Quality of life in men with Klinefelter syndrome: a multicentre study

Background: Klinefelter syndrome (KS) is associated with an increased risk of lower socioeconomic status and a higher risk for morbidity and mortal ity, which may have a significant impact on quality of life (QOL). The objective of this study is to investigate QOL in a large European cohort of men with KS. Design: Cross-sectional multicentre study. Methods: Two-hundred-eighteen men with KS were recruited from 14 clinic al study centres in 6 European countries which participated in the Europ ean dsd-LIFE study. Male normative data from a healthy and a psychiatric reference population were used for comparison. The validated World Health Organization (WHO) Q OL (WHOQOL)-BREF questionnaire was used to investigate five main domains of quali ty of life (WHOQOL): global, physical, psychological, environment, and social. Results: The QOL physical domain score was lower for men with KS compar ed to the healthy reference population (KS: 66.9; s.d. 19.4, n = 193; healthy reference population: 76.5; s.d. 16.2, n = 1324, P < 0.001) but higher compared to the psychiatric reference population (54.6; s.d. 20.6; n = 77, P < 0.001). The WHOQOL-psychological domain score was lower for men with KS compared to the healthy reference pop ulation (KS: 63.6; s.d. 17.8, n = 193; healthy reference population: 67.8; s.d. 15.6, n = 1324, P < 0.05) but higher compared to the psychiatric reference population (45.9; s.d. 26.0), n = 77, P < 0.001). The social domain score on the WHOQOL questionnaire was found t o be lower in men with Klinefelter syndrome (KS) compared to the healthy referenc e population (KS: 60.0; s.d. 21.6, n = 193; healthy reference population: 68.2; s.d. 13.8, n = 1324, P < 0.001). However, this score was similar to that of the psychiatric refe rence population (61.0; s.d. 17.0, n = 77, P = 0.5). The WHO environment domain score of men with KS (70.0; s.d. 15.0, n = 193) was similar to the healthy reference population (70.5; s.d. 20.7, n = 1324) but higher compared to the psychiatric reference population (61 .9; s.d. 20.8, n = 77, P = 0.002). Experienced discrimination, less social activities, and the presence of chronic health problems were associated with significantly decreased QOL in men with KS. Conclusion: Overall QOL in European men with KS is significantly worse comp ared to a healthy European reference population. Especially, the presen ce of discrimination, less social activities, and chronic health problems is associat ed with lower physical, psychological, and social QOL. Further studies are necessary to investigate if a multidisciplinary approach may help to provide adequate counsel ling and psychosocial support to improve QOL

Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults

Levothyroxine (LT4) is a safe, effective means of hormone replacement therapy for hypothyroidism. Here, we review the pharmaceutical, pathophysiological and behavioural factors influencing the absorption, distribution, metabolism and excretion of LT4. Any factor that alters the state of the epithelium in the stomach or small intestine will reduce and/or slow absorption of LT4; these include ulcerative colitis, coeliac disease, bariatric surgery, Helicobacter pylori infection, food intolerance, gastritis, mineral supplements, dietary fibre, resins, and various drugs. Once in the circulation, LT4 is almost fully bound to plasma proteins. Although free T4 (FT4) and liothyronine concentrations are extensively buffered, it is possible that drug- or disorder-induced changes in plasma proteins levels can modify free hormone levels. The data on the clinical significance of genetic variants in deiodinase genes are contradictory, and wide- scale genotyping of hypothyroid patients is not currently justified. We developed a decision tree for the physician faced with an abnormally high thyroid-stimulating hormone (TSH) level in a patient reporting adequate compliance with the recommended LT4 dose. The physician should review medications, the medical history and the serum FT4 level and check for acute adrenal insufficiency, heterophilic anti-TSH antibodies, antibodies against gastric and intestinal components (gastric parietal cells, endomysium, and tissue transglutaminase 2), and Helicobacter pylori infection. The next step is an LT4 pharmacodynamic absorption test; poor LT4 absorption should prompt a consultation with a gastroenterologist and (depending on the findings) an increase in the LT4 dose level. An in- depth etiological investigation can reveal visceral disorders and, especially, digestive tract disorders

DataSheet1_Identification and Economic Evaluation of Differentiated Thyroid Cancer Care Consumption Patterns Using Sequence Analysis.docx

Objectives: This study aims to assess the impact of care consumption patterns and individual characteristics on the cost of treating differentiated thyroid carcinoma (DTC), in France, with a specific emphasis on socioeconomic position.Methods: The methodology involved a net cost approach utilising cases from the EVATHYR cohort and controls from the French National Health Insurance database. Care consumption patterns were created using Optimal Matching and clustering techniques. The individual characteristics influence on patterns was assessed using multinomial logistic regression. The individual characteristics and patterns influence on care costs was assessed using generalised estimating equations.Results: The findings revealed an average cost of €13,753 per patient during the initial 3 years. Regression models suggested the main predictors of high DTC specific care consumption tended to include having a high risk of cancer recurrence (OR = 4.97), being a woman (OR = 2.00), and experiencing socio-economic deprivation (OR = 1.26), though not reaching statistical significance. Finally, high DTC-specific care consumers also incurred higher general care costs (RR = 1.35).Conclusion: The study underscores the increased costs of managing DTC, shaped by consumption habits and socioeconomic position, emphasising the need for more nuanced DTC management strategies.</p

TLR8 escapes X chromosome inactivation in human monocytes and CD4+ T cells

Abstract Background Human endosomal Toll-like receptors TLR7 and TLR8 recognize self and non-self RNA ligands, and are important mediators of innate immunity and autoimmune pathogenesis. TLR7 and TLR8 are, respectively, encoded by adjacent X-linked genes. We previously established that TLR7 evades X chromosome inactivation (XCI) in female immune cells. Whether TLR8 also evades XCI, however, has not yet been explored. Method In the current study, we used RNA fluorescence in situ hybridization (RNA FISH) to directly visualize, on a single-cell basis, primary transcripts of TLR7 and TLR8 relative to X chromosome territories in CD14+ monocytes and CD4+ T lymphocytes from women, Klinefelter syndrome (KS) men, and euploid men. To assign X chromosome territories in cells lacking robust expression of a XIST compartment, we designed probes specific for X-linked genes that do not escape XCI and therefore robustly label the active X chromosome. We also assessed whether XCI escape of TLR8 was associated with sexual dimorphism in TLR8 protein expression by western blot and flow cytometry. Results Using RNA FISH, we show that TLR8, like TLR7, evades XCI in immune cells, and that cells harboring simultaneously TLR7 and TLR8 transcript foci are more frequent in women and KS men than in euploid men, resulting in a sevenfold difference in frequency. This transcriptional bias was again observable when comparing the single X of XY males with the active X of cells from females or KS males. Interestingly, TLR8 protein expression was significantly higher in female mononuclear blood cells, including all monocyte subsets, than in male cells. Conclusions TLR8, mirroring TLR7, escapes XCI in human monocytes and CD4+ T cells. Co-dependent transcription from the active X chromosome and escape from XCI could both contribute to higher TLR8 protein abundance in female cells, which may have implications for the response to viruses and bacteria, and the risk of developing inflammatory and autoimmune diseases

Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients

International audienceObjectiveFamilial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss‐of‐function mutations of the calcium‐sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1.Design and patientsThis observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012.ResultsHypercalcaemia was diagnosed at a median age of 53 years [IQR: 38‐61]. The diagnosis was made after clinical manifestations, routine analysis or familial screening in 56, 34 and 10% of cases, respectively, (n = 58; data not available for 19 patients). Chondrocalcinosis was present in 11/51 patients (22%), bone fractures in 8/56 (14%) and renal colic in 6/55 (11%). The median serum calcium was 2.74 mmol/L [IQR: 2.63‐2.86 mmol/L], the median plasma parathyroid hormone level was 4.9 pmol/L [3.1‐7.1], and the median 24‐hour urinary calcium excretion was 2.8 mmol/24 hours [IQR: 1.9‐4.0]. Osteoporosis (dual X‐ray absorptiometry) or kidney stones (renal ultrasonography) were found in 6/38 patients (16%) and 9/32 patients (28%), respectively. Fourteen patients (18%) underwent parathyroid surgery; parathyroid adenoma was found in three patients (21%) and parathyroid hyperplasia in nine patients (64%). No correlation between genotype and phenotype was established.ConclusionThis large cohort study demonstrates that FHH1 clinical characteristics can be atypical in 33 patients (43%). Clinicians should be aware of this rare differential diagnosis in order to adopt an appropriate treatment strategy

ESTIMation of the ABiLity of prophylactic central compartment neck dissection to modify outcomes in low-risk differentiated thyroid cancer: a prospective randomized trial

Abstract Background Prophylactic central neck dissection in clinically low-risk cT1bT2N0 papillary thyroid carcinoma is controversial, due to a large number of conflicting retrospective studies, some showing an advantage in terms of locoregional recurrence, others showing no advantage. These previous studies all show high rates of excellent response. We aim to demonstrate the non-inferiority of thyroidectomy alone as compared to total thyroidectomy with prophylactic central neck dissection in conjunction with adjuvant RAI 30 mCi with rTSH stimulation in terms of excellent response at 1 year. Trial design and methods Prospective randomized open multicenter phase III trial including patients with 11–40-mm papillary thyroid carcinoma (Bethesda VI) or suspicious cytology (Bethesda V) confirmed malignant on intra-operative frozen section analysis, with no suspicious lymph nodes on a specialized preoperative ultrasound examination. Patients will be randomized 1:1 into two groups: the reference group total thyroidectomy with bilateral prophylactic central neck dissection, and the comparator group total thyroidectomy alone. All patients will receive an ablative dose of 30mCi of radioactive iodine (RAI) within 4 months of surgery. The primary outcome is to compare the rate of excellent response at 1 year after surgery between the groups, as defined by an unstimulated serum thyroglobulin (Tg) level ≤ 0.2 ng/mL with no anti-Tg antibodies, an normal neck ultrasound and no ectopic uptake on the post-RAI scintiscan. Non-inferiority will be demonstrated if the rate of patients with excellent response at 1 year after randomization does not differ by more than 5%. Setting the significance level at 0.025 (one-sided) and a power of 80% requires a sample size of 598 patients (299 per group). Secondary outcomes are to compare Tg levels at 8 +/− 2 postoperative weeks, before RAI ablation, the rate of excellent response at 3 and 5 years, the rate of other responses at 1, 3, and 5 years (biochemical incomplete, indeterminate, and structurally incomplete responses), complications, quality of life, and cost-utility. Discussion (potential implications) If non-inferiority is demonstrated with this high-level evidence, prophylactic neck dissection will have been shown to not be necessary in clinically low-risk papillary thyroid carcinoma. Trial registration NCT 03570021. June 26,201

Correction: ESTIMation of the ABiLity of prophylactic central compartment neck dissection to modify outcomes in low-risk differentiated thyroid cancer: a prospective randomized trial

International audienceNo abstract availabl