Annual Fluctuation in Chigger Mite Populations and Orientia Tsutsugamushi Infections in Scrub Typhus Endemic Regions of South Korea

OBJECTIVES: Chigger mites are vectors for scrub typhus. This study evaluated the annual fluctuations in chigger mite populations and Orientia tsutsugamushi infections in South Korea.METHODS: During 2006 and 2007, chigger mites were collected monthly from wild rodents in 4 scrub typhus endemic regions of South Korea. The chigger mites were classified based on morphological characteristics, and analyzed using nested PCR for the detection of Orientia tsutsugamushi.RESULTS: During the surveillance period, the overall trapping rate for wild rodents was 10.8%. In total, 17,457 chigger mites (representing 5 genera and 15 species) were collected, and the average chigger index (representing the number of chigger mites per rodent), was 31.7. The monthly chigger index was consistently high (> 30) in Spring (March to April) and Autumn (October to November). The mite species included Leptotrombidium pallidum (43.5%), L. orientale (18.9%), L. scutellare (18.1%), L. palpale (10.6%), and L. zetum (3.6%). L. scutellare and L. palpale populations, were relatively higher in Autumn. Monthly O. tsutsugamushi infection rates in wild rodents (average: 4.8%) and chigger mites (average: 0.7%) peaked in Spring and Autumn.CONCLUSION: The findings demonstrated a bimodal pattern of the incidence of O. tsutsugamushi infections. Higher infection rates were observed in both wild rodents and chigger mites, in Spring and Autumn. However, this did not reflect the unimodal incidence of scrub typhus in Autumn. Further studies are needed to identify factors, such as human behavior and harvesting in Autumn that may explain this discordance.

Subacute Thyroiditis and Painless Thyroiditis: Clinical Characteristics of 221 Patients Diagnosed between 2009 and 2015

BACKGROUND AND OBJECTIVES: In the past, subacute thyroiditis causing thyrotoxicosis included both painful and painless subgroup, but it is representative for the painful subacute thyroiditis these days. So we evaluated the clinical and laboratory characteristics of subacute thyroiditis and compared with the painless (silent) thyroiditis, and identified predictive factors of permanent hypothyroidism and recurrence. MATERIALS AND METHODS: This was a retrospective case series study analyzing clinical data of 221 consecutive patients diagnosed between 2009 and 2015. Medical records were reviewed for diagnostic route, age distribution, laboratory data, clinical course and long-term follow up outcome. RESULTS: The mean age was 48 years; female v/s male ratio 3.4:1. Median disease duration was 110 days; mean peak free T4 level was 2.9 ng/dL. 56.7% of painless thyroiditis patients were diagnosed on health checkup or routine thyroid function test with symptoms not typically associated with thyrotoxicosis. Permanent hypothyroidism was not uncommon (11/221; 5.0%). Higher peak thyroid-stimulating hormone (TSH) was associated with permanent hypothyroidism in painless thyroiditis. Lower peak TSH was associated with recurrence rate in both subacute and painless thyroiditis. In painless thyroiditis, short duration of thyrotoxicosis phase was also associated with recurrence rate. CONCLUSION: Considerable numbers of painless thyroiditis without symptoms were diagnosed on health checkup. Higher peak TSH was associated with permanent hypothyroidism in painless thyroiditis. Recurrence rate was related with lower peak TSH in both groups.

Subacute Thyroiditis and Painless Thyroiditis: Clinical Characteristics of 221 Patients Diagnosed between 2009 and 2015

BACKGROUND AND OBJECTIVES: In the past, subacute thyroiditis causing thyrotoxicosis included both painful and painless subgroup, but it is representative for the painful subacute thyroiditis these days. So we evaluated the clinical and laboratory characteristics of subacute thyroiditis and compared with the painless (silent) thyroiditis, and identified predictive factors of permanent hypothyroidism and recurrence. MATERIALS AND METHODS: This was a retrospective case series study analyzing clinical data of 221 consecutive patients diagnosed between 2009 and 2015. Medical records were reviewed for diagnostic route, age distribution, laboratory data, clinical course and long-term follow up outcome. RESULTS: The mean age was 48 years; female v/s male ratio 3.4:1. Median disease duration was 110 days; mean peak free T4 level was 2.9 ng/dL. 56.7% of painless thyroiditis patients were diagnosed on health checkup or routine thyroid function test with symptoms not typically associated with thyrotoxicosis. Permanent hypothyroidism was not uncommon (11/221; 5.0%). Higher peak thyroid-stimulating hormone (TSH) was associated with permanent hypothyroidism in painless thyroiditis. Lower peak TSH was associated with recurrence rate in both subacute and painless thyroiditis. In painless thyroiditis, short duration of thyrotoxicosis phase was also associated with recurrence rate. CONCLUSION: Considerable numbers of painless thyroiditis without symptoms were diagnosed on health checkup. Higher peak TSH was associated with permanent hypothyroidism in painless thyroiditis. Recurrence rate was related with lower peak TSH in both groups.

The Efficacy and Safety of Cordyceps militaris in Korean Adults Who Have Mild Liver Dysfunction

PURPOSE: The aim of this study is to determine the efficacy and safety of Cordyceps militaris in Korean adults with mild liver dysfunction. C. militaris is a mushroom traditionally used for several clinical purposes in East Asian territory, including China, and has been found to be effective in improving liver function through animal studies. METHODS: The C. militaris group was administered 1.5 g/day of C. militaris (2 capsules per dose, twice per day) and the placebo group was administered the same volume of placebo. Laboratory test (white blood cell, hemoglobin, platelet, aspartate aminotransferase, alanine aminotransferase, gamma glutamyltranspeptidase, lactic dehydrogenase, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine), liver computed tomography (CT) were performed, and visual analogue scale score for subjective symptoms and fatigue severity scale were measured. RESULTS: In analysis of the liver CT scan at 8 weeks after administration compared to baseline, the mean ratio of change of Hounsfield unit of 8 segments of liver increased by an average of 21.43%+/-45.11% in the C. militaris group and 9.64%+/-11.41% in the placebo group. Others showed no statistically significant inter-group difference. CONCLUSION: C. militaris extract was used safely as a functional food in patients with mild liver dysfunction, and is expected to protect against progression of fatty liver or cirrhosis caused by suppression of lipid accumulation in hepatocytes.

The corrected QT (QTc) prolongation in hyperthyroidism and the association of thyroid hormone with the QTc interval / 소아과

PURPOSE: Ventricular repolarization is assessed using the QT interval corrected by the heart rate (QTc) via an electrocardiogram (ECG). Prolonged QTc is associated with an increased risk of arrhythmias and cardiac mortality. As there have been few reports regarding the effects of hyperthyroidism on ventricular repolarization, we studied the association between serum free thyroxine (free T4 [fT4]) and thyroid stimulating hormone (TSH) levels and the QTc interval. METHODS: Thirty-eight patients with hyperthyroidism (<30 years old) were included, and we used their clinical records and available ECGs (between August 2003 and August 2011) to evaluate the association between their fT4 and TSH levels and their QTc interval. In addition, we studied the ECGs of 72 age-matched patients with no hyperthyroidism (control group) and compared their data with that from the patients group. RESULTS: The QTc duration in patients with hyperthyroidism was significantly prolonged compared to that in the control subjects (P<0.001). In addition, the number of hyperthyroid patients with abnormal prolonged QTc was significantly higher than that in the control group (P<0.001). Among the patients with hyperthyroidism, patients with prolonged QTc and borderline QTc had higher fT4 levels and there was positive correlation between their fT4 levels and their QTc interval (P<0.05). However, no correlation was observed between their TSH levels and their QTc interval. CONCLUSION: We report that hyperthyroidism is associated with QTc prolongation. The correlation between the fT4 levels and the QTc interval suggests that thyroid status is associated with QTc values and the risk of cardiac mortality.

Spontaneous perforation and dissection of the sinus of Valsalva and interventricular septum with intracardiac thrombus in a patient with Behcet's disease

No abstract available.

A Case of Arachnoid Cyst in the Internal Auditory Canal / 대한이비인후과학회지

Arachnoid cysts are intra-arachnoid collections of cerebrospinal fluid; congenital in origin, they account for about 1% of all atraumatic intracranial mass lesions. Arachnoid cysts confined to the internal auditory canal are extremely rare. In most patients who has arachnoid cysts in the internal auditory canal, no direct intervention is necessary, but if the neurologic symptoms are progressive, the arachnoid cyst could be drained surgically to relieve the symptoms caused by compression of structures adjacent to the cyst. We present one case of a arachnoid cyst in the left internal auditory canal which was diagnosed by a temporal bone magnetic resonance imaging.

Identification of a novel mutation in a patient with pseudohypoparathyroidism type Ia / 소아과

Pseudohypoparathyroidism type Ia (PHP Ia) is a disorder characterized by multiform hormonal resistance including parathyroid hormone (PTH) resistance and Albright hereditary osteodystrophy (AHO). It is caused by heterozygous inactivating mutations within the Gs alpha-encoding GNAS exons. A 9-year-old boy presented with clinical and laboratory abnormalities including hypocalcemia, hyperphosphatemia, PTH resistance, multihormone resistance and AHO (round face, short stature, obesity, brachydactyly and osteoma cutis) which were typical of PHP Ia. He had a history of repeated convulsive episodes that started from the age of 2 months. A cranial computed tomography scan showed bilateral calcifications in the basal ganglia and his intelligence quotient testing indicated mild mental retardation. Family history revealed that the patient's maternal relatives, including his grandmother and 2 of his mother's siblings, had features suggestive of AHO. Sequencing of the GNAS gene of the patient identified a heterozygous nonsense mutation within exon 11 (c.637 C>T). The C>T transversion results in an amino acid substitution from Gln to stop codon at codon 213 (p.Gln213*). To our knowledge, this is a novel mutation in GNAS.

Effect of intranasal steroids on chronic cough caused by upper airway cough syndrome

PURPOSE: Although upper airway cough syndrome (UACS) is one of the most common causes of chronic cough, there are few reports on the effects of intranasal steroids (INS) on improvement of cough in patients with chronic cough caused by UACS. Here, we observed improvement in cough depending on prescribed medications, including INS, in patients with chronic cough caused exclusively by UACS in the clinical setting. METHODS: Patients with chronic cough caused exclusively by UACS were selected by the retrospective review of medical records. Durations and kinds of prescribed medications, nasal and postnasal drip symptoms, and results of paranasal sinus series at first visit were evaluated. According to the improvement of cough at the second visit, the patients were divided into the improved and unimproved groups. Odds ratios of each medication in the improved group were analyzed by logistic regression adjusted for age, sex, smoking history, duration of treatment, prescriptions of medications, presence of nasal and postnasal drip symptoms, and results of paranasal sinus series. RESULTS: A total of 122 patients with chronic cough caused exclusively by UACS were comprised of 38 patients in the improved group and 84 patients in the unimproved group. INS were prescribed to 45 patients, and the number of patients with INS prescription were significantly higher in the unimproved group than that in not-improved group (55.3% vs. 28.6%, P=0.008). The odds ratio of INS prescription was significantly higher in the improved group (odds ratio, 4.78; 95% confidence interval, 1.03-22.3; P=0.046). CONCLUSION: INS could improve cough symptom in patients with UACS. These results warrant further evaluation.

Comparison between Group I in Which Non-Supine Apnea-Hypopnea Index> or =5 and Group II in Which Non-Supine Apnea-Hypopnea Index<5 in Patients with Positional Sleep Apnea / 수면정신생리

OBJECTIVES: The aim of this study was to evaluate the differences in patients with positional dependent sleep apnea according to their non-supine apnea-hypopnea index (AHI, > or =5 vs. or =5 ; group II was non-supine AHI having less than 5. Statistical analysis was performed to find the difference between two groups. RESULTS: In 92 patients, the number of group I patients was 11 (12%) and the number of group II patients was 81 (88%). In the severe AHI group, percentage of group I was dominated (70%) and showing a significant difference compared with the mild and moderate AHI groups (p or =5 than non-supine AHI<5.

A Clinical Study of the Relationship between Obesity and Pubertal Development in Girls / 대한소아소화기영양학회지

PURPOSE: Recently, public interest in obesity and earlier pubertal development has been increasing. The purpose of this study was to analyze the relationship between obesity and pubertal development in girls. METHODS: A total of 158 girls presenting with earlier pubertal development from July 2008 to June 2010 were included in the study. Their mean age was 8.27+/-1.3 years and the mean bone age advancement was 1.86+/-0.3 years. RESULTS: Based on weight-for-height percentiles, their obesity rate was 9.2% and overweight rate was 15.8%. However, for body mass index (BMI), the result was a bit different; with an obesity rate of 13.2% and overweight rate of 24.3%. About 40% of the girls had a family history of early maturation. Among them, 25.7% had a maternal history, 4.6% paternal and 7.2% both. However, 60% of them had no family history. We then classified these girls into families with one son and one daughter, and those with two daughters. In one-son/one-daughter families, 69.3% were the first children and 30.7% were second. In two-daughter families, 65.3% were the first and 34.7% were second. We found that 67.5% had a history of taking herbal medicine. CONCLUSION: The obesity and overweight rates in girls with earlier pubertal development were higher than those of normal girls, but with a small discrepancy between weight-for-height percentile and BMI-based results. Furthermore, taking herbal medicine seems to be a potential factor for earlier pubertal development in Korea.

A Case of Central Serous Chorioretinopathy Associated with Systemic Corticosteroid Treatment of Bell's Palsy / 대한이비인후과학회지

Central serous chorioretinopathy (CSCR) is potential ophthalmologic sequelae of steroid use characterized by an idiopathic serous detachment of neurosensory retina within the macula. Its etiology and pathophysiology are still unknown, but what has been implicated to cause CSCR is the the use of corticosteroid via multiple administration routes including oral, intravenous, inhaled, intranasal, epidural and intraarticular as well as topical forms. We report, with a review of the literature, an additional case of CSCR, which developed during systemic corticosteroid treatment in a Bell's palsy patient.

Hutchinson-Gilford Progeria Syndrome with G608G LMNA Mutation

Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp veins and sclerodermatous skin. This abnormal appearance began at age of 1 yr. On serological and hormonal evaluation, all values are within normal range. He was neurologically intact with motor and mental development. An echocardiogram showed calcification of aortic and mitral valves. Hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography. He is on low dose aspirin to prevent thromboembolic episodes and on regular follow up. Gene study showed typical G608G (GGC- > GGT) point mutation at exon 11 in LMNA gene. This is a rare case of Hutchinson-Gilford progeria syndrome confirmed by genetic analysis in Korea.

Prenatal detection of skeletal dysplasia using ultrasound and molecular diagnosis / 대한산부인과학회지

OBJECTIVE: To determine the accuracy and usefulness of prenatal ultrasonographic and molecular genetic diagnosis in detection of skeletal dysplasia. METHODS: This study was based upon data of the 17 cases of skeletal dysplasia diagnosed by prenatal ultrasound and 7 cases by molecular diagnosis performed among the 17 cases and the 2 cases who has familial skeletal dysplasia by molecular diagnosis during the first trimester at Ewha and Eulji University from March 1998 to August 2005. A final diagnosis was sought on the basis of radiographic studies, molecular testing, or both. RESULTS: The mean gestational age at diagnosis was 24.9 weeks (range, 17 to 35 weeks). Nine cases were diagnosed before 24 weeks. A final diagnosis was obtained in 16 cases (94.1%). There was 1 false-positive diagnosis. The antenatal diagnosis was correct in 14 cases (82.4%). The 8 cases were prenatally confirmed and 1 case was postpartum confirmed using molecular genetic testing and accurate antenatal diagnosis and prediction was done. We were able to rule out skeletal dysplasia through chorionic villus sampling during the first trimester in the 2 cases with the family history with skeletal dysplasia. CONCLUSION: Prenatal diagnosis of skeletal dysplasia can be a considerable diagnostic challenge. However, skeletal dysplasia is correctly diagnosed on the basis of prenatal meticulous ultrasound and antenatal prediction of lethality was highly accurate. Using prenatal molecular diagnosis, skeletal dysplasia can be diagnosed at first trimester of pregnancy and nonlethal skeletal dysplasia can be confirmed when prenatal ultrasound was nonspecific.

The effect of granulocyte-macrophage-stimulating factor on the gene expression in human trophoblast of early pregnancy / 대한산부인과학회지

OBJECTIVE: Granulocyte-macrophage colony-stimulating factor (GM-CSF) facilitates mammalian embryonic development and implantation. However, its biological function after implantation is not elucidated. The aim of this study is to assess the changes of gene expression by GM-CSF in human trophoblast obtained in early pregnancy. METHODS: Human trophoblast obtained in early pregnancy was cultured with or without GM-CSF. The difference of gene expression was evaluated with microarray and selected genes were reevaluated with real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Microarray analysis revealed that the expressions of 468 genes were increased while those of 40 genes were decreased by GM-CSF. These genes were evaluated according to the known biologic pathways. The regulation of actin cytoskeleton and focal adhesion pathways were mostly influenced by GM-CSF. Annexin A2, thymosin-like 3, vimentin, myogenin, ACK1, and tensin1 genes were selected for real-time RT-PCR. The increased expressions of of vimentin and ACK1, and decreased expressions of tensin1 were confirmed by real-time RT-PCR. CONCLUSION: GM-CSF activates focal adhesion pathway in human trophoblast by increasing the expression of vimentin and ACK1, and decreasing the expression of tensin1.

Inherited metabolic diseases in the urine organic acid analysis of complex febrile seizure patients / 소아과

PURPOSE: Seizure associated with fever may indicate the presence of underlying inherited metabolic diseases. The present study was performed to investigate the presence of underlying metabolic diseases in patients with complex febrile seizures, using analyses of urine organic acids. METHODS: We retrospectively analyzed and compared the results of urine organic acid analysis with routine laboratory findings in 278 patients referred for complex febrile seizure. RESULTS: Of 278 patients, 132 had no abnormal laboratory findings, and 146 patients had at least one of the following abnormal laboratory findings: acidosis (n=58), hyperammonemia (n=55), hypoglycemia (n=21), ketosis (n=12). Twenty-six (19.7%) of the 132 patients with no abnormal findings and 104 (71.2%) of the 146 patients with statistically significant abnormalities showed abnormalities on the organic acid analysis (P<0.05). Mitochondrial respiratory chain disorders (n=23) were the most common diseases found in the normal routine laboratory group, followed by PDH deficiency (n=2 ) and ketolytic defect (n=1). In the abnormal routine laboratory group, mitochondrial respiratory chain disorder (n=29) was the most common disease, followed by ketolytic defects (n=27), PDH deficiency (n=9), glutaric aciduria type II (n=9), 3-methylglutaconic aciduria type III (n=6), biotinidase deficiency (n=5), propionic acidemia (n=4), methylmalonic acidemia (n=2), 3-hydroxyisobutyric aciduria (n=2), orotic aciduria (n=2), fatty acid oxidation disorders (n=2), 2-methylbranched chain acyl CoA dehydrogenase deficiency (n=2), 3-methylglutaconic aciduria type I (n=1), maple syrup urine disease (n=1), isovaleric acidemia (n=1), HMG-CoA lyase deficiency (n=1), L-2-hydroxyglutaric aciduria (n=1), and pyruvate carboxylase deficiency (n=1). CONCLUSION: These findings suggest that urine organic acid analysis should be performed in all patients with complex febrile seizure and other risk factors for early detection of inherited metabolic diseases.

The Useful Clinical Indicators of Performing a Spinal Tapping During an Outbreak of Enteroviral Meningitis

PURPOSE: Although spinal tapping and cerebrospinal fluid analysis is essential for diagnosis of aseptic meningitis, it is equivocal that all patients with headache and vomiting should receive spinal tapping for diagnosis of meningitis during an outbreak of enteroviral meningitis in summer seasons. The purpose of this study was to find clinical indicators that may be useful for differentiation of bacterial meningitis, and also to compare the clinical course between spinal tapping group and non-spinal tapping group confirmed enteroviral infection. METHODS: We retrospectively reviewed medical record of 65 cases of reverse transcription-polymerase chain reaction(RT-PCR) proven enteroviral meningitis, and 30 cases of culture proven bacterial meningitis admitted in Chunchon Sacred Heart Hospital. We compared the difference of clinical factors between bacterial and enteroviral meningitis groups and also clinical course between spinal tapping and non-spinal tapping groups. RESULTS: Children with bacterial meningitis had younger age onset, high incidence of seizure and altered consciousness, increased C-reactive protein(CRP) levels(P0.05). Children with spinal tapping group with enteroviral meningitis had longer hospital stay and duration of fever as compared to children in non-spinal tapping group(P<0.05), but no difference in duration of headache in both groups. CONCLUSION: We recommend children with younger age, altered consciousness, having seizure and increased CRP levels receive spinal tapping for the differentiation of bacterial meningitis during an outbreak of enteroviral meningitis, and introduction of rapid diagnostic technique may reduce unnecessary spinal tapping, hospital stay and antibiotics therapy.

Angiographic findings and effect of superselective embolization for early and late postpartum bleeding / 대한산부인과학회지

OBJECTIVE: Treatment of postpartum bleeding with uterine artery embolization has been well-described so far. However, angiographic differences between early and late postpartum bleeding has not been elucidated. The purpose of this study was to evaluate angiographic differences between early and late postpartum bleeding and therapeutic effect of superselective embolization. METHODS: Medical records and angiographic images of 12 patients (7 early and 5 late) with postpartum bleeding were evaluated. Timing of bleeding, mode of delivery, angiographic findings and treatment outcome were primary variables evaluated. RESULTS: Among 12 patients, 11 patients had been successfully treated with superselective embolization. One patient with amniotic fluid embolism and disseminated intravascular coagulation had expired. Among the early postpartum bleeding, uterine atony was found in every patients except post-cesarean hysterectomy cases. Pseudoaneurysm of uterine artery was found in all patients with late postpartum bleeding. CONCLUSION: Superselective embolization is an effective method to control postpartum bleeding. Pseudoaneurysm of uterine artery is a main cause of late postpartum bleeding.

A Case of a Primary Esophageal Bezoar after a Total Gastrectomy / 대한소화기내시경학회지

An esophageal bezoar, although uncommon, is now recognized as a distinct clinical entity. An esophageal bezoar is rare but can form due to regurgitation of a gastric bezoar, motor disorder or anatomical abnormality, or following a gastrectomy. In general, bezoars are most often found in the stomach, and are formed by the accumulation of foreign ingested materials, including vegetable material and hair. In Korea, no case of a primary esophageal bezoar has been reported after a total gastrectomy. We report a case of an endoscopically treated primary esophageal bezoar that occurred after a total gastrectomy, without complications.

Who is more appropriate to do metabolic control of pregnancy complicated by diabetes?: Comparison of internist and obstetrician / 대한산부인과학회지

OBJECTIVE: To compared obstetric outcomes of pregnancies complicated by diabetes according to the managing department and to consider role of obstetrician and endocrinologist METHODS: A retrospective analysis of 72 pregnant women managed for diabetes during March 2004 to December 2006 was performed. Eighteen women had been managed by obstetricians (Group I) while 54 women had been managed by endocrinologists of internal medicine (Group II) during their pregnancies at Eulji Hospital. None of these patients had multiple pregnancies, abnormal karyotype, or other medical disorders other than diabetes. Pregnancy outcomes were compared between two groups. RESULTS: No difference was found with regard to the age, parity, BMI (body mass index), weight gain during the pregnancy, and the gestational weeks of delivery. There was also no difference in the blood glucose levels after 100 gm OGTT (oral glucose tolerance test) and HbA1C levels in two groups. The neonatal birth weight of group I (2.89+/-0.21 kg) was significantly lower than that of group II (3.38+/-0.08 kg, P=0.040). The 1 min APGAR score, which was corrected by weight through ANCOVA test, was also significantly lower in group I (7.11+/-0.51 vs 8.11+/-0.19, P=0.028). But There was no difference in 5 min APGAR score. The incidence of birth weight over 3.8kg was significantly higher in group II [37/54 (68.5%) vs 1/17 (5.6%), P=0.030]. Neonatal hypoglycemia was also higher in group II (37.0% vs 11.1%, P=0.043). Other neonatal and maternal complications associated with diabetes were not significantly different between two groups. CONCLUSIONS: In medical point of view, obstetrician can effectively manage diabetes during pregnancy as good as internist. Besides, the management by obstetricians may be more economic, less annoying, and can induce more compliance and motivation of the patients.