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Incidence and prevalence of thyroid disease in elderly women: results from the longitudinal population study of elderly people in Gothenburg, Sweden.

The incidence and prevalence of thyroid dysfunction were estimated in a longitudinal study of a representative sample of elderly women at ages 70, 75, 79 and 81. Thyroid-stimulating-hormone concentrations were measured in frozen samples obtained at the ages of 70 and 75 that had been stored for ten and five years, respectively. At the ages of 79 and 81 the serum concentrations of thyroid-stimulating hormone were determined in connection with the sampling. For comparison, thyroid-stimulating-hormone concentrations were also measured in another representative population sample of women at ages 70 (n = 297) and 76 (n = 342), in whom measurements were carried out in direct connection to the clinical study. History of previous thyroid disease, e.g. thyroid surgery and thyroid hormone treatment, was obtained through a questionnaire. Information about previous treatment with radio-iodine was obtained from records. At the age of 70, 1.9% had had thyroid surgery but none had been treated with radio-iodine. L-Thyroxine had been prescribed for 3.5%, and another 3.9% had high thyroid-stimulating-hormone concentrations (greater than 10.0 mU/l) indicating thyroid hypofunction. Between 70 and 79 years of age, eight of the 514 women had developed high concentrations of thyroid-stimulating hormone and another two women had received treatment with L-thyroxine. Three women had received radio-iodine therapy. In addition, one woman at the age of 81 was discovered to have hyperthyroidism. The retrospective analysis showed that markedly elevated TSH concentrations had been present in several women for at least nine years.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Polymorphisms of HLA class II predispose children and adolescents with type 1 diabetes mellitus to autoimmune thyroid disease.

To determine the prevalence of autoimmune thyroid disease (AITD) in children and adolescents with type 1 diabetes mellitus (DM), and assess whether the development of AITD is correlated with specific DQ-A and DQ-B loci of the HLA class II antigens, we analyzed thyroid function using anti-thyroid antibodies and HLA-DQ-A and -DQ-B polymorphisms in 69 patients with type 1 DM, in 75 normal healthy controls, and in 21 patients with AITD but without type 1 DM. Eighteen patients (26%) in the diabetic patients had AITD. In the diabetic patients, DQA1*0301 and DQB1*0302 occurred more frequently than in controls [DQA1*0301: OR = 1.939, 95% CI = 1.210-3.109 (P = 0.008, P(c) (corrected P) < 0.05); DQB1*0302: OR = 2.558, 95% CI = 1.354-4.832 (P = 0.005, P(c), > 0.05)]. Compared with controls, non-diabetic subjects with AITD showed higher frequency of DQA1*0301 (P(c), < 0.05) and DQB1*0601 (P(c) > 0.05), but these alleles were not contributing factors in the development of AITD in diabetic patients. In diabetic patients, DQB1*0201, known as susceptible allele of type 1 DM was not a contributing factor in the development of AITD in diabetic patients. Unlike DQB1*0201, DQB1*0401 was more frequently found in diabetic patients with AITD than in controls [OR = 4.053, 95% CI = 1.607-10.221 (P = 0.0017, P(c) < 0.05)] or than in non-diabetic AITD patients [OR = 15.769, 95% CI = 1.905-130.530(P = 0.002, P(c) < 0.05)]. In non-diabetic subjects, DQB1*0401 did not provide susceptibility for AITD. Our results suggest that HLA DQB1*0401 is a predisposing genetic marker for the development of AITD in patients with type 1 DM in Korea.

Adolescent↗

Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

In Hashimoto's thyroiditis, Fas-induced apoptosis is one of the mechanisms leading to cell destruction, whereas thyroid tissue in Graves' disease is prevented from it. The soluble form of the Fas molecule produced by alternative splicing prevents from apoptosis. We measured soluble Fas in the sera of 112 patients with Graves' disease, 21 patients with toxic goiter, and 24 patients with subclinical hyperthyroidism due to suppressive therapy with levothyroxine after near-total resection of the thyroid gland for nodular goiter. Soluble Fas was increased in thyrotoxic patients, toxic goiter, and patients with subclinical hyperthyroidism. Decreased levels of soluble Fas were found in euthyroid patients with Graves' disease after surgery, whereas soluble Fas was normal in euthyroid patients with Graves' disease receiving antithyroid drug treatment and in patients in stable remission. There was a good correlation between soluble Fas with free T(3) (r = 0.6) and free T(4) (r = 0.5). Our results show that soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

Adult↗

Lymphocytic interstitial pneumonitis in autoimmune thyroid disease.

Four patients are described who were found to have autoimmune thyroid disease associated with lymphocytic interstitial pneumonitis. The patients were not receiving any medications known to cause lymphocytic interstitial pneumonitis. Their response to steroid therapy and the relapse of their clinical symptoms after steroid withdrawal support an underlying immunologic dysfunction. It is proposed that lymphocytic interstitial pneumonitis may be yet another manifestation of immune dysfunction in autoimmune thyroid disease.

Adult↗

Characterization of TSH antagonist activity in the serum of patients with thyroid disease.

The ability of sera from patients with thyroid disease to block TSH stimulation of cyclic AMP release from isolated porcine thyroid cells has been assessed and the blocking activity characterized. TSH receptor binding activity was also measured. No blocking or receptor binding activity was detectable in patients with primary myxoedema (n = 23), Hashimoto's disease (n = 11), multinodular goitre (n = 6), or rheumatoid arthritis (n = 10). However, analysis of sera from 23 patients (out of an initial screen of 110 patients) with treated Graves' disease which did not stimulate cyclic AMP production in the bioassay showed that two of these sera contained powerful blocking and receptor binding activity. Both these patients had been treated with 131I. Analysis of the two sera by gel filtration on Sephadex G-200 indicated that blocking and TSH receptor binding activity were associated only with the IgG fraction. Digestion of the IgG with pepsin followed by reduction showed that both (Fab)2 and Fab fragments contained high levels of blocking and binding activity. Antibody divalency was not necessary therefore for TSH antagonist activity. However, our studies suggest that autoantibodies of this type with TSH antagonist activity do not occur frequently in patients from the Cardiff region with primary myxoedema, Hashimoto's or treated Graves' disease.

Biological Assay↗

The influence of cyclosporin A on the induction of experimental autoimmune thyroid disease in the PVG/c rat.

Using an experimental model of autoimmune thyroid disease we have investigated the influence of cyclosporin A (CyA) on the induction of the disease and its potential ability to prevent disease development. PVG/c rats (n = 80) neonatally thymectomized (day 21) and thence sublethally irradiated were divided into eight groups and received either no CyA or oral CyA (10 mg/kg body weight) for varying periods prior to and during disease induction. Serial serum measurements of thyrotropin (TSH) by radioimmunoassay and anti-thyroglobulin autoantibody by enzyme linked immunosorbent assay showed a progressive rise in untreated animals. The rise in serum TSH levels from 349 +/- 15 ng/ml (mean +/- s.e., normal less than 400 ng/ml) at 7 weeks of age to 526 +/- 61 ng/ml at 11 weeks and 820 +/- 54 ng/ml at 15 weeks was not significantly different in animals treated with CyA for periods ranging from 24 h prior to thymectomy to 7 days post-thymectomy. In contrast animals treated for 28 days post-thymectomy showed significantly lower levels of TSH at both 11 weeks (391 +/- 26; P less than 0.02) and 15 weeks (587 +/- 37; P less than 0.005) as compared with untreated animals. Similar though less dramatic changes were seen in intermediate groups. Autoantibody levels in untreated animals rose from initially undetectable levels to 0.451 +/- 0.07 OD (mean +/- s.e.) at 11 weeks and 0.581 +/- 0.041 OD at 15 weeks. Animals treated for at least 4 weeks after thymectomy with CyA had significantly lower levels of antibody at both 11 weeks (0.213 +/- 0.01; P less than 0.001) and 15 weeks (0.337 +/- 0.03; P less than 0.001) of age. Intermediate groups ranged in antibody levels depending on the duration of CyA treatment. Thyroid gland weight (12.7 +/- 2.4 mg/100 g body weight, mean +/- s.e.) and histological grade of thyroiditis (1.8 +/- 0.4, mean +/- s.e.) in the animals treated with CyA for 4 weeks, assessed when the animals were killed at 15 weeks, were smaller and had less severe thyroiditis than untreated thymectomized and irradiated animals (23.8 +/- 2.8 mg/100 g, P less than 0.02 and 2.9 +/- 0.2, P less than 0.05) killed at the same time. CyA given for long enough during induction of experimentally-induced autoimmune thyroid disease delayed the onset of disease and reduced its severity but could not prevent it given over time courses ranging from 48 h prior to thymectomy to 4 weeks after.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Antinuclear antibody positivity in pediatric patients with autoimmune thyroid disease.

OBJECTIVE: The incidence of antinuclear antibody (ANA) positivity was investigated in pediatric patients with autoimmune thyroid diseases. METHODS: Subjects were 21 untreated patients with Graves' disease, 12 untreated patients with Hashimoto's disease, and 16 untreated patients with non-autoimmune thyroid disease, including one patient with Plummer's disease, 11 patients with simple goiter (probable), and 4 patients with cretinism. Patients with Graves' disease were treated with either propylthiouracil or methimazole. ANA was measured using HEp-2 cells. Anti-dsDNA antibody was measured using double stranded DNA derived from an Escherichia coli plasmid. RESULTS: The incidence of ANA positivity was significantly higher in patients with untreated Graves' disease (n = 21; age range 9-15 yrs) than in Hashimoto's thyroiditis (n = 12; age range 7-15 yrs) (p < 0.03, Fisher's exact probability test). However, the 2 diseases were not significantly different with respect to anti-dsDNA antibody positivity. Most of the ANA positive patients with Graves' disease required treatment for more than 2 years, unlike the 6 ANA negative patients (p < 0.002, Fisher's exact probability test). CONCLUSION: We conclude that ANA positivity may predict a poor response to antithyroid drugs in Graves' disease.

Adolescent↗

Coexisting Hashimoto's thyroiditis with differentiated thyroid cancer and benign thyroid diseases: indications for thyroidectomy.

Hashimoto's thyroiditis is a medical disease that affects about 5% of the population. In cases of goitre, hashitoxicosis or associated differentiated thyroid cancer, surgical treatment is recommended. The aim of this study was to evaluate the indications for thyroidectomy in Hashimoto's thyroiditis, the frequency of coexistence of Hashimoto's thyroiditis and differentiated thyroid cancer, and the impact of Hashimoto's thyroiditis on the management of differentiated thyroid cancer. From January 1998 to May 2002, 344 patients underwent thyroidectomy in our department. Among 44 patients with HT, the authors carried out a retrospective comparative study of 33 patients with a cytological diagnosis of differentiated thyroid cancer (group A) and 11 patients with non-neoplastic conditions (group B). Surgical indications based on cytological findings and management characteristics were considered. The frequency of the association of Hashimoto's thyroiditis and differentiated thyroid cancer was 23.8% as compared to a 6.7% frequency of coexisting Hashimoto's thyroiditis and benign thyroid diseases (P = 0.000). The sensitivity of cytology in the diagnosis of papillary carcinoma in Hashimoto's thyroiditis was 92%. Cytological diagnosis of hyperplastic follicular and hyperplastic Hürthle cell nodules in Hashimoto's thyroiditis was impossible in some cases. Intraoperatively distinguishing between chronic lymph-node reactivity and tumour involvement was difficult, but the morbidity rate was not increased very much by Hashimoto's thyroiditis. In conclusion, an adequate follow up of patients with Hashimoto's thyroiditis may permit an early diagnosis of differentiated thyroid cancer and its appropriate management.

Adolescent↗

Alpha 2-adrenergic activity is normal in patients with thyroid disease.

OBJECTIVE: Several studies indicate an inverse relationship between the sympathetic nervous system activity and thyroid function. Altered adrenoceptor sensitivity, particularly alpha 1 and beta, have been described in hypothyroid and hyperthyroid patients. No information in patients with thyroid disease is available on the main mechanism regulating sympathetic nervous system outflow, i.e. the alpha 2-adrenoceptor pathway. In our study we evaluated alpha 2-adrenergic activity in patients with thyroid disease by the assessment of cardiovascular and catecholamine response to clonidine, a central alpha 2 adrenergic agonist. PATIENTS: Ten patients with hypothyroidism, six patients with hyperthyroidism before and during adequate therapy, and ten healthy subjects. MEASUREMENTS: After three blood samples for the basal determination of noradrenaline and adrenaline, the subjects swallowed 4 micrograms/kg body weight of clonidine. Blood pressure and pulse rate were measured 30, 60, 90, 120, 130 and 140 minutes after clonidine administration; blood samples for determination of catecholamines were drawn at 120, 130 and 140 minutes. RESULTS: At presentation the decrease in plasma noradrenaline after clonidine in the patients was similar to that of the control group (hypothyroids: 1.07 +/- 0.23 nmol/l mean +/- SEM; hyperthyroids: 0.54 +/- 0.06 nmol/l; controls; 0.36 +/- 0.10 nmol/l; F = 1.2, P = NS). No differences were detected in the fall in adrenaline and mean arterial pressure (MAP) after clonidine. The adequate therapy induced in hypothyroid patients a decrease in the basal levels of noradrenaline (1.88 +/- 0.28 vs 0.67 +/- 0.10 nmol/l; P < 0.05) and a lesser fall in mean arterial pressure after clonidine (delta MAP 20.4 +/- 2.0 vs 9.7 +/- 2.8 mmHg; P < 0.05). No variations were detected in hyperthyroid patients after therapy either in basal hormones levels or in the magnitude of decrement in MAP and noradrenaline induced by clonidine. CONCLUSIONS: We conclude that in spite of the previously reported abnormalities in alpha 1 and beta-adrenergic receptor activity, the inhibitory alpha 2-receptor pathway is normal in patients with altered thyroid function.

Adult↗

Human autoimmune thyroid disease: risk factors.

Genetics sets the groundwork for the predisposition to autoimmune thyroid disease, and in certain individuals, such as the juveniles presented here, very little impetus is needed to push normal immune reactions to autoimmune disease. However, in individuals who inherit only a few of these traits, the accumulation of many developmental and environmental insults may promote the development of disease.

Animals↗

[Clinical features and surgical treatment of chronic tonsillitis in patients with thyroid diseases].

Out of 715 patients with thyroid disorders chronic tonsillitis was detected in 23.8, 35.5, 43.1, 45.7 and 52.1% of patients with euthyroid goiter, hypothyroidism, autoimmune thyroidism, subacute strumitis and diffuse toxic goiter, respectively. In hyperthyroidism chronic tonsillitis ran with severe clinical symptoms, in hypothyroidism it took a latent course. Tonsillectomy was performed in 118 patients. In patients with diffuse toxic goiter and subacute strumitis there was abnormal intraoperative bleeding and postoperative pharyngeal reactions, in those with autoimmune thyroidism and hypothyroidism reparative activity was low. Timely tonsillectomy favourably influences the course of thyroid diseases and prevents goiter recurrence after its surgical treatment.

Adolescent↗

Effect of interferon-beta on thyroid function in patients of chronic hepatitis C without preexisting autoimmune thyroid disease.

The effect of interferon-beta (IFN-beta) on thyroid function was studied in patients with chronic hepatitis who had no preexisting thyroid disease. Eleven patients (9 males and 2 females) aged 20 to 65 years, with a mean age of 47.7 +/- 13.5 years, were treated with 6 million units of IFN-beta intravenously every day for 8 weeks. During IFN-beta administration (4th to 8th week of treatment), both serum free thyroxine (FT4) and free triiodothyronine (FT3) concentrations decreased significantly (P < 0.0005 and P < 0.05, respectively): FT4, 1.37 +/- 0.17 to 1.09 +/- 0.12 ng/dl, and FT3, 3.71 +/- 0.45 to 3.28 +/- 0.34 pg/ml. On the other hand, serum TSH increased significantly from a baseline of 1.70 +/- 0.82 to 3.34 +/- 1.98 microU/ml during IFN-beta administration (P < 0.005). Four to eight weeks after cessation of treatment, the mean serum FT4 concentration was similar to that during IFN-beta administration (1.04 +/- 0.14 ng/dl), but mean serum FT3 and TSH concentrations returned to pre-treatment levels (FT3, 3.57 +/- 0.42 pg/ml and TSH, 1.60 +/- 0.84 microU/ml). Both reverse T3 and thyroglobulin were essentially unchanged. Tests for anti-thyroglobulin and anti-microsomal antibodies were negative in all the patients. These results indicate that IFN-beta may inhibit thyroid function in patients without preexisting thyroid disease irrespective of humoral immune responses.

Adult↗

Transgenic mice producing major histocompatibility complex class II molecules on thyroid cells do not develop apparent autoimmune thyroid diseases.

The expression of major histocompatibility complex (MHC) class II molecules on thyrocytes has been demonstrated in autoimmune thyroid diseases. However, the role of this aberrant MHC class II in disease development is controversial. In particular, it remains unknown whether MHC class II expression on thyrocytes, which are nonprofessional antigenpresenting cells, plays a role in inducing autoimmune processes. To clarify this issue, we have produced transgenic mice harboring an MHC class II gene ligated to the promoter of the rat TSH receptor. We obtained three lines of transgenic mice, and the expression of MHC class II by the thyrocytes was demonstrated by immunofluorescence staining and flow cytometry. Our examination revealed no obvious abnormalities in thyroid histology or in thyroid autoantibody production in these transgenic mice. Although serum-free T(4) levels were slightly lower than those of their nontransgenic littermates, no transgenic mouse suffered from clinical hypothyroidism or hyperthyroidism. Furthermore, thyroid lymphocytic infiltration was absent, and MHC class II-expressing thyrocytes obtained from transgenic mice failed to stimulate the proliferation of autologous T cells in vitro. Taken together, these results show that transgenic mice with MHC class II molecules on their thyrocytes do not develop apparent autoimmune thyroid diseases, suggesting that aberrant MHC class II expression alone is not sufficient to induce thyroid autoimmunity.

Animals↗

Telomerase activity in benign and malignant thyroid diseases.

BACKGROUND: Telomerase, an enzyme associated with cellular immortality, is expressed by most malignant cells and is inactive in most normal somatic cells, with the excitation of proliferative stem cells, male germ cells, and activated lymphocytes. The measurement of telomerase activity in clinically obtained tissue samples may provide useful information as both a diagnostic and prognostic marker. In this study, we sought to determine whether telomerase activity might prove helpful in the assessment of benign and malignant thyroid tumors. METHODS: A modified, semiquantitative polymerase chain reaction-based telomeric repeat amplification protocol assay was used for detection of telomerase activity in 59 samples obtained at thyroidectomy, including 15 thyroid cancers, 22 benign thyroid diseases, and 22 adjacent normal thyroid tissues. RESULTS: Four of 13 differentiated thyroid carcinomas (30%) and 2 of 2 medullary carcinomas (100%) expressed telomerase activity. Unexpectedly, we also detected activity in 3 of 22 (14%) adjacent normal thyroid tissues and 6 of 22 (28%) benign thyroid diseases. Pathologic review of the telomerase-positive benign specimens revealed that many contained extensive lymphoid infiltrates with germinal centers (six of nine, 67%), as did two of four telomerase-positive papillary carcinomas. CONCLUSIONS: In contradistinction to other epithelial carcinomas, telomerase does not appear to be frequently reactivated in differentiated thyroid carcinomas.

Adult↗

The treatment of benign thyroid disease.

The treatment of benign forms of thyroid disease is reviewed. Endemic goiter is a public health problem preventable by the addition of iodine to the food or water supply. Endemic and familial goiters are treated with replacement doses of I-thyroxine, as are sporadic colloid goiters and goiters resulting from chronic thyroiditis. Hyperfunctioning autionomous nodules without thyrotoxicosis and cystic nodules require no specific therapy. Prophylaxis against diffuse or nodular goiter after radiation to the head or neck for therapeutic purposes with thyroxine replacement therapy is debatable. All forms of hypothyroidism, including incipient types, require replacement thyroxine therapy, but this should be undertaken cautiously in older patients and in those with evidence of ischemic myocardial disease. Myxedema coma requires vigorous treatment and detailed supervision because of dismal mortality rates. Iodine 131 is the treatment of choice in diffuse toxic goiter, but alternative forms.

Adolescent↗

Spontaneous in vitro production of thyroglobulin specific helper factor in patients with autoimmune thyroid diseases.

We have investigated regulatory cell abnormalities in patients with autoimmune thyroid diseases through in vitro thyroglobulin (Tg) specific helper factor production. Helper activities were measured in the mice spleen cell assays, using hapten-carrier system. Peripheral blood leukocytes (PBL) from 5 out of 6 patients produced the Tg specific helper factor not only when they were stimulated in vitro with Tg but also when they were not stimulated. On the contrary, normal PBL did not produce the factor when they were not stimulated in vitro. However, 3 out of 5 normal PBL did produce the factor when they were stimulated in vitro with Tg. From several lines of studies, this helper factor was specific for Tg in its production and action. From these results it is concluded that (a) Tg specific helper T cells are already activated in vivo in patients with autoimmune thyroid diseases, indicating the presence of immunoregulatory abnormalities in these patients, and that (b) normal PBL have a potential to produce this helper factor when they are appropriately stimulated.

Biological Assay↗

[Normal course of autoimmune thyroid disease in diabetic children].

BACKGROUND: Autoimmune thyroid disease (AITD) represents the most frequent associated manifestation of the autoimmune disease in children with Type 1 diabetes mellitus (T1DM). The aim of the study was to evaluate the prevalence and natural course of AITD in unselected cohort of diabetic children. METHODS AND RESULTS: TSH, free thyroxin, thyreoglobulin autoantibodies (Ab-hTG), peroxidase autoantibodies (Ab-TPO) and thyroid sonography were prospectively evaluated (1 to 6 years; 323 patient-years) in 110 patients with T1DM (age 2.1-20.8 years; 60 boys). Mild elevation of Ab-hTG and/or Ab-TPO levels (> 100, < 1000 mIU/l) was found in 19 patients (17%; boys:girls 1:2.2). Out of these, only 2 had increased thyroid volume and/or abnormal echotexture. In 9 of these patients, levels of autoantibodies subsequently declined below 100 mIU/l, remained unchanged in 9 patients and only in one case increased over 1000 mIU/l ("benign form" of AITD). All patients remained euthyroid. Severe elevation of Ab-hTG and/or Ab-TPO (> 1000 mIU/l) was found in 12 patients (11%; boys:girls 1:1). Out of these, eight had increased thyroid volume and ten had abnormal echotexture. Subclinical hypothyroidism developed within the observation period in nine of them (boys:girls 2:1). CONCLUSIONS: AITD was found in 31 (28%) children and adolescents with T1DM. Whereas mild elevation of Ab-hTG and/or Ab-TPO levels was not accompanied with morphological changes of the thyroid and did not predict functional disorder, severely elevated levels were associated with the early risk of subclinical hypothyroidism.

Adolescent↗

Total thyroidectomy for the treatment of thyroid diseases in an endemic area.

INTRODUCTION: Thyroidectomy is a common operation with very low mortality and an acceptable morbidity rate. Total thyroidectomy has become the predominant type of surgery used today for the treatment of thyroid diseases. In this retrospective study, we analyzed the complications of thyroid surgery according to the operative technique used in our department. MATERIAL AND METHODS: A retrospective analysis was performed for all patients who underwent thyroid surgery during the previous 11 years. The period under study was divided into two sections: phase A (1995-1999) and phase B (2000-2005). Patient characteristics, type of operation, histologic diagnoses and postoperative complications were compared in the two study periods according to the type of surgery. RESULTS: A total of 264 patients between the ages of 18 and 89 underwent thyroid surgery during the study period (133 in phase A and 131 in phase B). Overall histopathological diagnoses were nodular goiter (54.9%), hyperplastic nodules (14.7%), adenoma (8.3%), thyroid cancer (18.2%), and Hashimoto thyroiditis (3.8%). Total thyroidectomy was performed in 91 patients in phase A versus 115 patients in phase B (P < 0.001), whereas the use of subtotal thyroidectomy and lobectomy decreased over time. A trend toward increased morbidity was noted in phase B. Seven patients had hypocalcemia in phase A, whereas 11 patients had hypocalcemia in phase B. Similarly, 5 patients had some degree of vocal cord paralysis in phase A, compared with 7 in phase B (P > 0.05). Morbidity was significantly increased in the case of cancer or reoperation. CONCLUSION: Despite the slightly higher risk of complication associated with total thyroidectomy, this has gradually replaced more conservative approaches for the treatment of both benign and malignant thyroid diseases. Reoperations and surgery for thyroid cancer carried a higher risk of complications.

Adult↗