STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179.

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants' thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary-thyroid feedback regulation.

Survey of potentially inappropriate prescriptions for common cold symptoms in Japan: A cross-sectional study.

BACKGROUND: Common cold is among the main reasons patients visit a medical facility. However, few studies have investigated whether prescriptions for common cold in Japan comply with domestic and international evidence. OBJECTIVE: To determine whether prescriptions for common cold complied with domestic and international evidence. METHODS: This cross-sectional study was conducted between October 22, 2020, and January 16, 2021. Patients with cold symptoms who visited the two dispensing pharmacies and met the eligibility criteria were interviewed. MAIN OUTCOME MEASURE: The pharmacists at each store and a physician classified the patients into two groups: the potentially inappropriate prescribing group and the appropriate prescribing group. RESULTS: Of the 150 selected patients, 14 were excluded and 136 were included in the analysis. Males accounted for 44.9% of the total study population, and the median patient age was 34 years (interquartile range [IQR], 27-42). The prevalence rates of potentially inappropriate prescriptions and appropriate prescriptions were 89.0% and 11.0%, respectively and the median drug costs were 602.0 yen (IQR, 479.7-839.2) [$5.2 (IQR, 4.2-7.3)] and 406.7 yen (IQR, 194.5-537.2) [$3.5 (IQR, 1.7-4.7)], respectively. The most common potentially inappropriate prescriptions were the prescription of oral cephem antibacterial agents to patients who did not have symptoms of bacterial infections (50.4%) and ß2 stimulants to those who did not have respiratory symptoms due to underlying disease or history (33.9%). CONCLUSIONS: Approximately 90% of prescriptions for common cold symptoms in the area were potentially inappropriate. Our findings could contribute to the monitoring of the use of medicines for the treatment of common cold symptoms.

Background factors associated with academic motivation for attending medical school immediately after admission in Japan: A single-center study.

Background: To become a doctor with a high level of professionalism and ethical standards, it is important to have and maintain a high level of motivation right from medical school. However, studies in Japan have not quantitatively investigated the factors related to motivation immediately after enrollment. This study aimed to identify the demographic factors that influence the motivation of medical students immediately after admission. Methods: A cross-sectional single-center study was conducted. First-year medical students answered our questionnaire three weeks after the admission. The questionnaire comprised 16 demographic items and the 28-item Academic Motivation Scale, which was used to quantify motivation. Results: Our analysis showed that amotivation, representing low levels of self-determinant motivation, was significantly higher in students whose parents were medical professionals and in students who did not talk about their problems than in those whose parents were not medical professionals and those who did talk about their problems. Intrinsic motivation, which indicates the level of self-determinant motivation, was significantly lower in students who belonged to a sports club. Conclusions: We suggest that having parents who are medical professionals may be associated with an individual's decreased motivation when entering medical school in Japan. Though this is a novel finding, further research is needed to analyze this relationship.

Cognitive Bias and Diagnostic Errors among Physicians in Japan: A Self-Reflection Survey.

This cross-sectional study aimed to clarify how cognitive biases and situational factors related to diagnostic errors among physicians. A self-reflection questionnaire survey on physicians' most memorable diagnostic error cases was conducted at seven conferences: one each in Okayama, Hiroshima, Matsue, Izumo City, and Osaka, and two in Tokyo. Among the 147 recruited participants, 130 completed and returned the questionnaires. We recruited primary care physicians working in various specialty areas and settings (e.g., clinics and hospitals). Results indicated that the emergency department was the most common setting (47.7%), and the highest frequency of errors occurred during night-time work. An average of 3.08 cognitive biases was attributed to each error. The participants reported anchoring bias (60.0%), premature closure (58.5%), availability bias (46.2%), and hassle bias (33.1%), with the first three being most frequent. Further, multivariate logistic regression analysis for cognitive bias showed that emergency room care can easily induce cognitive bias (adjusted odds ratio 3.96, 95% CI 1.16-13.6, p-value = 0.028). Although limited to a certain extent by its sample collection, due to the sensitive nature of information regarding physicians' diagnostic errors, this study nonetheless shows correlations with environmental factors (emergency room care situations) that induce cognitive biases which, in turn, cause diagnostic errors.

Japan's Academic Barriers to Gender Equality as Seen in a Comparison of Public and Private Medical Schools: A Cross-Sectional Study.

Background: Gender inequalities persist in Japanese academic medicine. Some public medical schools have introduced various types of career support for women physicians, whereas few private schools have. Few studies describe the representation of women at different academic ranks and adequacy of career support in public and private medical schools in Japan. Study Design: Cross-sectional descriptive study. Methods: We used publicly available data from the 2018 National Survey on Career Support for Japanese Women Physicians published by the Association of Japanese Medical Colleges in March 2019, which was answered by departments regarding supporting women physicians. Participants represented 51 public and 29 private medical schools in Japan. The proportion of women at academic ranks and career support availability in private and public medical schools were determined using chi-squared test or Fisher's exact test. Results: The proportion of women in senior ranks was significantly higher in private (28.2%) than in public medical schools (25.4%) (p < 0.001). Excluding associate professors, the proportion of professors, lecturers, and assistant professors was significantly higher in private medical schools (3.8% vs. 5.8%, p = 0.002; 12.2% vs. 16.0%, p < 0.001; 20.5% vs. 29.9%, p < 0.001). More public medical schools provided position support and support for other job aspects (43.1% vs. 20.7%, p = 0.043; 70.6% vs. 20.7%, p < 0.001). Conclusions: Public medical schools have lower proportions of women in the academic hierarchy but provide more career support than do private medical schools. Further study is needed to reveal the possible causes of this pattern.

Factors and impact of physicians' diagnostic errors in malpractice claims in Japan.

BACKGROUND: Diagnostic errors are prevalent and associated with increased economic burden; however, little is known about their characteristics at the national level in Japan. This study aimed to investigate clinical outcomes and indemnity payment in cases of diagnostic errors using Japan's largest database of national claims. METHODS: We analyzed characteristics of diagnostic error cases closed between 1961 and 2017, accessed through the national Japanese malpractice claims database. We compared diagnostic error-related claims (DERC) with non-diagnostic error-related claims (non-DERC) in terms of indemnity, clinical outcomes, and factors underlying physicians' diagnostic errors. RESULTS: All 1,802 malpractice claims were included in the analysis. The median patient age was 33 years (interquartile range = 10-54), and 54.2% were men. Deaths were the most common outcome of claims (939/1747; 53.8%). In total, 709 (39.3%, 95% CI: 37.0%-41.6%) DERC cases were observed. The adjusted total billing amount, acceptance rate, adjusted median claims payments, and proportion of deaths were significantly higher in DERC than non-DERC cases. Departments of internal medicine and surgery were 1.42 and 1.55 times more likely, respectively, to have DERC cases than others. Claims involving the emergency room (adjusted odds ratio [OR] = 5.88) and outpatient office (adjusted OR = 2.87) were more likely to be DERC than other cases. The initial diagnoses most likely to lead to diagnostic error were upper respiratory tract infection, non-bleeding digestive tract disease, and "no abnormality." CONCLUSIONS: Cases of diagnostic errors produced severe patient outcomes and were associated with high indemnity. These cases were frequently noted in general exam and emergency rooms as well as internal medicine and surgery departments and were initially considered to be common, mild diseases.

The Utility of Virtual Patient Simulations for Clinical Reasoning Education.

Virtual Patient Simulations (VPSs) have been cited as a novel learning strategy, but there is little evidence that VPSs yield improvements in clinical reasoning skills and medical knowledge. This study aimed to clarify the effectiveness of VPSs for improving clinical reasoning skills among medical students, and to compare improvements in knowledge or clinical reasoning skills relevant to specific clinical scenarios. We enrolled 210 fourth-year medical students in March 2017 and March 2018 to participate in a real-time pre-post experimental design conducted in a large lecture hall by using a clicker. A VPS program (®Body Interact, Portugal) was implemented for one two-hour class session using the same methodology during both years. A pre-post 20-item multiple-choice questionnaire (10 knowledge and 10 clinical reasoning items) was used to evaluate learning outcomes. A total of 169 students completed the program. Participants showed significant increases in average total post-test scores, both on knowledge items (pre-test: median = 5, mean = 4.78, 95% CI (4.55-5.01); post-test: median = 5, mean = 5.12, 95% CI (4.90-5.43); p-value = 0.003) and clinical reasoning items (pre-test: median = 5, mean = 5.3 95%, CI (4.98-5.58); post-test: median = 8, mean = 7.81, 95% CI (7.57-8.05); p-value < 0.001). Thus, VPS programs could help medical students improve their clinical decision-making skills without lecturer supervision.

Primary care doctor fostering and clinical research training in Sweden: Implications for Japan.

In 2018, a new training program for primary care physicians was launched in Japan. As physicians responsible for the training of new primary care physicians, we have faced many problems, particularly in rural areas. The influence of this new program on primary care physicians in rural areas of Japan has not been sufficiently investigated. The aim of this research was to improve training for primary care physicians in Japan by examining training programs in Sweden, where the population challenges are similar to those seen in Japan. In this paper, we will express our opinions and describe the differences in the primary care fostering systems and clinical research training for generalist in Japan and Sweden.

A case of an infant with congenital combined pituitary hormone deficiency and normalized liver histology of infantile cholestasis after hormone replacement therapy.

Congenital combined pituitary hormone deficiency (CPHD) may present with cholestasis in the neonate or during early infancy. However, its precise mechanism is unknown. A 3-mo-old boy presented with cryptorchidism and hypoplastic scrotum after birth. Neonatal jaundice was noted but temporarily improved with phototherapy. Jaundice recurred at 2 mo of age. Elevated direct bilirubin (D-Bil) and liver dysfunction were found but cholangiography showed no signs of biliary atresia (BA). Liver biopsy findings showed giant cell formation of hepatocytes with hypoplastic bile ducts. Subsequent magnetic resonance imaging (MRI) of the head revealed a hypoplastic pituitary gland with an ectopic posterior lobe, and the patient was diagnosed with congenital CPHD based on decreased secretion of cortisol and GH by the pituitary anterior lobe load test. D-Bil levels promptly improved after hydrocortisone (HDC) replacement. We subsequently began replacement with levothyroxine (L-T4) and GH, and liver histology showed normal interlobular bile ducts at 8 mo old. This is the first case report of proven histological improvement after hormone replacement therapy. This suggested that pituitary-mediated hormones, especially cortisol, might be involved in the development of the bile ducts.

Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision).

Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The "Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)" published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients.

Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision).

Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

Frequencies of spontaneous breast development and spontaneous menarche in Turner syndrome in Japan.

The Growject® database on human GH treatment in Turner syndrome was analyzed in the Turner Syndrome Research Collaboration, and the relationships of the frequencies of spontaneous breast development and spontaneous menarche with karyotype and GH treatment were investigated. One hundred and three cases started GH treatment with 0.5 IU/kg/ week (0.5 IU group), and their dose was increased to 0.35 mg/kg/wk midway through the treatment course. Another 109 cases started GH at a dose of 0.35 mg/kg/wk (0.35 mg group). Spontaneous breast development was observed in 77 (36.3%) of the 212 patients, and spontaneous menarche occurred in 31 patients (14.6%). The frequency of spontaneous breast development was significantly lower in patients with the 45,X karyotype and significantly higher in patients with a structural abnormality of the second X chromosome. The frequency of spontaneous menarche was significantly higher in patients with mosaicism characterized by X monosomy and a cellular line with no structural abnormality of the X chromosome. No significant differences in frequencies of spontaneous breast development and spontaneous menarche were observed between the two dose groups, indicating that GH treatment does not increase the frequency of spontaneous puberty.

Resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) or thyroid hormone action defect (THAD) is the most frequent form of syndromes of reduced sensitivity to thyroid hormone. It is characterized by variable tissue hyposensitivity to thyroid hormone. RTHß (formerly only RTH) is caused by mutations in the thyroid hormone receptor ß gene (THRB). The clinical phenotype reflects the dysbalance between resistance of tissues predominantly expressing the thyroid hormone receptor ß-isoforms 1 and 2 and the overstimulation of tissues mainly expressing the thyroid hormone receptor α-isoform to thyroid hormones. The hallmark of RTHß is goiter, sinus tachycardia, attention deficit hyperactivity disorder in the context of increased levels of triiodothyronine/free thyroxine and nonsuppressed thyroid-stimulating hormone. Only recently have mutations in the thyroid hormone receptor α gene (THRA) been identified causing a new form of RTH, RTHα. The few patients described so far suffered from mental retardation of variable degree, short stature with decreased subischial leg length, chronic constipation and bradycardia. This review provides an overview of clinical, biochemical and genetic aspects of RTHα and RTHß relevant for diagnosis, treatment and counseling of affected patients and families.

[Thyroid hormone and skeletal metabolism].

The role of the hypothalamic-pituitary-thyroid axis is important in normal skeletal development, gain of bone mass, and regulation of adult bone metabolism. Hypothyroidism in childhood causes delayed bone maturation and growth disturbance and thyroid dysfunction in adult induces altered bone remodeling and an increased risk of bone fracture. Thyroid hormone actions in skeletal cells are mainly mediated by thyroid hormone receptor α (TRα) . The responses to thyroid hormone are regulated by type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3) , which convert prohormone (T4) to active hormone (T3) . Euthyroid status is necessary for the homeostasis of human bone metabolism.

Clinical and genetic aspects of hypophosphatasia in Japanese patients.

OBJECTIVE: We examined the clinical and genetic features of hypophosphatasia (HPP) in Japanese patients. HPP is a rare metabolic bone disorder of bone mineralisation caused by mutations in the liver/bone/kidney alkaline phosphatase (ALPL) gene, which encodes tissue-non-specific alkaline phosphatase isoenzyme.  METHODS: We retrospectively investigate the incidence and clinical features of 52 patients with paediatric HPP who were born between 1999 and 2010. Mutations of the ALPL gene were analysed in 31 patients. RESULTS: The annual incidence of perinatal lethal HPP (PLH) was estimated to be 2-3/1 000 000 births. The most frequent clinical type was PLH followed by prenatal benign. In addition to bone symptoms, cerebral manifestations were frequently observed including convulsion, mental retardation, deafness and short stature with growth hormone deficiency. Respiratory failure was the most significant predictor of a poor prognosis for PLH. The first and second most frequent mutations in the ALPL gene were c.1559delT and c.T979C (p.F327L), respectively. The c.1559delT homozygous mutation was lethal with respiratory failure. Patients with the p.F327L compound heterozygous mutation had the different non-lethal type with short stature and a gradual improvement in ALP level and bone mineralisation. CONCLUSIONS: The most frequent clinical type was the PLH type with prognosis related to respiratory failure, biochemical/radiological changes and ALPL mutations. Cerebral manifestations frequently occurred. Genotype-phenotype correlations were associated with specific outcomes in the PLH type, whereas different clinical features were associated with the same genotype in the non-lethal type.

[Monogenic obesity in human].

Obesity is a heterogeneous pathologic condition that is driven by interactions between multiple genetic and environmental factors. The discovery of leptin has provided the useful clue to the molecular dissection of central pathways involved in the regulation of food intake and body weight. Monogenic obesity in human has been documented. Several obesity causing genes within the leptin-POMC-melanocortin axis have been identified: Leptin, leptin receptor, proopiomelanocortin (POMC), prohormone convertase 1 (PC1), and melanocortin receptor-4 (MC4-R) genes. The patients who have a mutation of such genes developed early onset of obesity and distinct metabolic abnormalities. Also, several gene mutations have been identified in some syndromes presenting hereditary symptomatic obesity.

Long-term 3,5,3'-triiodothyroacetic acid therapy in a child with hyperthyroidism caused by thyroid hormone resistance: pharmacological study and therapeutic recommendations.

BACKGROUND: The effectiveness of short-term 3,5,3'-triiodothyroacetic acid (TRIAC) therapy for the treatment of hyperthyroidism caused by thyroid hormone resistance (RTH) has been documented. Here, we report a 3-year course of TRIAC therapy in an RTH boy, with a quantitative evaluation of the therapeutic effects and pharmacological study of TRIAC. PATIENT FINDINGS: The gene encoding the thyroid hormone receptor beta (THRB) of the patient carries a P453T mutation. During treatment with up to 3.0 mg TRIAC per day, reduction in the thyroid volume, resolution of supraventricular arrhythmia, and decrease in thyroid-stimulating hormone (TSH) and free-thyroxine (FT4) levels were achieved. In addition, attention-deficit hyperactivity disorder (ADHD) symptoms improved, with a concomitant decline in the ADHD Rating Scale score. SUMMARY: A TRIAC pharmacokinetic study, conducted using triiodothyronine level as a surrogate for TRIAC level, demonstrated that TRIAC disappears from the circulation rapidly and has a shorter duration of TSH secretion inhibitory effect in the RTH patient compared to that in the control subject. Studies of TSH and FT4 levels over a period of 3 years indicated that the TRIAC effect is dose dependent. CONCLUSIONS: TRIAC was effective and safe in ameliorating the effects of hyperthyroidism and ADHD symptoms in a child with known genetic RTH. Further, it was demonstrated that TRIAC has a short half-life and functions dose dependently.

Homozygous thyroid hormone receptor ß-gene mutations in resistance to thyroid hormone: three new cases and review of the literature.

CONTEXT: The most common cause of resistance to thyroid hormone (RTH) is heterozygous thyroid hormone receptor ß (THRB) gene mutations. Homozygous mutations in the THRB gene are a rare event. OBJECTIVE: In this study, the clinical findings of three new patients (belonging to two families) homozygous for mutations in the THRB gene are compared to three other families in which affected individuals lack a normal TRß. METHODS: We conducted clinical studies and genetic analyses. RESULTS: The clinical presentation in all three homozygous subjects was unusually severe; their phenotype was characterized by compromised intellectual development, tachycardia, goiter, growth retardation, and hearing loss. This was comparable with one other reported patient homozygous for mutant TRß, but not in RTH due to THRB gene deletions. CONCLUSION: We report three new subjects, from two families, in whom RTH was associated with homozygous mutations in the THRB gene. They represent an important addition to the single known patient homozygous for a mutant TRß. The clinical and laboratory abnormalities indicate a strong dominant-negative effect and are in agreement with data obtained from mice expressing a mutant Thrb in both alleles. This report strengthens the concept that the mutated TRß interferes with the function of the TRα1 in humans.

Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation.

OBJECTIVE: Mutations in the selenocysteine insertion sequence binding protein 2 gene (SECISBP2 also known as SBP2) lead to a multisystemic disorder. Our objectives are to examine the clinical manifestations of the present patient and evaluate the effects of GH and triiodothyronine (T(3)) for longitudinal bone growth and maturation. METHODS: A Japanese boy presented with unusual thyroid function tests (normal or slightly elevated TSH, low-normal or slightly decreased free T(3) (FT(3)), and elevated free thyroxine (FT(4))), short stature without GH deficiency, and delayed bone maturation. The entire coding region of the patient's SBP2 was analyzed. GH treatment was initiated when the patient was 4 years old, and combination therapy with GH plus T(3) was started when the patient was 10 years old. We monitored the patient's height and bone age until he was 11 years old. RESULTS: The patient showed typical symptoms of SBP2 deficiency, and novel compound heterozygous mutations were identified in SBP2 (p.M515fsX563/p.Q79X). Six years of GH monotherapy improved the patient's height s.d. from -3.4 to -1.7 without accelerating bone maturation, whereas 6 months of T(3) treatment combined with GH almost normalized the thyroid function tests and improved both longitudinal bone growth and maturation. CONCLUSIONS: In the growth plate, GH may compensate for decreased local T(3) effects on longitudinal bone growth; however, GH does not appear to compensate for the effects of T(3) on bone maturation. We believe that the present case has important implications for understanding the mechanism of thyroid hormone and GH on longitudinal bone growth and maturation.