Browse
You are looking at 1 - 10 of 1,472 items
Tanaka Medical Clinic, Yoichi, Japan
Search for other papers by Marenao Tana in
Google Scholar
PubMed
Search for other papers by Tomohito Gohda in
Google Scholar
PubMed
Institute for Clinical Research, NHO Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
Search for other papers by Nozomu Kamei in
Google Scholar
PubMed
Search for other papers by Maki Murakoshi in
Google Scholar
PubMed
Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan
Search for other papers by Tatsuya Sato in
Google Scholar
PubMed
Search for other papers by Mitsunobu Kubota in
Google Scholar
PubMed
Search for other papers by Michiyoshi Sanuki in
Google Scholar
PubMed
Search for other papers by Erika Ishiwata in
Google Scholar
PubMed
Search for other papers by Keisuke Endo in
Google Scholar
PubMed
Search for other papers by Yusuke Suzuki in
Google Scholar
PubMed
Search for other papers by Masato Furuhashi in
Google Scholar
PubMed
Background
Fatty acid-binding protein 4 (FABP4) is an adipokine that plays significant roles in the development of insulin resistance and atherosclerosis. High levels of soluble tumor necrosis factor receptors (TNFRs) including TNFR1 and TNFR2 are associated with renal dysfunction and increased mortality in patients with diabetes mellitus (DM). However, the association between circulating levels of FABP4 and TNFRs remains unclear.
Methods
We investigated the associations of FABP4 with TNFRs and metabolic markers in Japanese patients with type 1 DM (T1DM, n = 76, men/women: 31/45) and type 2 DM (T2DM, n = 575, men/women: 312/263).
Results
FABP4 concentration was positively correlated with levels of TNFR1 and TNFR2 in both patients with T1DM and those with T2DM. Multivariable regression analyses showed that there were independent associations of FABP4 concentration with body mass index (BMI) and estimated glomerular filtration rate (eGFR) after adjustment for age and sex in both patients with T1DM and those with T2DM. FABP4 concentration was independently associated with circulating levels of TNFR1 and TNFR2 after adjustment for the confounders in patients with T2DM but not in those with T1DM. Similarly, levels of TNFR1 and TNFR2 were independently associated with FABP4 concentration after adjustment for age, sex, systolic blood pressure, duration of DM and levels of eGFR, high-density lipoprotein cholesterol, and C-reactive protein in patients with T2DM but not in those with T1DM.
Conclusion
FABP4 concentration is independently associated with levels of TNFRs in patients with DM, but the association is more evident in patients with T2DM than in those with T1DM.
Search for other papers by Danzhou Fang in
Google Scholar
PubMed
Search for other papers by Shiying Li in
Google Scholar
PubMed
Search for other papers by Changgu Zhou in
Google Scholar
PubMed
Search for other papers by Yirui Wang in
Google Scholar
PubMed
Search for other papers by Gengbiao Yuan in
Google Scholar
PubMed
Search for other papers by HuiHui Zhang in
Google Scholar
PubMed
Search for other papers by Maohua Rao in
Google Scholar
PubMed
Objective
Hyperthyroidism, a prevalent endocrine disorder, can lead to complications such as liver failure due to the liver's essential role in thyroid hormone metabolism. The study aimed to elucidate the respective contributions of 131I and/or ALSS in managing hyperthyroidism alongside liver failure.
Methods
A retrospective analysis was carried out on 74 patients diagnosed with severe liver failure in the context of Graves' disease. Patients were categorized into three groups: group A (n = 34) received 131I treatment, group B (n = 17) underwent 131I and ALSS treatment, and group C (n = 24) received artificial liver support system (ALSS) treatment alone.
Results
Throughout the treatment period, the liver function indexes in all groups exhibited a declining trend. The thyroid function of group A and group B treated with 131I was significantly improved compared to that before treatment. There was no significant change in thyroid function in group C. After the correction of hyperthyroidism, significant improvements were observed in the liver function of individuals in groups A and B, particularly with more noticeable amelioration compared to group C. After two months of treatment, the efficacy rates for the three groups were 79.41%, 82.35%, and 60.87% respectively. Mortality rates of the three groups were 5.88%, 17.65%, and 36% (P < 0.01). Group B, receiving both 131I and ALSS treatments, exhibited a lower mortality rate than group C.
Conclusion
In cases of severe liver failure accompanied by hyperthyroidism, prompt administration of 131I is recommended to alleviate the adverse effects of hyperthyroidism on liver function and facilitate a conducive environment for the recovery of liver functionality.
Office for Rare Conditions, University of Glasgow, Glasgow, UK
Search for other papers by Salma R Ali in
Google Scholar
PubMed
Search for other papers by Melissa Gardner in
Google Scholar
PubMed
Search for other papers by Yiqiao Xin in
Google Scholar
PubMed
Search for other papers by Stuart O’Toole in
Google Scholar
PubMed
Search for other papers by Martyn Flett in
Google Scholar
PubMed
Search for other papers by Boma Lee in
Google Scholar
PubMed
Search for other papers by Mairi Steven in
Google Scholar
PubMed
Search for other papers by David E Sandberg in
Google Scholar
PubMed
Office for Rare Conditions, University of Glasgow, Glasgow, UK
Search for other papers by S Faisal Ahmed in
Google Scholar
PubMed
Background
There is a paucity of information on health-related quality of life (HRQoL) outcomes in parents and children with conditions affecting sex development. The objective of this study was to develop short forms of HRQoL questionnaires which consist of a 63-item and 25-item parent self-report (PSR) and parent proxy-report (PPR), respectively, optimizing use in routine clinical settings.
Methods
Short questionnaires were developed following exploratory factor analysis using raw data from 132 parents. Long and short PSRs were completed by 24 parents of children with conditions affecting sex development, with a median age of 3.6 years (range 0.1, 6.6); 21 (88%) were boys, and 11 (46%) had proximal hypospadias. A subset of 19 parents completed both long and short PPRs.
Results
Item selection, based on factor loadings of >0.8 and expert consultation, produced short PSRs and PPRs containing 16 and 7 items, respectively. There was no statistically significant difference in 11 out of 12 (92%) scales on the PSR and 4 out of 5 (80%) scales on the PPR when comparing short and long questionnaire scores. The short and long questionnaires took <1 min and 5 min to complete, respectively. Eighteen parents (75%) reported that the time taken to complete the short questionnaires was acceptable; 10 (42%) preferred short questionnaires. Ten (42%) versus 6 (25%) stated a preference for completing the short versus long questionnaires.
Conclusion
The short versions were largely representative of the long questionnaires and are acceptable for evaluating psychosocial distress in young children and their caregivers. Further psychometric validation of the short forms is warranted.
Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Search for other papers by Theodoros Karampitsakos in
Google Scholar
PubMed
Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Search for other papers by Fotini Kanouta in
Google Scholar
PubMed
Search for other papers by Christos Chatzakis in
Google Scholar
PubMed
Search for other papers by Vassilios Bakoulas in
Google Scholar
PubMed
Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Search for other papers by Alexandros Gryparis in
Google Scholar
PubMed
Search for other papers by Petros Drakakis in
Google Scholar
PubMed
Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Search for other papers by Djuro Macut in
Google Scholar
PubMed
Search for other papers by George Mastorakos in
Google Scholar
PubMed
Introduction
To investigate whether synthetic (s) glucocorticoids (GCs) administered between the 24th and the 34th gestational weeks in pre-term labor might precipitate labor, studies on sGCs administration were reviewed. The physiology of endogenous glucocorticoid-related increase in fetal–maternal circulation and its association with labor, followed by a scoping review of studies on exogenous sGCs administered for fetal lung maturation and the timing of labor, were included.
Materials and methods
The methodology of systematic reviews was followed. MEDLINE, Cochrane Library, and Google Scholar databases were searched until October 2023, for original studies investigating the administration of sGCs in pregnancies risking pre-term labor. Duplicates were removed, and 1867 abstracts were excluded as irrelevant. Six controlled and four non-controlled studies were included. The index group consisted of 6001 subjects and 7691 controls in the former, while in the latter, the index group consisted of 2069 subjects.
Results
In three out of the six controlled studies, gestational age at labor was significantly lower in sGC-treated women than in controls, while in three studies, gestational age at labor was lower in sGC-treated women than in controls, with a trend toward statistical significance. In one study, gestational age at labor was significantly lower in controls than in sGC-treated women. In the non-controlled studies, the majority of women delivered less than 1 week from the day of sGC administration.
Conclusions
In this scoping review, studies lack homogeneity. However, in the controlled studies, a pattern of earlier labor emerges among sGC-treated pregnant women. The use of multiple courses of antenatal sGCs appears to be associated with precipitated labor. Their use should be carefully weighed. Carefully designed trials should examine this ongoing scientific query.
National Center for Children’s Health, Beijing, China
Search for other papers by Yi Wang in
Google Scholar
PubMed
Search for other papers by Yingying Xu in
Google Scholar
PubMed
Search for other papers by Rongrong Xie in
Google Scholar
PubMed
National Center for Children’s Health, Beijing, China
Search for other papers by Bingyan Cao in
Google Scholar
PubMed
National Center for Children’s Health, Beijing, China
Search for other papers by Yuan Ding in
Google Scholar
PubMed
National Center for Children’s Health, Beijing, China
Search for other papers by Jiayun Guo in
Google Scholar
PubMed
National Center for Children’s Health, Beijing, China
Search for other papers by Xiaoqiao Li in
Google Scholar
PubMed
National Center for Children’s Health, Beijing, China
Search for other papers by Xiaolin Ni in
Google Scholar
PubMed
National Center for Children’s Health, Beijing, China
Search for other papers by Zheng Yuan in
Google Scholar
PubMed
Search for other papers by Linqi Chen in
Google Scholar
PubMed
Search for other papers by Liyang Liang in
Google Scholar
PubMed
National Center for Children’s Health, Beijing, China
Search for other papers by Chunxiu Gong in
Google Scholar
PubMed
Objective
Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is rare, and manifestations of autonomic dysregulation are diverse and may be overlooked. We aimed to evaluate the incidence of these manifestations.
Methods
Patients with ROHHAD syndrome reported before and after 2019 were divided into groups 1 and 2. Patients who were diagnosed at three regional hospitals in China were included in group 3. We collected the age of each specific term of the ROHHAD (neurogenic tumor, NET) acronym and the detailed manifestations of each term, and compared them among the three groups.
Results
A total of 16 patients were diagnosed within the 2-year period. Two had neurogenic tumors and cognitive and behavioral abnormalities before developing rapid obesity. At least 93.8% of the patients had ≥ 4 symptoms of autonomic dysregulation. When comparing autonomic dysregulation among groups 1–3, the rates of cardiovascular manifestations were NA vs 12.8% vs 81.2%; gastrointestinal disturbances were 11.4% vs 8.5% vs 62.5%; strabismus was 25.7% vs 12.8% vs 62.5%; sleep disturbance was NA vs 6.4% vs 50.0%; and abnormal pain threshold was NA vs 10.6% vs 25.0% (all P < 0.05). The rates of cognitive and behavioral abnormalities were NA vs 29.8% and 87.5% (P < 0.01).
Conclusion
Rapid-onset obesity is not always the first sign of ROHHAD syndrome. Higher rates of autonomic dysregulation and cognitive and behavioral abnormalities with multiple manifestations of autonomic dysregulation coexisted in our cohort, indicating that evaluations of autonomic function and the limbic system should be strengthened when assessing this condition.
Search for other papers by Laura Hasse in
Google Scholar
PubMed
Search for other papers by Dagmar Jamiolkowski in
Google Scholar
PubMed
Search for other papers by Felix Reschke in
Google Scholar
PubMed
Search for other papers by Kerstin Kapitzke in
Google Scholar
PubMed
Search for other papers by Jantje Weiskorn in
Google Scholar
PubMed
Search for other papers by Olga Kordonouri in
Google Scholar
PubMed
Search for other papers by Torben Biester in
Google Scholar
PubMed
Search for other papers by Hagen Ott in
Google Scholar
PubMed
Search for other papers by Hana Vítková in
Google Scholar
PubMed
Department of Gynaecology, Obstetrics and Neonatology, First Faculty of Medicine Charles University and General University Hospital in Prague, Prague, Czech Republic
Search for other papers by Kateřina Anderlová in
Google Scholar
PubMed
Search for other papers by Jan Krátký in
Google Scholar
PubMed
Search for other papers by Radovan Bílek in
Google Scholar
PubMed
Search for other papers by Drahomíra Springer in
Google Scholar
PubMed
Search for other papers by Felix Votava in
Google Scholar
PubMed
Search for other papers by Tomáš Brutvan in
Google Scholar
PubMed
Search for other papers by Adéla Krausová in
Google Scholar
PubMed
Search for other papers by Kristýna Žabková in
Google Scholar
PubMed
Search for other papers by Eliška Potluková in
Google Scholar
PubMed
Search for other papers by Jan Jiskra in
Google Scholar
PubMed
Introduction
Maternal urinary iodine concentration and blood neonatal thyroid-stimulating hormone (TSH) concentration reflect iodine status in pregnancy and serve as markers of iodine deficiency. As dietary measures in gestational diabetes mellitus (GDM) could affect iodine intake, our study aimed to investigate iodine supply in women with GDM compared to healthy pregnant women and to evaluate its relationship to maternal and neonatal thyroid function.
Methods
Urinary iodine concentration (UIC) and serum TSH, free thyroxine (FT4), and autoantibodies against thyroid peroxidase (TPOAb) were analyzed in 195 women with GDM and 88 healthy pregnant women in the second trimester. Subsequently, neonatal TSH concentrations measured 72 h after delivery in a subgroup of 154 newborns (115 of mothers with GDM and 39 controls) from the national register were analyzed.
Results
Median UIC was significantly lower in women with GDM compared to controls (89.50 µg/L vs. 150.05 µg/L; P < 0.001). Optimal iodine intake was found only in nine women with GDM (4.6%) and 33 healthy pregnant women (37.5%) (P < 0.001). Most pregnant women with GDM (88.7%) compared to one half of controls (50%) had iodine deficiency (P < 0.001). Although serum TSH and the prevalence of hypothyroidism (TSH > 4.0 mIU/L) were not different in both groups, hypothyroxinaemia was more prevalent in GDM compared to controls (12.3% vs 3.4%, P = 0.032). Consistently, neonatal TSH > 5.0 mIU/L indicating iodine deficiency, was found in 6 (5.2%) newborns of women with GDM as compared to none in controls. In women with GDM, the prevalence of perinatal complications was significantly lower in those who were taking dietary iodine supplements compared to those who were not (3/39 (7.69%) vs 46/156 (28.85%), P <0.001). In the multiple logistic and linear regression models in women with GDM, hypothyroxinaemia was associated with preterm births, and a negative association of serum FT4 and HbA1c was found.
Conclusion
Iodine deficiency in pregnancy was more prevalent among women with GDM compared to healthy pregnant controls. Serum FT4 negatively correlated with HbA1c, and hypothyroxinaemia was associated with preterm births in women with GDM. Conversely, women with GDM who used dietary iodine supplements had a lower risk of perinatal complications.
Search for other papers by Rohit Barnabas in
Google Scholar
PubMed
Search for other papers by Swati Jadhav in
Google Scholar
PubMed
Search for other papers by Anurag Ranjan Lila in
Google Scholar
PubMed
Search for other papers by Sirisha Kusuma Boddu in
Google Scholar
PubMed
Search for other papers by Saba Samad Memon in
Google Scholar
PubMed
Search for other papers by Sneha Arya in
Google Scholar
PubMed
Search for other papers by Samiksha Chandrashekhar Hegishte in
Google Scholar
PubMed
Search for other papers by Manjiri Karlekar in
Google Scholar
PubMed
Search for other papers by Virendra A Patil in
Google Scholar
PubMed
Search for other papers by Vijaya Sarathi in
Google Scholar
PubMed
Search for other papers by Nalini S Shah in
Google Scholar
PubMed
Search for other papers by Tushar Bandgar in
Google Scholar
PubMed
Background
The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series.
Methods
We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of three patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described.
Results
Three 46,XY patients (age 6–18 years) from our center, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n = 70, 56 raised as females) presented with pubertal delay (n = 41) or atypical genitalia (n = 17). Sinnecker score ≥3 (suggesting antenatal human chorionic gonadotropin (hCG) inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/mL) in 77.4% (24/31), whereas puberty/postpubertal age, high luteinizing hormone (LH) (97.6%, 41/42) and low (<1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs 0/5, P = 0.033). 46,XX patients (n = 18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2–38).
Conclusion
In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential actions for LH and hCG.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
Search for other papers by Xu-Feng Chen in
Google Scholar
PubMed
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
Search for other papers by Cong He in
Google Scholar
PubMed
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
Search for other papers by Peng-Cheng Yu in
Google Scholar
PubMed
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
Search for other papers by Wei-Dong Ye in
Google Scholar
PubMed
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
Search for other papers by Pei-Zheng Han in
Google Scholar
PubMed
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
Search for other papers by Jia-Qian Hu in
Google Scholar
PubMed
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
Search for other papers by Yu-Long Wang in
Google Scholar
PubMed
Next-generation sequencing (NGS) is of great benefit to clinical practice in terms of identifying genetic alterations. This study aims to clarify the gene background and its influence on thyroid tumors in the Chinese population. NGS data and corresponding clinicopathological features (sex, age, tumor size, extrathyroidal invasion, metastasis, multifocality, and TNM stage) were collected and analyzed retrospectively from 2844 individual thyroid tumor samples from July 2021 to August 2022. Among the cohort, 2337 (82%) cases possess genetic alterations, including BRAF (71%), RAS (4%), RET/PTC (4%), TERT (3%), RET (2.2%), and TP53 (1.4%). Diagnostic sensitivity before surgery can be significantly increased from 0.76 to 0.91 when cytology is supplemented by NGS. Our results show that BRAF-positive papillary thyroid cancer (PTC) patients tend to have older age, smaller tumor size, less vascular invasion, more frequent tumor multifocality, and a significantly higher cervical lymph node metastatic rate. Mutation at RET gene codons 918 and 634 is strongly correlated with medullary thyroid cancer. However, it did not display more invasive clinical characteristics. TERT-positive patients are more likely to have older age, and have larger tumor size, more tumor invasiveness, and more advanced TNM stage, indicating a poor prognosis. Patients with TERT, RET/PTC1, and CHEK2 mutations are more susceptible to lateral lymph node metastasis. In conclusion, NGS can be a useful tool that provides practical gene evidence in the process of diagnosis and treatment in thyroid tumors.
Faculty of Medicine, The University of Sydney, Sydney, Australia
Search for other papers by Ayanthi Wijewardene in
Google Scholar
PubMed
Faculty of Medicine, The University of Sydney, Sydney, Australia
Search for other papers by Matti Gild in
Google Scholar
PubMed
Faculty of Medicine, The University of Sydney, Sydney, Australia
Search for other papers by Lyndal Tacon in
Google Scholar
PubMed
Faculty of Medicine, The University of Sydney, Sydney, Australia
Search for other papers by Venessa Tsang in
Google Scholar
PubMed
Department of Anatomical Pathology, NSW Health Pathology, Royal North Shore Hospital, Sydney, Australia
Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Australia
Search for other papers by Anthony J Gill in
Google Scholar
PubMed
Department of Endocrine Surgery, Royal North Shore Hospital, Sydney, Australia
Search for other papers by Anthony Robert Glover in
Google Scholar
PubMed
Department of Endocrine Surgery, Royal North Shore Hospital, Sydney, Australia
Search for other papers by Mark Sywak in
Google Scholar
PubMed
Department of Endocrine Surgery, Royal North Shore Hospital, Sydney, Australia
Search for other papers by Stan Sidhu in
Google Scholar
PubMed
Faculty of Medicine, The University of Sydney, Sydney, Australia
Search for other papers by Bruce Robinson in
Google Scholar
PubMed
Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, Australia
Search for other papers by Paul Roach in
Google Scholar
PubMed
Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, Australia
Search for other papers by Geoffrey Schembri in
Google Scholar
PubMed
Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, Australia
Search for other papers by Jeremy Hoang in
Google Scholar
PubMed
Faculty of Medicine, The University of Sydney, Sydney, Australia
Search for other papers by Roderick Clifton-Bligh in
Google Scholar
PubMed
Summary
Background
Noise, an unwanted variability in judgment, is ubiquitous in medicine, including in the prescription of radioactive iodine (RAI). Building upon our recently developed predictive risk model, we created an online clinical support tool to facilitate the translation of our model into clinical practice. The aim of this study is to assess the utility of an online clinical support tool to reduce noise in the treatment for patients with differentiated thyroid cancer (DTC).
Methods
The tool was accessible via weblink or a QR code. Activity recommendations were applied to the calculator’s four risk categories: 0 GBq for very low risk, 1 GBq for low risk, 4 GBq for intermediate risk, and 6 GBq for high risk. The tool was applied prospectively to 103 patients who received RAI at Royal North Shore Hospital between 2021 and 2022 and retrospectively to 393 patients treated with RAI between 2017 and 2021.
Results
A significant difference was observed in administered activity between the 2021–2022 and 2017–2021 cohorts in patients stratified as intermediate risk (median activity 3.95 GBq, interquartile range 2.03–4.04 vs 4 GBq, 4–4) and high risk (4.07 GBq, 3.95–5.7 vs 6 GBq, 6–6) with P-values of 0.01 and <0.01, respectively. No difference was seen in low-risk patients (2.01 GBq, 1.03–3.98 vs 1 GBq, 1–4, P = 0.30). Additionally, no clinically significant recurrence was observed between the two cohorts (6.6% vs 4.5%; P = 0.628).
Conclusion
Optimal risk classification and activity recommendation continue to be established. Our data suggest that providing risk stratification and activity recommendation in an easy-to-access online tool can reduce noise and variability in activity prescription for patients with DTC.
