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Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients., (© 2022. The Author(s).)

Small-particle analysis is a highly promising emerging forensic tool for analysis of interdicted special nuclear materials. Integration of microstructural, morphological, compositional, and molecular impurity signatures could provide significant advancements in forensic capabilities. We have applied rapid, high-sensitivity, hard X-ray synchrotron chemical imaging to analyze impurity signatures in two differently fabricated fuel pellets from the 5th Collaborative Materials Exercise (CMX5) of the IAEA Nuclear Forensics International Working Group. The spatial distributions, chemical compositions, and morphological and molecular characteristics of impurities were evaluated using X-ray absorption near-edge structure (XANES) and X-ray fluorescence chemical imaging to discover principal impurities, their granularity, particle sizes, modes of occurrence (distinct grains vs incorporation in the UO 2 lattice), and sources and mechanisms of incorporation. Differences in UO 2+ x stoichiometry were detected at the microscale in nominally identical UO 2 ceramics (CMX5-A and CMX5-B), implying the presence of multiple UO 2 host phases with characteristic microstructures and feedstock compositions. Al, Fe, Ni, W, and Zr impurities and integrated impurity signature analysis identified distinctly different pellet synthesis and processing methods. For example, two different Al, W, and Zr populations in the CMX5-B sample indicated a more complex processing history than the CMX5-A sample. K-edge XANES measurements reveal both metallic and oxide forms of Fe and Ni but with different proportions between each sample. Altogether, these observations suggest multiple sources of impurities, including fabrication (e.g., force-sieving) and feedstock (mineral oxides). This study demonstrates the potential of synchrotron techniques to integrate different signatures across length scales (angstrom to micrometer) to detect and differentiate between contrasting UO 2 fuel fabrication techniques.

Purpose: To describe the clinical characteristics, management and pregnancy outcome of women with prepregnancy hypopituitarism (HYPO) that received care at our center., Methods: Retrospective study describing 12 pregnancies in women with prepregnancy HYPO (two or more pituitary hormonal deficiencies under replacement treatment) that received care during pregnancy at Hospital Santa Creu i Sant Pau. Clinical characteristics, management and pregnancy outcome were systematically collected., Results: Average patients' age was 35 years and HYPO duration at the beginning of pregnancy was 19 years. The most frequent cause of HYPO was surgical treatment of a sellar mass (8 pregnancies). Eight pregnancies were in primigravid women and 10 required assisted reproductive techniques. The hormonal deficits before pregnancy were as follows: GH in 12 women, TSH in 10, gonadotropin in 9, ACTH in 5 and ADH in 2. All deficits were under hormonal substitution except for GH deficit in 4 pregnancies. During pregnancy, 4 new deficits were diagnosed. The dosage of replacement treatment for TSH, ACTH and ADH deficits was increased and GH was stopped. Average gestational age at birth was 40 weeks, gestational weight gain was excessive in 9 women, 8 patients required induction/elective delivery and cesarean section was performed in 6. Average birthweight was 3227 g. No major complications were observed. Five women were breastfeeding at discharge., Conclusions: In this group of women with long-standing HYPO, with careful clinical management (including treatment of new-onset hormonal deficits) pregnancy outcome was satisfactory but with a high rate of excessive gestational weight gain and cesarean section., (© 2021. The Author(s).)

Acromegaly is caused by excess growth hormone (GH) produced by a pituitary tumor. First-generation somatostatin receptor ligands (SRLs) are the first-line treatment. Several studies have linked E-cadherin loss and epithelial-mesenchymal transition (EMT) with resistance to SRLs. Our aim was to study EMT and its relationship with SRLs resistance in GH-producing tumors. We analyzed the expression of EMT-related genes by RT-qPCR in 57 tumors. The postsurgical response to SRLs was categorized as complete response, partial response, or nonresponse if IGF-1 was normal, had decreased more than 30% without normalization, or neither of those, respectively. Most tumors showed a hybrid and variable EMT expression profile not specifically associated with SRL response instead of a defined epithelial or mesenchymal phenotype. However, high SNAI1 expression was related to invasive and SRL-nonresponsive tumors. RORC was overexpressed in tumors treated with SRLs before surgery, and this increased expression was more prominent in those cases that normalized postsurgical IGF-1 levels under SRL treatment. In conclusion, GH-producing tumors showed a heterogeneous expression pattern of EMT-related genes that would partly explain the heterogeneous response to SRLs. SNAI1 and RORC may be useful to predict response to SRLs and help medical treatment decision making.

Transient appearances of oxygen have been inferred before the Great Oxygenation Event (GOE) [∼2.3 billion years (Ga) ago] based on redox-sensitive elements such as Mo and S—most prominently from the ∼2.5-Ga Mount McRae Shale in Western Australia. We present new spatially resolved data including synchrotron-based x-ray spectroscopy and secondary ion mass spectrometry to characterize the petrogenesis of the Mount McRae Shale. Sediments were primarily composed of organic matter and volcanic ash (a potential source of Mo), with U-Pb ages revealing extremely low sedimentation rates. Catagenesis created bedding-parallel microfractures, which subsequently acted as fluid pathways for metasomatic alteration and recent oxidative weathering. Our collective observations suggest that the bulk chemical datasets pointing toward a “whiff” of oxygen developed during postdepositional events. Nonzero Δ 33 S in trace-metal–poor, early diagenetic pyrite and the unusually enriched organic carbon at low sedimentation rates instead suggest that environmental oxygen levels were negligible ∼150 million years before the GOE.

Objective: Gamma knife radiosurgery (GKRS) has proven to be an effective adjuvant treatment for patients with acromegaly. We performed the present study to investigate, which would be the outcome of GKRS, independently on the response to somatostatin receptor ligand (SRL)., Design: Retrospective, observational study., Patients: Ninety-six patients with active acromegaly were included., Measurements: The cumulative probability of normalisation of insulin-like growth factor 1 (IGF-1) levels after GKRS was assessed by the Kaplan-Meier method. The association of several clinical characteristics with GKRS outcomes was explored with the use of a Cox proportional-hazard model with the relative hazard ratio and 95% confidence interval (CI)., Results: Resistance to SRL occurred in 39 of the 96 patients (40.6%). After GKRS, patients resistant to SRL had a 5- and 10-year probability of remission of 40.7% (95% CI: 23.7%-57.7%) and 75.9% (95% CI: 57.9%-93.9%), respectively. Patients responding to SRL had a 5- and 10-year probability of remission of 46.8% (95% CI: 32.2%-61.4%) and 58.1% (95% CI: 41.5%-74.7%), respectively. The difference was not significant (p = .48 by the log-rank test). Multivariate Cox analysis confirmed that the only independent variables associated with GKRS outcome were basal growth hormone (GH; p = .001) and IGF-1 multiple of the upper limit of normal levels before GKRS (p = .013)., Conclusion: We demonstrate for the first time that the responsiveness to SRL has no effect on the probability to obtain remission of acromegaly after GKRS. The remission of disease occurred more frequently in patients who had lower GH and IGF-1 levels before GKRS., (© 2021 John Wiley & Sons Ltd.)

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified., Competing Interests: Declaration of interests MF has received grants to her institution from Novartis, Strongbridge, Novo Nordisk, Crinetics, Millendo, Ascendis, and Pfizer; personal honoraria for consulting and advisory boards from Crinetics, HRA Pharma, Novartis, Recordati, Strongbridge, Sparrow, Ascendis, Novo Nordisk, and Pfizer; and has served on the Board of the Pituitary Society. RA has received grants to his institution from Strongbridge Biopharma, Novartis Pharmaceuticals, and Corcept Therapeutics, and personal honoraria for consulting and advisory boards from Strongbridge Biopharma, Recordati Rare Diseases, Corcept Therapeutics, and Novartis Pharmaceuticals. IB has received grants and fees for consulting, advisory boards, and authorship to her institution from the National Institutes of Health (NIH), Strongbridge, Corcept, HRA Pharma, Sparrow Pharmaceutics, Adrenas Pharmaceutics, and Elsevier, and non-financial support to her institution from HRA Pharma. AB-S has received personal honoraria for advisory boards from Recordati. JB has received grants to his institution from Novartis, HRA Pharma, and Recordati, and personal honoraria for consulting, lectures, and meeting attendance from Novartis, HRA Pharma, Ipsen, and Recordati. NRB has served on the Board or as an advisor for European Neuroendocrine Association and the European Reference Network on Rare Endocrine Conditions. CLB has received grants and personal honoraria for lectures from Novartis and served on the Board or as an advisor for Sociedade Brasileira de Endocrinologia e Metabologia, Endocrine Society, and European Society of Endocrinology. MDB has received grants as principal investigator from Novartis. JDC has received grants to his institution from Novartis, Strongbridge, and Crinetics; personal honoraria for consulting and authorship from Recordati, Novo Nordisk, Corcept, and Merck Manual; and served on the Board or as an advisor for Pituitary Society, Endocrine Society, and American Association of Clinical Endocrinologists. FFC has served on the Board of the Pituitary Society. FC has received personal honoraria for consulting, lectures, and support for meeting attendance from Recordati Rare Diseases, Ipsen, and HRA Pharma. PC has received grants and honoraria to his institution for consulting and lectures from Novartis and Recordati. JF has received grants to his institution from Novartis and personal honoraria for consulting and advisory boards from Corcept, Recordati, and Novartis. MGa has received non-financial support from Novartis and Recordati and served on the Board or as an advisor for Pituitary Society and Brazilian Society of Endocrinology and Metabolism. EBG has received grants and personal honoraria for consulting, lectures, and advisory boards from Novartis, Corcept, Strongbridge, Bristol-Myers Squibb, Recordati, and HRA Pharma; and has served as an advisor for Cushing's Support & Research Foundation. AGi has received grants to his institution from Pfizer and personal honoraria for consulting and advisory boards from Abiogen, Novo Nordisk, and Recordati; and has served on the Board or as an advisor to European Society of Endocrinology and Glucocorticoid Induced Osteoporosis Skeletal Endocrinology Group. AGr has served as an advisor to Novartis and as an editor for Neuroendocrinology and Journal of Neuroendocrinology. MGu has received personal honoraria for consulting and lectures from Recordati Rare Diseases UK, HRA Pharma, and Ipsen; and is a Board member or advisor for UK Society for Endocrinology and European Society of Endocrinology. AGI has received grants to her institution from Recordati, Novartis, and Strongbridge; and personal honoraria for consulting from Recordati, HRA Pharma, and Strongbridge. UBK has received grants as co-investigator from Corcept; personal honoraria for consulting, advisory board, and lectures from Acerus Pharmaceuticals and Novo Nordisk; and serves as editor for Journal of Clinical Endocrinology and Metabolism and as Board member for Endocrine Society. NK has received personal honoraria for consulting from Recordati Rare Diseases and HRA Pharma, and has served as Board member or advisor for Pituitary Society, European Neuroendocrine Association, Endocrine Society, and European Society of Endocrinology. LK has received personal honoraria for consulting from Strongbridge and Recordati. DFK has received royalties from Mizuho. AL has received grants from Recordati and Corcept; personal honoraria for lectures, support for meeting attendance, and advisory boards from Pfizer, Ipsen, Corcept, and the European Journal of Endocrinology; royalties from UpToDate Endocrinology; and served as a Board member for International Society of Endocrinology. AM has received grants and personal honoraria for lectures or presentations and support for meeting attendance from Pfizer, Ipsen, Novartis, and Novo Nordisk, and served as a Council member for Endocrine Society of Australia. SM has received grants to his institution from US Food and Drug Administration and non-financial support from Cyclacel. MM has received grants to his institution from Corcept, Novartis, and Strongbridge; fees for expert testimony from Janssen and Corcept; and personal honoraria for advisory boards for Merck, Pfizer, Recordati, and Strongbridge. JN-P has received grants and honoraria to the institution for consulting and advisory boards from Diurnal Ltd and HRA Pharma, Recordati, and Novartis; and served as a Board member or advisor for Pituitary Foundation and Endocrine Society. LN has received royalties from UpToDate and support for meeting attendance from the NIH, and has served as a Board member for Endocrine Society. AMP has received grants to his institution from HRA Pharma and served as advisor for European Reference Network on Rare Endocrine Conditions and European Endocrine Society. SP has received personal honoraria for lectures and advisory boards from HRA Pharma, Recordati Pharma, Novartis Pharma, and Crinetics Pharmaceuticals. RP has received grants to his institution from Novartis, Pfizer, Ipsen, Shire, IBSA Farmaceutici, HRA Pharma, Cortendo AB, Corcept Therapeutics, and Merck Serono, and personal honoraria for consulting, lectures, support for meeting attendance, and advisory boards from Novartis, Shire, HRA Pharma, Cortendo AB, Pfizer, Recordati, IBSA Farmaceutici, and Crinetics Pharmaceuticals. HR has received personal honoraria for consulting from Cerium and non-financial support from Corcept. MR has received personal honoraria for consulting, lectures, and advisory boards from Novartis, Recordati, HRA Pharma, and Ipsen. RS has received grants to his institution from Corcept and Crinetics, and personal honoraria for consulting from Strongbridge, Corcept, HRA Pharma, and Sterotherapeutics. CS has received grants and personal honoraria for lectures from Pfizer, Novartis, Recordati Rare Diseases, and HRA Pharma. IS has received personal honoraria for consulting from Medison Pharma. CAS has received grants from Pfizer; personal honoraria for consulting and support for meeting attendance from Lundbeck Pharma and the NIH; holds patents on the genetics of PRKAR1A, PDE11A, and GPR101; and has served as a Board member or advisor for Society for Pediatric Research, Children's Inn at NIH, and Cushing's Foundation. AT has received grants to his institution from HRA Pharma, and personal honoraria for consulting, lectures, and support for meeting attendance from HRA Pharma, Recordati Rare Diseases, and Ipsen. YT has received personal honoraria for consulting and lectures from Novo Nordisk, Recordati Rare Diseases, Bohringer Ingelheim, and Sumitomo Dainippon Pharma. MT has served as an advisor to European Society of Endocrinology. ST has received grants to his institution from Strongbridge, Crinetics, and Novartis, and personal honoraria for lectures, advisory boards, and support for meeting attendance from Recordati, Pfizer, and Ipsen. EV has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting, lectures, and advisory boards from HRA Pharma, HRA Pharma Spain, and Recordati Rare Diseases. GV has received grants to her institution from Novartis, Recordati, and Corcept; personal honoraria and honoraria to the institution for consulting and lectures from HRA Pharma and Recordati; and served as an advisor for Cushing's Hub. SMW has received grants through the European Society of Endocrinology from HRA Pharma, Novartis, Recordati, and Corcept, and received personal honoraria for consulting and lectures from HRA Pharma and Recordati Rare Diseases. MCZ has served as a Board member for European Neuroendocrine Association. BMKB has received grants to her institution from Novartis, Opko, Strongbridge, and Millendo; personal honoraria for consulting from Aeterna Zentaris, Ascendis, Crinetics, Merck Serono, Novartis, Novo Nordisk, Recordati, Strongbridge, and Sparrow; and served as an advisor for Endocrine Society. MB, KH, PM, BS, EVV, and JW have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Context: Chronic exposure to glucocorticoids (GCs) or stress increases the risk of medical disorders, including cardiovascular and neuropsychiatric disorders. GCs contribute to accelerated aging; however, while the link between chronic GC exposure and disease onset is well established, the underpinning mechanisms are not clear., Objective: We explored the potential nexus between GCs or stress exposure and telomere length., Methods: In addition to rats exposed to 3 weeks of chronic stress, an iatrogenic mouse model of Cushing syndrome (CS), and a mouse neuronal cell line, we studied 32 patients with CS and age-matched controls and another cohort of 75 healthy humans., Results: (1) Exposure to stress in rats was associated with a 54.5% (P = 0.036) reduction in telomere length in T cells. Genomic DNA (gDNA) extracted from the dentate gyrus of stressed and unstressed rats showed 43.2% reduction in telomere length (P = 0.006). (2) Mice exposed to corticosterone had a 61.4% reduction in telomere length in blood gDNA (P = 5.75 × 10-5) and 58.8% reduction in telomere length in the dentate gyrus (P = 0.002). (3) We observed a 40.8% reduction in the telomere length in patients with active CS compared to healthy controls (P = 0.006). There was a 17.8% reduction in telomere length in cured CS patients, which was not different from that of healthy controls (P = 0.08). For both cured and active CS, telomere length correlated significantly with duration of hypercortisolism (R2 = 0.22, P = 0.007). (4) There was a 27.6% reduction in telomere length between low and high tertiles in bedtime cortisol levels of healthy participants (P = 0.019)., Conclusion: Our findings demonstrate that exposure to stress and/or GCs is associated with shortened telomeres, which may be partially reversible., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cushing's syndrome (CS) is associated with skeletal muscle structural and functional impairment which may persist long-term despite surgical removal of the source of cortisol excess. Prevalence of sarcopenia and its impact on Health-Related-Quality of Life (HRQoL) in 'cured' CS is not known. There is a need to identify easy biomarkers to help the clinicians recognise patients at elevated risk of suffering sustained muscle function., Patients and Methods: We studied 36 women with CS in remission, and 36 controls matched for age, body mass index, menopausal status, and level of physical activity. We analysed the skeletal muscle mass using dual-energy X-ray absorptiometry, muscle fat fraction using two-point Dixon magnetic resonance imaging and muscle performance and strength using the following tests: hand grip strength, gait speed, timed up and go and 30-s chair stand. We assessed HRQoL with the following questionnaires: SarQoL, CushingQoL, SF-36. We calculated the sarcopenia index (SI; serum creatinine/serum cystatin C × 100)., Results: Prevalence of sarcopenia, according to the European Working Group on Sarcopenia in Older People (EWGSOP), was greater in CS as compared with controls (19% vs. 3%; p < .05). Patients with sarcopenia had a lower SarQoL score than those without sarcopenia (61 ± 17 vs. 75 ± 14; p < .05), and scored worse on the items pain, easy bruising and worries on physical appearance (p < .05 for all comparisons) of the CushingQoL questionnaire. Patients with sarcopenia had poorer physical functioning on SF-36 than those without sarcopenia (60 ± 23 vs. 85 ± 15; p < .01). SI was lower in patients with sarcopenia than those without (71 ± 3 vs. 77 ± 2; p = .032), and was associated with intramuscular fatty infiltration, worse performance on the 30-s chair stand test, slower gait speed, and worse muscle weakness-related HRQoL, as measured using the SarQoL questionnaire (p < .05). The optimised cut-off value for the SI ratio to diagnose sarcopenia was 72, which yielded a sensitivity of 73% and a specificity of 90%., Conclusions: Sarcopenia is common in patients with CS in long-term remission, and associated with impaired quality of life. The SI is a potential biomarker allowing clinicians to identify patients at high risk of muscle dysfunction., (© 2021 John Wiley & Sons Ltd.)

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4447 cancer patients treated with ICI antibodies, 37 (0.8%) (23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 years)) were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n = 20, 54.1%), followed by melanoma (n = 8, 21.6%). The most common ICI antibody inhibitors reported were nivolumab (n = 18, 48.6%), pembrolizumab (n = 16, 43.2%), and ipilimumab (n = 8, 21.6%). About half of the patients (n = 19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n = 10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit, all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting the treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected.

Under anaerobic conditions, ferrous iron reacts with sulfide producing FeS, which can then undergo a temperature, redox potential, and pH dependent maturation process resulting in the formation of oxidized mineral phases, such as greigite or pyrite. A greater understanding of this maturation process holds promise for the development of iron-sulfide catalysts, which are known to promote diverse chemical reactions, such as H + , CO 2 and NO 3 - reduction processes. Hampering the full realization of the catalytic potential of FeS, however, is an incomplete knowledge of the molecular and redox processess ocurring between mineral and nanoparticulate phases. Here, we investigated the chemical properties of iron-sulfide by cyclic voltammetry, Raman and X-ray absorption spectroscopic techniques. Tracing oxidative maturation pathways by varying electrode potential, nanoparticulate n(Fe 2+ S 2- ) (s) was found to oxidize to a Fe 3+ containing FeS phase at -0.5 V vs. Ag/AgCl (pH = 7). In a subsequent oxidation, polysulfides are proposed to give a material that is composed of Fe 2+ , Fe 3+ , S 2- and polysulfide (S n 2- ) species, with its composition described as Fe 2+ 1-3x Fe 3+ 2x S 2- 1-y (S n 2- ) y . Thermodynamic properties of model compounds calculated by density functional theory indicate that ligand oxidation occurs in conjunction with structural rearrangements, whereas metal oxidation may occur prior to structural rearrangement. These findings together point to the existence of a metastable FeS phase located at the junction of a metal-based oxidation path between FeS and greigite (Fe 2+ Fe 3+ 2 S 2- 4 ) and a ligand-based oxidation path between FeS and pyrite (Fe 2+ (S 2 ) 2- ).

Objective: Pituitary adenomas (PA) are rare in young patients, and additional studies are needed to fully understand their pathogenesis in this population. We describe the clinical and genetic characteristics of apparently sporadic PA in a cohort of young patients., Design: Clinical and molecular analysis of 235 patients (age ≤ 30 years) with PA. Clinicians from several Spanish and Chilean hospitals provided data., Methods: Genetic screening was performed via next-generation sequencing and comparative genomic hybridization array. Clinical variables were compared among paediatric, adolescent (<19 years) and young adults' (≥19-30 years) cohorts and types of adenomas. Phenotype-genotype associations were examined., Results: Among the total cohort, mean age was 17.3 years. Local mass effect symptoms were present in 22.0%, and prolactinomas were the most frequent (44.7%). Disease-causing germline variants were identified in 22 individuals (9.3%), more exactly in 13.1 and 4.7% of the populations aged between 0-19 and 19-30 years, respectively; genetically positive patients were younger at diagnosis and had larger tumour size. Healthy family carriers were also identified., Conclusions: Variants in genes associated with syndromic forms of PAs were detected in a large cohort of apparently sporadic pituitary tumours. We have identified novel variants in well-known genes and set the possibility of incomplete disease penetrance in carriers of MEN1 alterations or a limited clinical expression of the syndrome. Despite the low penetrance observed, screening of AIP and MEN1 variants in young patients and relatives is of clinical value.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Desert varnish is a dark rock coating that forms in arid environments worldwide. It is highly and selectively enriched in manganese, the mechanism for which has been a long-standing geological mystery. We collected varnish samples from diverse sites across the western United States, examined them in petrographic thin section using microscale chemical imaging techniques, and investigated the associated microbial communities using 16S amplicon and shotgun metagenomic DNA sequencing. Our analyses described a material governed by sunlight, water, and manganese redox cycling that hosts an unusually aerobic microbial ecosystem characterized by a remarkable abundance of photosynthetic Cyanobacteria in the genus Chroococcidiopsis as the major autotrophic constituent. We then showed that diverse Cyanobacteria, including the relevant Chroococcidiopsis taxon, accumulate extraordinary amounts of intracellular manganese-over two orders of magnitude higher manganese content than other cells. The speciation of this manganese determined by advanced paramagnetic resonance techniques suggested that the Cyanobacteria use it as a catalytic antioxidant-a valuable adaptation for coping with the substantial oxidative stress present in this environment. Taken together, these results indicated that the manganese enrichment in varnish is related to its specific uptake and use by likely founding members of varnish microbial communities., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Introduction: Patients with acromegaly show musculoskeletal symptoms which may persist despite disease control. Increased i.m. fat fraction is a known cause of muscle dysfunction in several disorders., Objective: To assess the degree of fat fraction in thigh muscles of controlled acromegaly patients and its relationship with muscle dysfunction., Methods: In a cross-sectional study, we included 36 patients with controlled acromegaly and 36 matched controls. We assessed the percentage of fat fraction in each thigh muscle, using MRI 2-point Dixon sequence, and muscle performance and strength using the gait speed, timed up and go, 30-s chair stand, and hand grip strength tests. We evaluated joint symptoms using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC)., Results: Intramuscular fat fraction was greater in patients than controls (P < 0.05 for muscle compartments, rectus femoris (RF), vastus intermedius (VI), adductor magnus (AM) and semimembranosus). Patients had slower gait speed and poorer performance on the 30-s chair stand and timed up and go tests than controls (P < 0.05). The greater fat fraction in the combined anterior-posterior compartment and in each muscle was associated with worse performance on timed up and go (P < 0.05). The fat fraction in the anterior-posterior compartment predicted performance on timed up and go after adjusting for muscle area, IGF-I and WOMAC functional and pain scores (β = 0.737 P < 0.001)., Conclusions: Patients with controlled acromegaly have greater thigh i.m. fatty infiltration, which is associated with muscle dysfunction. Futures studies are needed to elucidate the mechanisms underlying this relationship.

Purpose of Review: The aim of this article is to review and discuss recent evidence of psychological complications in Cushing's syndrome., Recent Findings: Recent research has described the presence of depression, anxiety, posttraumatic stress disorder, mania, bipolar disorder and psychotic symptoms in patients with Cushing's syndrome. Furthermore, the perspective of patients' partners has also been emphasized., Summary: Recent literature highlights the importance of screening for psychological alterations in Cushing's syndrome, as these alterations can be present in many patients, having a high impact in daily life. Depression is a very common symptom, although in rare cases, patients can also present mania or psychosis. Some studies highlight the importance of screening for organic disease (including Cushing's syndrome) in patients with unexpected or first onset psychiatric symptoms. Finally, the perspective of the patients' partners makes it clear that the partners can also suffer due to the disease of the patient. Intervention programmes involving patient's partners could be helpful to improve both patient and partner wellbeing., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas., Design: We performed a multicenter retrospective study., Patients: 24 patients bearing large GH-producing tumours., Measurements: Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression., Results: From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P ˂ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity., Conclusions: High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery., (© 2020 John Wiley & Sons Ltd.)

The most common form of congenital adrenal hyperplasia (CAH) results from a deficiency of the 21-hydroxylase enzyme (21-OHD), presenting with a broad spectrum of clinical phenotypes according to the CYP21A2 gene mutations. Of the 59 patients with suspected CAH, 62.7% presented a positive genetic result. Of them, 78.4% and 18.9% presented with non-classical and classical forms, respectively. An overall phenotype-genotype correlation of 88.9% was observed. Biochemically, 17-hydroxiprogesterone concentrations were significantly higher in genetically confirmed patients. Genetically, 36 patients presented with previously reported pathogenic variants, and one presented a new variant in homozygosis. Among the 74 alleles tested, point mutations were found in 89.2% and large rearrangements were found in the rest. The most prevalent pathogenic variant was p.(Val282Leu). The inclusion of relatives revealed one further case. Interestingly, 87.5% of relatives were carriers of a pathogenic variant, including two siblings initially classified as genetically positive. In addition, the study of male partners with gestational desire identified several carriers of mild mutations. Studying the allelic distribution of the variants also allowed for reclassifying one patient. In conclusion, a genetic approach including Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis, and allelic distribution of the pathogenic variants represents a beneficial tool for better classifying patients with 21-OHD.

Objective: Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown., Methods: We used synchrotron X-ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients., Results: Immunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17-127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3-64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = -40 to -14%, p < 0.001). When normalizing the iron content of early active lesions to that of surrounding periplaque white matter, the ratio is significantly higher in immunopattern II (p < 0.001). Microfocused X-ray fluorescence imaging shows that iron in immunopattern II lesions localizes to macrophages, whereas macrophages in immunopattern III lesions contain little iron., Interpretation: Iron distribution and content are heterogeneous in early active MS lesions. Iron accumulates in macrophages in immunopattern II, but not immunopattern III lesions. This heterogeneity in the two most common MS immunopatterns may be explained by different macrophage polarization, origin, or different demyelination mechanisms, and paves the way for developing new or using existing iron-sensitive magnetic resonance imaging techniques to differentiate among immunopatterns in the general nonbiopsied MS patient population. ANN NEUROL 2021;89:498-510., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Patients' perceptions on quality of care and gaps in diagnosis/management of rare endocrine diseases (RED) were collected in a 21-item questionnaire, answered on-line in the patients' language. There were 598 (66% females) responses from 29 countries reflecting pituitary, adrenal, thyroid, parathyroid, gonadal, genetic and autoimmune diseases. While in 36% a diagnosis was made in <1 year, in 28% it took >5 years. In 64% it took 2-7 professionals for a correct diagnosis, after which in >50% a specialist/specific treatment was available within 1 month; 60% were satisfied with current treatment. Most (59-67%) would have liked access to psychological support, social worker, dietician or physiotherapist/rehabilitation specialists. Half were satisfied with information received, treatment and health care follow-up; 87% contacted patient/support groups; 78% agreed that "The personal limitations related to the disease, impact on my everyday quality of life". Conclusion: Diagnostic delay in RED is still unsatisfactory in Europe, as well as specific needs impacting QoL.

Ettringite is a naturally occurring mineral found in cementitious matrices that is known for its ability to incorporate environmentally mobile oxyanion contaminants. To better assess this immobilization mechanism for contaminants within cementitious waste forms intended for nuclear waste storage, this work explores how mixed oxyanion contaminants compete for ettringite incorporation and influence the evolving mineralogy. Ettringite was precipitated in the presence of TcO 4 - , IO 3 - , and/or CrO 4 2- , known contaminants of concern to nuclear waste treatment, over pre-determined precipitation periods. Solution analyses quantified contaminant removal, and the collected solid was characterized using bulk and microprobe X-ray diffraction coupled with pair distribution function and microprobe X-ray fluorescence analyses. Results suggest that ≥96% IO 3 - is removed from solution, regardless of ettringite precipitation time or the presence of TcO 4 - or CrO 4 2- . However, TcO 4 - removal remained <20%, was not significantly improved with longer ettringite precipitation times, and decreased to zero in the presence of IO 3 - . When IO 3 - is co-mingled with CrO 4 2- , calcite and gypsum are formed as secondary mineral phases, which allows for oxyanion partitioning, e.g., IO 3 - incorporation into ettringite, and CrO 4 2- incorporation into calcite. Results from this work exemplify the importance of competitive immobilization when assessing waste form performance and environmental risk of contaminant release.

Climate change is driving an expansion of marine oxygen-deficient zones, which may alter the global cycles of carbon, sulfur, nitrogen, and trace metals. Currently, however, we lack a full mechanistic understanding of how oxygen deficiency affects organic carbon cycling and burial. Here, we show that cryptic microbial sulfate reduction occurs in sinking particles from the eastern tropical North Pacific oxygen-deficient zone and that some microbially produced sulfide reacts rapidly to form organic sulfur that is resistant to acid hydrolysis. Particle-hosted sulfurization could enhance carbon preservation in sediments underlying oxygen-deficient water columns and serve as a stabilizing feedback between expanding anoxic zones and atmospheric carbon dioxide. A similar mechanism may help explain more-extreme instances of organic carbon preservation associated with marine anoxia in Earth history., (Copyright © 2021, American Association for the Advancement of Science.)

Background: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population., Aim: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly., Patients and Methods: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated., Results: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65-83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57-118) months. DI at last visit was associated with a lower survival., Conclusion: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population., (© 2020 S. Karger AG, Basel.)

Measurement of Health-Related Quality of Life (HRQoL) is emerging as an important clinical endpoint which complements diagnostic workup and contributes to place patients at the centre of the decision-making process through the recognition of their needs, concerns, goals and expectations. Chronic excessive cortisol exposure in Cushing's syndrome (CS) causes severe physical and psychological morbidity which invariably affects HRQoL during the active phase of the disease and even after successful treatment. This sustained deterioration of patient's wellbeing is partly related to the persistence of several features associated with prior cortisol excess, including affective disorders, cognitive dysfunctions and negative illness perception. The aim of this review is to summarize the most recent evidence on HRQoL in CS, including the main determinants of its impairment and the results of some educational programs specifically addressed to improve patient's coping abilities. The preliminary results of an unpublished survey on patient's unmet needs will also be presented., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform., Aims: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD., Design: On-line survey in endocrine centres throughout Europe., Patients and Methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018., Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved., Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

Context: Hypertension is a major cardiovascular risk factor related to increased mortality in acromegaly. Surgical cure of acromegaly is associated with improvement in blood pressure levels, however little is known about the effect of pegvisomant (PEGV) treatment in patients with hypertension. This analysis evaluates outcomes in patients with hypertension and acromegaly included in ACROSTUDY., Methods: ACROSTUDY is a global non-interventional surveillance study of long-term treatment with PEGV, monitoring its safety and efficacy. The cohort was retrospectively divided in two subgroups: patients with and without hypertension. Stepwise logistic regression and Kaplan-Meyer analyses were performed for testing predictors of mortality., Results: The total cohort included 2,090 patients with acromegaly treated with PEGV who were followed for a median of 6.8 years (range up to 12.1 years). In ACROSTUDY there were 1,344 patients with hypertension (52.3% males). This subgroup was older, had a higher BMI, and higher prevalence of diabetes, hyperlipidemia, and cardiovascular disease (CVD) when compared to patients without hypertension. During ACROSTUDY, 68 deaths were reported in the hypertension cohort, vs 10 in the cohort without hypertension. Both CVD (p<0.0001) and anterior pituitary deficiencies (p=0.0105) at study entry independently predicted mortality in patients with acromegaly and hypertension; Kaplan-Meier analysis confirmed that CVD significantly impairs survival., Conclusions: Hypertension is common in patients with acromegaly and significantly increases mortality, especially when there is concomitant CVD. These data suggest that treatment goals should extend beyond IGF-I normalization, and include optimisation of substitution of pituitary deficiencies and scrutinous screening and treatment of CVD., Competing Interests: GV has received research grants to her institution from Chiasma and Novartis, and consultancy- and/or speakers fees from Pfizer, Novartis and Ipsen. AL has received lecture and/or consulting honoraria from Ipsen, Novartis, and Pfizer; research grants to the Medical University of Vienna from Ipsen and Pfizer. AJL has received grants, consultancy- and speaker’s fees from Pfizer. SN has received research grants and speaker fees from Ipsen, Novartis, and Pfizer, and consulting fees from Ipsen. SW has received honoraria as a member of the Acrostudy Advisory Board, and lecture fees from Pfizer, Novartis and Ipsen. BB has served as PI of research grants from Novartis, Crinetics and Ionis to Massachusetts General Hospital and has received occasional consulting honoraria from Novartis, Crinetics and Pfizer. SV and JH-H are Pfizer employees., (Copyright © 2020 Vila, Luger, van der Lely, Neggers, Webb, Biller, Valluri and Hey-Hadavi.)

Duchenne muscular dystrophy (DMD) is a lethal genetic muscle wasting disorder, which currently has no cure. Supplementation with the drug taurine has been shown to offer therapeutic benefit in the mdx model for DMD, however the mechanism by which taurine protects dystrophic muscle is not fully understood. Mdx muscle is deficient in taurine, however it is not known if this deficiency occurs in the extracellular space, in other cells present in the tissue (such as immune cells) or in the myofibre itself. Likewise, the tissue location of taurine enrichment in taurine treated mdx muscle is not known. In this study we applied X-ray absorption near edge spectroscopy (XANES) at the sulfur K-edge in an imaging format to determine taurine distribution in muscle tissue. XANES is the only technique currently capable of imaging taurine directly in muscle tissue, at a spatial resolution approaching myocyte cell size (20-50 μm). Using a multi-modal approach of XANES imaging and histology on the same tissue sections, we show that in mdx muscle, it is the myofibres that are deficient in taurine, and taurine supplementation ameliorates this deficiency. Increasing the taurine content of mdx myofibres was associated with a decrease in myofibre damage (as shown by the percentage of intact myofibres) and inflammation. These data will help drive future studies to better elucidate the molecular mechanisms through which taurine protects dystrophic muscle; they also support the continued investigation of taurine as a therapeutic intervention for DMD.

Transition metal ions (Fe, Mn, Cu, Zn) are essential for healthy brain function, but altered concentration, distribution, or chemical form of the metal ions has been implicated in numerous brain pathologies. Currently, it is not possible to image the cellular or sub-cellular distribution of metal ions in vivo and therefore, studying brain-metal homeostasis largely relies on ex vivo in situ elemental mapping. Sample preparation methods that accurately preserve the in vivo elemental distribution are essential if one wishes to translate the knowledge of elemental distributions measured ex vivo toward increased understanding of chemical and physiological pathways of brain disease. The choice of sample preparation is particularly important for metal ions that exist in a labile or mobile form, for which the in vivo distribution could be easily distorted by inappropriate sample preparation. One of the most widely studied brain structures, the hippocampus, contains a large pool of labile and mobile Zn. Herein, we describe how sucrose cryoprotection, the gold standard method of preparing tissues for immuno-histochemistry or immuno-fluorescence, which is also often used as a sample preparation method for elemental mapping studies, drastically alters hippocampal Zn distribution. Based on the results of this study, in combination with a comparison against the strong body of published literature that has used either rapid plunge freezing of brain tissue, or sucrose cryo-protection, we strongly urge investigators in the future to cease using sucrose cryoprotection as a method of sample preparation for elemental mapping, especially if Zn is an analyte of interest.

Psychiatric and neurocognitive symptoms due to hypercortisolism were already described by Harvey Cushing in his original paper on patients with Cushing's syndrome (CS). Nowadays, it is well known that psychiatric and cognitive complaints are two of the most common, and most distressing, symptoms in patients with CS. Psychiatric symptoms are indeed a major clinical manifestation of CS. The most commonly observed psychiatric conditions are depression and anxiety, whilst mania and psychosis are less common. Several domains of cognitive function are impaired at diagnosis, including episodic and working memory, executive function and attention. Following treatment, one-fourth of the patients still experience depressed mood, and the cognitive impairments are only partially restored. Consequently, quality of life in patients with CS is severely and persistently affected. Neuroimaging studies have also illustrated the deleterious effects of hypercortisolism on the brain by demonstrating reduced grey matter volumes and cortical thickness, altered resting-state functional responses and during cognitive tasks, as well as widespread reduced white matter integrity, especially in structures important for cognitive function and emotional processing, both before and after successful abrogation of hypercortisolism. In this paper, we summarize the current knowledge on the psychiatric and neurocognitive consequences of hypercortisolism in patients with CS, both before, and after successful treatment. In addition, we review the structural and functional brain abnormalities associated with hypercortisolism and discuss the influence of these factors on quality of life., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Bud dormancy allows deciduous perennial plants to rapidly grow following seasonal cold conditions. Although many studies have examined the hormonal regulation of bud growth, the role of nutrients remains unclear. Insufficient accumulation of the key micronutrient zinc (Zn) in dormant buds affects the vegetative and reproductive growth of perennial plants during the subsequent year, requiring the application of Zn fertilizers in orchard management to avoid growth defects in fruit trees. However, the mechanisms of seasonal Zn homeostasis in perennial plants remain poorly understood. Here, we provide new insights into Zn distribution and speciation within reproductive and vegetative buds of apple ( Malus domestica ) and four other deciduous fruit trees (peach [ Amygdalus persica ], grape [ Vitis vinifera ], pistachio [ Pistacia vera ], and blueberry [ Vaccinium spp.]) using microscopic and spectroscopic characterization techniques comprising synchrotron-based x-ray fluorescence and x-ray absorption near-edge-structure analyses. By establishing a link between bud development and Zn distribution, we identified the following important steps of Zn storage and use in deciduous plants: Zn is preferentially deposited in the stem nodes subtending apical and axillary buds; Zn may then be sequestered as Zn-phytate prior to dormancy; in spring, Zn effectively releases for use during budbreak and subsequent meristematic growth. The mechanisms of Zn homeostasis during the seasonal cycles of plant growth and dormancy described here will contribute to improving orchard management, and to selection and breeding of deciduous perennial species., (© 2020 American Society of Plant Biologists. All Rights Reserved.)

One of the greatest benefits of synchrotron radiation is the ability to perform chemical speciation analysis through X-ray absorption spectroscopies (XAS). XAS imaging of large sample areas can be performed with either full-field or raster-scanning modalities. A common practice to reduce acquisition time while decreasing dose and/or increasing spatial resolution is to compare X-ray fluorescence images collected at a few diagnostic energies. Several authors have used different multivariate data processing strategies to establish speciation maps. In this manuscript, the theoretical aspects and assumptions that are often made in the analysis of these datasets are focused on. A robust framework is developed to perform speciation mapping in large bulk samples at high spatial resolution by comparison with known references. Two fully operational software implementations are provided: a user-friendly implementation within the MicroAnalysis Toolkit software, and a dedicated script developed under the R environment. The procedure is exemplified through the study of a cross section of a typical fossil specimen. The algorithm provides accurate speciation and concentration mapping while decreasing the data collection time by typically two or three orders of magnitude compared with the collection of whole spectra at each pixel. Whereas acquisition of spectral datacubes on large areas leads to very high irradiation times and doses, which can considerably lengthen experiments and generate significant alteration of radiation-sensitive materials, this sparse excitation energy procedure brings the total irradiation dose greatly below radiation damage thresholds identified in previous studies. This approach is particularly adapted to the chemical study of heterogeneous radiation-sensitive samples encountered in environmental, material, and life sciences.

Primary production in Mono Lake, a hypersaline soda lake rich in dissolved inorganic arsenic, is dominated by Picocystis strain ML. We set out to determine if this photoautotrophic picoplankter could metabolize inorganic arsenic and in doing so form unusual arsenolipids (e.g., arsenic bound to 2- O -methyl ribosides) as reported in other saline ecosystems and by halophilic algae. We cultivated Picocystis strain ML on a seawater-based medium with either low (37 µM) or high (1000 µM) phosphate in the presence of arsenite (400 µM), arsenate (800 µM), or without arsenic additions (ca 0.025 µM). Cultivars formed a variety of organoarsenic compounds, including a phytyl 2- O -methyl arsenosugar, depending upon the cultivation conditions and arsenic exposure. When the cells were grown at low P, the organoarsenicals they produced when exposed to both arsenite and arsenate were primarily arsenolipids (~88%) with only a modest content of water-soluble organoarsenic compounds (e.g., arsenosugars). When grown at high P, sequestration shifted to primarily water-soluble, simple methylated arsenicals such as dimethylarsinate; arsenolipids still constituted ~32% of organoarsenic incorporated into cells exposed to arsenate but < 1% when exposed to arsenite. Curiously, Picocystis strain ML grown at low P and exposed to arsenate sequestered huge amounts of arsenic into the cells accounting for 13.3% of the dry biomass; cells grown at low P and arsenite exposure sequestered much lower amounts, equivalent to 0.35% of dry biomass. Extraction of a resistant phase with trifluoroacetate recovered most of the sequestered arsenic in the form of arsenate. Uptake of arsenate into low P-cultivated cells was confirmed by X-ray fluorescence, while XANES/EXAFS spectra indicated the sequestered arsenic was retained as an inorganic iron precipitate, similar to scorodite, rather than as an As-containing macromolecule. Samples from Mono Lake demonstrated the presence of a wide variety of organoarsenic compounds, including arsenosugar phospholipids, most prevalent in zooplankton ( Artemia ) and phytoplankton samples, with much lower amounts detected in the bottom sediments. These observations suggest a trophic transfer of organoarsenicals from the phytoplankton ( Picocystis ) to the zooplankton ( Artemia ) community, with efficient bacterial mineralization of any lysis-released organoarsenicals back to inorganic oxyanions before they sink to the sediments.

Fossil melanosomes, micron-sized granules rich in melanin in vivo, provide key information for investigations of the original coloration, taxonomy and internal anatomy of fossil vertebrates. Such studies rely, in part, on analysis of the inorganic chemistry of preserved melanosomes and an understanding of melanosome chemical taphonomy. The extent to which the preserved chemistry of fossil melanosomes is biased by biotic and abiotic factors is, however, unknown. Here we report the discovery of hierarchical controls on the inorganic chemistry of melanosomes from fossil vertebrates from nine biotas. The chemical data are dominated by a strong biota-level signal, indicating that the primary taphonomic control is the diagenetic history of the host sediment. This extrinsic control is superimposed by a biological, tissue-level control; tissue-specific chemical variation is most likely to survive in fossils where the inorganic chemistry of preserved melanosomes is distinct from that of the host sediment. Comparative analysis of our data for fossil and modern amphibians reveals that most fossil specimens show tissue-specific melanosome chemistries that differ from those of extant analogues, strongly suggesting alteration of original melanosome chemistry. Collectively, these findings form a predictive tool for the identification of fossil deposits with well-preserved melanosomes amenable to studies of fossil colour and anatomy.

Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.

Context: Muscle weakness is common in patients with Cushing's syndrome (CS) and may persist after the resolution of hypercortisolism. Intramuscular fatty infiltration has been associated with the deterioration of muscle performance in several conditions., Objectives: To quantify the degree of fatty infiltration in the thigh muscles of "cured" CS patients and evaluate the relationship between intramuscular fatty infiltration and physical performance., Design: This was a cross-sectional study., Setting: Tertiary referral center., Patients: Thirty-six women with CS in remission, and 36 controls matched for age, BMI, menopausal status, and level of physical activity., Main Outcome Measures: We analyzed the percentage fat fraction (FF) of the thigh muscles in the anterior, posterior, and combined anterior and posterior compartments using MRI and 2-point Dixon sequence. We assessed muscle function and strength using the following tests: gait speed (GS), timed up and go (TUG), 30-second chair stand, and hand grip strength., Results: Fat fraction in all the compartments analyzed was increased in patients as compared with controls. The performance on TUG, 30-second chair stand, and GS was more impaired in CS patients versus controls. In patients, greater FF was negatively associated with performance on functional tests. Fat fraction in the combined anterior and posterior compartments predicted performance on TUG (ß 0.626, P < 0.000) and GS (ß -0.461, P = 0.007), after adjusting for age, BMI, menopausal status, and muscle mass., Conclusions: Thigh muscle fatty infiltration is increased in "cured" CS patients and is associated with poorer muscle performance. Future studies are needed to establish therapeutic strategies to improve muscle weakness in these patients., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding Cd uptake and distribution in rice roots is important for breeding varieties that do not accumulate Cd in the grain to any large extent. Here, we examined the physiological and molecular factors responsible for Cd uptake and transport differences between two japonica rice cultivars prescreened as high (zhefu7) or low (Xiangzaoxian45) accumulators of Cd in the grain. No significant differences in Cd uptake between the two cultivars were observed; however, Xiangzaoxian45 retained most of the absorbed Cd in the roots, whereas zhefu7 showed higher transport of Cd from the root to the shoot, regardless of the duration of exposure to Cd. The inability to sequester Cd into root vacuoles caused high accumulation of Cd in the grain in zhefu7, whereas inefficient transport of Cd from roots to shoots in Xiangzaoxian45 caused low accumulation of Cd in the grain. Cd sequestration in the roots and transport from the root to the shoot were greatly influenced by the expression patterns of transport-related genes OsHMA3 and OsHMA2, respectively. Further, micro-X-ray fluorescence spectroscopy mapping confirmed that more Cd was sequestered in the roots of Xiangzaoxian45 than in those of zhefu7, with a significant amount of Cd localized in the root hairs, as well as in the meristematic and elongation zones, and dermal and stele tissues. Therefore, we propose that effective Cd sequestration in root vacuoles was the major determinant of divergent Cd-accumulation patterns in the two rice cultivars under study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Over the last 2 decades, advances in the diagnosis and management of pituitary diseases have made it possible to attain an endocrine "cure" in a large proportion of patients. In other words, tumors can be excised or controlled with drugs, mass effects of the lesion on surrounding structures can be solved, and pituitary deficiencies can be substituted with all relevant hormones. While this is considered a satisfactory outcome for health care providers, patients often suffer from an aftermath of prior endocrine dysfunction exposure, with irreversible effects, both physically and psychologically, which have a great impact on their everyday life. Diagnostic delay, often of several years, adds a negative impact on health perception. This affects their social, professional, and family domains and determines their future life. Understanding that this may occur is important, and health care providers should offer information to prepare the patient for this difficult journey, especially in the case of acromegaly, Cushing disease, or hypopituitarism. In order to maintain a good quality of life (QoL) in the long-term, patients need to adapt to this new situation, something that may be difficult, since they often cannot continue with all the activities and rhythm they used to do. Depression is often the consequence of maladaptation to the new situation, leading to impaired QoL., (© 2020 S. Karger AG, Basel.)

Cushing's disease (and by extension, Cushing's syndrome) is a rare disease due to a chronic cortisol excess, which usually has an important impact on quality of life (QoL). It can lead to numerous comorbidities that can interfere with daily life, as fatigability, myopathy, bone loss and fragility, increased cardiovascular risk, depression, and cognitive alterations. Of note, psychological alterations (including depression and anxiety) occur often, and are an important determinant of impaired quality QoL. QoL scores using different questionnaires are poorer in comparison to healthy controls, other pituitary adenomas and some chronic diseases. Even if some improvements can be observed after successful treatment, recovery does not seem to be complete, and comorbidities persist. This persistent QoL impairment has been found using both generic and disease-specific QoL questionnaires, and is also reported by the patients themselves, when asked directly. Multidisciplinary teams are essential to improve patients' well-being. Clinicians should take into account the whole scope of clinical problems and address the different comorbidites associated with the disease. Screening in the psychological sphere, with further intervention if necessary, can be helpful in the management of these patients. Interventions and programs have shown promising results, although there is a need for further development of new strategies for the benefit of these patients., (Copyright © 2019 Santos, Resmini, Martínez Momblán, Valassi, Martel and Webb.)

Apple trees are extensively cultivated worldwide but are often affected by zinc (Zn) deficiency. Limited knowledge regarding Zn remobilization within fruit crops has hampered the development of efficient strategies for providing adequate amounts of Zn. In the present study, Zn distribution and remobilization were compared among apple trees cultivated under different Zn conditions. Without Zn application, plants showed visible symptoms of Zn deficiency at the shoot tips after 1 year but appeared to grow normally during the first 6 months (early stage of Zn deficiency). Compared with apple plants under sufficient Zn treatment, plants suffering from early-stage Zn deficiency showed preferential Zn distribution to young leaves and higher Zn levels in phloem, demonstrating that hidden Zn deficiency triggers a highly efficient remobilization of Zn in this species. The in vivo Zn-nicotianamine complex in phloem tissues, combined with the significant enhanced expression of MdNAS3 and MdYSL6, suggested a positive role for nicotianamine in the phloem remobilization of Zn. These results strongly suggest that a proportion of Zn in the old leaves of apple trees can be efficiently remobilized by phloem transport to the shoot tips, partially in the form of Zn-nicotianamine, thus protecting apple trees against the early stages of Zn deficiency., (© 2019 John Wiley & Sons Ltd.)

Objective: Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality., Methods: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2-5.5) years., Results: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment., Conclusion: Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.

Screening pigments are essential for vision in animals. Vertebrates use melanins bound in melanosomes as screening pigments, whereas cephalopods are assumed to use ommochromes. Preserved eye melanosomes in the controversial fossil Tullimonstrum (Mazon Creek, IL, USA) are partitioned by size and/or shape into distinct layers. These layers resemble tissue-specific melanosome populations considered unique to the vertebrate eye. Here, we show that extant cephalopod eyes also show tissue-specific size- and/or shape-specific partitioning of melanosomes; these differ from vertebrate melanosomes in the relative abundance of trace metals and in the binding environment of copper. Chemical signatures of melanosomes in the eyes of Tullimonstrum more closely resemble those of modern cephalopods than those of vertebrates, suggesting that an invertebrate affinity for Tullimonstrum is plausible. Melanosome chemistry may thus provide insights into the phylogenetic affinities of enigmatic fossils where melanosome size and/or shape are equivocal.

Recent discoveries of nonintegumentary melanosomes in extant and fossil amphibians offer potential insights into the physiological functions of melanin not directly related to color production, but the phylogenetic distribution and evolutionary history of these internal melanosomes has not been characterized systematically. Here, we present a holistic method to discriminate among melanized tissues by analyzing the anatomical distribution, morphology, and chemistry of melanosomes in various tissues in a phylogenetically broad sample of extant and fossil vertebrates. Our results show that internal melanosomes in all extant vertebrates analyzed have tissue-specific geometries and elemental signatures. Similar distinct populations of preserved melanosomes in phylogenetically diverse vertebrate fossils often map onto specific anatomical features. This approach also reveals the presence of various melanosome-rich internal tissues in fossils, providing a mechanism for the interpretation of the internal anatomy of ancient vertebrates. Collectively, these data indicate that vertebrate melanins share fundamental physiological roles in homeostasis via the scavenging and sequestering of metals and suggest that intimate links between melanin and metal metabolism in vertebrates have deep evolutionary origins., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Objective: Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing's disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors., Design: We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors., Methods: We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM., Results: We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones., Conclusions: By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.

Elemental sulfur (S 0 ) is produced and degraded by phylogenetically diverse groups of microorganisms. For Chlorobaculum tepidum , an anoxygenic phototroph, sulfide is oxidized to produce extracellular S 0 globules, which can be further oxidized to sulfate. While some sulfur-oxidizing bacteria (e.g., Allochromatium vinosum ) are also capable of growth on commercial S 0 as an electron donor, C. tepidum is not. Even colloidal sulfur sols, which appear indistinguishable from biogenic globules, do not support the growth of C. tepidum . Here, we investigate the properties that make biogenic S 0 globules distinct from abiotic forms of S 0 . We found that S 0 globules produced by C. tepidum and abiotic S 0 sols are quite similar in terms of mineralogy and material properties, but the two are distinguished primarily by the properties of their surfaces. C. tepidum 's globules are enveloped by a layer of organics (protein and polysaccharides), which results in a surface that is fundamentally different from that of abiotic S 0 sols. The organic coating on the globules appears to slow the aging and crystallization of amorphous sulfur, perhaps providing an extended window of time for microbes in the environment to access the more labile forms of sulfur as needed. Overall, our results suggest that the surface of biogenic S 0 globules may be key to cell-sulfur interactions and the reactivity of biogenic S 0 in the environment.

Objective: Impaired quality of life (QoL) in primary hyperparathyroidism (PHPT) is commonly present. Patients may complain about nonspecific neurocognitive symptoms which can be difficult to quantify. Two different disease-specific questionnaires have been developed, that is, the parathyroid assessment of symptoms score (PAS) and the primary hyperparathyroidism quality of life (PHPQoL). Using these two questionnaires, we assessed relationship between QoL and biochemical indices in PHPT and effects of parathyroidectomy (PTX)., Design: A prospective cohort study., Methods: Patients with PHPT diagnosed from 2015 to 2017 were asked to answer the questionnaires before and 12 months after PTX. Biochemistry was obtained on both occasions., Results: A total of 104 PHPT patients answered PAS and PHPQoL questionnaires at baseline, with a median age of 64 years (73% females). PHPQoL score correlated inversely with ionized calcium and PTH at baseline (P ˂ 0.04). Total PAS and PHPQoL score did not differ between those with and without osteoporosis, renal calcifications and impaired renal function. Based on levels of ionized calcium, PHPQoL differed significantly between patients with mild- and moderate-severe hypercalcemia (P = 0.01). Fifty-three patients answered PAS and PHPQoL 12 months after PTX showing an improved QoL at follow-up (P all  ˂ 0.02). Stratifying patients into groups based on levels of ionized calcium showed a significantly improved PHPQoL score in patients with mild (˂1.45 mmol/L) as well as moderate-severe hypercalcemia (≥1.45 mmol/L) at follow-up (P all  ˂ 0.03)., Conclusion: Quality of life improved 12 months after PTX in PHPT patients. Impaired QoL seems to be associated with the degree of hypercalcemia rather than organ manifestations attributable to PHPT., (© 2018 John Wiley & Sons Ltd.)

Background Biochemical control of GH/IGF-I excess in acromegaly (ACRO) is associated with persistent impairment of trabecular microstructure leading to increased risk of vertebral fractures. Circulating miRNAs modulate the activity of osteoblasts and osteoclasts, and may be potential biomarkers of osteoporosis. Aims Identify differentially expressed miRNAs in the serum of patients with controlled ACRO vs controls and correlate miRNA levels with both biochemical and structural bone parameters. Patients and methods Twenty-seven patients with controlled ACRO (11 males, 16 females; mean age, 48 ± 5 years; BMI, 28 ± 4 kg/m2) and 27 age-, gender- and BMI-matched controls were recruited. Areal BMD at lumbar spine and femur, and trabecular bone score were assessed; volumetric BMD was measured by quantitative computed tomography QCT-Pro (Mindways). Twenty miRNAs, chosen by their putative role in bone, were quantified in serum using real-time qPCR. Results In ACRO patients, miR-103a-3p and miR-191-5p were found overexpressed, whereas miR-660-5p was underexpressed (P < 0.001). miR-103a-3p levels were negatively associated with both trabecular vBMD at trochanter and serum osteoprotegerin concentrations (P < 0.05) and positively with vitamin D concentrations (P < 0.01) and total cross-sectional area of the femoral neck (P < 0.05). miR-660-5p levels were correlated with both trabecular vBMD at trochanter and OPG concentrations (P < 0.05), but were negatively associated with vitamin D levels (P < 0.05). A negative correlation between miR-103-a-3p and miR-660-5p was found in both groups (P < 0.001). Conclusions Circulating miR-103a-3p and miR-660-5p are differentially expressed in controlled ACRO patients and associated with bone structural parameters. miRNAs may be one of the mechanisms involved in the pathogenesis of bone disease and could be used as biomarkers in ACRO patients.

Four highly similar genes (W08E12.2, W08E12.3, W08E12.4 and W08E12.5) which are consecutively aligned on chromosome IV of the C. elegans genome are predicted to code for small (120-141aa) yet cysteine rich (18-19 cysteines) proteins. Cloning and sequencing of the genomic regions of the isoforms confirmed the presence and order of all genes. The generation of transgenic worms strains with an integrated single copy or extrachromosomal multi-copy PW08E12.3;W08E12.4::GFP uncovered that W08E12.3 and W08E12.4 are constitutively expressed in the pharynx and significantly induced in worms exposed to 100 μM Zn. Knockdown by RNAi did not have a marked consequence on reproductive performance nor was a Zn-dependent effect on nematode growth observed. However, RNAi of these genes led to an accumulation of Zn in the intestinal cells. W08E12.3 was recombinantly expressed in E. coli and the purified protein was shown to be able to bind up to 6.5 Zn molecules at neutral pH. Zn-binding was acid-labile and the apo protein was observed at pH < 4.3. This characterization suggests W08E12.2, W08E12.3, W08E12.4 and W08E12.5 belong to a family of putative Metalloproteins which, akin to metallothioneins, may play an important role in Zn-sensing, homeostasis and/or detoxification.

Objectives ACROSTUDY is an international, non-interventional study of acromegaly patients treated with pegvisomant (PEGV), a growth hormone receptor antagonist and has been conducted since 2004 in 15 countries to study the long-term safety and efficacy of PEGV. This report comprises the second interim analysis of 2090 patients as of May 12, 2016. Methods Descriptive analyses of safety, pituitary imaging and outcomes on PEGV treatment up to 12 years were performed. Results Prior to starting PEGV, 96% of patients had reported surgery, radiation, medical therapy or any combinations of those. At start of PEGV, 89% of patients had IGFI levels above the upper limit of normal (ULN). The percentage of patients with normal IGFI levels increased from 53% at year 1 to 73% at year 10, and the average daily dose of PEGV increased from 12.8 mg (year 1) to 18.9 mg (year 10). A total of 4832 adverse events (AEs) were reported in 1137 patients (54.4%), of which 570 were considered treatment related in 337 patients (16.1%). Serious AEs were reported in 22% of patients, of which 2.3% were considered treatment related. Locally reported MRIs showed most patients (72.2%) had no change in tumor size relative to the prior scan; 16.8% had a decrease, 6.8% an increase and 4.3% both. In patients with normal liver tests at PEGV start, an ALT or AST elevation of >3× ULN at any time point during their follow-up was reported in 3%. Conclusions This second interim analysis confirms that long-term use of PEGV is an effective and safe treatment in patients with acromegaly.