasma aldosterone response after ACTH stimulation under dexamethasone suppression among angiotensin II responsive APA (n=16) or angiotensin II unresponsive APA (n=11) compared with BAH (n=19) (55). Although several studies mostly from Japan have shown moderate to high predictive performance (area under the curve [AUC] ranges from 0.70 to 0.95) to differentiate APA from BAH by using ACTH stimulation test (17, 18, 49–52, 54) over the last two decades, these findings are not comparable across studies due to the lack of uniformity in protocols in each study (e.g., ACTH dosage, with or without 1 mg DST, different cut-off time or values, etc), inconsistent definition of outcomes (e.g., diagnosis of APA and BAH based on AVS, histopathological findings, etc.), and study design (sample size, single-center or multi-center, prospective or retrospective, etc.). These limitations have made the clinical usefulness of the ACTH stimulation test inconclusive. For example, we previously demonstrated that the predictive performance of the ACTH stimulation test for subtype diagnosis of PA could vary by the definition of lateralization during AVS with ACTH stimulation (51); i.e., whether evaluating the ratio of aldosterone to cortisol at adrenal central veins (21) or evaluating the absolute value of aldosterone at adrenal tributary veins (56). Compared with the subtype diagnosis of PA, the evidence about the definite diagnosis of PA has been very limited and has not been consistent (49–51). As the current literature on this topic is mostly based on small sample size and a single-center or a specific country, further investigations with larger sample size from multi-center cohort are needed to understand whether the ACTH stimulation test should be routinely included during the process of PA diagnosis and which parameters are useful to minimize the use of AVS which is more invasive and challenging than peripheral blood examination.
Whether ACTH stimulation is recommended during AVS for subtype diagnosis or not is another important topic in PA management. ACTH stimulation may maximize cortisol secretion from the adrenal gland and minimize the pulsatile adrenocortical hormone secretion. A recent meta-analysis showed that AVS with ACTH stimulation did not significantly reduce the number of incorrect lateralization but significantly reduced the number of unsuccessful cannulations compared with AVS without ACTH stimulation (57). However, the evidence is still limited and under debate which is beyond the scope of this review and can be found in prior review literature (58).
Aldosterone responsiveness to ACTH may vary by a genetic mutation. Our group recently reported a larger decrease in aldosterone levels during 1 mg DST among KCNJ5 mutated APAs than KCNJ5 wild-type APAs, indicating that the ACTH pathway may be more sensitive and activated among KCNJ5 mutated APAs (20). We also reported that aldosterone levels were more responsive to ACTH stimulation among APAs with somatic mutation of CACNA1D than those without the mutation (59). APAs with these mutations are likely to consist of ZF-like clear cells than others, and ZF cells are responsible for cortisol secretion and express a higher level of ACTH receptor than ZG cells (59, 60). Given that nearly 90% of APAs had somatic mutations based on the CYP11B2 immunohistochemistry-guided, full gene-based next-generation sequencing (61–63), future multi-center studies are warranted to identify the heterogeneous aldosterone response to synthetic ACTH by these genetic mutations.
Although these previous studies were well-conducted and prismatic, they have suffered from biases that are sometimes substantial. Herein, we describe the common types of biases (confounding, overadjustment, information bias, selection bias, and sampling bias) in epidemiological studies related to PA by using directed acyclic graphs (DAGs), a graphical tool to represent causal relationships between variables by linking them through single-headed arrows (64). In this section, to make a simple explanation, we assume that the exposure of interest is PA with subclinical hypercortisolemia (PA/SH) and the outcome of interest is CVD.
In observational studies, we generally cannot rule out the possibility of unmeasured confounding. This is also the case for PA studies when some common causes of PA/SH and CVD are missing (Figure 2A). To minimize this bias, researchers should include variables that are causes of the exposure and related to the outcome, or variables that are causes of the outcome and related to the exposure (65). If some important variables are missing, quantitative bias analysis may need to be considered to investigate the potential impact of uncontrolled confounding by the unmeasured confounders (22). This method can also be applied in the meta-analysis of observational studies (66, 67). Calculating E-value is an alternative approach to simply assess how much confounding is needed to explain away the observed association (68). Furthermore, if there is information on a genetic mutation that would affect CVD only through PA/SH phenotype and does not modify the effect of PA/SH on CVD, mendelian randomization may be considered to obtain a less biased estimate (69).
Figure 2 Causal diagram representing each bias scenario in primary aldosteronism study. Notation: Exposure, primary aldosteronism/subclinical hypercortisolemia (PA/SH); Outcome, cardiovascular disease (CVD); solid arrow from X to Y, the causal effect of X on Y; [X], conditioning on X; dash line between X and Y, the nonexistent association between X and Y that could be introduced by conditioning on a variable affected by X and Y; UX, factors that affect the measurement of X; X*, measured X (which could be different from the actual X). (A) Confounding bias due to uncontrolled common causes of exposure (PA/SH) and outcome (CVD). (B) Overadjustment and collider bias due to conditioning on an intermediate variable (blood pressure [BP]) that underestimate the total effect of PA/SH on CVD and introduce additional bias by linking PA/SH and uncontrolled common causes of BP and CVD (dashed line). (C) Measurement error, dependent (i.e., common factors affect measurements of exposure and outcome) and differential (i.e., exposure affects measurements of outcome, or vice versa). (D) Measurement error, independent and nondifferential. (E) Selection bias due to selecting participants by exposure and outcome status. (F) Selection bias due to loss to follow-up.
Overadjustment and Collider Bias
Another important point to select covariates in the model is overadjustment. Controlling for intermediate variable such as blood pressure (BP) that lies within the causal pathway between PA/SH and CVD would introduce a biased estimate (Figure 2B) because we (i) fail to include the effect of PA/SH on CVD that is mediated through BP, and (ii) introduce the nonexistent relationship between PA/SH and CVD through uncontrolled BP-CVD confounders by controlling for BP, so-called "collider bias" (70, 71). A data-driven approach (including machine learning algorithms) is sometimes useful to efficiently select covariates included in the model, but does not take account of this bias, and therefore, researchers need to carefully select the potential confounders based on prior knowledge and causal diagram (65).
When there is an interest to estimate the mediation effect of such intermediate variables for the PA/SH-CVD association, causal mediation analysis may be a powerful tool to answer such research questions. For example, using causal mediation analysis, a recent study showed that elevated BP mediated 45% of the total association between serum aldosterone levels and coronary artery calcium score among general adults from a multi-ethnic group (72). This finding provided novel insight into both the direct effect (not through BP) and indirect effect (through BP) of elevated aldosterone on subclinical atherosclerosis. Meanwhile, it is also noteworthy that causal mediation analysis requires several strong assumptions and limitations. One of the hurdles of applying this method in PA studies is that relatively large sample size is generally needed to find the significant direct and indirect effect of the exposure on the outcome. Further details on this method can be found in the tutorial and methodological review paper (73).
Related to the overadjustment issue, temporal ordering between exposure, confounders, and outcome is crucial to obtain a less biased estimate. In PA studies, given the negative feedback system of RAAS and the HPA axis, it is often challenging to assume which variables (e.g., biomarker concentrations and medical conditions) occurred first at cross-sectional data. When the variables can be both confounders and mediators, researchers need to carefully interpret the results of stratified analysis by such variables because the seemingly heterogeneous findings could be biased (74). Temporal ordering can be established in longitudinal cohorts where the extraction of biosample and other information precedes the outcome assessment.
Measurement Error (Information Bias)
Because analyses are generally based on data, we need to be careful about the measurement error or misclassification of variables (23). When exposure status (i.e., whether subjects have PA/SH or not) affects the reporting of CVD and/or there are common features between exposure assessment and outcome assessment (e.g., physician diagnosis, subjects' awareness of diseases, subjects' cognitive performance, etc), our estimate would be biased (Figure 2C). For example, this type of bias could easily happen when the exposure assessment involves the results of the ACTH stimulation test in peripheral blood and the outcome assessment involves the results of ACTH stimulation during AVS. Recall bias is a similar type of bias that occurs when PA/SH assessment is affected by the presence of CVD. If the error for measured PA/SH status (or CVD status) is independent of the true CVD status (or PA/SH status) and there are no common features that affect PA/SH and CVD measurement (Figure 2D), the bias is generally considered to be towards the null (i.e., underestimate the effect) particularly when the exposure is binary.
Selection Bias and Loss to Follow-Up
If the study restricts patients to those with confirmatory tests for PA/SH and the selection is also affected by health outcome status or its risk factors (which is often the case in a case-control study), such selection introduces collider bias limiting internal validity (Figure 2E). Another example is a loss to follow-up in a cohort study or a randomized controlled trial when enrollees drop the study due to health conditions related to CVD, as known as attrition bias (Figure 2F). Multiple imputations for missing data or inverse probability weighting approach would be helpful to minimize this type of bias when missing mechanisms can be explained by measured covariates (75).
Sampling bias is also caused by selecting participants that limit the generalizability of the study findings. Sampling bias needs to be considered in almost all studies (including clinical trials) because the study sample is often different from the population to which clinical interventions or guidelines are targeted in the real-world. This bias requires attention in PA studies given the different prevalence of PA/SH and somatic mutations in APA across countries (62, 63, 76); i.e., study results from a specific region may not simply be applied to other regions. Moreover, as shown in our literature review, some topic has tended to be heavily interested in a specific region or country, that also limits the external validity. Recently, the concept and method of generalizability and transportability have received renewed interest in causal inference literature to extend the study findings to the target population (77, 78).
In this review paper, we summarized the current state of knowledge about primary aldosteronism with cortisol cosecretion and the role of ACTH stimulation test in PA diagnosis. In summary, there is increasing evidence about the relatively high prevalence of cortisol cosecretion in PA and its potential influence on adverse health outcomes. Further studies are warranted to clarify whether there is a clinically useful cut-off points for cortisol cosecretion (i.e., serum cortisol levels during the 1-mg DST) for the PA management. The clinical usefulness of the ACTH stimulation test for PA (subtype) diagnosis has been suggested by some studies, but the evidence is limited to make a specific recommendation in clinical practice. Multicenter studies using the uniform protocol and consistent definition are needed to produce robust evidence on this topic. Moreover, heterogeneous response to ACTH signaling among patients with PA according to genetic mutations should be further investigated. We also explained the common type of biases in these epidemiological studies and also introduced some advanced methods to minimize the biases. As these epidemiological perspectives have not sufficiently been considered in PA-related literature, we hope this review would contribute to a better understanding of possible biases in epidemiological studies and would help clinicians and researchers to produce further robust epidemiological evidence and balanced discussion on these topics.
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Conceptualization, KI, TK, and TN. Methodology, KI. Formal analysis, KI. Investigation, KI, TK, and TN. Writing—original draft preparation, KI. Writing—review and editing, KI, TK, YT, JS, MO, and TN. Visualization, KI. Supervision, TN. All authors contributed to the article and approved the submitted version.
KI was supported by the National Institutes of Health (NIH)/NIDDK grant F99DK126119, Toffler award at UCLA, and the Honjo International Foundation Scholarship. This article does not necessarily represent the views and policies of the NIH. The funders had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication.
1. Hundemer GL, Curhan GC, Yozamp N, Wang M, Vaidya A. Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. Lancet Diabetes Endocrinol (2018) 6:51–9. doi: 10.1016/S2213-8587(17)30367-4
2. Mulatero P, Monticone S, Bertello C, Viola A, Tizzani D, Iannaccone A, et al. Long-term cardio- and cerebrovascular events in patients with primary aldosteronism. J Clin Endocrinol Metab (2013) 98:4826–33. doi: 10.1210/jc.2013-2805
3. Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, et al. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med (2008) 168:80–5. doi: 10.1001/archinternmed.2007.33
4. Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension (2006) 48:232–8. doi: 10.1161/01.HYP.0000230444.01215.6a
5. Kem DC, Weinberger MH, Higgins JR, Kramer NJ, Gomez-Sanchez C, Holland OB. Plasma aldosterone response to ACTH in primary aldosteronism and in patients with low renin hypertension. J Clin Endocrinol Metab (1978) 46:552–60. doi: 10.1210/jcem-46-4-552
6. Arlt W, Lang K, Sitch AJ, Dietz AS, Rhayem Y, Bancos I, et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight (2017) 2:e93136. doi: 10.1172/jci.insight.93136
7. Hanslik G, Wallaschofski H, Dietz A, Riester A, Reincke M, Allolio B, et al. Increased prevalence of diabetes mellitus and the metabolic syndrome in patients with primary aldosteronism of the German Conn's Registry. Eur J Endocrinol (2015) 173:665–75. doi: 10.1530/EJE-15-0450
8. Beuschlein F, Reincke M, Arlt W. The impact of Connshing's syndrome - mild cortisol excess in primary aldosteronism drives diabetes risk. J Hypertens (2017) 35:2548. doi: 10.1097/HJH.0000000000001550
9. Wu V-C, Chueh S-CJ, Chen L, Chang C-H, Hu Y-H, Lin Y-H, et al. Risk of new-onset diabetes mellitus in primary aldosteronism: a population study over 5 years. J Hypertens (2017) 35:1698–708. doi: 10.1097/HJH.0000000000001361
10. Gerards J, Heinrich DA, Adolf C, Meisinger C, Rathmann W, Sturm L, et al. Impaired Glucose Metabolism in Primary Aldosteronism Is Associated With Cortisol Cosecretion. J Clin Endocrinol Metab (2019) 104:3192–202. doi: 10.1210/jc.2019-00299
11. Akehi Y, Yanase T, Motonaga R, Umakoshi H, Tsuiki M, Takeda Y, et al. High Prevalence of Diabetes in Patients With Primary Aldosteronism (PA) Associated With Subclinical Hypercortisolism and Prediabetes More Prevalent in Bilateral Than Unilateral PA: A Large, Multicenter Cohort Study in Japan. Diabetes Care (2019) 42:938–45. doi: 10.2337/dc18-1293
12. Hiraishi K, Yoshimoto T, Tsuchiya K, Minami I, Doi M, Izumiyama H, et al. Clinicopathological features of primary aldosteronism associated with subclinical Cushing's syndrome. Endocr J (2011) 58:543–51. doi: 10.1507/endocrj.k10e-402
13. Fujimoto K, Honjo S, Tatsuoka H, Hamamoto Y, Kawasaki Y, Matsuoka A, et al. Primary aldosteronism associated with subclinical Cushing syndrome. J Endocrinol Invest (2013) 36:564–7. doi: 10.3275/8818
14. Tang L, Li X, Wang B, Ma X, Li H, Gao Y, et al. Clinical Characteristics of Aldosterone- and Cortisol-Coproducing Adrenal Adenoma in Primary Aldosteronism. Int J Endocrinol (2018) 2018:4920841. doi: 10.1155/2018/4920841
15. Peng K-Y, Liao H-W, Chan C-K, Lin W-C, Yang S-Y, Tsai Y-C, et al. Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success. Hypertension (2020) 76:1537–44. doi: 10.1161/HYPERTENSIONAHA.120.15328
16. Funder JW. The Potential of ACTH in the Genesis of Primary Aldosteronism. Front Endocrinol (Lausanne) (2016) 7:40. doi: 10.3389/fendo.2016.00040
17. Sonoyama T, Sone M, Miyashita K, Tamura N, Yamahara K, Park K, et al. Significance of adrenocorticotropin stimulation test in the diagnosis of an aldosterone-producing adenoma. J Clin Endocrinol Metab (2011) 96:2771–8. doi: 10.1210/jc.2011-0573
18. Jiang Y, Zhang C, Wang W, Su T, Zhou W, Jiang L, et al. Diagnostic value of ACTH stimulation test in determining the subtypes of primary aldosteronism. J Clin Endocrinol Metab (2015) 100:1837–44. doi: 10.1210/jc.2014-3551
19. St-Jean M, Bourdeau I, Martin M, Lacroix A. Aldosterone is Aberrantly Regulated by Various Stimuli in a High Proportion of Patients with Primary Aldosteronism. J Clin Endocrinol Metab (2021) 106:e45–60. doi: 10.1210/clinem/dgaa703
20. Inoue K, Yamazaki Y, Kitamoto T, Hirose R, Saito J, Omura M, et al. Aldosterone Suppression by Dexamethasone in Patients with KCNJ5-Mutated Aldosterone-producing Adenoma. J Clin Endocrinol Metab (2018) 103:3477–85. doi: 10.1210/jc.2018-00738
21. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab (2016) 101:1889–916. doi: 10.1210/jc.2015-4061
22. Arah OA. Bias Analysis for Uncontrolled Confounding in the Health Sciences. Annu Rev Public Health (2017) 38:23–38. doi: 10.1146/annurev-publhealth-032315-021644
23. Hernán MA, Cole SR. Invited Commentary: Causal diagrams and measurement bias. Am J Epidemiol (2009) 170:959–962; discussion 963-964. doi: 10.1093/aje/kwp293
24. Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology (2004) 15:615–25. doi: 10.1097/01.ede.0000135174.63482.43
25. Fischer E, Adolf C, Pallauf A, Then C, Bidlingmaier M, Beuschlein F, et al. Aldosterone excess impairs first phase insulin secretion in primary aldosteronism. J Clin Endocrinol Metab (2013) 98:2513–20. doi: 10.1210/jc.2012-3934
26. Colussi G, Catena C, Lapenna R, Nadalini E, Chiuch A, Sechi LA. Insulin resistance and hyperinsulinemia are related to plasma aldosterone levels in hypertensive patients. Diabetes Care (2007) 30:2349–54. doi: 10.2337/dc07-0525
27. Nakajima Y, Yamada M, Taguchi R, Satoh T, Hashimoto K, Ozawa A, et al. Cardiovascular complications of patients with aldosteronism associated with autonomous cortisol secretion. J Clin Endocrinol Metab (2011) 96:2512–8. doi: 10.1210/jc.2010-2743
28. Fallo F, Bertello C, Tizzani D, Fassina A, Boulkroun S, Sonino N, et al. Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study. J Hypertens (2011) 29:1773–7. doi: 10.1097/HJH.0b013e32834937f3
29. Inoue K, Yamazaki Y, Tsurutani Y, Suematsu S, Sugisawa C, Saito J, et al. Evaluation of Cortisol Production in Aldosterone-Producing Adenoma. Horm Metab Res (2017) 49:847–53. doi: 10.1055/s-0043-119878
30. Adolf C, Köhler A, Franke A, Lang K, Riester A, Löw A, et al. Cortisol Excess in Patients With Primary Aldosteronism Impacts Left Ventricular Hypertrophy. J Clin Endocrinol Metab (2018) 103:4543–52. doi: 10.1210/jc.2018-00617
31. Ohno Y, Sone M, Inagaki N, Takeda Y, Kurihara I, Tsuiki M, et al. Latent Autonomous Cortisol Secretion From Apparently Nonfunctioning Adrenal Tumor in Nonlateralized Hyperaldosteronism. J Clin Endocrinol Metab (2019) 104:4382–9. doi: 10.1210/jc.2018-02790
32. Kometani M, Yoneda T, Demura M, Aono D, Gondoh Y, Karashima S, et al. Genetic and epigenetic analyses of aldosterone-producing adenoma with hypercortisolemia. Steroids (2019) 151:108470. doi: 10.1016/j.steroids.2019.108470
33. Bhatt PS, Sam AH, Meeran KM, Salem V. The relevance of cortisol co-secretion from aldosterone-producing adenomas. Hormones (Athens) (2019) 18:307–13. doi: 10.1007/s42000-019-00114-8
34. Handgriff L, Adolf C, Heinrich DA, Braun L, Nirschl N, Sturm L, et al. The Impact of Glucocorticoid Co-Secretion in Primary Aldosteronism on Thyroid Autoantibody Titers During the Course of Disease. Horm Metab Res (2020) 52:404–11. doi: 10.1055/a-1164-1944
35. O'Toole SM, Sze W-CC, Chung T-T, Akker SA, Druce MR, Waterhouse M, et al. Low-grade Cortisol Cosecretion Has Limited Impact on ACTH-stimulated AVS Parameters in Primary Aldosteronism. J Clin Endocrinol Metab (2020) 105:e3776–84. doi: 10.1210/clinem/dgaa519
36. Piaditis GP, Kaltsas GA, Androulakis II, Gouli A, Makras P, Papadogias D, et al. High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas. Clin Endocrinol (Oxf) (2009) 71:772–8. doi: 10.1111/j.1365-2265.2009.03551.x
37. Gomez-Sanchez CE, Qi X, Velarde-Miranda C, Plonczynski MW, Parker CR, Rainey W, et al. Development of monoclonal antibodies against human CYP11B1 and CYP11B2. Mol Cell Endocrinol (2014) 383:111–7. doi: 10.1016/j.mce.2013.11.022
38. Nakamura Y, Maekawa T, Felizola SJA, Satoh F, Qi X, Velarde-Miranda C, et al. Adrenal CYP11B1/2 expression in primary aldosteronism: immunohistochemical analysis using novel monoclonal antibodies. Mol Cell Endocrinol (2014) 392:73–9. doi: 10.1016/j.mce.2014.05.002
39. Fallo F, Castellano I, Gomez-Sanchez CE, Rhayem Y, Pilon C, Vicennati V, et al. Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: a case series. Endocrine (2017) 58:503–12. doi: 10.1007/s12020-017-1295-4
40. Gioco F, Seccia TM, Gomez-Sanchez EP, Rossi GP, Gomez-Sanchez CE. Adrenal histopathology in primary aldosteronism: is it time for a change? Hypertension (2015) 66:724–30. doi: 10.1161/HYPERTENSIONAHA.115.05873
41. Mihailidou AS, Loan Le TY, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension (2009) 54:1306–12. doi: 10.1161/HYPERTENSIONAHA.109.136242
42. Goupil R, Wolley M, Ahmed AH, Gordon RD, Stowasser M. Does concomitant autonomous adrenal cortisol overproduction have the potential to confound the interpretation of adrenal venous sampling in primary aldosteronism? Clin Endocrinol (Oxf) (2015) 83:456–61. doi: 10.1111/cen.12750
43. Mulatero P, Monticone S, Rainey WE, Veglio F, Williams TA. Role of KCNJ5 in familial and sporadic primary aldosteronism. Nat Rev Endocrinol (2013) 9:104–12. doi: 10.1038/nrendo.2012.230
44. Wu V-C, Wang S-M, Chueh S-CJ, Yang S-Y, Huang K-H, Lin Y-H, et al. The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes. Sci Rep (2017) 7:39121. doi: 10.1038/srep39121
45. Rhayem Y, Perez-Rivas LG, Dietz A, Bathon K, Gebhard C, Riester A, et al. PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas. J Clin Endocrinol Metab (2016) 101:3010–7. doi: 10.1210/jc.2016-1700
46. Young MJ, Funder JW. The renin-angiotensin-aldosterone system in experimental mineralocorticoid-salt-induced cardiac fibrosis. Am J Physiology-Endocrinology Metab (1996) 271:E883–8. doi: 10.1152/ajpendo.1996.271.5.E883
47. Young M, Funder JW. Eplerenone, But Not Steroid Withdrawal, Reverses Cardiac Fibrosis in Deoxycorticosterone/ Salt-Treated Rats. Endocrinology (2004) 145:3153–7. doi: 10.1210/en.2004-0005
48. Markou A, Sertedaki A, Kaltsas G, Androulakis II, Marakaki C, Pappa T, et al. Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension. J Clin Endocrinol Metab (2015) 100:2857–64. doi: 10.1210/jc.2015-1268
49. Umakoshi H, Xiaomei Y, Ichijo T, Kamemura K, Matsuda Y, Fujii Y, et al. Reassessment of the cosyntropin stimulation test in the confirmatory diagnosis and subtype classification of primary aldosteronism. Clin Endocrinol (Oxf) (2017) 86:170–6. doi: 10.1111/cen.13167
50. Terui K, Kageyama K, Nigawara T, Moriyama T, Sakihara S, Takayasu S, et al. Evaluation of the (1–24) adrenocorticotropin stimulation test for the diagnosis of primary aldosteronism. J Renin Angiotensin Aldosterone Syst (2016) 17:1470320315625703. doi: 10.1177/1470320315625703
51. Inoue K, Omura M, Sugisawa C, Tsurutani Y, Saito J, Nishikawa T. Clinical Utility of the Adrenocorticotropin Stimulation Test with/without Dexamethasone Suppression for Definitive and Subtype Diagnosis of Primary Aldosteronism. Int J Mol Sci (2017) 18:948. doi: 10.3390/ijms18050948
52. Moriya A, Yamamoto M, Kobayashi S, Nagamine T, Takeichi-Hattori N, Nagao M, et al. ACTH stimulation test and computed tomography are useful for differentiating the subtype of primary aldosteronism. Endocrine J (2017) 64:65–73. doi: 10.1507/endocrj.EJ16-0297
53. Kita T, Furukoji E, Sakae T, Kitamura K. Efficient screening of patients with aldosterone-producing adenoma using the ACTH stimulation test. Hypertension Res (2019) 42:801–6. doi: 10.1038/s41440-018-0191-5
54. Kidoguchi S, Sugano N, Kawauchi R, Nakashima D, Hayashi-Ishikawa N, Tokudome G, et al. Evaluation of various confirmatory tests for the diagnosis of aldosterone-producing adenoma. J Renin Angiotensin Aldosterone Syst (2020) 21:1470320320919610. doi: 10.1177/1470320320919610
55. Stowasser M, Klemm SA, Tunny TJ, Gordon RD. Plasma aldosterone response to ACTH in subtypes of primary aldosteronism. Clin Exp Pharmacol Physiol (1995) 22:460–2. doi: 10.1111/j.1440-1681.1995.tb02044.x
56. Kitamoto T, Kitamoto KK, Omura M, Takiguchi T, Tsurutani Y, Kubo H, et al. Precise Mapping of Intra-Adrenal Aldosterone Activities Provides a Novel Surgical Strategy for Primary Aldosteronism. Hypertension (2020) 76:976–84. doi: 10.1161/HYPERTENSIONAHA.119.14341.
57. Laurent I, Astère M, Zheng F, Chen X, Yang J, Cheng Q, et al. Adrenal venous sampling with or without adrenocorticotropic hormone stimulation: A meta-analysis. J Clin Endocrinol Meta (2018) 104:1060–8. doi: 10.1210/jc.2018-01324
58. Deinum J, Groenewoud H, van der Wilt GJ, Lenzini L, Rossi GP. Adrenal venous sampling: cosyntropin stimulation or not? Eur J Endocrinol (2019) 181:D15–26. doi: 10.1530/EJE-18-0844
59. Kitamoto T, Suematsu S, Yamazaki Y, Nakamura Y, Sasano H, Matsuzawa Y, et al. Clinical and Steroidogenic Characteristics of Aldosterone-Producing Adenomas With ATPase or CACNA1D Gene Mutations. J Clin Endocrinol Metab (2016) 101:494–503. doi: 10.1210/jc.2015-3284
60. Azizan EAB, Lam BYH, Newhouse SJ, Zhou J, Kuc RE, Clarke J, et al. Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors. J Clin Endocrinol Metab (2012) 97:E819–829. doi: 10.1210/jc.2011-2965
61. Nanba K, Omata K, Else T, Beck PCC, Nanba AT, Turcu AF, et al. Targeted Molecular Characterization of Aldosterone-Producing Adenomas in White Americans. J Clin Endocrinol Metab (2018) 103:3869–76. doi: 10.1210/jc.2018-01004
62. Nanba K, Omata K, Gomez-Sanchez CE, Stratakis CA, Demidowich AP, Suzuki M, et al. Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks. Hypertension (2019) 73:885–92. doi: 10.1161/HYPERTENSIONAHA.118.12070
63. Nanba K, Yamazaki Y, Bick N, Onodera K, Tezuka Y, Omata K, et al. Prevalence of Somatic Mutations in Aldosterone-Producing Adenomas in Japanese Patients. J Clin Endocrinol Metab (2020) 105:e4066–73. doi: 10.1210/clinem/dgaa595
64. Greenland S, Pearl J, Robins JM. Causal diagrams for epidemiologic research. Epidemiology (1999) 10(1):37–48.
65. VanderWeele TJ. Principles of confounder selection. Eur J Epidemiol (2019) 34:211–9. doi: 10.1007/s10654-019-00494-6
66. Goto A, Arah OA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ (2013) 347:f4533. doi: 10.1136/bmj.f4533
67. Inoue K, Beekley J, Goto A, Jeon CY, Ritz BR. Depression and cardiovascular disease events among patients with type 2 diabetes: A systematic review and meta-analysis with bias analysis. J Diabetes Complicat (2020) 34:107710. doi: 10.1016/j.jdiacomp.2020.107710
68. VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med (2017) 167:268–74. doi: 10.7326/M16-2607
69. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ (2018) 362:k601. doi: 10.1136/bmj.k601
70. Greenland S. Quantifying biases in causal models: classical confounding vs collider-stratification bias. Epidemiology (2003) 14:300–6. doi: 10.1097/01.EDE.0000042804.12056.6C
71. Cole SR, Platt RW, Schisterman EF, Chu H, Westreich D, Richardson D, et al. Illustrating bias due to conditioning on a collider. Int J Epidemiol (2010) 39:417–20. doi: 10.1093/ije/dyp334
72. Inoue K, Goldwater D, Allison M, Seeman T, Kestenbaum BR, Watson KE. Serum Aldosterone Concentration, Blood Pressure, and Coronary Artery Calcium: The Multi-Ethnic Study of Atherosclerosis. Hypertension (2020) 76:113–20. doi: 10.1161/HYPERTENSIONAHA.120.15006
73. VanderWeele TJ. Mediation Analysis: A Practitioner's Guide. Annu Rev Public Health (2016) 37:17–32. doi: 10.1146/annurev-publhealth-032315-021402
74. Inoue K, Goto A, Sugiyama T, Ramlau-Hansen CH, Liew Z. The Confounder-Mediator Dilemma: Should We Control for Obesity to Estimate the Effect of Perfluoroalkyl Substances on Health Outcomes? Toxics (2020) 8:125. doi: 10.3390/toxics8040125
75. Howe LD, Tilling K, Galobardes B, Lawlor DA. Loss to Follow-up in Cohort Studies. Epidemiology (2013) 24:1–9. doi: 10.1097/EDE.0b013e31827623b1
76. Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, et al. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension (2014) 64:354–61. doi: 10.1161/HYPERTENSIONAHA.114.03419
77. Bareinboim E, Pearl J. Causal inference and the data-fusion problem. PNAS (2016) 113:7345–52. doi: 10.1073/pnas.1510507113
78. Dahabreh IJ, Robertson SE, Steingrimsson JA, Stuart EA, Hernán MA. Extending inferences from a randomized trial to a new target population. Stat Med (2020) 39:1999–2014. doi: 10.1002/sim.8426
Keywords: cortisol, ACTH, primary aldosteronism, systematic review, bias, epidemiological methods
Citation: Inoue K, Kitamoto T, Tsurutani Y, Saito J, Omura M and Nishikawa T (2021) Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies. Front. Endocrinol. 12:645488. doi: 10.3389/fendo.2021.645488
Received: 23 December 2020; Accepted: 15 February 2021;
Published: 16 March 2021.
Vin-Cent Wu, National Taiwan University, Taiwan
Shao-Yu Yang, National Taiwan University Hospital, Taiwan
Leay Kiaw Er, Taipei Tzu Chi Hospital, Taiwan
Copyright © 2021 Inoue, Kitamoto, Tsurutani, Saito, Omura and Nishikawa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Tetsuo Nishikawa, tetsuon@yokohamah.johas.go.jp

redpajama_set_name: RedPajamaCommonCrawl


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text:
Who Have Valid Excuses
Sifat al-Salaah (description of the prayer)
How to pray when lying down
How should a person pray when he is lying down, on his side or on his back? How should he say the takbeer ("Allahu akbar"), bow and prostrate, and recite the tashahhud? How should he gesture?
Firstly:
With regard to a worshipper praying when lying down, there are two scenarios:
The first scenario:
The prayer is obligatory, and the worshipper is able to stand or sit. In this case, his prayer is not valid if it is offered whilst lying down, according to scholarly consensus, because the Prophet (blessings and peace of Allah be upon him) said to 'Imraan ibn Husayn, when he was sick: "Pray standing; if you cannot do that then pray sitting; if you cannot do that then pray on your side." Narrated by al-Bukhaari (1117).
Ibn 'Abd al-Barr (may Allah have mercy on him) said:
This confirms that standing (in the prayer) is obligatory and is not waived except when one is unable to do it. The same applies to sitting, if one is not able to do it, and so on and so forth. Things are waived when one is unable to do them until, when a person reaches the state of unconsciousness, all of that is waived.
End quote from at-Tamheed (1/135).
The second scenario:
The prayer is voluntary, in which case it is permissible for the worshipper to pray sitting, even though he is able to stand, but his reward will be half of the reward of one who prays standing.
Al-Qaadi 'Iyaad (may Allah have mercy on him) said:
The entire hadith has to do with someone offering a voluntary prayer, because it says that it is "better" [to stand] when one is able to stand, but he chooses to sit.
End quote from Ikmaal al-Mu'allim (3/77).
This has been discussed previously in the answer to question no. 9307.
Secondly:
Is it permissible to offer a voluntary prayer lying down, when one is able to sit?
Most of the scholars are of the view that that is not permissible.
Shaykh al-Islam Ibn Taymiyah (may Allah have mercy on him) said:
Most of the scholars denounced that and regarded it as an innovation that has been introduced into Islam. They said: it is not known that anyone in Islam ever prayed lying on his side when he was in sound health. If that were allowed, the Muslims would have done that at the time of their Prophet (blessings and peace of Allah be upon him) or after that, and the Prophet (blessings and peace of Allah be upon him) would have done that, even if only once, to show that it is permissible. He used to offer voluntary prayers sitting, and would pray on his mount, facing whatever direction the mount was facing, and he would pray Witr on his mount, but he did not offer any obligatory prayer on his mount. If that were acceptable, he would have done it, even if only once, or his companions would have done it.
End quote from Majmoo' al-Fataawa (23/235).
Some scholars regard it as permissible to offer voluntary prayers lying down. That was narrated from al-Hasan al-Basri, and it is one view in the Maaliki, Shaafa'i and Hanbali madhhabs. Their evidence for that is the general meaning of the hadith of 'Imraan ibn Husayn, who said: I asked the Prophet (blessings and peace of Allah be upon him) about a man praying whilst sitting, and he said: "Whoever prays standing, that is better. Whoever prays sitting will have half the reward of the one (who prays) standing. And the one who prays 'sleeping' will have half the reward of the one (who prays) sitting."
Narrated by al-Bukhaari (1116). He said: What is meant by 'sleeping' here is lying down. End quote.
According to the view that it is permissible in that case, then lying down takes the place of standing only, and the worshipper must sit up in order to bow and prostrate, and he should lean forward for bowing, and prostrate if he is able to do so.
An-Nawawi (may Allah have mercy on him) said:
Ar-Raafi'i said: If we assume that it is permissible to offer voluntary prayers lying down, when a person is able to stand, then is it sufficient to gesture only for bowing and prostrating? Or is it stipulated that he should bow and prostrate like one who prays sitting?
There are two views, the more sound of which is the second. Imam al-Haramayn said: In our view, those who say that it is permissible to pray lying down do not say that it is permissible to limit oneself, when saying essential dhikrs of the prayer, such as the tashahhud, takbeer and so on, to saying them in the heart only without moving the lips.
It is essential to note what Imam al-Haramayn said: it is definitely not sufficient to say the words only in one's heart, because in that case there will be nothing left of the outward form of the prayer. Rather the hadith points out that there is a concession with regard to standing and sitting only; all other parts of the prayer remain as they are usually done. And Allah knows best.
End quote from al-Majmoo' (3/276).
Al-Mirdaawi al-Hanbali (may Allah have mercy on him) said:
He said that it is not valid to pray lying down, whilst Ibn Haani' narrated that it is valid to do so, and some of the scholars favoured that view.
Then (we may ask) can he gesture or must he prostrate? There are two views, the first of which is that he should prostrate. I say: This is the apparent meaning of the words of al-Majd in his commentary and elsewhere, and it is the correct view.
End quote from al-Furoo' wa Tasheeh al-Furoo' (2/400).
Thirdly:
If the worshipper is not able to pray standing or sitting, then it is permissible for him to pray lying down in the case of both obligatory and voluntary prayers, because of the hadith of 'Imraan ibn Husayn quoted above.
With regard to the one who has no choice but to pray lying down, the validity of his prayer is based on two important principles:
The first principle is that the Muslim is only obliged to do what he is able to do.
Allah, may He be exalted, says (interpretation of the meaning):
"Allah does not burden any soul with more than it can bear"
[al-Baqarah 2:286]
"So fear Allah as much as you are able"
[at-Taghaabun 64:16].
Whoever examines the texts of the Qur'an and Sunnah, it will become clear to him that the obligation to do religious duties depends on one's ability to learn and act. If someone is incapable of doing either, then what is beyond him is waived in his case, for Allah does not burden any soul with more than it can bear.… Hence the Prophet (blessings and peace of Allah be upon him) said to 'Imraan ibn Husayn: "Pray standing; if you cannot do that then pray sitting; if you cannot do that then pray on your side."
The second principle is that the one who is able to do and say what is required of him is obliged to do it, and it is not waived in his case. The principle according to the scholars is that what one is able to do cannot be waived because of what one is not able to do.
'Izz ad-Deen ibn 'Abd as-Salaam (may Allah have mercy on him) said:
The principle is that the one who has a religious duty to do and is able to do some of it and unable to do some of it must do what he is able to do, and what he is unable to do is waived in his case…
End quote from Qawaa'id al-Ahkaam (2/7)
The one who has no choice but to pray lying down may pray on his side, and if he is not able to do that, then he may pray lying on his back and gesture with his head for bowing and prostration. If he is not able to do that, then he should pray intending those movements in his heart, and he should recite the words of dhikr verbally.
The same applies to the tashahhud and takbeer. If he is able to raise his hands (when saying takbeer) and to move his finger (when reciting the tashahhud), then he must do that, otherwise it is sufficient to say the words.
Shaykh Ibn 'Uthaymeen (may Allah have mercy on him) said:
The Prophet (blessings and peace of Allah be upon him) said to 'Imraan ibn Husayn: "… if you cannot do that then pray on your side." He did not state which side it should be, so we say that he has the choice between lying on his right side or his left side.
The best is for him to do whatever is easiest for him. If both sides are the same for him, then the right side is better. The Prophet (blessings and peace of Allah be upon him) liked to start with the right when putting on his shoes, combing his hair, purifying himself, and in all his affairs.
If he prays lying on his back, with his feet towards the qiblah, that is valid…
The second view is that it is not valid if he is able to lie on his side, because the Prophet (blessings and peace of Allah be upon him) said to 'Imraan ibn Husayn: "…if you cannot do that then pray on your side." This position is specifically referred to in the religious text, and is better than lying on one's back, because the face of the sick person can face the qiblah, whereas if he is lying on his back, his face will be facing upwards. So if he is lying on his side, it is easier for him to face the qiblah. This view is the correct one.
So in order of preference, the options for the sick person when praying are as follows:
He should pray standing, but if he is not able to do that then he should pray sitting. If he is not able to pray sitting, then he should pray lying on his side, and if he is not able to do that then he should pray lying on his back with his feet towards the qiblah. The latter is the fourth option according to the correct view.
If he is lying on his side, then he may gesture for bowing and prostration.
But how should he gesture? Should he gesture with his head towards the ground, like one who is turning his head, or should he gesture with his head tilting it towards his chest?
The answer is that he should tilt his head towards his chest, because tilting it towards the ground is a kind of turning away from the qiblah, unlike tilting it towards his chest, because in that case he is still facing towards the qiblah. So his gesture when he is lying down should be done by tilting his head slightly towards his chest for bowing and a little more than that for prostration.
If he is not able to do that, then there are three scholarly views:
The first view is that if he is unable to gesture with his head, he should gesture with his eyes.
The second view is that the actions of the prayer are waived in his case, but the words are not waived.
The third view is that both the words and the actions are waived in his case; in other words he does not have to pray at all. This view was favoured by Shaykh al-Islam Ibn Taymiyah (may Allah have mercy on him).
The correct view out of these three is the view that only the actions of the prayer are waived in this case, because they are what he is unable to do. The words of the prayer are not waived, because he is able to say them, and Allah, may He be exalted, says (interpretation of the meaning):
So we say that he should say takbeer, recite Qur'an, intend to bow, say takbeer, recite the tasbeeh of bowing, then intend to stand up and say, Sami'a Allahu liman hamidah Rabbana wa laka al-hamd (Allah hears those who praise Him; our Lord to You be praise)", then intend to prostrate, say takbeer, say the tasbeeh of prostration, because this is in accordance with the shar'i guideline: "So fear Allah as much as you are able" [at-Taghaabun 64:16].
If a person is unable to speak or do the actions of prayer, such as if he is paralysed and unable to speak, what should he do?
The answer is that both the words and the actions are waived in his case, but there remains the intention. So he should intend that he is praying, and intend to recite, and intend to bow, prostrate, stand up and sit down.
This is the correct view, because the prayer is words and actions done with the intention. If the words and actions are waived because one is unable to do them, what remains is the intention. Moreover, if we say to the sick person that he does not have to pray, this may be a cause of his forgetting Allah, because if a day and night pass without him praying, he may end up forgetting Allah, may He be glorified and exalted. But if we keep reminding him to pray, and he has to do it even if it is by means of intention alone, that is better than telling him that he does not have to pray.
End quote from ash-Sharh al-Mumti' (4/328-332).
And Allah knows best.
Those who pray on chairs in the mosque
You can ask your question on the website via this link: https://islamqa.info/en/ask


text:
Majority of Renault cars in Europe may not offer diesel engine
Team OD Updated: September 07, 2016, 08:41 PM IST
Renault expects majority of its cars sold in Europe won't offer a diesel engine option. According to a Reuters report, Renault arrived at this conclusion after taking into account the costs involved in complying with the stricter European emission norms.
Ever since the Volkswagen emission scandal became public, diesel has faced a lot of flak from the public as well as government agencies. It is being reported that automobile companies are doubtful about diesel engines regaining popularity among car buyers. The Reuters report states that during an internal meeting held in July, the company's chief competitiveness officer, Thierry Bollore, had commented that the outlook for diesel investment had dimmed significantly.
Bollore had reportedly stated that Renault is now wondering if diesel would survive and he wouldn't have had such doubts at the start of this year. He said that the tougher standards and testing methods will ensure that the technology costs increase by such a significant margin that diesel will be forced to go off the market.
On its A-segment models, Renault no longer offers a diesel engine. The company feels that with the tougher Euro-VI emission norms, it won't make economical sense to offer diesel engines even in the B and C segments. It expects that these three segments won't have a diesel engine option by 2020. The A, B and C segments accounted for majority of the group's 1.6 million sales in 2015, and 60 per cent of them were diesels.
Owing to the Volkswagen emission scandal, the disparity in nitrogen oxide (NOx) emission during laboratory and regular driving tests gained prominence in the public. From 2019, the emission tests will be conducted while vehicles are being driven on public roads in typical everyday conditions. This will require automobile manufacturers to equip their new vehicles with advanced emission treatment technologies. Which means this will increase diesel vehicle costs.
Also, with batteries getting cheaper and offering a longer range, electric vehicles are gaining prominence. In this scenario, it will be tougher for diesel engines to appeal to prospective car buyers.
In January this year, Renault's headquarters were raided by the French government's anti-fraud investigators as a part of a probe into vehicle emissions. At that time the government had said that preliminary tests had shown emission levels to be higher than the legal limits. Later in April, Renault made an official announcement that it would reduce NOx emissions from its diesel vehicles.
Renault Duster 2020 Full Spec
Tags: Renault | volkswagen emission scandal | Volkswagen dieselgate | NOx | nitrous oxide | nitrous oxide emissions | NOx emissions | european emission norms | reanult headquarters raided | renault diesel engines |
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Majority of Renault cars in Europe may not offer diesel engine Majority of Renault cars in Europe may not...


With academic programs from the associate to the doctoral level, Rivier University in Nashua, NH has been educating students to transform the world for more than 80 years. We provide convenient, affordable, career-advancing online degree programs with a foundation in the liberal arts and a focus on active learning. We embrace individuality, and the ability to develop analytical thinkers, who have sound judgment and a strong desire to serve their community.


Joe is looking forward to being back home in Hull for a special Easter Saturday concert at The Comedy Lounge.
Tickets are on sale online at COMEDY LOUNGE and by contacting The Comedy Lounge Ticket Sales on T: 0844 249 1000.
For Information and general queries please call T: 01482 221113 (Mon-Fri 9am-5pm).


Named mob that you need to kill is at 50, 50 up the hill where the snow begins. He will be on the edge of the cliff.
Okay, there are no problems to find and kill Gritassangue Crawliac, they located in 52 48 spot, path starts in 53.0 48.5 spot.
To retake the Skyhorn, you have to go upper, where you will see a giant horn next to Agna, a Ave and Skawn mobs — 51.2 50.0. Kill them and quest will be done. If there are no amny mobs next to the horn — just wait, they need some time to respawn.
Just did this for first time, and spawn rate for Crawliac Bloodscreamers was insane as I went up path toward Agna & Skawn. Long after I'd killed 5, they just kept swarming, faster than I could kill them. Finally just ran through them for top of hill (and they eventually dropped away).


on one. Use prohibited by NEC section 384-16 (e)beginning with the 1978 edition.
The date on the box is May 27 1963, so it's almost as old as I am.
The reason they were no longer permitted in Article 384 went something like this — They were used to provide one 3ø circuit in a 1ø 3w panelboard. The 1ø panelboard could serve a 3ø load such as a package air conditioner in a retail store where everything else on the feeder/service entrance was 1ø.
They were shot down as a potential shock hazard—where the 1ø panelboard disconnect was opened, there could be backfeed through the highleg in the 'outboard'/'delta' 3ø circuit through the served 3ø load.
Norcal's pictured '4-space/3-pole' breaker has 4 cable connections (lugs) and two bus clips to connect to two (1ø) 'hot' busses in the panelboard. The sole highleg breaker pole had 'in and out' cable lugs. It was a strangely fitting compliment to 4-wire delta electric service with an 'outboard' transformer for 240/120 4-wire (in some cases open-)delta systems.
Wow even though there was a potential shock hazard, it was still marked "safetybreaker" on the box!!
What is called the Cutler-Hammer "Classic" now had "Safetybreaker" on the package for many years.
Scott,thank you for replaceing the photos the detail is much clearer.


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Sajari enabled Foxtel to replace our physical search appliance in weeks rather than months, with no backend changes. Our search results come through faster, are more relevant, and can now be fine-tuned by the online producers who have intimate knowledge of site content.
We moved from Solr to Sajari and have only one regret; we didn't do it sooner!


"The Price of Forgetting To Love"
Biography: I am an amateur photographer from Lower Hutt, New Zealand and have been involved in taking photos from my teenage years. I am mostly interested in landscape photography, with the main focus being a creation of a symbolic response to the world around me. For me photography is an art so closely tied to our perception of life. Each of my images carry a fragment of feeling I had in that particular moment of time, and hopefully, all of them together will one day recreate what was an emotional landscape of my life.


text:
What President Obama has said about ISIS in the past year and a half
By Rebecca Shabad
November 17, 2015 / 6:55 PM / CBS News
Pres. Obama's evolving rhetoric on ISIS 02:14
President Obama has been criticized in recent days for his changing rhetoric on the threat posed by the Islamic State in Iraq and Syria (ISIS) over the last few years.
In an interview with The New Yorker, Mr. Obama compared ISIS with a "jayvee team."
"The analogy we use around here sometimes, and I think is accurate, is if a jayvee team puts on Lakers uniforms, that doesn't make them Kobe Bryant."
NBC News' Chuck Todd asked the president about his "jayvee team" comment in an interview.
"Keep in mind I wasn't specifically referring to ISIL. I said that regionally, there were a whole series of organizations that were focused primarily locally, weren't focused on the homeland, because a lot of us, when we think about terrorism, the model is Osama bin Laden and 9/11."
Mr. Obama told ABC News in an interview hours before the Paris terrorist attacks that ISIS was "contained."
"From the start, our goal has been first to contain, and we have contained them. They have not gained ground in Iraq," he said. "And in Syria, they'll come in, they'll leave. But you don't see this systematic march by ISIL across the terrain."
At the G-20 summit in Antalya, Turkey, Obama addressed the Paris attacks and ISIS at a press conference.
"This is precisely why we're' in Iraq and why we're operating in Syria as we speak. It's precisely why we have mobilized 65 countries to go after ISIL," he said. "There has been an acute awareness on the part of my administration from the start."
Rebecca Shabad
Rebecca Shabad is a video reporter for CBS News Digital.
The Fight Against ISIS
The Fight Against ISIS More
Iran killing, U.S. troop cuts could make Mideast thornier for Biden
Dozens beheaded by ISIS-linked militants in Mozambique
14 arrested in wake of deadly terror attack in Austria
2 ISIS "Beatles" members charged with hostage-taking of Americans
ISIS accused of selling fake PPE online to finance terrorism


Consult with professionals before entering the damaged building. It might come as a temptation to grab your valuables when the fire has been extinguished, but you need approval from experts first. Understand that if the place is severely damaged, you may not enter until safety measures are implemented.
In the case of emergency, set up a point of contact that can help after the incident. This should be a family member that doesn't live with you so that they can help in times of need.
After that, contact your insurance company, so they assist you with the documentation process. Also, they'll be able to work on your insurance claims to help you with emergency lodging and living expense.
You should know what happens during a fire report as this documents the state of the property before the fire. It also covers the time of the incident, where it was involved, and when it happened. You want to give them the specifics since this helps the investigation.
Many insurance policies require you to secure your home after a fire. You want to do this because it prevents looting, but before going about this task, make sure that you have the okay to do so from emergency services.
You may have to clean up if your home was only damaged rather than destroyed. There's more to damages than meets the eye, so spend a bit of time to assess the property before going through a clean-up process.
If you decide to do the clean-up process without professional help, make sure you understand the precautions. Soot and smoke damage might create a film on the walls and residue from the extinguishers might be present.
If possible, open windows and doors while you're cleaning even if it is cold outside. You want a bit of fresh air circulating through the room during this process so that you're not breathing dangerous chemicals.
This could be a traumatizing time for you and your family which is why we suggest seeking counsel. Depending on the severity of the issue, you may find it helpful to have someone who can guide you through the coping process.


text:
Q: jQuery attribute exists or not How do I find a certain attribute exists or not for a selected item in jQuery?
For example, selected element jQuery('.button'), now this can have an attribute 'xyz'. How do I get whether it is having that or not?

A: You can use the hasAttribute method:
// Attach the event to the button
$('button').on('click', function() {
  // This will refer the element from where event has originated
  if (this.hasAttribute("style")) {
    alert('yes')
  } else {
    alert('no')
  }

})

If you want to use the jQuery library, you can directly use the attr method in the if condition.
if($('#yourElement').attr('someProp')){}

Alternatively, you can also use the jQuery is selector:
if ($(this).is('[style]')) {// rest of the code}

DEMO

A: You have two solutions that I know of. 1) Native Javascript has a function for this .hasAttribute() (e.g. $(this)[0].hasAttribute('name');). 2) Using jQuery, you can check if $(this).attr('name') is undefined or not.

redpajama_set_name: RedPajamaStackExchange


Welcome to the new Life-Sound Studio!
7. September 2016 Heidi Kommentare deaktiviert für Welcome to the new Life-Sound Studio!
We are excited about introducing the evolution of the Life-Sound Studio. What began as my Private Singing Studio is now a multi-disciplinary network of caring coaches.
I began to realize a common thread with numerous students, they were coming to sing for their sanity. It wasn't just a hobby, but rather, the one place where they could feel free, relaxed, silly, while discovering something unique to only them – their voices. I watch peoples confidence grow on a daily basis. But the dissatisfaction in other aspects of their lives was continuing. Whether it be at their jobs, their health (both mental and physical), or their relationships (especially the one with themselves).
I looked around and realized that I had contact with a number of people who had something they could offer these students, whether it be career counselling to find a more suited job, self-development workshops to learn new skills of awareness, German classes so they could integrate better here in Germany, piano lessons, or a vocal ensemble (The most fun you'll have on a Saturday – Colin, ensemble participant), even a shiatsu session to let go of some of those kinks!!! So we decided to come together as a group and offer a one-stop-shop for the health of mind and body in HOBBIES, CAREER, and HEALTH!
The intention as I feel it from everyone involved, is to offer something that they love, and that will make someone else's life happier and freer – and well more affordable!!! Hobbies are expensive, career coaching is expensive!! So we have created fees that we hope are fair for both the students and the coaches.
The atmosphere of working with these coaches is not easy to describe but I can tell you, these people are coming from their hearts, and they have brains! I hope you'll let us be YOUR team!
Nächster Beitrag:Is singing a Hobby or Therapy?


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Anyone seen these? I've just started searching. Might be in my GS book.
No photobucket, but good photo here.
I've been curious about the weight of those GS frames (they look lighter than the stock frame), but I also get the impression that the torsional rigidity of those frames is less than the stock frame.
The GS book has some good photos and some tube OD dimensions. They also show the frame being stress tested. They were concerned about torsion according to the authors. 2500 lb-ft per degree was attained. Apparently without the roll bar.
Luckily, google books has this section available, link above.
Add a full cage and it would be pretty stiff.
I'm seeing a bump on the drivers floor, I didn't think they channeled the body. Maybe it is for the exhaust.
2500 lbs/degree is not that great (by modern standards) and might be optimistic depending on the conditions it was measured. Seems like some well placed gussets might help with torsional strength.
The photos show no roll bar on the test stand. I'm thinking it would go way up.
The Mongoose uses some smaller tubing, so it may be less.
My interest, it is so simple and c4's are being given away. Could probably be built with some pie cuts.
How does the body mount/fasten onto that frame?
Last edited by rtj; 08-23-2017 at 11:17 AM..
I went through the photos and looks like some one removed them on the craigs list bargain. The ones above were Mongoose, I think.
Would not be to hard too scale it off, I'm looking for the easy way first.
There are 4 or 5 detailed GS assembly vids in the "misc vintage racing thread."


Image 1 Sections CB04a and CB04b forming part of the flight deck arrived in Rosyth on 3 December.
Image 2 The flight deck sections will sit on top of LB04 creating the hanger space beneath.
Image 3 Most of HMS Queen Elizabeth's hull is now in the dock. There is a 19 metre gap between the two large sections. This is scheduled to be closed when the sections are carefully skidded together over Christmas.
Image 4 HMS Queen Elizabeth looms over the photographer in this picture taken from the dock bottom on December 6, 2012. The recently completed sponson SP02 can be seen in the top right of the shot.
You can see a computer animation of the blocks being assembled at the link below.


I have been assisting borrowers in the Helena Area for over nine years with their financial needs. During this time, I have been blessed to help families gain control of their finances and makes their lives easier to manage. It is important that I create meaningful relationships that last for years to come.
I live in the Helena Valley with my husband of 19 years, and we have two wonderful, busy boys. We enjoy spending time in the outdoors, riding four wheelers, and attending sporting events. My friends and family also enjoy doing volunteer work.
If you are a first-time homeowner, a seasoned buyer, or someone looking to save money with a refinance, I am here to help you achieve your lending needs.


Here is a new website I created for Strands Hair and Beauty in Holloways Beach. I really like the look they wanted to go for. This is a content management system that they an update from a mobile phone.
Sculptor Mehdi Rasulle first arrived in Australia from Afghanistan in 2001 as a refugee. He now has a thriving Sculpture and Heritage Restoration business with his brothers and a beautiful new family of his own. It is not unusual to read an article on Mehdi in the local paper or to see a new project he has created for a private or public commission in Perth, Australia.
I hope to be able to see his sculptures in person one day and to meet him. His story and his work are inspirational.
Here is a website I recently created for Cairns Oral Surgery. I will be able to add many photos of smiling happy people.
I recently created a new website for Blazing Saddles Adventures. This website is actually 3 with additional WordPress installations for Chinese and Japanese translations.
Sometimes my job does not feel like work at all. Especially when I receive the freedom to be as creative as I like and I see that my customer is enthusiastic about the process and the end result. That pretty much sums up my experience with Mungalli Falls. The website for Mungalli Falls is actually 3 websites in one. Chinese and Japanese versions are being translated as we speak. Not by me though!
I am very happy to present a new website that I have built for Daniel and ShMaya Houtman.
I am very happy to introduce Artist Karen Barnes to the Entire World! One at a time please. Karen is a gentle and contemplative artist both on and off the canvas. A very good soul and a talented artist from whom we will continue to see great things in the years to come.
Meet Artist Janey Emery. Janey has the ability to capture momentous aspects of those things we find most exquisite. The beauty of the female form. The immense tranquility of an unoccupied forest. See for yourself!
Feng Shui is an art that is all about change, flexibility and flow. But don't take it from me, take it from a expert! Pauline Elphinshone will change your home and work environment to help you achieve your maximum potential and maximum bliss.
This website is still in progress so check back often to see what new workshops an events Pauline has in store.
I am pleased to present a new website for Dr Daniel Houtman, the Spirit Doctor. After 10 seconds with Daniel you will be certain that you are speaking to the right person to help you right your course.


text:
Q: How to Bundle google cloud endpoint message class in android To pass data from an Activity to a Fragment, naturally, I think of using a Bundle. The problem in my case is that the Object I need to pass is a Google Cloud Endpoint message, which is neither Parcelable nor Serializable. So how might I pass the data?
For clarity, a Google Cloud Endpoint message is a POJO that is used to pass data to and from endpoint methods. I assume they would be Serializable, but to my surprise they aren't.

A: You can:

*

*Subclass and implement Serializable or Parcelable on that class

*Or use any other strategy to pass data inside of the app:

*

*Singleton class holding any memory cache you may use

*If the fragment is inside of the activity you can access the fragment from the activity and pass the variable in

*In the worst of cases you can always use SharedPreferences or any kind of disk persistence


CARTI's mission is to promote the finest quality cancer treatment and compassionate care and to improve our knowledge through education and research.
We began fulfilling that mission in 1976, when we opened our doors to what was then known as Central Arkansas Radiation Therapy Institute. As a single, centrally located treatment facility solely devoted to one modality of cancer treatment, namely radiation therapy, the cancer treatment institution grew quickly as convenient radiation therapy treatment facilities were opened throughout the state, adding facilities in Little Rock, North Little Rock, Conway, Searcy and Mountain Home.