L Lorente-Poch et al. Brain calcifications in surgical 9:10 955–962 hypoparathyroidism RESEARCH Prevalence of basal ganglia and carotid artery calcifications in patients with permanent hypoparathyroidism after total thyroidectomy Leyre Lorente-Poch1,2, Sílvia Rifà-Terricabras2, Juan José Sancho1,2, Danilo Torselli-Valladares1, Sofia González-Ortiz3 and Antonio Sitges-Serra1,2 1 Endocrine Surgery Unit, Hospital del Mar, Barcelona, Spain 2 Departament de Cirurgia, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Department of Radiology, Hospital del Mar, Barcelona, Spain Correspondence should be addressed to L Lorente-Poch: lorentepoch@live.com Abstract Objective: Permanent hypoparathyroidism is an uncommon disease resulting most Key Words frequently from neck surgery. It has been associated with visceral calcifications but ff permanent few studies have specifically this in patients with post-surgical hypoparathyroidism. hypoparathyroidism The aim of the present study was to assess the prevalence of basal ganglia and carotid ff total thyroidectomy artery calcifications in patients with long-term post-thyroidectomy hypoparathyroidism ff carotid calcifications compared with a control population. ff basal ganglia calcifications Design: Case–control study. Methods: A cross-sectional review comparing 29 consecutive patients with permanent postoperative hypoparathyroidism followed-up in a tertiary reference unit for Endocrine Surgery with a contemporary control group of 501 patients who had an emergency brain CT scan. Clinical variables and prevalence of basal ganglia and carotid artery calcifications were recorded. Results: From a cohort of 46 patients diagnosed with permanent hypoparathyroidism, 29 were included in the study. The mean duration of disease was 9.2 ± 7 years. Age, diabetes, hypertension, smoking and dyslipidemia were similarly distributed in case and control groups. The prevalence of carotid artery and basal ganglia calcifications was 4 and 20 times more frequent in patients with permanent hypoparathyroidism, respectively. After propensity score matching of the 28 the female patients, 68 controls were matched for age and presence of cardiovascular factors. Cases showed a four- fold prevalence of basal ganglia calcifications, whereas that of carotid calcifications was similar between cases and controls. Conclusion: A high prevalence of basal ganglia calcifications was observed in patients with post-surgical permanent hypoparathyroidism. It remains unclear whether carotid artery Endocrine Connections calcification may also be increased. (2020) 9, 955–962 Introduction Permanent hypoparathyroidism is a rare disorder Immune-mediated destruction of the parathyroid glands, characterized by low or inappropriately normal idiopathic and inherited hypoparathyroidism such as levels of parathyroid hormone leading to low DiGeorge syndrome and activating mutations in the calcium and increased phosphate serum levels (1). extracellular calcium-sensing receptor or mutations in https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0387 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. L Lorente-Poch et al. Brain calcifications in surgical 9:10 956 hypoparathyroidism the pre-proPTH, are uncommon causes of permanent analyzing a cohort of 1133 patients suspected of acute hypoparathyroidism (1). ischemic stroke, female gender, hypertension, diabetes, The commonest etiology of permanent parathyroid hyperlipidemia, smoking and previous stroke were failure (up to three quarters of the cases (2, 3)) is associated with BGC; a low BMI and older age were postoperative hypoparathyroidism mostly due to identified as the most powerful predicting risk factors (13). intraoperative injury to the parathyroid glands, It has been reported that alteration in calcium, autotransplantation or inadvertent parathyroidectomy phosphate and parathyroid hormone homeostasis is a (4), all leading to a reduction of the functional parathyroid predisposing factor for vascular calcification and increases parenchyma. the risk of cardiovascular disease in patients with end- As total thyroidectomy has been gaining popularity stage renal disease (14, 15). This same relationship in during the last three decades for the management of a patients with permanent hypoparathyroidism remains variety of thyroid disorders, postoperative parathyroid unexplored. Underberg et al., showed the cardiovascular failure has emerged as the most common early adverse risk was increased in non-surgical hypoparathyroidism effect of thyroidectomy, eventually progressing to but not in post-surgical hypoparathyroidism (8). The permanent hypoparathyroidism, a complication requiring Rotterdam study (16) found current smoking, age, life-long medical supervision and treatment. hypertension, hypercholesterolemia and diabetes were The estimated prevalence of permanent risk factors for calcifications in carotid, coronary and hypoparathyroidism after total thyroidectomy varies aortic arch branches. between 0 and 3% as reported in literature reviews (5) No studies have specifically investigated the and 6–12% according to more realistic national registries occurrence of visceral calcifications in patients with and multicenter studies (6). Some studies dealing with permanent hypoparathyroidism of surgical etiology. current management policies, quality of life and the risk Thus, the aim of the present work was to investigate the of complications have been published in recent years and prevalence of BGC and carotid calcification in patients reviewed in the European Guidelines (7). with post-thyroidectomy hypoparathyroidism compared A Danish case–control study (8) assessing 668 with that in the general population. patients with post-surgical hypoparathyroidism showed that they had almost five-fold increase the rate of renal stones in comparison with the normal population. One Methods year later, the same authors reported a significantly increased risk of hospitalization due to infections and A case–control study was designed as a cross-sectional depression/bipolar affective disorders (9). The PARADOX review comparing the prevalence of visceral calcifications. study also captured a significant impact of permanent Cases were 46 consecutive patients (Fig. 1) with hypoparathyroidism on the quality of life (10). Our group permanent postoperative hypoparathyroidism whose previously reported at least one clinical adverse event data was obtained from a single-center prospectively was observed in 56.3% of patients with post-surgical maintained clinical database. These patients had either permanent hypoparathyroidism and a slight decrease total thyroidectomy (with or without lymph node of the punctuation in the SF-36 questionnaire for the dissection) or either for benign or malignant condition perceived quality of life that was only significant for the or thyroparathyroidectomy for concomitant primary emotional role (11). hyperparathyroidism between 1984 and 2017. Patients Another well-known complication of long-term with secondary hyperparathyroidism were excluded. hypoparathyroidism with uncertain clinical significance is All the procedures were performed by the same team basal ganglia calcifications (BGC). Mitchell et al. (2) found of experienced endocrine surgeons at the Hospital the prevalence of BGC was 51.6%. Even a higher prevalence Universitari del Mar in Barcelona, Spain, a referral center of 74% was found by Goswami et al. (12) in 145 patients for Endocrine Surgery. with idiopathic hypoparathyroidism. These two authors Patients diagnosed with permanent suggested chronic hyperphosphatemia may contribute hypoparathyroidism were followed-up in our outpatient to basal ganglia calcifications in hypoparathyroidism. clinic every 6 months monitoring intact PTH (iPTH), serum Patients with post-surgical hypoparathyroidism were calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, few or not included in these studies. In a recent study and kidney function (creatinine and estimated glomerular https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0387 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. L Lorente-Poch et al. Brain calcifications in surgical 9:10 957 hypoparathyroidism Figure 1 Patient flow diagram. filtration). Typically, patients received treatment with Sample size calcium salts (1.5–3.0 g of calcium/day) and vitamin D The case-cohort consisted of 46 patients with permanent analogues: calcitriol (Rocaltrol®), 0.25–1.00 µg/day and/or hypoparathyroidism diagnosed and followed at a single calcifediol (Hidroferol®), 266 mg, one to three times/week. center. The relatively small sample size for this study There was no formal criterion to use one or the other (11) reflects the low-rate of this complication in a specialized but calcifediol was the preferred drug for patients with unit (about 4.5% of all total thyroidectomies). creatinine >1 mg/dL. The estimated prevalence of basal ganglia calcification iPTH levels were determined using either an immune- in the general population lies somewhere between 2 and radiometric second generation assay using IRMA Total 12.5% (17, 18). Large population studies have reflected Intact assay (Scantibodies Laboratory Inc. Santee, CA, a prevalence of carotid calcifications ranging between 2 USA) or a solid-phase, two-site chemiluminescent and 4% (19, 20). To obtain a minimum number of BGC enzyme-labeled assay IMMULITE 2000 Intact PTH assay and carotid calcifications, a control sample of 500 patients (Siemens Healthcare Diagnostics Spain, Madrid, Spain); was selected. with a normal range of 13–65 pg/mL and a detection limit Prevalence of basal ganglia and carotid artery of 3 pg/mL. In addition to routine kidney ultrasound, calcifications was assessed with CT scan and supra-aortic bone mineral density scan (DXA), 24-h urine calcium test, ultrasound when available. some patients agreed to undergo CT-scan to assess BGC and carotid calcifications. Definitions The control group consisted of patients (n = 501) who attended the Emergency Department for either head Permanent hypoparathyroidism was defined as a trauma, stroke or headache and had a cranial CT-scan subnormal iPTH concentration (<13 pg/mL) and need for between January and April 2018 (Fig. 1). Information on calcium replacement with or without activated vitamin smoking, blood pressure and lipid-lowering medication D metabolites for more than 1 year after surgery (6, 21). use was obtained through the medical records and A few patients recovering after this time period were not electronic prescription system. included (22). The study was approved by Hospital del Mar Ethics Regarding cardiovascular risk factors, the subjects were Committee. Written informed consent was obtained from categorized as current, past and non-smokers. We defined all the cases. hypertension, hypercholesterolemia and diabetes as the https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0387 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. L Lorente-Poch et al. Brain calcifications in surgical 9:10 958 hypoparathyroidism use of blood pressure-lowering medication, lipid reducing and underwent a brain CT scan (Fig. 1). All but one were medication or of anti-diabetic drugs, respectively. Height females (23). Mean age was 62 ± 17 years. Thyroidectomy and weight were measured in cases, and the BMI was had been performed for benign goiter in 20 (69%) patients calculated (weight(kg)/height(m)2). We defined obesity as and for thyroid cancer in 9 (31%) patients. The mean a BMI >30 kg/m2. length of follow-up was 9.2 ± 7 years. Carotid calcifications were defined as calcifications Control brain CT scans were obtained from 501 reported by radiologists in the brain CT scan and/or patients who attended the emergency department for a described in a supra-aortic Doppler ultrasound. BGC variety of reasons (Fig. 1). Around half of the controls was defined according to findings on the brain CT-scan were male patients with a mean age of 66 ± 21 years. reviewed by a Neuroradiologist. Age and risk factors for BGC and carotid calcifications such as diabetes, hypertension, smoking and dyslipidemia were similarly distributed in both groups. Male gender Statistical analysis was less common among the cases. Overall visceral Comparison of proportions was investigated with the calcifications (including both, carotid and BGC), were Chi-square or exact Fisher tests as appropriate. The almost seven times more prevalent in the case group. The Kolmogorov–Smirnov test was used to assess the normal prevalence of carotid calcification was four-fold in the distribution of quantitative variables. Quantitative and case group. BGC was located mainly in globus pallidus and normally distributed variables were compared using tended to be bilateral in both, cases and controls (Table 1). unpaired Student’s t-test and values were expressed as Figures 2, 3 and 4 show CT scan imagine of basal ganglia mean ± s.d. and vascular calcifications. Patients with permanent Statistical significance was set at P < 0.05. Stepwise hypoparathyroidism had a 20 times higher prevalence of forward binomial logistic regression analysis was used BGC (Table 2). to isolate the independent predicting factors for supra- After propensity score matching of the 28 the aortic and basal ganglia calcifications. Propensity Score female patients, 68 controls were matched for age and Matching was used to select a minimum of two controls presence of cardiovascular factors (Table 3). Cases showed for case. Statistical analyses were carried out using SPSS almost a four-fold prevalence of BGC, whereas that of IBM Statistics v.22.0. carotid calcifications was similar between female cases and controls. In multivariate analysis of both cohorts (530 patients), gender, age, permanent hypoparathyroidism, Results smoking, hypertension, dyslipidemia and diabetes From a total of 46 patients diagnosed with permanent were coded as dichotomous variables. The binomial hypoparathyroidism, 29 agreed to be included in the study logistic regression model (Table 4) isolated permanent Table 1 Description of basal ganglia calcifications in five controls and six cases. Patient Case/control Gender Age Location Side Measurements (mm) (AP/LL/CC) FUF Control M 53 Globus pallidus Bilateral 7*7*8 (right) 6*2*3(left) MEWV Control F 77 Globus pallidus Bilateral 3*1*4 (right) 5*1*5(left) ABP Control F 80 Globus pallidus Bilateral 7*4*8 (right) 8*6*7(left) JME Control F 80 Globus pallidus Bilateral 10*5*10 (right) 14*5*9 (left) EAC Control F 51 Globus pallidus Bilateral 8*5*8(right) 11*4*8(left) Lenticular nucleus 10*2*5 (right) 6*2*3 (left) Thalamus 8*7*8 (right) 9*6*9 (left) Caudate nucleus 18*6*16 (right) 11*6*13 (left) SSC Case F 43 Globus pallidus Left 1*1*8x MBM Case F 86 Globus pallidus Right 1*1*3 JLM Case F 70 Globus pallidus Right 1*1*4 DPJ Case F 68 Globus pallidus Bilateral 9*6*7 (right) 8*4*8 (left) CGV Case F 81 Globus pallidus Left 2*1*7 AMG Case F 68 Globus pallidus Bilateral 7*3*8 (right) 8*5*9 (left) AP, anteroposterior; CC, caudocranial; LL, latero-lateral. https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0387 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. L Lorente-Poch et al. Brain calcifications in surgical 9:10 959 hypoparathyroidism to small sample size. Episodes of hypercalcemia (35.3% vs 40%, P = 1) or hypocalcemia (38.9% vs 10%, P = 0.194) did not correlate with BGC. Additionally, there was no relation with the type of active vitamin D drugs they were receiving (calcitriol (35% vs 40%); and calcifediol (65% vs 60%), P = 1). Patients with BGC was receiving significantly higher doses of daily calcium (2.6 vs 1.4 g, P = 0.030). All patients with BGC was receiving vitamin D analogues, whereas only 56.3% of patients without BGC did (P = 0.123). Figure 2 CT scan imaging of a hypoparathyroid 68-year-old female patient with Discussion bilateral globus pallidus (A) and dentate nuclei of cerebellum (B) calcifications. Few authors have investigated the long-term clinical implications of hypoparathyroidism and even fewer hypoparathyroidism, diabetes and dyslipidemia as have assessed the prevalence of visceral calcifications. independent predictors of overall visceral and carotid To our knowledge, the present study is the only one calcifications; for the latter, hypertension and smoking comparing the prevalence of BGC between patients were also predictive factors. Only hypoparathyroidism with postoperative permanent hypoparathyroidism and and to a lesser extent, smoking habit were independent the general population and specifically assessing carotid factors for BGC. calcifications. The close patient monitoring carried out at An independent analysis was performed to compare our Unit differs from the previous publications (2, 8, 9), those patients with permanent hypoparathyroidism who whose data were mostly collected from national registries. developed (n = 10) or did not develop (n = 19) calcifications Cross-sectional brain imaging was available in 60% (3 of them had both carotid and BG calcifications). No of our post-surgical hypoparathyroid patients showing a association could be identified between and the absence vs prevalence of BGC of 24%. This is lower than the 50–73% presence of BGC and BMI (29.9 vs 28.6 kg/m2, P = 0.633), reported by other authors. Etiology and duration of disease age (50.3 vs 57.4 years, P = 0.372), duration of disease (10 may be the main reason. Goswamy et al. assessed patients vs 12 years, P = 0.441) or phosphate (4.32 vs 4.24 mg/dL, with idiopathic hypoparathyroidism and in the study P = 0.841) and creatinine serum levels (0.78 vs 1.13 mg/dL, done by Mitchell et al. a mix of idiopathic, autoimmune P = 0.351). Whether PTH was undetectable (4.3% vs 20%) and post-surgical hypoparathyroidism was included or low but detectable (95.7% vs 80%), did not have an and CT scan was only available for 26% of the cohort. impact on the prevalence of BGC (P = 0.362), probably due Nevertheless, other previous cohort studies observed basal ganglia calcifications in 12–36% (24, 25). In neither of these studies were patients routinely screened for BGC. Our analysis revealed that patients with post-surgical hypoparathyroidism had a four-fold risk for BGC when compared with a matched population. Unlike a recent cohort-study of acute ischemic stroke patients (13), female gender, hypertension, diabetes, hyperlipidemia and older age were not associated with BGC. Some authors have suggested that BGC could be associated with the duration of illness (26). In our cohort, however, there was no correlation between duration of permanent hypoparathyroidism and the development of calcifications. Figure 3 In the present study, carotid calcifications were CT scan imaging of a 51-year-old female control with bilateral calcifications of globus pallidus, lenticular nucleus, thalamus and five times more prevalent in patients with permanent caudate nucleus. hypoparathyroidism, than in the control group. https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0387 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. L Lorente-Poch et al. Brain calcifications in surgical 9:10 960 hypoparathyroidism Figure 4 CT scan imaging of a hypoparathyroid 90 years old female patient with calcification in (A) right subclavia artery (arrow) and surgical clips (*), and (B) left carotid bifurcation (arrow) after thyroidectomy for benign goiter. After matching, however, this difference disappeared. predictor. On the contrary, age was not associated with The relatively small sample precludes any final conclusion. carotid calcifications. The Rotterdam study (16) assessed vascular A case–control study from India assessing thirty patients calcifications in 1003 patients and found that with sporadic idiopathic hypoparathyroidism found hypertension, hypercholesterolemia and diabetes were thicker ultrasound measured intima-media in carotid, significant or near significant risk factors for carotid, aortic aortic and renal arteries when compared with healthy arch and coronary calcifications and age and current subjects. In these patients, serum calcium, iPTH levels smoking were the strongest independent risk factors. In were low, whereas serum phosphate levels significantly the multivariate-adjusted model, current smoking was higher. No significant correlation was observed, however, associated with carotid calcification both in women and between biochemical and intima-media thickness or other in men. All these risk factors were similar between cases cardiovascular risk factors (27). The authors concluded and controls in our study. Consistently, binomial logistic that vascular risk was increased in patients with sporadic regression isolated diabetes, dyslipidemia, hypertension idiopathic hypoparathyroidism (28). and current smoking as predictors for carotid calcifications, Carotid artery calcifications, particularly those close being permanent hypoparathyroidism the most powerful to carotid bifurcation, may result in important vascular obstruction causing stroke. Calcified atheroma plaques in Table 2 Demographic variables, cardiovascular risk factors carotid arteries may represent an independent marker for and prevalence of basal ganglia and carotid calcifications of ischemic symptoms (29, 30, 31). 29 patients with postoperative permanent Underberg et al. analyzed the occurrence of ischemic hypoparathyroidism (cases) and 501 controls. heart disease, stroke and heart failure and concluded that Cases (n = 29) Controls (n = 501) P Table 3 Prevalence of basal ganglia and carotid calcifications Age (years)a 62 ± 17 (26–95) 66 ± 21 (4–100) 0.352 in female patients after propensity score matching by age, Gender <0.001b Male 1 (3.4) 264 (52.7) presence of diabetes, hypertension, dyslipidemia and smoke Female 28 (96.6) 237 (47.3) status to mate cases–controls. Diabetes 5 (17.2) 129 (25.7) 0.383 Cases (n = 28) Controls (n = 68) P Hypertension 13 (44.8) 276 (55.1) 0.281 Dyslipidaemia 11 (37.9) 165 (32.9) 0.579 Age (years) 62.3 ± 17 63.5 ± 21 0.739 Smoker status 0.695 Diabetes 4 (14.3) 23 (33.8) 0.079a Non-smoker 22 (75.9) 411 (82) Hypertension 12 (42.8) 33 (48.5) 0.613 Smoker 4 (13.8) 54 (10.8) Dyslipidaemia 10 (35.7) 28 (41.2) 0.619 Ex-smoker 3 (10.3) 36 (7.2) Smoker 3 (10.7) 5 (7.4) 0.892a Carotid 7 (24.1) 26 (5.2) <0.001 Carotid calcifications 6 (21.4) 9 (13.2) 0.315 calcifications BG calcifications 6 (21.4) 4 (5.9) 0.031a BG calcifications 6 (20.7) 5 (1) <0.001 Values in parentheses are percentages. Quantitative values are expressed Values in parentheses are percentages unless indicated otherwise. in mean ± s.d. a Values are mean ± s.d. (range); bFisher’s exact test. a Fisher’s exact test. BG, basal ganglia. BG, basal ganglia. https://ec.bioscientifica.com © 2020 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/EC-20-0387 Published by Bioscientifica Ltd Attribution-NonCommercial-NoDerivatives 4.0 International License. L Lorente-Poch et al. Brain calcifications in surgical 9:10 961 hypoparathyroidism Table 4 Binomial Logistic Regression analysis of independent predictors for carotid and basal ganglia calcifications in the 29 cases and 501 controls. 95% CI Risk factor Regression coefficient s.e. Wald P value OR Lower Upper Carotid calcifications PHP 2.347 0.602 15.209 <0.001 10.459 3.21 34.03 Diabetes 1.357 0.439 9.555 0.002 3.885 1.64 9.19 Dyslipidaemia 1.147 0.446 6.620 0.010 3.149 1.31 7.55 Hypertension 1.401 0.680 4.246 0.039 4.061 1.07 15.40 Smoker −0.935 0.519 3.247 0.072 0.393 0.14 1.08 Basal ganglia calcifications PHP 3.532 0.654 29.187 <0.001 34.19 9.49 123.12 Smoker 0.971 0.395 6.028 0.014 2.64 1.22 5.73 Binomial logistic regression parameters: Stepwise forward; F to enter 0.05; F to remove: 0.10; Cut point to classify = 0.5; Predicting variables: gender, hypertension, dyslipidemia, diabetes, smoking status and permanent hypoparathyroidism coded as dichotomous; age coded as continuous. PHP, permanent hypoparathyroidism. cardiovascular risk was not increased in post-surgical neither for BGC nor for vascular calcifications (7). hypoparathyroidism (8). In this study, however, the Although the clinical implications of BGC is unclear prevalence of carotid calcifications was not assessed, so (and need to be addressed in future studies), the present their possible association with cardiovascular could not findings indicate that patients should be probably be assessed. monitored for this. Whereas less than half of the controls were female, In conclusion, our study shows a higher prevalence of more than 96% of the cases were of female gender, BGC and, probably, of carotid calcifications among post- consistent with the usual proportion in thyroid disease surgical permanent hypoparathyroid patients in comparison requiring surgery. To minimize this confounding factor, with a control population. Further studies should be a propensity score matching was carried out excluding designed to assess the clinical meaning of these findings that male patients and selecting at least two similar female may have an impact on patients’s quality of life. controls for every patient matching for age, diabetes, hypertension, dyslipidemia and smoking status. Thus, in Declaration of interest female patients, the prevalence of carotid calcifications The authors declare that there is no conflict of interest that could be was similar in cases and controls, whereas the prevalence perceived as prejudicing the impartiality of the research reported. of BGC was four-fold in patients. A potential limitation of our study is that controls Funding were not representative of general populations and there This study was supported by an Investigator Initiated Research grant from may be a selection bias since almost 25% underwent a Shire International GmbH, a member of the Takeda group of companies CT-scan because a stroke was suspected. And yet, the (IIR-ESP-001471). control group had significantly less prevalence of carotid calcifications. Another limitation was that data of BMI was not available for the control group and it has been shown References to be a predictive factor for basal ganglia calcifications. 1 Shoback D. Clinical practice. Hypoparathyroidism. New England We did analyze, however, the influence of BMI on the Journal of Medicine 2008 359 391–403. (https://doi.org/10.1056/ prevalence of BGC and carotid calcifications in the cases NEJMcp0803050) 2 Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, and could not find an association. 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