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Open access

Brien Mehmet, Steve Gillard, Channa N Jayasena, and Sofia Llahana

Objective

Klinefelter syndrome (KS) is the second-most prevalent chromosomal disorder in men, though late diagnosis is very common and 50–75% of men remain undiagnosed. Evidence suggests that men with KS have impaired quality of life (QoL) but research on how the diagnosis of KS is associated with different QoL domains and what factors influence patients’ QoL is limited. This study aimed to provide a systematic review of the published evidence on factors that influence QoL in men with KS.

Design

Systematic review and meta-analysis with narrative synthesis.

Methods

Medline, Cochrane, Embase, Psychinfo, CINAHL, BASE and relevant publication reference lists were searched in January 2021. Eligible studies included randomised control trials, cohort studies, cross-sectional studies and epidemiology studies on KS and its effect on QoL and all domains of World Health Organisation (WHO) Quality of Life 100 (WHOQOL-100). Clinical studies with no date restriction published in English were included.

Results

Thematic analysis was completed on 13 studies, with a meta-analysis of intelligence quotient completed on 7 studies. Twelve out of the 13 studies suggested that KS negatively affected the QoL outcomes and KS was associated with impairments in physical, psychological, level independence and social relationship domains of WHOQOL-100. Meta-analysis suggested that men with KS have significantly lower full-scale Intelligence Quotient vs controls (P < 0.00001).

Conclusions

This is the first evidence synthesis of QoL in men with KS. Current evidence suggests that combined physical and psychological impairments affect men with KS who also experience impairments in relationships and independence in society. Further research is needed to identify factors that influence the QoL in men with KS.

Open access

Catherine Peters and Nadia Schoenmakers

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following the withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in the incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, for example, iodine deficiency and excess, anti- TSHR antibodies and exposure to antithyroid or iodine-rich medications, may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Restricted access

Patricia Sandqvist, Anders Sundin, Inga-Lena Nilsson, Per Grybäck, and Alejandro Sanchez-Crespo

Objective

Successful preoperative image localisation of all parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (pHPT) and multiglandular disease (MGD) remains challenging. We investigate whether a machine learning classifier (MLC) could predict the presence of overlooked PTA at preoperative localisation with 99mTc-Sestamibi-SPECT/CT in MGD patients.

Design

This study is a retrospective study from a single tertiary referral hospital initially including 349 patients with biochemically confirmed pHPT and cured after surgical parathyroidectomy.

Methods

A classification ensemble of decision trees with Bayesian hyperparameter optimisation and five-fold cross-validation was trained with six predictor variables: the preoperative plasma concentrations of parathyroid hormone, total calcium and thyroid-stimulating hormone, the serum concentration of ionised calcium, the 24-h urine calcium and the histopathological weight of the localised PTA at imaging. Two response classes were defined: patients with single-gland disease (SGD) correctly localised at imaging and MGD patients in whom only one PTA was localised on imaging. The data set was split into 70% for training and 30% for testing. The MLC was also tested on a subset of the original data based on CT image-derived PTA weights.

Results

The MLC achieved an overall accuracy at validation of 90% with an area under the cross-validation receiver operating characteristic curve of 0.9. On test data, the MLC reached a 72% true-positive prediction rate for MGD patients and a misclassification rate of 6% for SGD patients. Similar results were obtained in the testing set with image-derived PTA weight.

Conclusions

Artificial intelligence can aid in identifying patients with MGD for whom 99mTc-Sestamibi-SPECT/CT failed to visualise all PTAs.

Open access

Elin Pettersen Sørgjerd, Robin Mjelle, Vidar Beisvåg, Arnar Flatberg, Valdemar Grill, and Bjørn O Åsvold

Objective

Diabetes is a heterogeneous disease and a precise diagnosis of diabetes subgroups is necessary to initiate proper early treatment and clinical management of the disease. Circulating small RNAs (sRNAs) are potentially diagnostic biomarkers in diseases, including diabetes. Here we aimed to examine whether profiles of circulating sRNAs differed between patients with autoimmune and non-autoimmune diabetes and non-diabetic controls.

Design

This cross-sectional case–control study included participants from the third survey of the HUNT study.

Methods

We performed sRNA sequencing in serum from adult-onset type 1 diabetes (n = 51), type 2 diabetes (n = 50) and latent autoimmune diabetes in adult (LADA, n  = 51), as well as non-diabetic HUNT3 participants as control group (n = 51). Differential expression analysis of the sRNAs was performed in R using limma-voom.

Results

We identified differences in sRNA expression between autoimmune (type 1 diabetes and LADA) and non-autoimmune diabetes (type 2 diabetes) and between patients with diabetes and non-diabetic controls. Focusing on miRNA, we identified 10 differentially expressed mature miRNAs and 30 differentially expressed miRNA variants (isomiRs). We also identified significant changes within other sRNA classes, including a pronounced downregulation of a tRNA fragment in patients with diabetes compared to non-diabetic controls. We created cross-validated sRNA signatures based on the significant sRNAs that distinguished patients with diabetes from non-diabetic controls, and autoimmune from non-autoimmune diabetes, with high specificity and sensitivity. sRNA profiles did not distinguish between type 1 diabetes and LADA.

Conclusions

Circulating sRNAs are differentially expressed between patients with diabetes and non-diabetic controls and between autoimmune and non-autoimmune diabetes.

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Jose Italo Soares Mota, Rui Milton Patrício Silva-Júnior, Clarissa Silva Martins, Ana Carolina Bueno, Luiz Eduardo Wildemberg, Ximene Lima da Silva Antunes, Jorge Guilherme Okanobo Ozaki, Fernanda Borchers Coeli-Lacchini, Carlos Garcia-Peral, Antonio Edson Rocha Oliveira, Antônio Carlos Santos, Ayrton Custodio Moreira, Helio Rubens Machado, Marcelo Volpon dos Santos, Leandro M Colli, Monica R Gadelha, Sonir Roberto R Antonini, and Margaret de Castro

Objectives

To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations.

Design

Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions.

Methods

Clinicopathological features were retrieved from the patient’s charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths.

Results

Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297–0.597vs 0.607, IQR: 0.445–0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs.

Conclusions: CTNNB1

mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/β-catenin pathway and telomere biology in the pathogenesis of aCPs.

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Junichi Ishigami, Yasuyuki Honda, Amy B Karger, Josef Coresh, Elizabeth Selvin, Pamela L Lutsey, and Kunihiro Matsushita

Objective

Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population.

Design and methods

We analyzed 5458 participants of the Atherosclerosis Risk in Communities Study who had intact FGF23 and estimated glomerular filtration rate (eGFR) assessed during midlife (visit 3, 1993–1995, mean age: 58 years) and late life (visit 5, 2011–2013, 76 years) to examine the association of FGF23 change over 18 years from mid-life to late life with the subsequent risk of mortality in late life using Cox regression models.

Results

The median 18-year change in intact FGF23 was +17.3 pg/mL. During a median follow-up of 7.2 years following visit 5, 1176 participants died. In multivariable Cox models, elevated mortality was seen in the highest quartile of FGF23 change (ΔFGF23: ≥31.3 pg/mL) (adjusted hazard ratio (aHR): 1.61 (95%CI: 1.36–1.90), or 1.37 (1.15–1.64) after additionally adjusting for eGFR change, compared with the lowest quartile (≤6.4 pg/mL)). When both FGF23 change and FGF23 in late life were simultaneously entered into the Cox model, FGF23 in late life, but not FGF23 change, was an independent predictor of mortality; however, we observed a high correlation between FGF23 change from midlife to late life and FGF23 in late life (r = 0.77).

Conclusions

Serum intact FGF23 change from midlife to late life was associated with subsequent risk of mortality independent of decline in kidney function. Our findings further support the implications of FGF23 beyond its association with kidney function.

Restricted access

Cheng-Hsuan Tsai, Che-Wei Liao, Xue-Ming Wu, Zheng-Wei Chen, Chien-Ting Pan, Yi-Yao Chang, Bo-Ching Lee, Chia-Tung Shun, Wen-Fen Wen, Chia-Hung Chou, Vin-Cent Wu, Chi-Sheng Hung, Yen-Hung Lin, and the TAIPAI Study Group

Objective

The presence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) is common and potentially associated with poor outcomes. The aim of this study was to investigate the association between ACS and vascular remodeling in PA patients.

Design and methods

We prospectively enrolled 436 PA patients from October 2006 to November 2019. ACS (defined as a cortisol level >1.8 μg/dL after a 1 mg dexamethasone suppression test) was detected in 23% of the PA patients. Propensity score matching (PSM) with age, sex, systolic and diastolic blood pressure was performed. The brachial-ankle pulse wave velocity (baPWV) was examined at baseline and 1 year after targeted treatment. Small arteries of periadrenal fat in 46 patients were stained with Picro Sirus red to quantify the severity of vascular fibrosis.

Results

After PSM, the PA patients with ACS had a significantly higher prevalence of diabetes mellitus, higher plasma aldosterone concentration and higher aldosterone-to-renin ratio. The baseline mean baPWV was also significantly higher in the PA patients with ACS. After multivariable regression analysis, the presence of ACS was a significant predictor of worse baseline mean baPWV (β: 235.745, 95% CI: 59.602–411.888, P = 0.010). In addition, the PA patients with ACS had worse vascular fibrosis (fibrosis area: 25.6 ± 8.4%) compared to those without ACS (fibrosis area: 19.8 ± 7.7%, P = 0.020). After 1 year of PA treatment, baPWV significantly improved in both groups.

Conclusion

The presence of ACS in PA patients is associated with worse arterial stiffness and vascular remodeling.

Restricted access

Chao Ling, Xiafei Hong, Mengyue Xu, Yutong Wang, Xiaosen Ma, Yunying Cui, Rui Jiang, Dingyan Cao, Huanwen Wu, Anli Tong, Yupei Zhao, and Wenming Wu

Objectives

The pancreatic neuroendocrine tumors (PanNETs) are a group of clinically heterogeneous neoplasms. Although previous studies illustrated the somatic mutation pattern for PanNETs, the germline mutation pattern is still unclear. Here, we comprehensively screened the underlying germline mutations in a cohort of multiple endocrine neoplasia type 1 (MEN1)-related and sporadic PanNETs to reveal the characteristics of germline mutation in PanNET patients.

Methods

Patients diagnosed with PanNETs by biopsy or surgical pathology were enrolled in this study. Peripheral blood samples were used for genomic DNA purification and subsequent sequencing. The following sequencing techniques were used and compared for validation: (1) targeted gene capture with a customized panel; (2) whole exome sequencing data from previous study.

Results

A total of 184 PanNET patients were enrolled, including 20 MEN1-related and 164 sporadic cases. In this study, MEN1 mutation rate in MEN1-related PanNETs was 60% (12/20), of which 50% were novel mutation sites. For sporadic PanNETs, the overall germline mutation rate was very low. Besides the rare MEN1 mutation, previously unreported germline variant in DAXX was found in one non-functional PanNET.

Conclusions

This study revealed distinctive germline mutation rates between MEN1-related and sporadic PanNETs. The novel MEN1 mutations contribute to revealing the spectrum of MEN1 mutations in PanNETs. The newly discovered germline variant of DAXX in sporadic PanNET implies a tendency of convergence between germline and somatic mutation genes.

Open access

Rasmus Juul Kildemoes, Christian Hollensen, Beverly M K Biller, Gudmundur Johannsson, Yutaka Takahashi, and Michael Højby Rasmussen

Objective

Growth hormone (GH) replacement therapy in patients with adult growth hormone deficiency (AGHD) is individually titrated due to variable dose–responses among patients. The aim of this study was to provide clinical guidance on dosing and titration of the novel long-acting GH derivative somapacitan based on analyses of somapacitan dose–insulin-like growth factor I (IGF-I) responses in AGHD patients.

Design

Analyses of dosing information, 4364 somapacitan concentration samples and 4880 IGF-I samples from 330 AGHD patients treated with somapacitan in three phase 3 trials.

Methods

Pharmacokinetic/pharmacodynamic modelling was used to evaluate starting dose groups by age and oral oestrogen therapy, characterise the dose–IGF-I response in the overall AGHD population and patient subgroups, predict the IGF-I response to dose changes and simulate missed dosing.

Results

The analyses supported the clinical recommendations of higher starting doses for younger patients and women on oral oestrogen replacement therapy. For patients switching from daily GH treatment, the mean maintenance dose ratio between somapacitan (mg/week) and somatropin (mg/day) was predicted to be 8.2 (observed interquartile range of 6.7–9.1). Simulations of IGF-I SDS profiles confirmed the appropriate time for IGF-I sampling to be 3–4 days after somapacitan dosing and supported somapacitan administration with up to 3 days delay in case of missed dosing. Subgroup analyses characterised the dose–exposure–IGF-I response in patient subgroups and indicated that dose requirements are mainly influenced by sex and oral oestrogen treatment.

Conclusions

This study extends the knowledge of the somapacitan dose–IGF-I response and provides information on clinical dosing of once-weekly somapacitan in patients with AGHD.

Restricted access

Marie Lindhardt Ljubicic, Alexander S Busch, Emmie N Upners, Margit Bistrup Fischer, Katharina M Main, Anna-Maria Andersson, Trine Holm Johannsen, Casper P Hagen, and Anders Juul

Objective

Little is known about the ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during infancy. This study aimed to evaluate serum and urinary LH/FSH as a marker of sex with age-specific cutoffs in healthy infants.

Design

A prospective, longitudinal cohort study of healthy infants aged 0–1.2 years.

Methods

In total, 236 healthy infants (122 boys and 114 girls) from The COPENHAGEN Minipuberty Study (ClinicalTrials.gov ID: NCT02784184), with 567 serum and 603 urine samples, were included. Measures of diagnostic accuracy, including sensitivity and specificity, were used to assess the ability of LH/FSH to detect sex in healthy infants.

Results

In both serum and urine, LH/FSH was highest in males with minimal overlap between the sexes. In contrast to isolated LH and FSH concentrations, LH/FSH ratios in both serum and urine were excellent markers of sex from 0 to 1.2 years with median sensitivities and specificities ranging from 93 to 100% with correspondingly narrow 95% CIs.

Conclusions

Serum and urinary LH/FSH ratios are excellent discriminators of sex in healthy infants during the entire first year of life. The clinical role and application of the ratio remain to be elucidated.