Background Low-income communities and communities of color have been shown to experience disproportionate exposure to agricultural pesticides, which have been linked to poorer neurobehavioral outcomes in infants and children. Few studies have assessed health impacts of pesticide mixtures in the context of socioeconomic adversity. Objectives To examine associations between residential proximity to toxicity-weighted organophosphate (OP) and carbamate pesticide use during pregnancy, household- and neighborhood-level poverty during childhood, and IQ scores in 10-year-old children. Methods We evaluated associations between both nearby agricultural pesticide use and poverty measures and cognitive abilities in 10-year-old children (n = 501) using data from a longitudinal birth cohort study linked with data from the California Pesticide Use Reporting system and the American Community Survey. Associations were assessed using multivariable linear regression. Results Children of mothers in the highest quartile compared to the lowest quartile of proximal pesticide use had lower performance on Full Scale IQ [β = −3.0; 95% Confidence Interval (CI) = (−5.6, −0.3)], Perceptual Reasoning [β = −4.0; (−7.6, −0.4)], and Working Memory [β = −2.8; (−5.6, −0.1)]. Belonging to a household earning an income at or below the poverty threshold was associated with approximately two point lower scores on Full Scale IQ, Verbal Comprehension, and Working Memory. Living in the highest quartile of neighborhood poverty at age 10 was associated with approximately four point lower performance on Full Scale IQ, Verbal Comprehension, Perceptual Reasoning, and Working memory. Conclusions Residential proximity to OP and carbamate pesticide use during pregnancy and both household- and neighborhood-level poverty during childhood were independently associated with poorer cognitive functioning in children at 10 years of age.

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.

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.

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, 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 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, and sortilin decreased cell survival and cell migration through decreased SRC and ERK activation. Together, these data reveal TrkA, p75, and sortilin as potential therapeutic targets in thyroid cancer.

Summary 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.

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.

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, HbA1c, 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.

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 p75NTR 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, p75NTR 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, p75NTR and sortilin. In conclusion, these data suggest a preferential therapeutic value of targeting the NGF-TrkA axis in squamous cell carcinomas of the lung.