Environmental arsenic exposure and its toxicological effect on thyroid function: a systematic review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Adeleh Esform ◽  
Tahereh Farkhondeh ◽  
Saeed Samarghandian ◽  
Maryam Rezaei ◽  
Ali Naghizadeh
Keyword(s):  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Arsenic Exposure ◽  
Experimental Studies ◽  
Urine Concentration ◽  
Thyrotropic Hormone ◽  
Toxicological Effect ◽  
Endocrine Disrupting ◽  
Thyroid Hormone Concentration ◽  
As Effects

Abstract Objectives This study was performed to review epidemiological evidence related to Arsenic (As) effects on the thyroid function by focusing on the serum thyroid hormone concentration. Content As, one of the main pollutants, has been recognized as an endocrine-disrupting agent that may affect the function of thyroid as shown by experimental studies. Summary This systematic study indicates the association between As exposure and thyroid dysfunction. The studies have shown an association between serum and urine concentration of arsenic and thyroid dysfunction. Most of them reported the association between increase in the serum or urine As levels and decrease in the triiodothyronine (T3) and thyroxine (T4), and also elevation in the thyrotropic hormone (TSH) levels. Outlook Our findings related to the effects of As on the function of thyroid in humans are still limited and future studies should be done to address this question.

THYROID DYSFUNCTION IN PATIENTS WITH CHRONIC KIDNEY DISEASE: THE STATE OF THE PROBLEM AND THE WAYS OF SOLVING

2018 ◽  
Vol 22 (4) ◽  
pp. 40-49 ◽  
Author(s):  
A. R. Volkova ◽  
O. D. Dygun ◽  
B. G. Lukichev ◽  
S. V. Dora ◽  
O. V. Galkina
Keyword(s):  
Chronic Kidney Disease ◽  
Thyroid Gland ◽  
Kidney Disease ◽  
Thyroid Hormones ◽  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
The Body ◽  
Type I ◽  
Low T3 ◽  
Iodine Excretion

Disturbance of the thyroid function is often detected in patients with different profiles. A special feature of patients with chronic kidney  disease is the higher incidence of various thyroid function  disturbances, especially hypothyroidism. It is known that in patients  with chronic kidney disease (CKD) iodine excretion from the body is  violated, since normally 90% of iodine is excreted in urine.  Accumulation of high concentrations of inorganic iodine leads to the  formation of the Wolf-Chaikoff effect: suppression of iodine  organization in the thyroid gland and disruption of the thyroid  hormones synthesis. Peripheral metabolism of thyroid hormones is  also disturbed, namely, deiodinase type I activity is suppressed and  peripheral conversion of T4 into T3 is inhibited (so-called low T3  syndrome). Therefore, patients with CKD are often diagnosed with  hypothyroidism, and the origin of hypothyroidism is not always  associated with the outcome of autoimmune thyroiditis. The article  presents an overview of a large number of population studies of  thyroid gland dysfunction in patients with CKD, as well as  experimental data specifying the pathogenetic mechanisms of  thyroid dysfunction in patients with CKD. Therapeutic tactics are still  not regulated. However, in a number of studies, replacement therapy with thyroid hormones in patients with CKD had some advantages.

scholarly journals Thyroid dysfunction is associated with the loss of hepatitis B surface antigen in patients with chronic hepatitis B undergoing treatment with α-interferon

2021 ◽  
Vol 49 (6) ◽  
pp. 030006052110251
Author(s):  
Wenfan Luo ◽  
Shuai Wu ◽  
Hongjie Chen ◽  
Yin Wu ◽  
Jie Peng
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Hepatitis B Surface Antigen ◽  
Hbv Dna ◽  
Interferon Treatment ◽  
Normal Thyroid ◽  
Normal Thyroid Function ◽  
Hbsag Loss

Objective To investigate the influence of thyroid dysfunction on the antiviral efficacy of α-interferon in adult patients with chronic hepatitis B (CHB). Methods We performed a retrospective study of 342 patients with CHB who underwent interferon treatment for >12 weeks. Patients with thyroid dysfunction before or during treatment were defined as the thyroid dysfunction group (n = 141) and those with normal thyroid function were defined as the normal thyroid function group (n = 201). The prevalences of hepatitis B virus (HBV) DNA undetectability, low hepatitis B surface antigen (HBsAg) titre (<250 IU/mL), HBsAg loss, and hepatitis B envelope antigen loss were compared. Results During interferon treatment, 69 of 270 (25.6%) participants with normal thyroid function at baseline developed thyroid dysfunction, whereas 11 of 72 (15.3%) with thyroid dysfunction at baseline regained normal thyroid function. The thyroid dysfunction group had significantly higher prevalences of low HBsAg titre (29.8% vs. 18.9%) and HBV DNA undetectability (66.0% vs. 40.3%). Multivariate logistic regression analysis showed that thyroid dysfunction was associated with HBsAg loss (odds ratio 4.945, 95% confidence interval 1.325–18.462). Conclusions These results suggest that thyroid dysfunction is not an absolute contraindication, but is associated with HBsAg loss, in patients with CHB undergoing α-interferon treatment.

scholarly journals Sample Timing, Diagnosis of Subclinical Thyroid Dysfunction and Mortality in Acute Myocardial Infarction: ThyrAMI1 Study

2019 ◽  
Vol 105 (4) ◽  
pp. e1299-e1306 ◽  
Author(s):  
Salman Razvi ◽  
Owain Leng ◽  
Avais Jabbar ◽  
Arjola Bano ◽  
Lorna Ingoe ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Reference Interval ◽  
Reference Ranges ◽  
Diagnosis And Prognosis ◽  
Time Period ◽  
All Cause Mortality ◽  
The Impact

Abstract Objective The objective of this study was to determine the impact of blood sample timing on the diagnosis of subclinical thyroid dysfunction (SCTD) and mortality in patients with acute myocardial infarction (AMI). Patients, Design, and Main Outcome Measures Patients with AMI had thyroid function evaluated on admission between December 2014 and December 2016 and those with abnormal serum thyrotropin (TSH) had repeat thyroid function assessed at least a week later. The association between sample timing and SCTD was evaluated by logistic regression analysis. Secondary outcomes were confirmation of SCTD on repeat testing and all-cause mortality up to June 2018. Results Of the 1806 patients [29.2% women, mean (± standard deviation) age of 64.2 (±12.1) years] analyzed, the prevalence of subclinical hypothyroidism (SCH) was 17.2% (n = 311) and subclinical hyperthyroidism (SHyper) was 1.2% (n = 22) using a uniform TSH reference interval. The risk of being diagnosed with SCTD varied by sample timing in fully-adjusted models. The risk of SCH was highest between 00.01 and 06.00 hours and lowest between 12.01 and 18.00 hours, P for trend &lt;.001, and risk of SHyper was highest between 12.01 hours and 18.00 hours and lowest between 00.01 hours and 06.00 hours. Furthermore, time of the initial sample was associated with the risk of remaining in a SCH state subsequently. Mortality in SCH patients was not elevated when a uniform TSH reference interval was utilized. However, when time period–specific TSH reference ranges were utilized, the mortality risk was significantly higher in SCH patients with HR (95% CI) of 2.26 (1.01–5.19), P = .04. Conclusions Sample timing impacts on the diagnosis and prognosis of SCH in AMI patients. If sample timing is not accounted for, SCH is systemically misclassified, and its measurable influence on mortality is lost.

scholarly journals Management of thyroid disease in pregnancy – Room for improvement in the first trimester

2016 ◽  
Vol 9 (3) ◽  
pp. 126-129 ◽  
Author(s):  
Helen Robinson ◽  
Philip Robinson ◽  
Michael D’Emden ◽  
Kassam Mahomed
Keyword(s):  
General Practitioner ◽  
Thyroid Function ◽  
Thyroid Disease ◽  
Thyroid Dysfunction ◽  
First Trimester ◽  
Antenatal Clinic ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Function Tests ◽  
In Pregnancy ◽  
Stimulating Hormone

Background First-trimester care of maternal thyroid dysfunction has previously been shown to be poor. This study evaluates early management of thyroid dysfunction in pregnancy in Australia. Methods Patients reviewed by the Obstetric Medicine team for thyroid dysfunction from 1 January 2012 to 30 June 2013 were included. Data were collected on gestation at referral from the patient’s general practitioner to the antenatal clinic, information provided in the referral letter, thyroid function tests and thyroid medications. Results Eighty-five women were included in the study. At the time of general practitioner referral to antenatal services, 19% of women with preexisting thyroid disease had no thyroid function tested. Forty-three percent had an abnormal thyroid-stimulating hormone defined as being outside the laboratory-specific pregnancy reference range if available, or outside the level of 0.1–2.5 mIu/L in the first trimester, 0.2–3.0 mIu/L in the second trimester and 0.3–3.0 mIu/L in the third trimester. Only 21% of women increased their thyroxine dose prior to their first antenatal clinic review. Conclusion This study highlights that a significant proportion of women with known thyroid disease either have untested thyroid function in the first trimester or a thyroid-stimulating hormone outside of levels recommended by guidelines.

THYROID PATHOLOGY IN CHILDREN WITH TYPE 1 DIABETES

Vestnik ◽  
2021 ◽  
pp. 107-111
Author(s):  
С.И. Сабирова ◽  
С.Г. Надырова ◽  
А.Б. Жанзак ◽  
А.Е. Манасбаева ◽  
Ж.Ж. Нургалиева
Keyword(s):  
Type 1 Diabetes ◽  
Thyroid Gland ◽  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Development Indicators ◽  
Clinical Hospital ◽  
Number Of Children ◽  
Thyroid Pathology ◽  
Number Of Patients

Целью научной работы является изучение структуры заболеваний щитовидной железы у больных сахарным диабетом 1 типа. В данной статье мы ретроспективно проанализировали 972 историй болезни больных детей с СД 1 типа, находившихся на стационарном лечении в ДГКБ №2 г. Алматы (Казахстан) в период с 2014 по 2019 гг. Были изучены и оценены показатели физического развития, объективные данные (кожные покровы, ЧСС, АД, пальпация ЩЖ), лабораторно - уровней гормонов ТТГ, свТ4, свТ3, а/т к ТПО, а/т к ТГ в сыворотки крови, инструментально - УЗИ ЩЖ. Всего за 2014-2019 гг. через отделение эндокринологии ДГКБ №2 прошли 972 детей с диагнозом СД 1 типа. Большинство детей (382 человек, 79,9%) имели стаж болезни СД до 5 лет. 88 детей (18,5%) со стажем от 5 до 10 лет, 8 человек (1,7%) страдали СД более 10 лет. СД1 в основном был диагностирован в возрасте 7-12 лет (245-51,3%), меньше всего выявили СД 1 типа у детей до 3 лет (21 - 4,4%). Из общего количества пациентов с СД1 (972) было обследовано на функцию ЩЖ 478 детей (49,2%). Среди них было выявлено 319 детей с дисфункцией ЩЖ, что составляет 66,7%. Так, за 2014 год из 92 детей - 7 (7,6%), обследованных на функцию щитовидной железы, в результате чего было выявлено 6 (85,7%) детей с дисфункцией щитовидной железы. С каждым годом росло количество детей, которых направляли на обследование ЩЖ, так в сравнении с 2014 годом, когда из 92 детей - 7 (7,6%) были обследованы на функцию щитовидной железы, в 2019 году были обследованы уже 222 (92,1%) детей из 241. Симптомы как гиперфункции, так и гипофункции ЩЖ, особенно их субклинические варианты протекают под маской других заболевании и не сразу обнаруживаются, исходя из этого следует сразу обследовать на функцию ЩЖ при поступлении и в дальнейшим их наблюдать в динамике. В ходе исследования дисфункция щитовидной железы диагностирована у 319 (67,7%) пациентов, что должно привлечь внимание не только эндокринологов, но и врачей общей практики, педиатров и настроить их на прицельный поиск этой патологии и своевременную коррекцию гипотиреоза или другой патологии ЩЖ при его наличии The purpose of this research is to study the structure of thyroid diseases in patients with type 1 diabetes. In this article, we retrospectively analyzed 972 case histories of sick children with type 1 diabetes who were treated in the children's city clinical hospital No. 2 in Almaty (Kazakhstan) in the period from 2014 to 2019. Physical development indicators, objective data (skin, heart rate, blood pressure, thyroid palpation), laboratory levels of TSH, thyroxine, triiodothyronine, antibodies to thyroperoxidase, antibodies to thyroglobulin in blood serum, instrumental ultrasound examination of the thyroid gland were studied and evaluated. In total, in 2014-2019, 972 children with a diagnosis of type 1 diabetes mellitus passed through the endocrinology Department of the children's city clinical hospital No. 2.The majority of children (382 people, 79.9%) had a history of diabetes up to 5 years. 88 children (18.5%) with experience from 5 to 10 years, 8 people (1.7%) had diabetes for more than 10 years. Type 1 diabetes was mainly diagnosed at the age of 7-12 years (245-51. 3%), the least detected type 1 diabetes in children under 3 years (21 - 4.4%). Out of the total number of patients with type 1 diabetes (972), 478 children (49.2%) were examined for thyroid function. Among them, 319 children with thyroid dysfunction were identified, which is 66.7%. So, in 2014, out of 92 children, 7 (7.6%) were examined for thyroid function, as a result of which 6 (85.7%) children had thyroid dysfunction. Every year, the number of children referred for thyroid examination increased, so compared to 2014, when out of 92 children - 7 (7.6%) were examined for thyroid function, in 2019, 222 (92.1%) children out of 241 were examined. Symptoms of both hyperfunction and hypofunction of the thyroid gland, especially their subclinical variants, occur under the guise of other diseases and are not immediately detected, so you should immediately investigate the function of the thyroid gland at admission and further observe them in dynamics. During the study, thyroid dysfunction was diagnosed in 319 (67.7%) patients, which should attract the attention of not only endocrinologists, but also General practitioners, pediatricians and set them up for a targeted search for this pathology and timely correction of hypothyroidism or other thyroid pathology if it is present.

THYROID FUNCTION TESTS: A REVIEW

2021 ◽  
pp. 73-76
Author(s):  
Vasudev Sankhla ◽  
Aman Deep
Keyword(s):  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Radioactive Iodine ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Function Tests ◽  
Function Tests ◽  
Tsh Secretion ◽  
Line Test ◽  
Radioactive Iodine Uptake

Thyroid function tests are one of the most common endocrine panels in general practice because a good understanding of when to order them, indications for treatment are important for the optimal treatment of thyroid dysfunction. Thyroid-stimulating hormone (TSH) should be the rst test to be performed on any patient with suspected thyroid dysfunction and in follow-up of individuals on treatment. It is useful as a rst-line test because even small changes in thyroid function are sufcient to cause a signicant increase in TSH secretion. Thyroxine levels may be assessed in a patient with hyperthyroidism, to determine the severity of hyperthyroxinemia. Antithyroid peroxidase measurements should be considered while evaluating patients with subclinical hypothyroidism and can facilitate the identication of autoimmune thyroiditis during the evaluation of nodular thyroid disease. The measurement of TSH receptor antibody must be considered when conrmation of Graves’ disease is needed and radioactive iodine uptake cannot be done.

scholarly journals Aspects of hormonal testing of thyroid function in patients with type 1 diabetes mellitus and chronic kidney disease

2021 ◽  
Vol 17 (1) ◽  
pp. 32-37
Author(s):  
A.G. Sazonova ◽  
T.V. Mokhort ◽  
N.V. Karalovich
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Thyroid Disorders ◽  
Free T4 ◽  
Free T3 ◽  
Peripheral Conversion

Background. Chronic kidney disease (CKD) is known to affect the thyroid axis, including thyroid hormone metabolism. It has been established that a decrease in renal function can be combined with changes in thyroid function. Thyroid dysfunction also has implications for renal blood flow, glomerular filtration rate (GFR), tubular transport, electrolyte homeostasis, and glomerular structure. The purpose of the study was to determine the features of thyroid function in patients with type 1 diabetes mellitus (T1DM) and CKD and develop recommendations for hormonal testing of thyroid pathology. Materials and methods. One hundred and twenty-one patients with T1DM with CKD were divided into 3 groups: group 1 — 78 individuals with GFR ≤ 60 ml/min/1.73 m2, group 2 — 20 people receiving renal replacement therapy (RRT), group 3 — 23 patients after renal transplantation (RT) with adequate graft function (the duration of the renal transplant is 3.62 (1.47; 4.28) years). Results. In T1DM and CKD group, the diagnostic value of thyroid-stimulating hormone is reduced due to the absence of differences in its values with a decrease in T4 and T3. Free T3 is the most sensitive marker of thyroid dysfunction in CKD. Thyroid disorders in T1D and CKD patients have a non-immune genesis. T1DM patients on RRT after hemodialysis (HD) procedure have an increase in total and free T4 and free T3, consequently, monitoring of thyroid disorders should be done immediately after the HD session. The restoration of normal values of peripheral conversion index and free T3 occurs within 1–2 years after TR, depending on the duration of RRT receiving. After more than 3 post-transplantation years, there is an increase in peripheral conversion index, which characterizes the imbalance of peripheral thyroid hormones towards a decrease in free T3 with relatively stable free T4. Conclusions. Thyroid dysfunctions are typical for all stages of the pathological process in CKD in patients with type 1 diabetes mellitus, including patients at the terminal stage and after successful kidney transplantation. The changes in thyroid hormones are associated with the RRT experience and can potentially affect the survival of patients.

scholarly journals Prevalence and course of thyroid dysfunction in neonates at high risk of Graves’ disease or with non-autoimmune hyperthyroidism

2021 ◽  
Vol 184 (3) ◽  
pp. 431-440
Author(s):  
Hassina Benlarbi ◽  
Dominique Simon ◽  
Jonathan Rosenblatt ◽  
Cecile Dumaine ◽  
Nicolas de Roux ◽  
...  
Keyword(s):  
High Risk ◽  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Genetic Disorder ◽  
Care Center ◽  
Receptor Gene ◽  
High Serum ◽  
Pediatric Care ◽  
Graves Disease ◽  
Neonatal Hyperthyroidism

Objective Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves’ disease (GD). Design and methods This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder. Results Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4). Conclusion These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

scholarly journals Association between ultrasonography echogenicity and heterogeneity and thyroid function in autoimmune diffuse thyroid diseases in children and adolescents 

2021 ◽  
Author(s):  
Ji Eun Park ◽  
Sook Min Hwang ◽  
Ji-Young Hwang ◽  
Jin Hee Moon ◽  
Ik Yang ◽  
...  
Keyword(s):  
Thyroid Function ◽  
Thyroid Dysfunction ◽  
Thyroid Stimulating Hormone ◽  
Thyroid Diseases ◽  
Overt Hypothyroidism ◽  
Thyroid Ultrasound ◽  
Thyroid Status ◽  
Children And Adolescent ◽  
Overt Hyperthyroidism

Abstract Purpose: To evaluate the association between thyroid echogenicity and heterogeneity seen on ultrasonography (US) and thyroid function in pediatric and adolescent populations with autoimmune diffuse thyroid diseases (AITD).Methods: From 2000 to 2020, we reviewed thyroid ultrasound (US) images and thyroid function statuses in 133 children and adolescent AITD patients. Our review of the images focused on decreased echogenicity and heterogeneity, which were classified into four grades.Results: Among patients with overt hypothyroidism or overt hyperthyroidism, 94.2% (65/69) showed a US grade of 3 or 4. In patients with subclinical hyper/hypothyroidism or euthyroidism, 45.3% (29/64) showed grades 1 or 2. There were no overt hyper/hypothyroidism patients with US grade 1. When we compared US grades according to thyroid status, more severe thyroid dysfunction was significantly associated with higher US grade (p=0.047). Thyroid stimulating hormone (TSH) level differed significantly according to US grades when we evaluated hyperthyroid (p=0.035) and hypothyroid (p=0.027) states independently. 11 patients showed both US grade and thyroid function status changes on follow-up US.Conclusions: In children and adolescent AITD patients, there was an association between decreased echogenicity and heterogeneity on US and thyroid dysfunction.

scholarly journals Status of Thyroid Function among Patients of National Medical College and Teaching Hospital

Med Phoenix ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. 64-70
Author(s):  
Anup Shamsher Budhathoki ◽  
Suprita Gupta ◽  
Sanjay Kumar Sah ◽  
Navin Kumar Sah ◽  
Navin Kumar Sah ◽  
...  
Keyword(s):  
Thyroid Function ◽  
Teaching Hospital ◽  
Thyroid Dysfunction ◽  
Thyroid Stimulating Hormone ◽  
Overt Hypothyroidism ◽  
Central Laboratory ◽  
National Medical College ◽  
Medical College ◽  
National Medical ◽  
High Prevalence

Background: Thyroid dysfunction is one of the most common endocrinopathies after Diabetes Mellitus. Thyroid dysfunction is defined as the alteration in Thyroid Stimulating Hormone (TSH) with normal or abnormal thyroid hormones. Nepalese population have a high risk for thyroid dysfunction with a high prevalence of iodine deficiency. Objective: To study the prevalence of thyroid dysfunction among the patients visiting National Medical College, Birgunj, Nepal for checkup and suggested to assess thyroid function. Materials and Methods: The hospital-based study was conducted in Central Laboratory, National Medical College and Teaching Hospital (NMCTH), Birgunj in collaboration with the Department of Biochemistry. Total 7040 patients visiting Central Laboratory for thyroid function assessment were included in the study between July 2017 to December 2019. The venous blood sample was collected and serum-free triiodothyronine(fT3), free tetraiodothyronine(fT4) and thyroid stimulating hormone (TSH) was estimated by Chemiluminescence Immunoassay (CLIA) method using Access 2 Beckman Coulter analyser. (Beckman Coulter Inc., California, USA). Results: Among 7040 subjects under study, 2138(30%) were found to have thyroid dysfunction with 13% having subclinical hypothyroidism, about 8% of overt hypothyroidism, about 4% with subclinical hyperthyroidism and 5% with overt hyperthyroidism. Majority of the thyroid dysfunction study group belonged to the 16-30 years age group followed by 31-45 years. Mean±SE for TSH, fT4 and fT3 levels show statistically significant differences in different thyroid disorders. Conclusion: The study revealed a high prevalence of subclinical hypothyroidism followed by overt hypothyroidism among the patients visiting National Medical College and Teaching Hospital, Birgunj, Nepal. A higher percentage of females were found to have thyroid dysfunction compared to male.

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