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The majority of the Earth's terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12-17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon-climate feedback that could accelerate climate change.

With the widespread use of 18F-fluorodeoxyglucose positron emission tomography (FDG PET/CT) in the investigation and staging of cancers, incidental discovery of FDG-avid thyroid nodules is becoming increasingly common, with a reported incidence in the range 1%-4% of FDG PET/CT scans. The risk of malignancy in an incidentally discovered FDG avid thyroid nodule is not clear due to selection bias in reported retrospective series but is likely to be less than 15%. Even in cases where the nodule is found to be malignant, the majority will be differentiated thyroid cancers with an excellent prognosis even without treatment. If, due to index cancer diagnosis, age and co-morbidities, it is unlikely that the patient will survive 5 years, further investigation of an incidental FDG avid thyroid nodule is unlikely to be warranted. We provide a consensus statement on the circumstances in which further investigation of FDG avid thyroid nodules with ultrasound and fine needle aspiration might be appropriate., (© 2023 John Wiley & Sons Ltd.)

Aims: Bespoke glycaemic control strategies following antenatal corticosteroids for women with diabetes in pregnancy (DIP) may mitigate hyperglycaemia. This study aims to identify predictive factors for the glycaemic response to betamethasone in a large cohort of women with DIP., Methods: Evaluation of a prospective cohort study of 347 consecutive DIP pregnancies receiving two doses of 11.4 mg betamethasone 24 h apart between 2017 and 2021 and treated with the Pregnancy-IVI intravenous insulin protocol. Regression modelling identified factors associated with maternal glycaemic time-in-range (TIR) and maternal insulin requirements following betamethasone. Factors associated with neonatal hypoglycaemia (glucose <2.6 mmol/L) in infants born within 48 h of betamethasone administration (n = 144) were investigated., Results: The mean maternal age was 31.9 ± 5.8 years, with gestational age at betamethasone of 33.5 ± 3.4 weeks. Gestational diabetes was present in 81% (12% type 1; 7% type 2). Pre-admission subcutaneous insulin was prescribed for 63%. On-infusion maternal glucose TIR (4.0-7.8 mmol/L) was 83% [IQR 77%-90%] and mean on-IVI glucose was 6.6 ± 0.5 mmol/L. Maternal hypoglycaemia (<3.8 mmol/L) was uncommon (0.47 h/100 on-IVI woman hours). Maternal glucose TIR was negatively associated with indicators of insulin resistance (type 2 diabetes, polycystic ovary syndrome), late-pregnancy complications (pre-eclampsia, chorioamnionitis) and the 1-h OGTT result. Intravenous insulin requirements were associated with type of diabetes, pre-eclampsia and intrauterine infection, the 1-h OGTT result and the timing of betamethasone administration. Neonatal hypoglycaemia was associated with pre-existing diabetes but not with measures of glycaemic control., Conclusion: An intravenous infusion protocol effectively controls maternal glucose after betamethasone. A risk-factor-based approach may allow individualisation of therapy., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Most thyroid cancer survivors regain their physical health-related quality of life, but psychological and social deficits persist. The nature of these detriments remains poorly understood and they are insufficiently captured by survey data alone. To address this, qualitative data exploring the breadth and depth of thyroid cancer survivors' experiences and priorities for supportive care are required. Methods: Twenty semistructured interviews were undertaken with a purposive, maximum variation sample of thyroid cancer survivors. Interviews were transcribed verbatim and coded independently by two researchers. A hybrid model of inductive and realistic codebook analysis was undertaken with themes developed. Results: Patient experiences centered around three themes: (1) impact of diagnosis and treatment, (2) thyroid cancer does not happen in isolation, and (3) role of clinicians and formalized support structures. The word "cancer" had negative connotations, but for many, the reality of their experience was more positive. Despite feeling "lucky" at the relative low-risk nature of thyroid cancer, many patients reported fatigue, weight gain, and difficulty returning to usual activities; concerns that were largely dismissed or minimized by clinicians. Few were offered any support beyond their treating doctors; where patients attempted to access formalized supportive care, little was available or appropriate. Life stage and concurrent family and social stressors greatly impacted patients' ability to cope with diagnosis and treatment. Addressing thyroid cancer in isolation felt inappropriate without appreciating the broader context of their lives. Interactions with clinicians were largely positive, particularly where information was communicated as a means of empowering patients to participate in shared decision-making and where clinicians "checked in" emotionally with patients. Information about initial treatments was largely adequate but information on longer term effects and follow-up was lacking. Many patients felt that clinicians focused on physical well-being and scan results, missing opportunities to provide psychological support. Conclusions: Thyroid cancer survivors can struggle to navigate their cancer journey, particularly with regard to psychological and social functioning. There is a need to acknowledge these impacts at the time of clinical encounters, as well as develop information resources and support structures that can be individualized to optimize holistic well-being for those in need.

Background: Patient reported outcomes measures (PROMs) can provide valuable metrics in clinical trials and cancer registries. To ensure relevance, patient participation must be optimized and PROMs be highly acceptable to patients. There are few data reporting methods to maximize recruitment and a lack of consensus regarding appropriate PROMs for thyroid cancer survivors., Methods: All patients with a new diagnosis of thyroid (excluding micropapillary and anaplastic) cancer within a single Australian health district between January 2020 and December 2021 were invited to complete PROMs electronically, and self-report ease of use and comprehensiveness of each tool. Participants completed Short Form-12 (SF-12), European Organization of Research and Treatment of Cancer (EORTC-QLQ-C30), City of Hope Quality of Life-Thyroid Version (COH-TV) and Thyroid Cancer Quality of Life Survey (ThyCaQoL). Semi-structured qualitative telephone interviews explored patient priorities. An enhanced, multimodal recruitment strategy was instituted after 12 months due to low response rates., Results: Survey completion improved under enhanced recruitment (37/62, 60% versus 19/64, 30%, P = 0.0007) with no differences in demographic or clinical characteristics. Few (4%-7%) respondents rated surveys as difficult to complete. No single PROM comprehensively captured health-related quality of life, with disease-specific tools performing marginally better (54% ThyCaQoL and 52% CoH-TV) compared to generic tools (38% SF-12 and 42% EOROTC-QLQ-C30). Qualitative data suggested that concurrent diagnoses, and survey invitation prior to surgery, made surveys more difficult to complete., Conclusion: A comprehensive and representative assessment of PROMs in thyroid cancer survivors requires the use of multiple survey tools and specialized staff to maximize recruitment., (© 2023 The Authors. ANZ Journal of Surgery published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Surgeons.)

Introduction: De-escalated treatment of hemithyroidectomy without radioactive iodine (RAI) is now accepted for patients with low-risk, well-differentiated thyroid cancer (WDTC). The benefit of long-term follow-up care remains controversial. This study aims to describe parameters associated with less than total thyroidectomy, and discharge from specialist follow-up in patients with low-risk WDTC in Australia., Methods: An online survey was distributed to Australian members of Endocrine Society of Australia, Australian and New Zealand Endocrine Surgeons, and Australian Society of Otolaryngology, Head and Neck Surgery. Clinicians completed a survey of management and follow-up care preferences for four clinical vignettes (all low-risk WDTC)., Results: 119 clinicians (48% endocrinologists, 55% male) answered at least one question. The majority (59%) of respondents recommended less than total thyroidectomy and omission of RAI in patients with WDTC <2 cm. Most (62%) would discharge a patient with micropapillary thyroid cancer within 1 year following total thyroidectomy. In contrast, for WDTC 1-4 cm, >90% of clinicians would continue specialist follow-up for at least 5 years. The majority of clinicians felt that patients experienced disproportionate fear of recurrence and were reassured by follow-up. After multivariable analysis, clinicians who participated in multidisciplinary teams (MDTs) were more likely to choose de-escalated care for both initial treatment (p = .005) and follow-up care (>5 years, p = .05)., Conclusion: Clinician attitudes captured by this survey reflect recent changes in guidelines towards hemithyroidectomy for low-risk WDTC, particularly amongst MDT attendees. There is a need to further examine the impact of de-escalated care on fear of recurrence and quality of life in thyroid cancer survivors., (© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Background: Thyroid cancer diagnoses are increasing and treatment can lead to significant morbidity. Long-term health-related quality of life (HRQoL) in thyroid cancer is understudied and lacks reference populations. This study compares long-term HRQoL between patients with thyroid cancer or benign disease, following thyroid surgery., Methods: Patients undergoing thyroidectomy between 2000 and 2017 were identified from a pathology database. 696 participants (278 malignant, 418 benign) were invited to complete a validated disease-specific HRQoL tool, City of Hope-Thyroid Version. Propensity scores were used to adjust for demographic and clinical differences between cohorts., Results: 206 patients (102 malignant, 104 benign), 71% female, returned surveys a median of 6.5 (range 1-19) years after thyroidectomy. Of the cancer cohort, 95% had differentiated thyroid cancer and 83% remained disease-free. There were no significant differences in overall HRQoL scores between groups. In comparison to the benign cohort, cancer patients showed a significant detriment in the social subdomain score (OR 0.10-0.96, p = 0.017) but not in other subdomains (physical, psychological, spiritual). Female gender, increasing BMI and cancer recurrence were significantly associated with decreased overall HRQoL. Compared to the benign cohort, cancer patients reported more personal and family distress associated with diagnosis and treatment, increased future uncertainty, poorer concentration and greater financial burden., Conclusion: Although no difference in overall HRQoL was found between patients undergoing thyroidectomy for benign or malignant disease, detriments in social well-being may persist many years after surgery. Thyroid cancer patients and their families may benefit from increased supports around the time of diagnosis and treatment., (© 2022. The Author(s).)

Accurate quantification of nerves in cancer specimens is important to understand cancer behaviour. Typically, nerves are manually detected and counted in digitised images of thin tissue sections from excised tumours using immunohistochemistry. However the images are of a large size with nerves having substantial variation in morphology that renders accurate and objective quantification difficult using existing manual and automated counting techniques. Manual counting is precise, but time-consuming, susceptible to inconsistency and has a high rate of false negatives. Existing automated techniques using digitised tissue sections and colour filters are sensitive, however, have a high rate of false positives. In this paper we develop a new automated nerve detection approach, based on a deep learning model with an augmented classification structure. This approach involves pre-processing to extract the image patches for the deep learning model, followed by pixel-level nerve detection utilising the proposed deep learning model. Outcomes assessed were a) sensitivity of the model in detecting manually identified nerves (expert annotations), and b) the precision of additional model-detected nerves. The proposed deep learning model based approach results in a sensitivity of 89% and a precision of 75%. The code and pre-trained model are publicly available at https://github.com/IA92/Automated&#95;Nerves&#95;Quantification., Competing Interests: The authors have declared that no competing interests exist.

Summary: We report concurrent metastatic prostatic adenocarcinoma (PC) and functioning androgen-secreting adrenocortical carcinoma (ACC) in a 77-year-old man. The failure to achieve adequate biochemical castration via androgen deprivation therapy (ADT) as treatment for PC metastases, together with elevated DHEA-S, androstenedione, and discordant adrenal tracer uptake on FDG-PET and PSMA-PET, suggested the presence of a concurrent functional primary adrenal malignancy. On histopathological analysis, scant foci of PC were present throughout the ACC specimen. Castration was achieved post adrenalectomy with concurrent drop in prostate-specific antigen. We outline the literature regarding failure of testosterone suppression on ADT and salient points regarding diagnostic workup of functioning adrenal malignancies., Learning Points: Failure to achieve castration with androgen deprivation therapy is rare and should prompt careful review to identify the underlying cause. All adrenal lesions should be evaluated for hormone production, as well as assessed for risk of malignancy (either primary or secondary). Adrenocortical carcinomas are commonly functional, and can secrete steroid hormones or their precursors (androgens, progestogens, glucocorticoids and mineralocorticoids). In this case, a co-incident, androgen-producing adrenocortical carcinoma was the cause of failure of testosterone suppression from androgen deprivation therapy as treatment for metastatic prostate cancer. Pathological adrenal androgen production contributed to the progression of prostate cancer.

Multidisciplinary team (MDT) meetings are the mainstay of the decision-making process for patients presenting with complex clinical problems such as papillary thyroid carcinoma (PTC). Adherence to guidelines by MDTs has been extensively investigated; however, scarce evidence exists on MDT performance and variability where guidelines are less prescriptive. We evaluated the consistency of MDT management recommendations for T1 and T2 PTC patients and explored key variables that may influence therapeutic decision making. A retrospective review of the prospective database of all T1 and T2 PTC patients discussed by the MDT was conducted between January 2016 and May 2021. Univariate analysis (with Bonferroni correction significance calculated at p < 0.006) was performed to establish clinical variables linked to completion thyroidectomy and Radioactive iodine (RAI) recommendations. Of 468 patients presented at thyroid MDT, 144 pT1 PTC and 118 pT2 PTC met the selection criteria. Only 18% ( n = 12) of pT1 PTC patients initially managed with hemithyroidectomy were recommended completion thyroidectomy. Mean tumour diameter was the only variable differing between groups ( p = 0.003). pT2 patients were recommended completion thyroidectomy in 66% ( n = 16) of instances. No measured variable explained the difference in recommendation. pT1 patients initially managed with total thyroidectomy were not recommended RAI in 71% ( n = 55) of cases with T1a status ( p = 0.001) and diameter ( p = 0.001) as statistically different variables. For pT2 patients, 60% ( n = 41) were recommended RAI post-total thyroidectomy, with no differences observed among groups. The majority of MDT recommendations were concordant for patients with similar measurable characteristics. Discordant recommendations for a small group of patients were not explained by measured variables and may have been accounted for by individual patient factors. Further research into the MDT decision-making process is warranted.

Aims: Hyperglycaemia following antenatal corticosteroids is common in women with diabetes in pregnancy, and validated algorithms to maintain pregnancy-specific glucose targets are lacking. The Pregnancy-IVI, an intravenous-insulin (IVI) algorithm, has been validated in gestational diabetes; however, its performance in pre-existing diabetes (Type 1 and Type 2 diabetes) is not known. We hypothesised that Pregnancy-IVI would be superior to a generic Adult-IVI protocol (prior standard of care) following betamethasone in women with pre-existing diabetes., Methods: A retrospective cohort study enrolled all women with pre-existing diabetes at a tertiary centre receiving betamethasone and treated with IVI according to one of two protocols: Adult-IVI (n = 73, 2014-2017) or Pregnancy-IVI (n = 62, 2017-2020). The primary outcome was on-IVI glycaemic time-in-range (capillary blood glucose (BGL) 3.8-7.0 mmol/L). Secondary outcomes included time with critical hyperglycaemia (BGL > 10 mmol/L); occurrence of maternal hypoglycaemia (BGL < 3.8 mmol/l) and incidence of neonatal hypoglycaemia (BGL ≤ 2.5 mmol/L). Analysis was stratified by diabetes type., Results: Overall, Pregnancy-IVI achieved a higher proportion of on-IVI time-in-range (70%, IQR 56-78%) compared to Adult-IVI (52%, IQR 41-69%, p < 0.0001). The duration of critical hyperglycaemia with Pregnancy-IVI was also reduced (2% [IQR 0-7] vs 8% [IQR 4-17], p < 0.0001), without an increase in hypoglycaemia. Glycaemic variability was significantly reduced with Pregnancy-IVI. No difference in the rate of neonatal hypoglycaemia was observed. The Pregnancy-IVI was most effective in women with Type 1 diabetes., Conclusion: The Pregnancy-IVI algorithm is safe and effective when used following betamethasone in type 1 diabetes in pregnancy. Further study of women with type 2 diabetes is required., (© 2020 Diabetes UK.)

Background: Symptoms of thyroid disease are common, and patients often seek initial assessment from their general practitioners., Objective: The aim of this article is to assist with identifying the appropriate sequence of investigations for thyroid disorders, and identify investigations with low diagnostic yield in certain clinical contexts., Discussion: Common thyroid disorders - such as hypothyroidism, hyperthyroidism and thyroid nodules - require different sequences of investigations to assist with formulating a diagnosis and plan. Thyroid disorders are frequent in women of childbearing age and require a specialised approach. Awareness of less common thyroid conditions allows for individualised workup in these cases.

Nerves are emerging promoters of cancer progression, but the innervation of esophageal cancer and its clinicopathologic significance remain unclear. In this study, nerves were analyzed by immunohistochemistry in a cohort of 260 esophageal cancers, including 40 matched lymph node metastases and 137 normal adjacent esophageal tissues. Nerves were detected in 38% of esophageal cancers and were more associated with squamous cell carcinomas (P = 0.04). The surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with reduced survival (P = 0.04). Nerves were found to express the following receptors for nerve growth factor (NGF): neurotrophic receptor tyrosine kinase 1 and nerve growth factor receptor. An association was suggested between high production of NGF by cancer cells and the presence of nerves (P = 0.02). In vitro, NGF production in esophageal cancer cells was shown by Western blot, and esophageal cancer cells were able to induce neurite outgrowth in the PC12 neuronal cells. The neurotrophic activity of esophageal cancer cells was inhibited by anti-NGF blocking antibodies. Together, these data suggest that innervation is a feature in esophageal cancers that may be driven by cancer cell-released NGF., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Nerve growth factor (NGF) and its receptors are increasingly implicated in cancer progression, but their expression in cervical cancer is unclear. The objective of this study was to define the protein expression of NGF, its precursor (proNGF), as well as their receptors, the tyrosine kinase receptor TrkA, the common neurotrophin receptor p75 NTR and the pro-neurotrophin receptor sortilin in cervical cancer. Immunohistochemistry was performed in a cohort of cervical cancers (n = 287), including the two major subtypes of the disease: squamous cell carcinomas (SCC) and adenocarcinomas (AC). Normal cervical tissues (n = 28) were also analyzed. Protein expression was determined by computer-based digital quantification of staining intensity and comparative statistical analyses were made with clinicopathological parameters including histological subtype, age, grade, tumor size, lymph node invasion, and stage. The expression of NGF, proNGF, TrkA, p75 NTR , and sortilin was higher in cervical cancer compared to normal cervical tissues. NGF and TrkA were found overexpressed in SCC compared to AC ( P  = .0006 and P  < .0001, respectively). The expression of NGF ( P  = .0053), proNGF ( P  = .0022), and p75 NTR ( P  = .0002), but not that of TrkA or sortilin, was associated with increasing grade in SCC. In addition, nerve infiltration into the tumor microenvironment was assessed using the pan-neuronal marker PGP9.5. Infiltrating nerves were detected in 27% of cervical tumors and expressed TrkA. Functional investigations using the HELA cervical cancer cell line indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability through decreased ERK1/2 activation. Together, these data reveal the overexpression of NGF and TrkA in cervical SCC, suggesting a potential therapeutic value of targeting the NGF-TrkA signaling pathway in this subtype of cervical cancer., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors.)

Nerves are emerging regulators of cancer progression and in several malignancies innervation of the tumour microenvironment is associated with tumour aggressiveness. However, the innervation of thyroid cancer is unclear. Here, we investigated the presence of nerves in thyroid cancers and the potential associations with clinicopathological parameters. Nerves were detected by immunohistochemistry using the pan-neuronal marker PGP9.5 in whole-slide sections of papillary thyroid cancer (PTC) (n = 75), compared to follicular thyroid cancer (FTC) (n = 13), and benign thyroid tissues (n = 26). Nerves were detected in most normal thyroid tissues and thyroid cancers, but nerve density was increased in PTC (12 nerves/cm 2 [IQR 7-21]) compared to benign thyroid (6 nerves/cm 2 [IQR: 3-10]) (p = 0.001). In contrast, no increase in nerve density was observed in FTC. In multivariate analysis, nerve density correlated positively with extrathyroidal invasion (p < 0.001), and inversely with tumour size (p < 0.001). The majority of nerves were adrenergic, although cholinergic and peptidergic innervation was detected. Perineural invasion was present in 35% of PTC, and was independently associated with extrathyroidal invasion (p = 0.008). This is the first report of infiltration of nerves into the tumour microenvironment of thyroid cancer and its association with tumour aggressiveness. The role of nerves in thyroid cancer pathogenesis should be further investigated.

Background: Nerves and neurotrophic growth factors are emerging promoters of cancer growth. The precursor for Nerve Growth Factor (proNGF) is overexpressed in thyroid cancer, but its potential role as a clinical biomarker has not been reported. Here we have examined the value of proNGF as a serum and biopsy-rinse biomarker for thyroid cancer diagnosis., Methods: Patients presenting for thyroid surgery or biopsy were enrolled in separate cohorts examining serum (n = 204, including 46 cases of thyroid cancer) and biopsy-rinse specimens (n = 188, including 26 cases of thyroid cancer). ProNGF levels in clinical samples were analysed by ELISA. Univariate and multivariate statistical analyses were used to compare proNGF levels with malignancy status and clinicopathological parameters., Results: ProNGF was not detected in the majority of serum samples (176/204, 86%) and the detection of proNGF was not associated with thyroid cancer diagnosis. In the few cases where proNGF was detected in the serum, thyroidectomy did not affect proNGF concentration, demonstrating that the thyroid was not the source of serum proNGF. Intriguingly, an association between hyperthyroidism and serum proNGF was observed (OR 3.3, 95% CI 1.6-8.7 p = 0.02). In biopsy-rinse, proNGF was detected in 73/188 (39%) cases, with no association between proNGF and thyroid cancer. However, a significant positive association between follicular lesions and biopsy-rinse proNGF was found (OR 3.3, 95% CI 1.2-8.7, p = 0.02)., Conclusions: ProNGF levels in serum and biopsy-rinse are not increased in thyroid cancer and therefore proNGF is not a clinical biomarker for this condition.

Metastases in thyroid cancer are associated with aggressive disease and increased patient morbidity, but the factors driving metastatic progression are unclear. The precursor for nerve growth factor (proNGF) is increased in primary thyroid cancers, but its expression or significance in metastases is not known. In this study, we analysed the expression of proNGF in a retrospective cohort of thyroid cancer lymph node metastases ( n = 56), linked with corresponding primary tumours, by automated immunohistochemistry and digital quantification. Potential associations of proNGF immunostaining with clinical and pathological parameters were investigated. ProNGF staining intensity (defined by the median h-score) was significantly higher in lymph node metastases (h-score 94, interquartile range (IQR) 50-147) than in corresponding primary tumours (57, IQR 42-84) ( p = 0.002). There was a correlation between proNGF expression in primary tumours and corresponding metastases, where there was a 0.68 (95% CI 0 to 1.2) increase in metastatic tumour h-score for each unit increase in the primary tumour h-score. However, larger tumours (both primary and metastatic) had lower proNGF expression. In a multivariate model, proNGF expression in nodal metastases was negatively correlated with lateral neck disease and being male. In conclusion, ProNGF is expressed in locoregional metastases of thyroid cancer and is higher in lymph node metastases than in primary tumours, but is not associated with high-risk clinical features., Competing Interests: HH holds intellectual property for the use of proNGF as a diagnostic test in cancer. The other authors report nothing to disclose.

Aim: Overweight and obesity are frequently reported in young persons with type 1 diabetes, however its relative magnitude in comparison to the general population is not well understood. This study compared the prevalence of overweight and obesity in young persons with type 1 diabetes to a reference population and explored possible associated factors, including gender, age, HbA 1c , insulin regimen, age at diagnosis, diabetes duration, socio-economic status and cardiovascular disease risk factors., Methods: A cross-sectional review was undertaken of data collected from youth (3-17 years) in 2016 and young adults (18-30 years) in 2015 with a diagnosis of type 1 diabetes for > 3 months attending diabetes centres in Newcastle, Australia. Rates of overweight and obesity were compared with matched population survey results., Results: Data from 308 youth and 283 young adults were included. In girls, significantly higher prevalence of overweight and obesity were seen in the 5-8 (43% vs. 18%), 13-16 (41% vs. 27%), 18-24 (46% vs. 34%) and 25-30 (60% vs. 43%) years age groups; whereas in boys increased prevalence was observed in the 5-8 years age group only (41% vs. 18%). Rates of overweight and obesity increased with age across sexes. In youth, BMI standard deviation score was correlated with socio-economic status, insulin regimen, blood pressure and blood lipids (P < 0.05). In adults, BMI was positively associated with blood pressure, and longer diabetes duration (P < 0.02)., Conclusions: Overweight and obesity are over-represented in young persons with type 1 diabetes, particularly girls. As overweight is associated with other cardiovascular disease markers early intervention is paramount., (© 2019 Diabetes UK.)

Objective: Post-thyroidectomy hypocalcaemia is a significant cause of morbidity and prolonged hospitalization, usually due to transient parathyroid gland damage, treated with calcium and vitamin D supplementation. We present a randomized, double-blinded placebo-controlled trial of preoperative loading with high-dose cholecalciferol (300 000 IU) to reduce post-thyroidectomy hypocalcaemia., Patients and Measurements: Patients (n = 160) presenting for thyroidectomy at tertiary hospitals were randomized 1:1 to cholecalciferol (300 000 IU) or placebo 7 days prior to thyroidectomy. Ten patients withdrew prior to surgery. The primary outcome was post-operative hypocalcaemia (corrected calcium <2.1 mmol/L in first 180 days)., Results: The study included 150 patients undergoing thyroidectomy for Graves' disease (31%), malignancy (20%) and goitre (49%). Mean pre-enrolment vitamin D was 72 ± 26 nmol/L. Postoperative hypocalcaemia occurred in 21/72 (29%) assigned to cholecalciferol and 30/78 (38%) participants assigned to placebo (P = 0.23). There were no differences in secondary end-points between groups. In pre-specified stratification, baseline vitamin D status did not predict hypocalcaemia, although most individuals were vitamin D replete at baseline. Post-hoc stratification by day 1 parathyroid hormone (PTH) (<10 pg/mL, low vs ≥10 pg/mL, normal) was explored due to highly divergent rates of hypocalcaemia in these groups. Using a Cox regression model, the hazard ratio for hypocalcaemia in the cholecalciferol group was 0.56 (95%CI 0.32-0.98, P = 0.04) after stratification for Day 1 PTH. Further clinical benefits were observed in these subgroups., Conclusions: Pre-thyroidectomy treatment with high-dose cholecalciferol did not reduce the overall rate of hypocalcaemia following thyroidectomy. In subgroups stratified by day 1 PTH status, improved clinical outcomes were noted., (© 2018 John Wiley & Sons Ltd.)

Aims: Marked hyperglycaemia is common following betamethasone administration in women with gestational diabetes (GDM), and may contribute to neonatal hypoglycaemia. Validated protocols to deliver glycaemic stability following betamethasone are lacking. We hypothesized that an intravenous insulin (IVI) protocol for pregnancy-specific glycaemic targets (Pregnancy-IVI) would achieve greater at-target glycaemic control than a generic adult intravenous insulin protocol (Adult-IVI), and may reduce neonatal hypoglycaemia., Methods: A retrospective cohort study of the performance Adult-IVI and Pregnancy-IVI following betamethasone in GDM, sequentially implemented at a tertiary hospital, without change in indication for IVI. Cases were identified by electronic record search. Primary outcome was percentage of on-IVI time with at-target glycaemia [blood glucose level (BGL) 3.8-7 mmol/l]. Secondary outcomes were time with critical hyperglycaemia (BGL > 10 mmol/l), occurrence of maternal hypoglycaemia (BGL < 3.8 mmol/l), and incidence of neonatal hypoglycaemia (BGL ≤ 2.5 mmol/l) if betamethasone was administered within 48 h of birth., Results: The cohorts comprised 151 women (Adult-IVI n = 86; Pregnancy-IVI n = 65). The primary outcome was 68% time-at-target [95% confidence interval (CI) 64-71%) for Pregnancy-IVI compared with 55% (95% CI 50-60%) for Adult-IVI (P = 0.0002). Critical maternal hyperglycaemia (0% vs. 2%, P = 0.02) and hypoglycaemia (2% vs. 12%, P = 0.02) were both lower with Pregnancy-IVI than Adult-IVI. Neonatal hypoglycaemia was less common after Pregnancy-IVI (29%) than after Adult-IVI (54%, P = 0.03). A multiple logistic regression model adjusting for potential confounders gave an odds ratio for neonatal hypoglycaemia with Pregnancy-IVI of 0.27 (95% CI 0.10-0.76, P = 0.01)., Conclusions: An IVI protocol designed for pregnancy effectively controlled maternal hyperglycaemia following betamethasone administration in GDM. This is the first intervention to show a reduction in betamethasone-associated neonatal hypoglycaemia, linked with optimum maternal glycaemic control., (© 2018 Diabetes UK.)

The neurotrophic tyrosine kinase receptor TrkA (NTRK1) and its ligand nerve growth factor (NGF) are emerging promoters of tumor progression. In lung cancer, drugs targeting TrkA are in clinical trials, but the clinicopathological significance of TrkA and NGF, as well as that of the precursor proNGF, the neurotrophin co-receptor p75 NTR and the proneurotrophin co-receptor sortilin, remains unclear. In the present study, analysis of these proteins was conducted by immunohistochemistry and digital quantification in a series of 204 lung cancers of different histological subtypes versus 121 normal lung tissues. TrkA immunoreactivity was increased in squamous cell carcinoma compared with benign and other malignant lung cancer histological subtypes (p < 0.0001). NGF and proNGF were also increased in squamous cell carcinoma, as well as in adenocarcinoma (p < 0.0001). In contrast, p75 NTR was increased across all lung cancer histological subtypes compared to normal lung (p < 0.0001). Sortilin was higher in adenocarcinoma and small cell carcinoma (p < 0.0001). Nerves in the tumor microenvironment were negative for TrkA, NGF, proNGF, p75 NTR and sortilin. In conclusion, these data suggest a preferential therapeutic value of targeting the NGF-TrkA axis in squamous cell carcinomas of the lung.

Neurotrophin receptors are emerging targets in oncology, but their clinicopathologic significance in thyroid cancer is unclear. In this study, the neurotrophin tyrosine receptor kinase TrkA (also called NTRK1), the common neurotrophin receptor p75 NTR , and the proneurotrophin receptor sortilin were analyzed with immunohistochemistry in a cohort of thyroid cancers (n = 128) and compared with adenomas and normal thyroid tissues (n = 62). TrkA was detected in 20% of thyroid cancers, compared with none of the benign samples (P = 0.0007). TrkA expression was independent of histologic subtypes but associated with lymph node metastasis (P = 0.0148), suggesting the involvement of TrkA in tumor invasiveness. Nerves in the tumor microenvironment were positive for TrkA. p75 NTR was overexpressed in anaplastic thyroid cancers compared with papillary and follicular subtypes (P < 0.0001). Sortilin was overexpressed in thyroid cancers compared with benign thyroid tissues (P < 0.0001). Neurotrophin receptor expression was confirmed in a panel of thyroid cancer cell lines at the mRNA and protein levels. Functional investigations using the anaplastic thyroid cancer cell line CAL-62 found that siRNA against TrkA, p75 NTR , and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75 NTR , and sortilin as potential therapeutic targets in thyroid cancer., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Aims: To assess the relationship between insulin resistance (IR), retinopathy and maculopathy in young adults with Type 1 diabetes mellitus., Methods: A cross-sectional study at a regional Australian tertiary hospital. Retinal pathology, assessed by colour fundus photography, was correlated with two surrogate measures of IR: estimated Glucose Disposal Rate (eGDR) and Insulin Sensitivity Score (ISS), where lower scores reflect greater IR., Results: 107 patients were recruited, with mean age 24.7years, 53% male, and mean duration of disease 10.8years. Mean eGDR scores (5.6vs 8.0 p<0.001) and ISS (4.7vs 7.9, p<0.001) were lower in subjects having at least moderate non-proliferative diabetic retinopathy (NPDR; relative to nil/mild-NPDR). Similarly, mean eGDR (4.2vs 6.2, p=0.001) and ISS (3.8vs 6.1, p=0.003) were lower in patients with maculopathy. Multivariate logistic regression modelling was used to control for confounding. For retinopathy severity, a unit increase in eGDR or ISS (representing lower IR) was associated with a 50% decrease in odds of moderate-NPDR or worse (eGDR OR 0.5, 95%CI 0.32-0.77, p=0.002; ISS OR 0.49, 95%CI 0.29-0.84, p=0.01). A unit increase in eGDR or ISS was associated with a 46-56% decrease in odds of maculopathy (eGDR OR 0.54, 95%CI 0.37-0.81, p=0.003; ISS OR 0.44, 95%CI 0.22-0.88, p=0.02)., Conclusions: IR correlates with more severe retinopathy in young adults with Type 1DM. This is the first description of a correlation between IR and maculopathy in Type 1DM, warranting further evaluation. Prospective studies examining whether reducing IR can improve microvascular complications are required., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted., (© 2017 Society for Endocrinology.)

Medullary thyroid cancer (MTC) is an uncommon thyroid cancer that requires a high index of suspicion to facilitate diagnosis of early-stage disease amenable to surgical cure. The challenges of diagnosis, as well as management in the setting of persistent disease, are explored in the context of a case presenting with the incidental finding of elevated carcinoembryonic antigen (CEA) and an (18) F-fluorodeoxyglucose positron emission tomography ((18) F-FDG-PET)-positive thyroid incidentaloma detected following treatment of colorectal cancer. Strategies to individualize prognosis, and emerging PET-based imaging modalities, particularly the potential role of (18) F-DOPA-PET in staging, are reviewed., (© 2016 John Wiley & Sons Ltd.)

To create expected differences in oxidation ground beef samples from grass-fed and grain-fed animals were utilized in six differing percentages with 4 different packaging types. Percentages of grass-fed and grain-fed ground beef (GB) consisted of 100% grain fed GB; 80% grain-fed: 20% grass-fed GB; 60% grain-fed: 40% grass-fed GB; 40% grain-fed: 60% grass-fed GB; 20% grain-fed: 80% grass-fed GB; and 100% grass-fed GB. Packaging treatments included: high oxygen (HO; 80% O2: 20% CO2), low oxygen (LO; 65% N2: 35% CO2), carbon monoxide (CO; 65% N2: 34.6% CO2: 0.4% CO), and overwrap (OV; polyvinyl chloride film wrapped over a styrofoam tray). The modified TBARS method showed greater sensitivity and increased differences between treatments with less variability. The original extraction method showed fewer differences between treatments with greater variability. Data suggest that the modified method of TBARS determination could provide researchers with a better assay to find differences while decreasing the amount of labor., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Metastatic thyroid cancer is an uncommon condition to be present at the time of pregnancy, but presents a challenging paradigm of care. Clinicians must balance the competing interests of long-term maternal health, best achieved by iatrogenic hyperthyroidism, regular radioiodine therapy and avoidance of dietary iodine, against the priority to care for the developing foetus, with inevitable compromise. Additionally, epidemiological and cellular data support the role of oestrogen as a growth factor for benign and malignant thyrocytes, although communicating the magnitude of this risk to patients and caregivers, as well as the uncertain impact of any pregnancy on long-term prognosis, remains challenging. Evidence to support treatment decisions in this uncommon situation is presented in the context of a case of a pregnant teenager with known metastatic papillary thyroid cancer and recent radioiodine therapy., Learning Points: Pregnancy is associated with the growth of thyroid nodules due to stimulation from oestrogen receptors on thyrocytes and HCG cross-stimulation of the TSH receptor.Thyroid cancer diagnosed during pregnancy has not been shown to be associated with increased rates of persistent or recurrent disease in most studies.There is little evidence to guide the management of metastatic thyroid cancer in pregnancy, where both maternal and foetal wellbeing must be carefully balanced.

The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.

USDA Select striploins (n = 20) were cut into thirds (anterior, medial, and posterior) and randomly assigned to 1 of 6 treatments. Treatments included: (1) control (C); (2) 0.006% BHA (butylated hydroxyl anisole)/BHT (butylated hydroxytoluene) (70%/30%) (BB); (3) 0.4% trisodiumphosphate (CT); (4) 0.4% sodiumtripolyphosphate with 0.5% salt (BH); (5) sodiumtripolyphosphate, 0.5% salt, and 0.006% BHA/BHT (70%/30%) (SB); (6) 0.2% sodiumtripolyphosphate, 0.2% trisodiumphosphate, and 0.5% salt (STB). Muscle sections were injected to 110% (10% pump) of their weight with their respective treatments. Inclusion of BHA/BHT allowed for lower mean oxidation values. Regardless of phosphate type, muscles treated with both phosphate and salt had lower retail purge (P < 0.05). Sensory panelists rated (P < 0.05) STB, SB, and BH to be juicier than all other treatments. These data suggest that inclusion of both salt and phosphate can enhance palatability, lower cook loss, and retail purge.

USDA Select striploins (IMPS 180; n= 24) were cut into thirds (anterior, medial, and posterior) and assigned to 1 of 8 treatments utilizing a randomized incomplete block design. Treatments included (1) control (C); (2) 1.5% conjugated linoleic acid (conjugated linoleic acid = CLA) (CGA); (3) 0.4% sodium tripolyphosphate (PHO); (4) 0.5% salt (SAL); (5) 0.4% sodium tripolyphosphate, 0.5% salt (SPH); (6) 0.4% sodium tripolyphosphate, 1.5% CLA (PCL); (7) 0.5% salt, 1.5% CLA (SCL); and (8) 0.4% sodium tripolyphosphate, 0.5% salt, 1.5% CLA (SPC). Treatments were injected with solutions to 110% (10% pump) of their original weight. Treatments with CLA had higher (P < 0.05) marbling scores than treatments that did not. Not including SAL, treatments with salt, or phosphate or a combination of the two had higher tenderness values when sampled by panelists. Fresh steaks with inclusion of CLA had greater amounts (P < 0.05) of the CLA isomers than steaks not having CLA. Cooked steaks having CLA also had greater amounts (P < 0.05) of CLA, except for SCL, which were not different (P > 0.05) from the non-CLA treatments. Day was a significant source of variability for a*, b*, and saturation index. Treatment x day interactions were significant (P < 0.05) for hue angle and L* values. These data suggest that inclusion of CLA can increase amounts of CLA isomers without major deleterious effects to instrumental, physical, and quality characteristics of beef striploin steaks.

Three Dimensional Printing is a novel technique used in the fabrication of complex oral dosage delivery pharmaceuticals. It is possible to engineer devices with complicated internal geometries, varying densities and diffusivities, and multiple actives and excipients. Samples were fabricated using this technique using standard pharmaceutical materials. Erosion mechanism delayed-release tablets were constructed with varying polymer content from 8.9 to 17. 9%. Lag times varied between 25 and 50 min with a corresponding decrease in release rate as polymer content increased. Diffusion mechanism tablets were constructed with varying polymer content from 9.0 to 16.7%. The peak release rate decreased and the time to exhaustion increased with polymer content, whereas lag time was not affected. Active delivery studies with fluorescein indicated that Three Dimensional Printing is capable of accurately constructing dosage forms with active content as low as 10(-12) moles per tablet. Hardness and friability testing indicated that samples fabricated with this technique are comparable to other standard pharmaceutical products.

Four types of complex oral drug delivery devices have been fabricated using the three dimensional printing process. Immediate-extended release tablets were fabricated which were composed of two drug-containing sections of different pH-based release mechanisms. Pulsed release of chlorpheniramine maleate occurred after a lag time of 10 min followed by extended release of the compound over a period of 7 h. Breakaway tablets were fabricated composed of three sections. An interior fast-eroding section separating two drug-releasing sub-units eroded in 30-45 min in simulated gastric fluid. Enteric dual pulsatory tablets were constructed of one continuous enteric excipient phase into which diclofenac sodium was printed into two separated areas. These samples showed two pulses of release during in vitro USP dissolution at 1 and 8 h with a lag time between pulses of about 4 h. Dual pulsatory tablets were also fabricated. These samples were composed of two erosion based excipient sections of opposite pH based solubility. One section eroded immediately during the acid dissolution stage releasing diclofenac during the first 30 min, and the second section began eroding 5 h later during the high pH stage.