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Peddada, Shyamal D., and Joseph K. Haseman. "Analysis of Nonlinear Regression Models: A Cautionary Note." Dose-Response 3, no. 3 (2005): dose—response.0. http://dx.doi.org/10.2203/dose-response.003.03.005.
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Regression models are routinely used in many applied sciences for describing the relationship between a response variable and an independent variable. Statistical inferences on the regression parameters are often performed using the maximum likelihood estimators (MLE). In the case of nonlinear models the standard errors of MLE are often obtained by linearizing the nonlinear function around the true parameter and by appealing to large sample theory. In this article we demonstrate, through computer simulations, that the resulting asymptotic Wald confidence intervals cannot be trusted to achieve the desired confidence levels. Sometimes they could underestimate the true nominal level and are thus liberal. Hence one needs to be cautious in using the usual linearized standard errors of MLE and the associated confidence intervals.
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Bovbjerg, Marit L., Anna Maria Siega-Riz, Kelly R. Evenson, and William Goodnight. "Exposure Analysis Methods Impact Associations Between Maternal Physical Activity and Cesarean Delivery." Journal of Physical Activity and Health 12, no. 1 (2015): 37–47. http://dx.doi.org/10.1123/jpah.2012-0498.
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Background:Previous studies report conflicting results regarding a possible association between maternal physical activity (PA) and cesarean delivery.Methods:Seven-day PA recalls were collected by telephone from pregnant women (n = 1205) from North Carolina, without prior cesarean, during 2 time windows: 17 to 22 weeks and 27 to 30 weeks completed gestation. PA was treated as a continuous, nonlinear variable in binomial regressions (log-link function); models controlled for primiparity, maternal contraindications to exercise, preeclampsia, pregravid BMI, and percent poverty. We examined both total PA and moderate-tovigorous PA (MVPA) at each time. Outcomes data came from medical records.Results:The dose-response curves between PA or MVPA and cesarean risk at 17 to 22 weeks followed an inverse J-shape, but at 27 to 30 weeks the curves reversed and were J-shaped. However, only (total) PA at 27 to 30 weeks was strongly associated with cesarean risk; this association was attenuated when women reporting large volumes of PA (> 97.5 percentile) were excluded.Conclusion:We did not find evidence of an association between physical activity and cesarean birth. We did, however, find evidence that associations between PA and risk of cesarean may be nonlinear and dependent on gestational age at time of exposure, limiting the accuracy of analyses that collapse maternal PA into categories.
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Falchook, Gerald Steven, Johanna C. Bendell, Susanna Varkey Ulahannan, et al. "Pen-866, a miniature drug conjugate of a heat shock protein 90 (HSP90) ligand linked to SN38 for patients with advanced solid malignancies: Phase I and expansion cohort results." Journal of Clinical Oncology 38, no. 15_suppl (2020): 3515. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3515.
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3515 Background: PEN-866 is a miniature drug conjugate which links a HSP90 binding small molecule to a SN-38 cytotoxic payload. HSP90 is highly expressed in advanced malignancies. PEN-866 targets and binds to activated tumor HSP90 protein, releases its cytotoxic payload, and results in complete tumor regressions in multiple xenograft models. This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-866. Methods: Patients (pts) with progressive, advanced solid malignancies were enrolled in escalating cohorts of 2-9 pts. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PEN-866 given weekly (3 out of 4 weeks in a 28-day cycle). Results: 30 pts were treated in 8 cohorts (range 30-360 mg flat dosing or 150–200 mg/m2 BSA-based dosing). As of 9Jan20, the total median/mean exposure was 7.05/12.4 weeks. No dose limiting toxicities (DLTs) occurred in the first 4 cohorts (30-240 mg; 14 pts). In cohort 5 (360 mg), 1 of 3 pts had a DLT of grade (G) 3 transient diarrhea, and 2 other pts had G3 uncomplicated transient neutropenia. A change to BSA-based dosing was instituted for cohort 6 (175 mg/m2), on which no DLTs were observed, although 1 pt experienced G3 uncomplicated transient neutropenia. At 200 mg/m2, 2 of 5 pts experienced DLTs (G5 dehydration, G3 fatigue). The MTD and RP2D were determined to be 175 mg/m2. The most frequent (≥20% pts) related adverse events were nausea (50%), fatigue (43%), diarrhea (40%), vomiting (27%), and anemia (23%). PK was nonlinear. Plasma exposures increased greater than dose proportionally. Median t1/2 ~7 h. Cleaved SN38 never exceeded 3% of PEN-866 plasma AUC at all dose levels. Tissue PK confirmed tumor accumulation and retention of both the conjugate and released payload. As of 9Jan20, 26 pts were evaluable for response. 11 pts had stable disease at 8 weeks, of which 7 lasted 12–58 weeks. One pt with anal squamous cell carcinoma achieved a confirmed partial response. Decreased target lesion size was observed in 6 additional pts. Conclusions: PEN-866 was well tolerated and demonstrated preliminary evidence of antitumor activity. PEN-866 will be evaluated in Phase 2a expansion cohorts enrolling multiple solid tumors (NCT03221400). Clinical trial information: NCT03221400 .
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Bárdossy, András, István Bogárdi, and Lucien Duckstein. "Fuzzy nonlinear regression analysis of dose-response relationships." European Journal of Operational Research 66, no. 1 (1993): 36–51. http://dx.doi.org/10.1016/0377-2217(93)90204-z.
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NIELSEN, OLE K., CHRISTIAN RITZ, and JENS C. STREIBIG. "Nonlinear Mixed-Model Regression to Analyze Herbicide Dose–Response Relationships1." Weed Technology 18, no. 1 (2004): 30–37. http://dx.doi.org/10.1614/wt-03-070r1.
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Belz, Regina G., Karl Hurle, and Stephen O. Duke. "Dose-Response—A Challenge for Allelopathy?" Nonlinearity in Biology, Toxicology, Medicine 3, no. 2 (2005): nonlin.003.02.0. http://dx.doi.org/10.2201/nonlin.003.02.002.
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The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2 H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2 H-1,4-benzoxaxin-3(4 H)-one); BOA (benzoxazolin-2(3 H)-one); MBOA (6-methoxy-benzoxazolin-2(3 H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants ( Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.
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Gutjahr, Georg, and Björn Bornkamp. "Likelihood ratio tests for a dose-response effect using multiple nonlinear regression models." Biometrics 73, no. 1 (2016): 197–205. http://dx.doi.org/10.1111/biom.12563.
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Sakiyama, Yojiro, Katsuyo Ohashi, and Yukio Takahashi. "Application of nonlinear regression model to sigmoid dose-response relationship in pharmacological studies." Folia Pharmacologica Japonica 132, no. 4 (2008): 199–206. http://dx.doi.org/10.1254/fpj.132.199.
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Meddings, J. B., R. B. Scott, and G. H. Fick. "Analysis and comparison of sigmoidal curves: application to dose-response data." American Journal of Physiology-Gastrointestinal and Liver Physiology 257, no. 6 (1989): G982—G989. http://dx.doi.org/10.1152/ajpgi.1989.257.6.g982.
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A number of physiological or pharmacological studies generate sigmoidal dose-response curves. Ideally, data analysis should provide numerical solutions for curve parameters. In addition, for curves obtained under different experimental conditions, testing for significant differences should be easily performed. We have reviewed the literature over the past 3 years in six journals publishing papers in the field of gastrointestinal physiology and established the curve analysis technique used in each. Using simulated experimental data of known error structure, we have compared these techniques with nonlinear regression analysis. In terms of their ability to provide accurate estimates of ED50 and maximal response, none approached the accuracy and precision of nonlinear regression. This technique is as easily performed as the classic methods and additionally provides an opportunity for rigorous statistical analysis of data. We present a method of determining the significance of differences found in the ED50 and maximal response under different experimental conditions. The method is versatile and applicable to a variety of different physiological and pharmacological dose-response curves.
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Liu, Qin, Nancy R. Cook, Anna Bergström, and Chung-Cheng Hsieh. "A two-stage hierarchical regression model for meta-analysis of epidemiologic nonlinear dose–response data." Computational Statistics & Data Analysis 53, no. 12 (2009): 4157–67. http://dx.doi.org/10.1016/j.csda.2009.05.001.
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Bogen, Kenneth T. "Low-Dose Dose–Response for In Vitro Nrf2-ARE Activation in Human HepG2 Cells." Dose-Response 15, no. 2 (2017): 155932581769969. http://dx.doi.org/10.1177/1559325817699696.
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Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-like factor 2-related factor 2 (Nrf2), and the antioxidant response element (ARE) are interacting components of a master regulatory signaling pathway that coordinates redox homeostasis, cytoprotective responses, and shifts in stem cell state. This study reexamined detailed dose–response (DR) data reported for in vitro Nrf2-ARE activation in human hepatoblastoma HepG2 cell lines containing either a ARE- bla or ARE- luc reporter at 12 different concentrations of each of 15 chemicals. The normalized study data were combined among chemicals exhibiting a positive response, yielding n = 531 (179) DR data for 9 (7) chemicals using the ARE- bla (ARE- luc) assay. Three-parameter linear/ kth-power regression fits obtained to each combined set of ARE- bla- or ARE- luc-assay response data provided good fits ( R2 = .99 or .91, respectively, Pfit > .99) that each incorporate a highly significant negative initial linear slope ( P = 4 × 10−5 or .00025) and an overall J-shaped DR pattern. Results from this reanalysis of high-resolution ARE response data support the hypothesis that nonlinear ARE-mediated adaptive cellular responses to oxidative stress are governed by an ultrasensitive molecular switch.
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Bottai, Matteo, and Giovanna Cilluffo. "Nonlinear parametric quantile models." Statistical Methods in Medical Research 29, no. 12 (2020): 3757–69. http://dx.doi.org/10.1177/0962280220941159.
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Quantile regression is widely used to estimate conditional quantiles of an outcome variable of interest given covariates. This method can estimate one quantile at a time without imposing any constraints on the quantile process other than the linear combination of covariates and parameters specified by the regression model. While this is a flexible modeling tool, it generally yields erratic estimates of conditional quantiles and regression coefficients. Recently, parametric models for the regression coefficients have been proposed that can help balance bias and sampling variability. So far, however, only models that are linear in the parameters and covariates have been explored. This paper presents the general case of nonlinear parametric quantile models. These can be nonlinear with respect to the parameters, the covariates, or both. Some important features and asymptotic properties of the proposed estimator are described, and its finite-sample behavior is assessed in a simulation study. Nonlinear parametric quantile models are applied to estimate extreme quantiles of longitudinal measures of respiratory mechanics in asthmatic children from an epidemiological study and to evaluate a dose–response relationship in a toxicological laboratory experiment.
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Orsini, Nicola. "Weighted mixed-effects dose–response models for tables of correlated contrasts." Stata Journal: Promoting communications on statistics and Stata 21, no. 2 (2021): 320–47. http://dx.doi.org/10.1177/1536867x211025798.
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Recognizing a dose–response pattern based on heterogeneous tables of contrasts is hard. Specification of a statistical model that can consider the possible dose–response data-generating mechanism, including its variation across studies, is crucial for statistical inference. The aim of this article is to increase the understanding of mixed-effects dose–response models suitable for tables of correlated estimates. One can use the command drmeta with additive (mean difference) and multiplicative (odds ratios, hazard ratios) measures of association. The postestimation command drmeta_graph greatly facilitates the visualization of predicted average and study-specific dose–response relationships. I illustrate applications of the drmeta command with regression splines in experimental and observational data based on nonlinear and random-effects data-generation mechanisms that can be encountered in health-related sciences.
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Feder, P. I., C. T. Olson, D. W. Hobson, M. C. Matthews, and R. L. Joiner. "Statistical Analysis of Dose-Response Experiments by Maximum Likelihood Analysis and Iteratively Reweighted Nonlinear Least Squares Regression Techniques." Drug Information Journal 25, no. 3 (1991): 323–34. http://dx.doi.org/10.1177/009286159102500304.
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Rusnam and Baskaran Gunasekaran. "Grubb’s Test for the Presence of Outlier in the Four-parameter Logistic Model Used in Obtaining the IC50 Value for Salvia officinalis Extract Against Aeromonas hydrophila." Journal of Environmental Microbiology and Toxicology 7, no. 2 (2019): 32–34. http://dx.doi.org/10.54987/jemat.v7i2.496.
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The current trend in treating fish infection is to reduce the dependency to antibiotics. Active compounds from plants are being intensively studied as potential antibacterial to treat or to prevent infections caused by fish pathogens. A nonlinear regression exercise using the four-parameter dose response variable slope of the inhibition curve of the bacterium Aeromonas hydrophila using solvent extracts from the plant Salvia officinalis is checked for the presence of an outlier [at 95 or 99% of confidence). A potential outlier in a nonlinear regression is actually an extreme data point that is most certainly too extreme. This is normally done using the Grubb's test, which is the focus of this study. Grubb’s statistical tests for the residuals indicated that the nonlinear regression model i.e. the four-parameter logistic model is adequate in finding the IC50 value as there was no outlier present.
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Nan, Yaxing, and Yana Bai. "Sex-Based Differences in the Association between Serum Copper and Kidney Function: Evidence from NHANES 2011–2016." International Journal of Environmental Research and Public Health 19, no. 21 (2022): 14086. http://dx.doi.org/10.3390/ijerph192114086.
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Epidemiological evidence on the relationship between copper (Cu) and kidney function is rare, and few studies examine the sex differences in this association. We aimed to explore the overall and sex-based relationship between exposure to Cu and biomarkers of kidney function among 4331 participants of the 2011–2016 National Health and Nutrition Examination Survey. Multiple linear regression models were fitted to examine the overall and sex-specific associations between serum Cu and the kidney function indicator-estimated glomerular filtration rate (eGFR) and urinary albumin–creatinine ratio (UACR). Restricted cubic spline models (RCS) stratified by sex were performed to explore the sex-based dose–response associations. Serum Cu in the highest quartile was associated with higher levels of UACR (β = 0.203, 95% CI: 0.100 to 0.306) among overall participants. In males, there was an association of the highest Cu quartile with decreased eGFR (β = −0.023, 95% CI: −0.042 to −0.003) and increased UACR (β = 0.349, 95% CI: 0.171 to 0.527); serum Cu levels also demonstrated a negative nonlinear dose–response association with eGFR and a positive linear dose–response association with UACR in males, whereas females showed a marginally significant nonlinear positive association of eGFR with serum Cu levels. In conclusion, there were sex-specific and dose–response relationships between serum Cu and kidney function indicators. Further prospective and mechanistic studies are warranted.
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Sorani, Marco D., and Geoffrey T. Manley. "Dose–response relationship of mannitol and intracranial pressure: a metaanalysis." Journal of Neurosurgery 108, no. 1 (2008): 80–87. http://dx.doi.org/10.3171/jns/2008/108/01/0080.
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Object Brain edema can increase intracranial pressure (ICP), potentially leading to ischemia, herniation, and death. Edema and elevated ICP are often treated with osmotic agents to remove water from brain tissue. Mannitol is the osmotic diuretic most commonly used in the intensive care unit; however, despite its clinical importance, treatment protocols vary from center to center, and the dose–response relationship is not understood. The goal of this metaanalysis was to aggregate and analyze data from studies in which authors have described the dose–response relationship between mannitol and ICP. Methods The authors identified 18 studies that quantitatively characterized the dose–response relationship of mannitol and ICP. We also examined study designs and mannitol administration protocols. Results Meta-regression found a weak linear relationship between change in ICP (ΔICP) and dose (ΔICP = 6.6 × dose − 1.1; p = 0.27, R2 = 0.05). The lack of statistical significance could reflect the variation in protocols among studies and the variation in patients both within and among studies. However, the authors found a highly significant difference (p < 0.001) in decrease in ICP when the initial ICP was higher or lower than 30 mm Hg. Nonlinear regression suggested that ICP decrease is greatest shortly after mannitol is given (R2 = 0.63). Finally, the authors found that recent studies tend to include fewer patients and set a lower ICP threshold for mannitol administration but report more parameters of interest; the duration of mannitol's effect was the most frequently unreported parameter. Conclusions Despite its clinical importance, the determination of the mannitol dose–response curve continues to be challenging for many reasons. This metaanalysis highlights the need for a consensus of methods and results required to determine this important relationship.
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Kawabata, Osamu, and Joseph DeFrank. "A Flexible Function for Regressing Asymptotically Declining Responses of Plant Growth to Growth Retardants." HortScience 29, no. 11 (1994): 1357–59. http://dx.doi.org/10.21273/hortsci.29.11.1357.
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A modified power function, y = (A + B·x)–C, was developed for determining the relationship between plant growth and growth retardant treatment. This function accounts for the plant response characteristics by incorporating three coefficients: A, growth level of the nontreated plants; B, the degree of growth reduction; and C, the smallest effective dose of the growth inhibitor. The function accounted for 97% of the variation in purple nutsedge (Cyperus rotundus L.) leaf length as a function of the amount of a growth retardant applied. The procedure resulted in a smaller error sum of squares than several common nonlinear functions because of its greater shape flexibility.
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Ngan Kee, Warwick D., Kim S. Khaw, Floria F. Ng, Karman K. L. Ng, Rita So, and Anna Lee. "Synergistic Interaction between Fentanyl and Bupivacaine Given Intrathecally for Labor Analgesia." Anesthesiology 120, no. 5 (2014): 1126–36. http://dx.doi.org/10.1097/aln.0000000000000118.
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Abstract Background: Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. However, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. Methods: Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defined by percentage decrease in pain score from baseline at 15 and 30 min. Dose–response curves for individual drugs were fitted to a hyperbolic dose–response model using nonlinear regression. The nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug combinations with effects predicted by additivity. Results: The derived dose–response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater effects than those predicted by additivity at 15 min (P &lt; 0.001) and 30 min (P = 0.015) (mean differences, 9.1 [95% CI, 4.1–14.1] and 6.4 [95% CI, 1.2–11.5] units of the normalized response, respectively), indicating a synergistic interaction. Conclusions: The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics.
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Rota, Matteo, Rino Bellocco, Lorenza Scotti, et al. "Random-effects meta-regression models for studying nonlinear dose-response relationship, with an application to alcohol and esophageal squamous cell carcinoma." Statistics in Medicine 29, no. 26 (2010): 2679–87. http://dx.doi.org/10.1002/sim.4041.
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Li, J. M., and J. Kimura. "Translocation mechanism of Na-Ca exchange in single cardiac cells of guinea pig." Journal of General Physiology 96, no. 4 (1990): 777–88. http://dx.doi.org/10.1085/jgp.96.4.777.
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We have studied in single cardiac ventricular cells of guinea pig the ionic translocation mechanism of the electrogenic Na-Ca exchange, i.e., whether Na and Ca ions countercross the membrane simultaneously or consecutively with "ping pong" kinetics. The dose-response relation between the external Ca concentrations [( Ca]o) and the current density of the outward Na-Ca exchange current were measured at three different intracellular Na concentrations [( Na]i) in the absence of external Na. Nonlinear regression curves of the dose-response relation obtained by computer revealed Michaelis-Menten type hyperbola from which the [Ca]o giving a half-maximal response (apparent KmCao or K'mCao) and the apparent maximum current magnitude (I'max) were estimated at each [Na]i. As [Na]i increased, the K'mCao increased progressively and the value of K'mCao/I'max tended to decrease. These results are consistent with the simultaneous mechanism. The K'mCao/I'max values, however, were small and close to each other, so it was not possible to completely preclude a consecutive mechanism.
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Kee, Warwick D. Ngan, Floria F. Ng, Kim S. Khaw, Anna Lee, and Tony Gin. "Determination and Comparison of Graded Dose–Response Curves for Epidural Bupivacaine and Ropivacaine for Analgesia in Laboring Nulliparous Women." Anesthesiology 113, no. 2 (2010): 445–53. http://dx.doi.org/10.1097/aln.0b013e3181bdf9da.
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Background The potencies of bupivacaine and ropivacaine have been compared using up-and-down methodology, but their complete dose-response curves have not been compared. The authors performed a random allocation-graded dose-response study of epidural bupivacaine and ropivacaine given epidurally for labor analgesia. Methods Three hundred laboring nulliparous patients were randomly given epidural bupivacaine (5, 10, 15, 20, 30, or 40 mg) or ropivacaine (7, 15, 20, 30, 45, or 60 mg) in 20 ml of saline. Visual Analog Scale pain scores were recorded for 30 min. Response was defined by the percentage decrease in pain score from baseline at 30 min, and dose-response data were analyzed by using nonlinear regression. Results Sigmoidal Emax model dose-response curves were fitted to the datasets for bupivacaine (R = 0.53) and ropivacaine (R = 0.59). The curves had similar steepness (Hill coefficient 2.02 [95% CI, 1.55-2.50] vs. 2.25 [1.70-2.79], P = 0.55). The ED50 (dose of the drug that reduces pain score to 50% of baseline at 30 min, also known as D50) of ropivacaine was greater than that of bupivacaine (15.3 [95% CI 13.7-17.1] mg vs. 11.3 [10.0-12.7] mg, P = 0.0003), but ED90 (D90) was similar (40.6 [32.4-51.1] mg vs. 33.4 [26.2-42.7] mg, P = 0.29). The potency ratio at ED50 for ropivacaine:bupivacaine was 0.75 (95% CI, 0.65-0.88). Conclusions Ropivacaine is less potent than bupivacaine, but otherwise they have similar dose-response characteristics. The difference in potency is not statistically significant at ED90 doses.
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Hu, Kejia, David Frederick Callen, Jiayuan Li, and Hong Zheng. "Circulating Vitamin D and Overall Survival in Breast Cancer Patients: A Dose-Response Meta-Analysis of Cohort Studies." Integrative Cancer Therapies 17, no. 2 (2017): 217–25. http://dx.doi.org/10.1177/1534735417712007.
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Studies have shown that vitamin D could have a role in breast cancer survival; however, the evidence of the relationship between patients’ vitamin D levels and their survival has been inconsistent. This meta-analysis explores possible dose-response relationships between vitamin D levels and overall survival by allowing for differences in vitamin D levels among populations of the various studies. Studies relating vitamin D (25-OH-D [25-hydroxyvitamin D]) levels in breast cancer patients with their survival were identified by searching PubMed and Embase. A pooled HR (hazard ratio) comparing the highest with the lowest category of circulating 25-OH-D levels were synthesized using the Mantel-Haenszel method under a fixed-effects model. A two-stage fixed-effects dose-response model including both linear (a log-linear dose-response regression) and nonlinear (a restricted cubic spline regression) models were used to further explore possible dose-response relationships. Six studies with a total number of 5984 patients were identified. A pooled HR comparing the highest with the lowest category of circulating 25-OH-D levels under a fixed-effects model was 0.67 (95% confidence interval = 0.56-0.79, P < .001). Utilizing a dose-response meta-analysis, the pooled HR for overall survival in breast cancer patients was 0.994 (per 1 nmol/L), Pfor linear trend < .001. At or above a 23.3 nmol/L threshold, for a 10 nmol/L, 20 nmol/L, or 25 nmol/L increment in circulating 25-OH-D levels, the risk of breast cancer overall mortality decreased by 6%, 12%, and 14%, respectively. There was no significant nonlinearity in the relationship between overall survival and circulating 25-OH-D levels. Our findings suggest that there is a highly significant linear dose-response relationship between circulating 25-OH-D levels and overall survival in patients with breast cancer. However, better designed prospective cohort studies and clinical trials are needed to further confirm these findings.
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Vargas, L., D. S. Fraga, D. Agostinetto, F. Mariani, T. V. Duarte, and B. M. Silva. "Dose-response curves of Lolium multiflorum biotypes resistant and susceptible to clethodim." Planta Daninha 31, no. 4 (2013): 887–92. http://dx.doi.org/10.1590/s0100-83582013000400015.
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Chemical control with herbicides, especially glyphosate, is the main method used to control ryegrass. However, the repeated use of glyphosate has selected resistant ryegrass biotypes. Thus, the ACCase inhibitor herbicides have become the main alternative to control glyphosate-resistant biotypes, being widely used by farmers in Rio Grande do Sul. Repeated use of ACCase inhibitors, in turn, have selected ryegrass biotypes resistant to this herbicide mechanism. Thus, the objective of this study was to evaluate the response of ryegrass biotypes to different clethodim rates by dose-response curves. Increasing doses (0, 12, 24, 48, 72, 96, 144 and 192 g a.i. ha-1) of the herbicide clethodim were applied at the 3-4 ryegrass leaf stage. The variables control at 14 and 28 days after treatment (DAT) and shoot dry weight were evaluated. The data were fitted by nonlinear regression log-logistic and C50 and GR50 were calculated based on the equation. The resistance factor was obtained by the ratio of C50 or GR50 of the resistant biotype by matching the susceptible biotype. Based on the equation parameters, the doses of GR50 64.7 and 234.5 g a.i. ha-1 clethodim and C50 11.2 and 172.1 g a.i. ha-1 clethodim were obtained, at 28 DAT for the susceptible and resistant biotypes, respectively. The ryegrass biotype denominated Cotril is resistant to clethodim, being controlled with a dose 15.3 times greater than that of the susceptible biotype, and a 50% reduction of this biotype occurs with a dose 3.62 times higher than that of the susceptible one.
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Wang, Yi-Jie, Tzu-Lin Yeh, Ming-Chieh Shih, Yu-Kang Tu, and Kuo-Liong Chien. "Dietary Sodium Intake and Risk of Cardiovascular Disease: A Systematic Review and Dose-Response Meta-Analysis." Nutrients 12, no. 10 (2020): 2934. http://dx.doi.org/10.3390/nu12102934.
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Dietary sodium intake has received considerable attention as a potential risk factor of cardiovascular disease. However, evidence on the dose-response association between dietary sodium intake and cardiovascular disease risk is unclear. Embase and PubMed were searched from their inception to 17 August 2020 and studies that examined the association between sodium intake and cardiovascular disease in adolescents were not included in this review. We conducted a meta-analysis to estimate the effect of high sodium intake using a random effects model. The Newcastle-Ottawa Scale assessment was performed. A random-effects dose-response model was used to estimate the linear and nonlinear dose-response relationships. Subgroup analyses and meta-regression were conducted to explain the observed heterogeneity. We identified 36 reports, which included a total of 616,905 participants, and 20 of these reports were also used for a dose-response meta-analysis. Compared with individuals with low sodium intake, individuals with high sodium intake had a higher adjusted risk of cardiovascular disease (Rate ratio: 1.19, 95% confidence intervals = 1.08–1.30). Our findings suggest that there is a significant linear relationship between dietary sodium intake and cardiovascular disease risk. The risk of cardiovascular disease increased up to 6% for every 1 g increase in dietary sodium intake. A low-sodium diet should be encouraged and education regarding reduced sodium intake should be provided.
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Ngan Kee, Warwick D. "A Random-allocation Graded Dose–Response Study of Norepinephrine and Phenylephrine for Treating Hypotension during Spinal Anesthesia for Cesarean Delivery." Anesthesiology 127, no. 6 (2017): 934–41. http://dx.doi.org/10.1097/aln.0000000000001880.
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Abstract Background Norepinephrine has been investigated as a potential alterative to phenylephrine for maintaining blood pressure during spinal anesthesia for cesarean delivery with the advantage of less depression of maternal heart rate and cardiac output. However, the relative potencies of these two vasopressors have not been fully determined in this context. Methods In a random-allocation, graded dose–response study, 180 healthy patients undergoing spinal anesthesia for elective cesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenylephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension. The magnitude of response was measured as the percentage of full restoration of systolic blood pressure to the baseline value. Dose–response analysis was performed using nonlinear regression to derive four-parameter logistic dose–response curves, which were compared to determine relative potency. Results Data were analyzed for 180 patients. The estimated ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). The estimated relative potency ratio for the two drugs was 13.1 µg (95% CI, 10.4 to 15.8 µg). Conclusions Comparative dose–response analysis was completed for norepinephrine and phenylephrine given as a bolus to treat the first episode of hypotension in patients undergoing spinal anesthesia for cesarean delivery. The estimated dose equivalent to phenylephrine 100 µg was norepinephrine 8 µg (95% CI, 6 to 10 µg). These results may be useful to inform the design of future comparative studies.
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Harse, Janis D., Kun Zhu, Romola S. Bucks, et al. "Investigating Potential Dose–Response Relationships between Vitamin D Status and Cognitive Performance: A Cross-Sectional Analysis in Middle- to Older-Aged Adults in the Busselton Healthy Ageing Study." International Journal of Environmental Research and Public Health 19, no. 1 (2021): 450. http://dx.doi.org/10.3390/ijerph19010450.
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Low vitamin D status has been linked to adverse cognitive outcomes in older adults. However, relationships at higher levels remain uncertain. We aimed to clarify patterns of association between vitamin D status and cognitive performance, using flexible regression methods, in 4872 middle- to older-aged adults (2678 females) from the Busselton Healthy Ageing Study. Cross-sectional associations of serum levels of 25-hydroxyvitamin D (25OHD) and performance in cognitive domains were modelled using linear regression and restricted cubic splines, controlling for demographic, lifestyle, and health factors. Mean ± SD serum 25OHD levels were 78 ± 24 nM/L for women and 85 ± 25 nM/L for men. Increasing levels in women were associated with better global cognition (linear trend, p = 0.023) and attention accuracy (continuity of attention), with improvement in the latter plateauing around levels of 80 nM/L (nonlinear trend, p = 0.035). In men, increasing levels of serum 25OHD were associated with better attention accuracy (linear trend, p = 0.022), but poorer semantic verbal fluency (linear trend, p = 0.025) and global cognition (nonlinear trend, p = 0.015). We identified patterns of association between serum 25OHD levels and cognitive performance that may reflect early dose–response relationships, particularly in women. Longitudinal analyses extending through to older ages may help to clarify the nature, strength, and temporality of these relationships.
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Xu, Minrui, Mingtao Huang, Deren Qiang, et al. "Hypertriglyceridemic Waist Phenotype and Lipid Accumulation Product: Two Comprehensive Obese Indicators of Waist Circumference and Triglyceride to Predict Type 2 Diabetes Mellitus in Chinese Population." Journal of Diabetes Research 2020 (December 2, 2020): 1–12. http://dx.doi.org/10.1155/2020/9157430.
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Purpose. To determine whether hypertriglyceridemic waist (HTGW) and high lipid accumulation product (LAP) preceded the incidence of type 2 diabetes mellitus (T2DM), and to investigate the interactions of HTGW and LAP with other components of metabolic syndrome on the risk of T2DM. Methods. A total of 15,717 eligible participants without baseline T2DM and aged 35 and over were included from a Chinese rural cohort. Cox proportional hazards regression models were used to estimate the association of HTGW and LAP with the incidence of T2DM, and the restricted cubic spline model was used to evaluate the dose-response association. Results. Overall, 867 new T2DM cases were diagnosed after 7.77 years of follow-up. Participants with HTGW had a higher hazard ratio for T2DM (hazard ratio (HR): 6.249, 95% confidence interval (CI): 5.199-7.511) after adjustment for potential confounders. The risk of incident T2DM was increased with quartiles 3 and 4 versus quartile 1 of LAP, and the adjusted HRs (95% CIs) were 2.903 (2.226-3.784) and 6.298 (4.911-8.077), respectively. There were additive interactions of HTGW (synergy index (SI): 1.678, 95% CI: 1.358-2.072) and high LAP (SI: 1.701, 95% CI: 1.406-2.059) with increased fasting plasma glucose (FPG) on the risk of T2DM. Additionally, a nonlinear ( P nonlinear < 0.001) dose-response association was found between LAP and T2DM. Conclusion. The subjects with HTGW and high LAP were at high risk of developing T2DM, and the association between LAP and the risk of T2DM may be nonlinear. Our study further demonstrates additive interactions of HTGW and high LAP with increased FPG on the risk of T2DM.
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Taylor, Gregory J., Kenneth J. Stadt, and Mark R. T. Dale. "Modelling the phytotoxicity of aluminum, cadmium, copper, manganese, nickel, and zinc using the Weibull frequency distribution." Canadian Journal of Botany 69, no. 2 (1991): 359–67. http://dx.doi.org/10.1139/b91-049.
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The toxic effects of aluminum, cadmium, copper, manganese, nickel, and zinc stress on root growth of Triticum aestivum were modelled using a modified version of the Weibull frequency distribution. The modified Weibull function is a continuous, nonlinear mathematical function that provides direct estimates of several important biological parameters, including maximum growth, minimum growth, growth response, toxicity threshold, and maximum unit toxicity. The function was fit to experimental data using standard nonlinear regression techniques. Despite variation among metals in the characteristics of observed dose responses, the Weibull function provided a close fit for each of the metals tested (0.96 ≤ R2 ≤ 0.99). Estimates of maximum unit toxicities indicated that cadmium was most toxic to T. aestivum (152% growth reduction (GR)/(μmol∙L)), followed by copper (19.0% GR/(μmol∙L)), nickel (3.9% GR/(μmol∙L)), aluminum (1.3% GR/(μmol∙L)), zinc (0.5% GR/(μmol∙L)), and manganese (0.2% GR/((μmol∙L)). Estimated toxicity thresholds also indicated that cadmium was most toxic. Cadmium showed the lowest threshold for metal injury (0.02 μM), followed by copper (3.4 μM), nickel (11 μM), aluminum (18 μM), manganese (37 μM), and zinc (45 μM). The shift in the relative position of Mn and Zn suggests that unit toxicity and the toxicity threshold may be independent measures of the response of plants to metal stress. These experiments clearly demonstrate the utility of the Weibull function in modelling the response of plants to metal stress. Furthermore, the ability of the function to model primary growth data directly provides a suitable technique for investigation of potential interactions between phytotoxic metals. Key words: dose response, modelling, metal stress, toxicity threshold, unit toxicity.
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Vincent, Melissa J., Bruce Allen, Orsolya M. Palacios, Lynne T. Haber, and Kevin C. Maki. "Meta-regression analysis of the effects of dietary cholesterol intake on LDL and HDL cholesterol." American Journal of Clinical Nutrition 109, no. 1 (2018): 7–16. http://dx.doi.org/10.1093/ajcn/nqy273.
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ABSTRACTBackgroundElevated low-density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular disease. Dietary guidance recommends reducing saturated fatty acid, trans fatty acid, and cholesterol intakes to reduce circulating LDL cholesterol. Cholesterol intake may also affect high-density lipoprotein (HDL)–cholesterol concentrations, but its impact has not been fully quantified.ObjectivesThe aims of this study were to investigate the dose-response relation between changes in dietary cholesterol intake and changes in lipoprotein-cholesterol markers for cardiovascular disease risk and to provide a reference for clinicians on how changes in dietary cholesterol intake affect circulating cholesterol concentrations, after accounting for intakes of fatty acids.MethodsWe used a Bayesian approach to meta-regression analysis, which uses Markov chain Monte Carlo techniques, to assess the relation between the change in dietary cholesterol (adjusted for dietary fatty acids) and changes in LDL and HDL cholesterol based on the use of data from randomized dietary intervention trials.ResultsFifty-five studies (2652 subjects) were included in the analysis. The nonlinear Michaelis-Menten (MM) and Hill models best described the data across the full spectrum of dietary cholesterol changes studied (0–1500 mg/d). Mean predicted changes in LDL cholesterol for an increase of 100 mg dietary cholesterol/d were 1.90, 4.46, and 4.58 mg/dL for the linear, nonlinear MM, and Hill models, respectively.ConclusionsThe change in dietary cholesterol was positively associated with the change in LDL-cholesterol concentration. The linear and MM models indicate that the change in dietary cholesterol is modestly inversely related to the change in circulating HDL-cholesterol concentrations in men but is positively related in women. The clinical implications of HDL-cholesterol changes associated with dietary cholesterol remain uncertain.
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Eng, Jui Yee, Foong Ming Moy, Awang Bulgiba, and Sanjay Rampal. "Dose–Response Relationship between Western Diet and Being Overweight among Teachers in Malaysia." Nutrients 12, no. 10 (2020): 3092. http://dx.doi.org/10.3390/nu12103092.
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The rising prevalence of overweight and obesity is partly due to nutrition transition. The reported association between dietary patterns and overweight/obesity has been controversial because of inconsistent results and weak observed associations. Although it has been hypothesized that an unhealthy diet can increase obesity risk, none of the previous studies have examined the dose–response association using nonlinear dose–response analyses. This study aimed to examine the dose–response association between major dietary patterns and overweight/obesity. This was a cross-sectional study involving teachers selected through stratified multistage sampling from public schools in three Malaysian states. Dietary intake was assessed using a food frequency questionnaire, and two major dietary patterns (Western and Prudent diet) were extracted using factor analysis. Logistic regression followed by trend analysis was used to test the difference in odds of overweight and obesity in each quintile of diet score. A further analysis using restricted cubic spline models was performed to examine the dose–response associations of dietary patterns with odds of overweight/obesity. The logistic regression analysis showed that participants with the highest quintile of Western diet score were 1.4 times more likely to be overweight/obese compared to those in the lowest quintile (95% CI: 1.11, 1.83, p-trend < 0.001). The odds of overweight/obesity showed a significant increasing trend across quintiles of Western diet among both men and women (p-trend < 0.001). In the dose–response analysis, a positive linear association (Pnonlinearity = 0.6139) was observed where overweight/obesity was more likely to occur among participants with a Western diet score greater than a mean score of zero. There was an inverse trend of odds of overweight/obesity across quintiles of Prudent diet score, significant only for men (p for trend < 0.001). Linear association was found between Prudent diet score and odds of overweight/obesity among both men (Pnonlinearity = 0.6685) and women (Pnonlinearity = 0.3684) in the dose–response analysis. No threshold at the level of adherence to Prudent diet was linked to odds of overweight/obesity. Dose–response analysis indicated that women with a Western diet score greater than zero were more likely to be overweight or obese among women. In men, higher adherence to Western diet was associated with increased odds of overweight/obesity, while greater adherence to Prudent diet decreased the odds of overweight/obesity. Promoting and enhancing the consumption of Prudent diet and limit in Western diet may be used to guide the development of evidence-based diet interventions to curb overweight and obesity.
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Hibino, Makoto, Yoichiro Otaki, Elsa Kobeissi, et al. "Blood Pressure, Hypertension, and the Risk of Aortic Dissection Incidence and Mortality: Results From the J-SCH Study, the UK Biobank Study, and a Meta-Analysis of Cohort Studies." Circulation 145, no. 9 (2022): 633–44. http://dx.doi.org/10.1161/circulationaha.121.056546.
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Background: Hypertension or elevated blood pressure (BP) is an important risk factor for aortic dissection (AD); however, few prospective studies on this topic have been published. We investigated the association between hypertension/elevated BP and AD in 2 cohorts and conducted a meta-analysis of published prospective studies, including these 2 studies. Methods: We analyzed data from the J-SHC study (Japan-Specific Health Checkups) and UK Biobank, which prospectively followed up 534 378 and 502 424 participants, respectively. Multivariable Cox regression was used to estimate hazard ratios and 95% CIs for the association of hypertension/elevated BP with AD incidence in the UK Biobank and AD mortality in the J-SHC Study. In the meta-analysis, summary relative risks were calculated with random-effects models. A potential nonlinear dose-response relationship between BP and AD was tested with fractional polynomial models, and the best-fitting second-order fractional polynomial regression model was determined. Results: In the J-SHC study and UK Biobank, there were 84 and 182 ADs during the 4- and 9-year follow-up, and the adjusted hazard ratios of AD were 3.57 (95% CI, 2.17–6.11) and 2.68 (95% CI, 1.78–4.04) in hypertensive individuals, 1.33 (95% CI, 1.05–1.68) and 1.27 (95% CI, 1.11–1.48) per 20–mm Hg increase in systolic BP (SBP), and 1.67 (95% CI, 1.40–2.00) and 1.66 (95% CI, 1.46–1.89) per 10-mm Hg increase in diastolic BP (DBP), respectively. In the meta-analysis, the summary relative risks were 3.07 (95% CI, 2.15–4.38, I 2 =76.7%, n=7 studies, 2818 ADs, 4 563 501 participants) for hypertension and 1.39 (95% CI, 1.16–1.66, I 2 =47.7%, n=3) and 1.79 (95% CI: 1.51–2.12, I 2 = 57.0%, n=3) per 20–mm Hg increase in SBP and per 10–mm Hg increase in DBP, respectively. The AD risk showed a strong, positive dose-response relationship with SBP and even more so with DBP. The risk of AD in the nonlinear dose-response analysis was significant at SBP >132 mm Hg and DBP >75 mm Hg. Conclusions: Hypertension and elevated SBP and DBP are associated with a high risk of AD. The risk of AD was positively dose dependent, even within the normal BP range. These findings provide further evidence for the optimization of BP to prevent AD.
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HOLZHÜTTER, HERMANN-GEORG, and JÖRN QUEDENAU. "MATHEMATICAL MODELLING OF CELLULAR RESPONSES TO EXTERNAL SIGNALS." Journal of Biological Systems 03, no. 01 (1995): 127–38. http://dx.doi.org/10.1142/s0218339095000125.
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An empirical mathematical model is proposed to describe the response (growth rate, metabolic activity etc.) of a cell population to various intensities of an external signal (hormone, antibody, pharmacon etc.). The model is based on the assumption that the signal causes the target system to pass consecutively through i=1, …, N distinct population states having response coefficients Ri. Describing the interaction of the system with the signal according to the rules of chemical kinetics by two phenomenological parameters (k - sensitivity, n - cooperativity index) one arrives at a series expansion for Ri which is linear in the Ri’s but nonlinear with respect to k and n (“R-decomposition”). The pattern of expansion coefficients Ri is characteristic of a given signal and can be used to reveal similarities in the responses of the cell population to various signals. A user-friendly microcomputer program has been developed to fit the model equation to experimental data by means of constraint nonlinear regression analysis and to determine all characteristic curve parameters (number and location of extremal values, inflection points etc.). The robustness and benefit of the model is demonstrated by applications to various types of “exotic” dose-reponse-curves obtained from a neutral-red assay of fibroblasts. Similarities between response curves are studied.
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GUO, PENGFEI, and ALWELL JULIUS OYET. "ON WAVELET METHODS FOR TESTING EQUALITY OF MEAN RESPONSE CURVES." International Journal of Wavelets, Multiresolution and Information Processing 07, no. 03 (2009): 357–73. http://dx.doi.org/10.1142/s0219691309002969.
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In this article, we exploit the adaptive properties of wavelets to develop some procedures for testing the equality of nonlinear and nonparametric mean response curves which are assumed by an experimenter to be the underlying functions generating several groups of data with possibly hetereoscedastic errors. The essential feature of the techniques is the transformation of the problem from the domain of the input variable to the wavelet domain through an orthogonal discrete wavelet transformation or a multiresolution expansion. We shall see that this greatly simplifies the testing problem into either a wavelet thresholding problem or a linear wavelet regression problem. The size and power performances of the tests are reported and compared to some existing methods. The tests are also applied to data on dose response curves for vascular relaxation in the absence or presence of a nitric oxide inhibitor.
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Kluess, Heidi A., John B. Buckwalter, Jason J. Hamann, and Philip S. Clifford. "Acidosis attenuates P2X purinergic vasoconstriction in skeletal muscle arteries." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 1 (2005): H129—H132. http://dx.doi.org/10.1152/ajpheart.00574.2004.
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Vasoconstriction via α2-receptors is known to be sensitive to acidic pH, but little is known about the pH sensitivity of P2X receptors. ATP is a cotransmitter released with norepinephrine from the sympathetic nerves and causes vasoconstriction via P2X purinergic receptors on vascular smooth muscle. We hypothesized that reductions in pH would attenuate P2X-mediated vasoconstriction in iliofemoral artery rings. Twenty-five rats were killed, and the iliac and femoral arteries were dissected out and placed in modified Krebs-Henseleit buffer. The arteries were cut into 2-mm sections and mounted in an organ tissue bath. Tension (g) was measured during a potassium chloride and norepinephrine challenge (maximal tension). The arteries were then exposed to α,β-methylene ATP (10−7-10−3 M; n = 13) or phenylephrine (10−7-10−4 M; n = 6) with a tissue bath pH of 7.8, 7.4, and 7.0. Dose-response curves were fit with nonlinear regression analysis to calculate the EC50 and slope. The peak tension with α,β-methylene ATP was lower during pH 7.0 (1.37 ± 0.09 g) compared with pH 7.8 (1.90 ± 0.12 g). EC50 was highest with pH 7.4 (−5.38 ± 0.18 log M α,β-methylene ATP) and lowest with pH 7.0 (−4.9 ± 0.10 log M α,β-methylene ATP). The slopes of the dose-response curves were not different. Pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) abolished contraction caused by the addition of α,β-methylene ATP ( n = 6). There was no effect of pH on phenylephrine dose-response curves. These data indicate that the vasoconstrictor response to α,β-methylene ATP is sensitive to pH and that lower pH attenuates the response of P2X purinergic receptors.
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Wei, Chaojie, Liping Liu, Renli Liu, Wenwen Dai, Weiwei Cui, and Dong Li. "Association between the Phytochemical Index and Overweight/Obesity: A Meta-Analysis." Nutrients 14, no. 7 (2022): 1429. http://dx.doi.org/10.3390/nu14071429.
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Some studies suggest that a higher phytochemical index (PI) is associated with a lower risk of overweight/obesity. This meta-analysis is performed to summarize published studies on the relationship of PI and the risk of overweight/obesity. We searched on PubMed, Cochrane Library and Web of Science from the inception dates to February 2022. The random-effect model was used based on heterogeneity. Meta-regression was used to explore potential sources of between-study heterogeneity. Publication bias was evaluated using Begg’s and Egger’s tests. The dose–response relationship was assessed using a restricted cubic spline model. Nine studies were included in the meta-analysis, with a total of 100,753 participants. The meta-analysis showed that the phytochemical index was associated with a decreased risk of overweight/obesity. The pooled OR (95% CI) was 0.81 (0.74–0.90). The findings from dose–response analysis showed a nonlinear association between the phytochemical index and the risk of overweight/obesity. The results of the meta-regression showed that gender and area were significant covariates influencing the heterogeneity between studies. There was no publication bias in the meta-analysis of this study. In conclusion, although this meta-analysis indicates that a high phytochemical index is associated with a reduced risk of overweight/obesity, all the studies included in this meta-analysis were cross-sectional studies with high heterogeneity. As such, more data from randomized controlled trials are required to confirm the efficacy of PI in evaluating the risk of overweight/obesity.
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Chirikova, Ekaterina, Elizabeth K. Cahoon, Alexander Rozhko, et al. "Association Between 131I Exposure After the Chernobyl Accident and Thyroid Volume in Children in Belarus." Journal of the Endocrine Society 5, Supplement_1 (2021): A856—A857. http://dx.doi.org/10.1210/jendso/bvab048.1748.
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Abstract Thyroid enlargement can cause problems with swallowing or breathing and a decrease in accuracy of screening for thyroid cancer. Exposure to radioactive iodines after the 1986 Chernobyl accident is known to increase risk of thyroid cancer in those exposed at a young age, but little is known about its effects on thyroid volume, which could have important clinical implications. The objective of this study is to characterize the dose-response association between iodine-131 (131I) exposure and thyroid volume using data from a Belarusian-American cohort study of residents of Belarus exposed during childhood. Persons exposed to Chernobyl fallout in Belarus at the age of 18 years or younger had individual 131I doses to the thyroid gland estimated from direct thyroid activity measurements, radioecological and biokinetic models, and interview data on whereabouts and dietary habits collected during baseline screening in 1996-2001 (N=11,970; median age 21 years). Thyroid volume was estimated from thyroid ultrasound measurements during screening. Individuals with diagnoses of benign or malignant tumors of thyroid gland, any thyroid surgery or aplasia, and missing thyroid volume measurements were excluded (n=1,104). Dose and thyroid volume were log-transformed due to right-skewed distributions. We used a multivariable linear regression to estimate the dose-response association between 131I dose to the thyroid and thyroid volume accounting for confounding effects of sex, age at screening, and place of residence at the time of screening, a proxy for endemic iodine deficiency. To examine nonlinear effects, we added a quadratic term for the log-transformed dose. Among 10,866 participants, dose to thyroid ranged from 0.0005 to 39 gray (Gy) (median=0.3 Gy). In a linear regression model adjusted for confounders, log thyroid volume was best described by a linear-quadratic function of log dose (p&lt;0.001 for log dose and log dose-squared coefficients). The largest effect was observed for doses 0.3-0.6 Gy (14%), then gradually decreased. Subjects with thyroid dose of 1 Gy had an average thyroid volume 13.6% (95% CI 8- 19.2%) higher compared to those with dose 1 mGy. Thyroid volume increased with age and was significantly higher for males compared to females and for those from Minsk city and area compared to other regions (both p&lt;0.001). The adjusted R2-value was 30%, suggesting unaccounted factors that might better explain this association. This is the first study to assess the dose-response association between exposure to 131I and thyroid volume. Although statistically significant, the observed increase in thyroid volume with dose was small. Availability of measurements of iodine deficiency and dietary habits around the time of an accident in the future studies of nuclear accidents will be essential for understanding the mechanism of association between radiation dose and thyroid volume in young people.
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Li, Peiyun, Zhilei Shan, Li Zhou, et al. "MECHANISMS IN ENDOCRINOLOGY: Parity and risk of type 2 diabetes: a systematic review and dose-response meta-analysis." European Journal of Endocrinology 175, no. 5 (2016): R231—R245. http://dx.doi.org/10.1530/eje-16-0321.
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Objective Epidemiologic studies regarding the association between parity and risk of type 2 diabetes have yielded inconsistent results. Therefore, we performed a systematic review and dose-response meta-analysis to determine the relation between parity and type 2 diabetes risk. Methods We searched PubMed and Embase for published epidemiologic studies that assessed the relation between parity and risk of type 2 diabetes up to 31 March 2016. A dose-response random-effects model was used to combine study-specific relative risks (RRs) and 95% confidence intervals (CIs). Potential sources of heterogeneity were explored by meta-regression and subgroup analyses. Results Seven cohort studies, 1 case-control study and 9 cross-sectional studies including 296 923 participants were eligible for inclusion. The combined RR for the highest versus lowest category of parity indicated a 54% increment in type 2 diabetes risk (95% CI: 29–83%). In the cubic spline model, a nonlinear association was found between parity and risk of type 2 diabetes (P = 0.02 for nonlinearity). Compared with nulliparous women, the estimated RR (95% CI) of type 2 diabetes for women with one to seven children was 1.01 (0.96–1.07), 1.08 (1.00–1.16), 1.20 (1.12–1.30), 1.32 (1.22–1.42), 1.37 (1.27–1.48), 1.39 (1.26–1.52) and 1.39 (1.23–1.57) respectively. Conclusions Higher parity is significantly associated with an increased risk of type 2 diabetes. Further studies are warranted to fully adjust for the potential confounders and explore the causality between parity and type 2 diabetes risk.
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Li, Weiqi, Qianhui Shang, Dan Yang, et al. "Abnormal Micronutrient Intake Is Associated with the Risk of Periodontitis: A Dose–response Association Study Based on NHANES 2009–2014." Nutrients 14, no. 12 (2022): 2466. http://dx.doi.org/10.3390/nu14122466.
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The association between micronutrient intake and the risk of periodontitis has received much attention in recent years. However, most studies focused on the linear relationship between them. This study aimed to explore the dose–response association between micronutrient intake and periodontitis. A total of 8959 participants who underwent a periodontal examination, and reported their micronutrient intake levels were derived from the US National Health and Nutrition Examination Survey (NHANES, 2009–2014) database. Logistic regression was performed to evaluate associations between micronutrient intake and periodontitis after propensity score matching (PSM), and restricted cubic splines (RCS) analysis was conducted to explore the dose–response associations. Following PSM, 5530 participants were included in the RCS analysis. The risk of periodontitis was reduced with sufficient intake of the following micronutrients: vitamin A, vitamin B1, vitamin B2, and vitamin E. In addition, the risk of periodontitis was increased with excessive intake of the following micronutrients: vitamin B1 (1.8 mg/day, males; 1.3 mg/day, females), vitamin C (90 mg/day, males), and copper (1.1 mg/day, combined). In conclusion, a linear association was found between vitamin A, vitamin B2, vitamin C, and copper and periodontitis—namely, a sufficient intake of vitamin A and vitamin B2 might help reduce the prevalence of periodontitis; by contrast, a high intake of vitamin C and copper increased the risk. In addition, a nonlinear dose–response association was found for the incidence of periodontitis with vitamin B1 and vitamin E. When within reasonable limits, supplemental intake helped reduce the prevalence of periodontitis, while excessive intake did not help significantly and might even increase the risk. However, confounding factors, such as health awareness, should still be considered.
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Jiang, Jingjing, Xue Liu, Xiaotian Liu, et al. "The effect of progesterone and pregnenolone on diabetes status in Chinese rural population: a dose–response analysis from Henan Rural Cohort." European Journal of Endocrinology 181, no. 6 (2019): 603–14. http://dx.doi.org/10.1530/eje-19-0352.
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Objective Previous studies have uncovered a progestin-only contraceptive association with an increased risk of diabetes, but limited studies have explored the relationship of endogenous progesterone and pregnenolone levels with diabetes status. A case–control study was conducted in Henan Rural Cohort (register number: ChiCTR-OOC-15006699) to evaluate the dose–response independent and interactive relationship of progesterone and pregnenolone levels with prediabetes and type 2 diabetes mellitus (T2DM) in Chinese rural population. Design A case-control study. Methods A total of 798 T2DM patients, 779 prediabetes patients, and 782 individuals with normal fasting plasma glucose were included in this study. Serum progesterone and pregnenolone were detected by liquid chromatography-tandem mass spectrometry. Logistic regression and restricted cubic splines were used to assess the independent effects of progesterone and pregnenolone on prediabetes and T2DM. Interactive plots were employed to examine the interaction effects of progesterone and pregnenolone. Results Progesterone in the fourth versus first quartile was positively associated with prediabetes (odds ratio (OR) (95% CI): 2.66 (1.99–3.55)) and T2DM (OR (95% CI): 6.41 (4.57–8.98)), whereas pregnenolone in the fourth versus first quartile was inversely related to prediabetes (OR (95% CI): 0.23 (0.16–0.33)) and T2DM (OR (95% CI): 0.44 (0.31–0.62)). Additionally, the nonlinear dose–response associations between progesterone and pregnenolone with prediabetes and T2DM were found. Interactive effects of progesterone and pregnenolone on prediabetes and T2DM were observed, and these significant associations remained in gender-stratified analysis. Conclusions Prediabetes and T2DM were positively linked to serum concentration of progesterone and negatively related to pregnenolone in a dose–response manner in Chinese rural population.
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Jodrell, D. I., M. J. Egorin, R. M. Canetta, et al. "Relationships between carboplatin exposure and tumor response and toxicity in patients with ovarian cancer." Journal of Clinical Oncology 10, no. 4 (1992): 520–28. http://dx.doi.org/10.1200/jco.1992.10.4.520.
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PURPOSE The study was undertaken to define the relationship between tumor response and carboplatin area under the curve (AUC) in patients with ovarian cancer; to study the relationship between carboplatin AUC and myelosuppression in the same population; to establish the true impact of carboplatin AUC, prior therapy, and pretreatment platelet and WBC counts on toxicity; and to define an optimal carboplatin exposure for treating patients with ovarian cancer. METHODS With the equation AUC = dose/(glomerular filtration rate [GFR]+25), carboplatin AUC (course 1) was calculated for 1,028 patients (450 previously untreated) who received single-agent carboplatin (40 to 1,000 mg/m2) for advanced ovarian cancer. GFR was measured (chromium-51-edathamil [51Cr-EDTA] or creatinine clearance) in all patients. RESULTS Regression analysis showed that carboplatin AUC, prior treatment, and Eastern Cooperative Oncology Group grade performance status (PS) are predictors of tumor response, thrombocytopenia, and leukopenia. Pretreatment platelet and WBC counts are additional predictors of thrombocytopenia and leukopenia, respectively. Although the likelihood of tumor response increased with increasing carboplatin AUC, this relationship was nonlinear. In all patient subsets, the likelihood of complete response (CR) or overall response did not increase significantly above a carboplatin AUC of 5 to 7 mg/mL x minutes. At any given carboplatin AUC, thrombocytopenia occurred more frequently than leukopenia, although both approached 100% as carboplatin AUC increased. Both thrombocytopenia and leukopenia were more frequent in pretreated than in untreated patients regardless of pretreatment count. At any carboplatin AUC, the influence of PS on likelihood of response and toxicity was profound. CONCLUSION Carboplatin dosing by AUC will lead to more predictable toxicity, and increasing carboplatin AUC above 5 to 7 mg/mL x minutes does not improve the likelihood of response but does increase myelotoxicity. Therefore, careful evaluation of high-dose carboplatin therapy in a prospective, randomized trial is needed before such treatment becomes accepted practice.
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Sun, Hao, Donghui Huang, Hailong Wang, et al. "Association between Serum Copeptin and Stroke in Rural Areas of Northern China: A Matched Case-Control Study." Disease Markers 2018 (October 4, 2018): 1–8. http://dx.doi.org/10.1155/2018/9316162.
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Background. Copeptin has been implicated as an effective prognostic biomarker of stroke outcome; however, few studies have investigated whether copeptin could be used as an etiological factor for stroke or not. The aim of our study was to evaluate the association of serum copeptin with stroke. Methods. In total, 238 participants including 119 cases (87 ischemic stroke and 32 hemorrhagic stroke) and 119 controls were included in this 1 : 1 matched case-control study. Conditional multivariate logistic regression was conducted to assess the Odds Ratios (ORs) and 95% confidence intervals (CI); restricted cubic spline in logistic regression model was used to evaluate the dose-response association between serum copeptin and total stroke, ischemic stroke, and hemorrhagic stroke. Results. The median serum copeptin was 20.90 pmol/L, 20.90 pmol/L, 6.53 pmol/L, and 8.42 pmol/L for total stroke, ischemic stroke, hemorrhagic stroke, and healthy subjects, respectively. The corresponding ORs (95% CIs) for the highest compared with the lowest quartile were 1.23 (0.62–2.44) for total stroke, 4.01 (1.47–10.96) for ischemic stroke, and 0.13 (0.22–0.69) for hemorrhagic stroke. No nonlinear dose-response relationship was found between serum copeptin and total stroke (Pnonlinear=0.278), ischemic stroke (Pnonlinear=0.362), and hemorrhagic stroke (Pnonlinear=0.314). Compared with the reference copeptin level, a significantly increasing trend was found between serum copeptin and ischemic stroke (Poverall=0.002), and a decreasing trend was found between serum copeptin and hemorrhagic stroke (Poverall=0.007). Conclusions. Elevated serum copeptin levels were positively associated with ischemic stroke and adversely associated with hemorrhagic stroke. Additional prospective studies with larger sample size are needed to confirm the present findings.
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Willett, Cammy D., Erin M. Grantz, Jung Ae Lee, Matthew N. Thompson, and Jason K. Norsworthy. "Soybean response to dicamba in irrigation water under controlled environmental conditions." Weed Science 67, no. 3 (2019): 354–60. http://dx.doi.org/10.1017/wsc.2019.4.
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AbstractWhile much research has focused on crop damage following foliar exposure to auxin herbicides, reports documenting the risk posed by exposure via root uptake of irrigation water are lacking. Herbicide residues circulated in tailwater recovery systems may pose threats of cross-crop impacts to nonresistant cultivars with known sensitivity to auxins. An auxin-susceptible soybean [Glycine max(L.) Merr.] cultivar was grown in a controlled growth chamber environment and exposed to dicamba dissolved in irrigation water applied to the soil surface, simulating furrow irrigation. Five herbicide treatment concentrations, ranging from 0.05 to 5.0 mg L−1and encompassing estimated field doses of 3.1 to 310g ha−1, were applied to the soil of potted soybean plants at V3/V4 or R1 growth stages. Plant injury (0% to 100%), dry mass, height, number of pods, and number of pod-bearing nodes were measured. Kruskal-Wallis and logistic regression analyses were performed to determine treatment differences and examine dose effects. Yield losses were projected using (1) 14 d after treatment plant injury assessments based on injury–yield relationships described for foliar exposures and (2) pod counts. Dicamba concentration was the main significant factor affecting all growth response metrics, and growth stage was a significant explanatory variable only for the height response metric. A nonlinear response to dicamba dose was observed, with the threshold response dose required to affect 50% of plants being three times greater for 40% crop injury compared with 20% injury. Yield projections derived from plant response to root uptake compared with foliar exposure indicate that soybean may express both magnitude of injury and specific symptomology differently when exposure occurs via root uptake. Drift exposure–based models may be incompatible to predict soybean yield loss when injury results from irrigation. Data are needed to develop correlations for predicting yield losses based on field-scale exposure to dicamba in irrigation water, as well as assessment of real-world concentrations of herbicide residues in tailwater recovery systems.
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Wang, Chong, Ting Yang, Xiao-fei Guo, and Duo Li. "The Associations of Fruit and Vegetable Intake with Lung Cancer Risk in Participants with Different Smoking Status: A Meta-Analysis of Prospective Cohort Studies." Nutrients 11, no. 8 (2019): 1791. http://dx.doi.org/10.3390/nu11081791.
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The results of epidemiological studies on the relationship between fruit and vegetable intake and lung cancer risk were inconsistent among participants with different smoking status. The purpose of this study was to investigate these relationships in participants with different smoking status with prospective cohort studies. A systematic literature retrieval was conducted using PubMed and Scopus databases up to June 2019. The summary relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were calculated by random-effects model. The nonlinear dose-response analysis was carried out with restricted cubic spline regression model. Publication bias was estimated using Begg’s test. Nine independent prospective studies were included for data synthesis. Dietary consumption of fruit was negatively correlated with lung cancer risk among current smokers and former smokers, and the summery RRs were 0.86 (95% CI: 0.78, 0.94) and 0.91 (95% CI: 0.84, 0.99), respectively. Consumption of vegetable was significantly associated with reduced risk of lung cancer for current smokers (summary RR = 87%; 95% CI: 0.78, 0.94), but not for former smokers and never for smokers. Dose-response analysis suggested that risk of lung cancer was reduced by 5% (95% CI: 0.93, 0.97) in current smokers, and reduced by 4% (95% CI: 0.93, 0.98) in former smokers with an increase of 100 grams of fruit intake per day, respectively. Besides, dose-response analysis indicated a 3% reduction in lung cancer risk in current smokers for 100 gram per day increase of vegetable intake (95% CI: 0.96, 1.00). The findings of this study provide strong evidence that higher fruit consumption is negatively associated with the risk of lung cancer among current smokers and former smokers, while vegetable intake is significantly correlated with reducing the risk of lung cancer in current smokers. These findings might have considerable public health significance for the prevention of lung cancer through dietary interventions.
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Matthews, Charles E., Steven C. Moore, Hannah Arem, et al. "Amount and Intensity of Leisure-Time Physical Activity and Lower Cancer Risk." Journal of Clinical Oncology 38, no. 7 (2020): 686–97. http://dx.doi.org/10.1200/jco.19.02407.
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PURPOSE To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity. METHODS Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend ( P < .05) and 95% CIs (< 1.0). RESULTS A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types. CONCLUSION Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
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Chang, Kaixi, Yupei Li, Zheng Qin та ін. "Association between Serum Soluble α-Klotho and Urinary Albumin Excretion in Middle-Aged and Older US Adults: NHANES 2007–2016". Journal of Clinical Medicine 12, № 2 (2023): 637. http://dx.doi.org/10.3390/jcm12020637.
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(1) Background: Preclinical and clinical studies on the anti-aging effect of α-Klotho are emerging. Urinary albumin excretion (UAE) is a well-known biomarker of kidney injury and generalized damage in the cardiovascular system. However, the potential relationship between α-Klotho and UAE is limited and controversial. This study aimed to quantify this relationship in the general middle-aged and elderly population from the National Health and Nutrition Survey (NHANES) 2007–2016. (2) Methods: Serum α-Klotho was measured by enzyme-linked immunosorbent assay. UAE was assessed by the albumin-to-creatinine ratio (ACR). After adjusting for several confounding variables, the relationship between α-Klotho and ACR was analyzed by weighted multivariable logistic regression, subgroup analysis, and interaction tests. A generalized additive model (GAM) with smooth functions using the two-piecewise linear regression model was used to examine the potential nonlinear relationship between α-Klotho and ACR. (3) Results: Among 13,584 participants aged 40–79 years, we observed an independent and significant negative correlation between α-Klotho and ACR (β = −12.22; 95% CI, −23.91, −0.53, p = 0.0448) by multivariable logistic regression analysis, especially in those with age ≥ 60 years, pulse pressure (PP) ≥ 60 mmHg, hypertension or diabetes. We further discovered the nonlinear relationship between α-Klotho and ACR by GAM, revealing the first negative and then positive correlations with an inflection point of 9.91 pg/mL between α-Klotho and ACR. (4) Conclusions: A dose-response relationship between α-Klotho and ACR was demonstrated, and the negative correlation therein indicated that α-Klotho has potential as a serum marker and prophylactic or therapeutic agent despite its metabolic and effective mechanisms needing to be further explored.
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Palma, Jose-Alberto, Lucy Norcliffe-Kaufmann, Jose Martinez, and Horacio Kaufmann. "Supine plasma NE predicts the pressor response to droxidopa in neurogenic orthostatic hypotension." Neurology 91, no. 16 (2018): e1539-e1544. http://dx.doi.org/10.1212/wnl.0000000000006369.
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ObjectiveTo test whether the plasma levels of norepinephrine (NE) in patients with neurogenic orthostatic hypotension (nOH) predict their pressor response to droxidopa.MethodsThis was an observational study, which included patients with nOH. All patients had standardized autonomic function testing including determination of venous plasma catecholamine levels drawn through an indwelling catheter while resting supine. This was followed by a droxidopa titration with 100 mg increments in successive days until relief of symptoms, side effects, or the maximum dose of 600 mg was reached. No response was defined as an increase of <10 mm Hg in systolic blood pressure (BP) after 3-minute standing 1 hour after droxidopa administration. Nonlinear regression models were used to determine the relationship between BP response and plasma NE levels.ResultsWe studied 20 patients with nOH due to Parkinson disease, pure autonomic failure, multiple system atrophy, or autoimmune autonomic neuropathies. Their supine plasma NE levels ranged from 44 to 850 pg/mL. Lower supine plasma NE levels were associated with greater pressor effect 1 hour after dose (R2 = 0.49) and higher standing BP (R2 = 0.45). Patients with no pressor response to droxidopa had higher NE levels (382 ± 100 vs 115 ± 20 pg/mL, p = 0.0014). A supine NE level of <219.5 pg/mL had 83% sensitivity and 93% specificity to predict a pressor response (area under the curve = 0.95, p = 0.0023).ConclusionsIn patients with nOH, lower supine resting plasma NE levels are associated with a greater pressor effect of droxidopa treatment. This finding should help identify patients with nOH most likely to respond to standard doses of droxidopa.Classification of evidenceThis study provides Class I evidence that lower supine plasma NE levels accurately identify patients with nOH more likely to have a greater pressor effect from droxidopa.
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Zhang, Qiaoyang, Min Zhang, Yun Chen, Yin Cao, and Guanzhong Dong. "Nonlinear Relationship of Non-High-Density Lipoprotein Cholesterol and Cognitive Function in American Elders: A Cross-Sectional NHANES Study (2011–2014)." Journal of Alzheimer's Disease 86, no. 1 (2022): 125–34. http://dx.doi.org/10.3233/jad-215250.
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Background: Serum non-high-density lipoprotein-cholesterol (non-HDL-C) levels may be associated with cognitive function. Objective: The objective of this study was to evaluate the association between non-HDL-C and cognitive function among American elders. Methods: We used data from the 2011 to 2014 U.S. National Health and Nutrition Examination Survey (NHANES). A total of 3,001 participants aged over 60 years were enrolled in our analysis. The cognitive function was evaluated with the word learning subtest from the Consortium to Establish a Registry for Alzheimer’s disease (CERAD W-L), the Animal Fluency Test (AFT), and the digit symbol substitution test (DSST). We also created a composite cognitive z-score to represent a global cognition. We applied multivariate linear regression analyses to estimate the associations between non-HDL-C levels and all domains of cognitive function. Further, the generalized additive model and the smooth curve were conducted to investigate the dose-response relationship between non-HDL-C and global cognition. Results: Serum non-HDL-C was positively associated with global cognition (β= 0.20, 95% CI: 0.11, 0.28), AFT score (β= 0.54, 95% CI: 0.33, 0.76), and DSST score (β= 1.13, 95% CI: 0.56, 1.69) after fully adjusted. While non-HDL-C was not related to CERAD W-L score. In addition, an inverted U-shape curve was observed in the dose-response relationship between non-HDL-C and global cognition (p for non-linearity < 0.001). Conclusion: Serum non-HDL-C is positively and nonlinearly associated with cognitive function among American older adults. Maintaining serum cholesterol levels at an appropriate range may be helpful to the cognitive health of the elderly.
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De Leenheer, Els M. R., Patrick L. M. Huygen, Richard J. H. Smith, Sigrid Wayne, and W. R. J. Cremers. "The DFNA10 Phenotype." Annals of Otology, Rhinology & Laryngology 110, no. 9 (2001): 861–66. http://dx.doi.org/10.1177/000348940111000910.
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We present a detailed analysis of the DFNA10 phenotype based on data from 25 hearing-impaired persons coming from a large American pedigree segregating for deafness at the DFNA10 locus (chromosome 6q22.3–23.2). Cross-sectional analysis of air conduction threshold—on—age data from all available last-visit audiograms (linear regression analysis, age over 15 years) showed progression of hearing loss at a rate of 0.6 dB/y over all frequencies, with a flat to gently sloping age-corrected threshold of about 50 dB. The results were significant at 0.25, 4, and 8 kHz, but only if corrections for presbycusis were not included. Longitudinal threshold analysis performed in 1 case, covering ages 6 to 32 years, showed progression of hearing loss at a rate of 2 to 3 dB/y over 0.25 to 8 kHz. Nonlinear regression analysis was performed on phoneme discrimination scores with use of sigmoidal dose-response curves with variable slope. On the basis of these data, the hearing loss phenotype in this American DFNA10 family can be described as postlingual, initially progressive, and resulting, without the influence of presbycusis, in largely stable, flat sensorineural deafness.
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Kluess, Heidi A., John B. Buckwalter, Jason J. Hamann, and Philip S. Clifford. "Elevated temperature decreases sensitivity of P2X purinergic receptors in skeletal muscle arteries." Journal of Applied Physiology 99, no. 3 (2005): 995–98. http://dx.doi.org/10.1152/japplphysiol.00319.2005.
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We hypothesized that elevated temperatures would attenuate but that reduced temperatures would potentiate the tension mediated by vascular P2X purinergic receptors. The femoral arteries of 24 rats were dissected out and placed in modified Krebs-Henseleit buffer. Arteries were cut into 2-mm sections and mounted in organ tissue baths. Maximal tension (g) was measured during a KCl and norepinephrine challenge. Tension was measured during doses of α,β-methylene ATP (10−7 to 10−3 M), phenylephrine (10−7 to 10−4 M), and acetylcholine (10−9 to 10−5 M), with tissue bath temperature adjusted to 35, 37, and 41°C. Dose-response curves were fit using nonlinear regression analysis to calculate the EC50 and slope. The peak tension was lower with α,β-methylene ATP during 41°C (1.49 ± 0.14 g) compared with 35°C (2.08 ± 0.09 g) and 37°C (1.94 ± 0.09 g; P < 0.05). Slope and EC50 were not affected by temperature. Tension produced by phenylephrine and relaxation to acetylcholine were not affected by temperature. These data indicate that the vasoconstrictor response to α,β-methylene ATP is sensitive to temperature. Moderate cooling does not potentiate P2X-mediated vasoconstriction, but elevated temperature attenuates the vasoconstrictor response to P2X purinergic receptors.