Treatment of Gestational Diabetes Mellitus Diagnosed Early in Pregnancy.

BACKGROUND: Whether treatment of gestational diabetes before 20 weeks' gestation improves maternal and infant health is unclear. METHODS: We randomly assigned, in a 1:1 ratio, women between 4 weeks' and 19 weeks 6 days' gestation who had a risk factor for hyperglycemia and a diagnosis of gestational diabetes (World Health Organization 2013 criteria) to receive immediate treatment for gestational diabetes or deferred or no treatment, depending on the results of a repeat oral glucose-tolerance test [OGTT] at 24 to 28 weeks' gestation (control). The trial included three primary outcomes: a composite of adverse neonatal outcomes (birth at <37 weeks' gestation, birth trauma, birth weight of ≥4500 g, respiratory distress, phototherapy, stillbirth or neonatal death, or shoulder dystocia), pregnancy-related hypertension (preeclampsia, eclampsia, or gestational hypertension), and neonatal lean body mass. RESULTS: A total of 802 women underwent randomization; 406 were assigned to the immediate-treatment group and 396 to the control group; follow-up data were available for 793 women (98.9%). An initial OGTT was performed at a mean (±SD) gestation of 15.6±2.5 weeks. An adverse neonatal outcome event occurred in 94 of 378 women (24.9%) in the immediate-treatment group and in 113 of 370 women (30.5%) in the control group (adjusted risk difference, -5.6 percentage points; 95% confidence interval [CI], -10.1 to -1.2). Pregnancy-related hypertension occurred in 40 of 378 women (10.6%) in the immediate-treatment group and in 37 of 372 women (9.9%) in the control group (adjusted risk difference, 0.7 percentage points; 95% CI, -1.6 to 2.9). The mean neonatal lean body mass was 2.86 kg in the immediate-treatment group and 2.91 kg in the control group (adjusted mean difference, -0.04 kg; 95% CI, -0.09 to 0.02). No between-group differences were observed with respect to serious adverse events associated with screening and treatment. CONCLUSIONS: Immediate treatment of gestational diabetes before 20 weeks' gestation led to a modestly lower incidence of a composite of adverse neonatal outcomes than no immediate treatment; no material differences were observed for pregnancy-related hypertension or neonatal lean body mass. (Funded by the National Health and Medical Research Council and others; TOBOGM Australian New Zealand Clinical Trials Registry number, ACTRN12616000924459.).

Pathophysiology from preconception, during pregnancy, and beyond.

Gestational diabetes is the most common medical complication in pregnancy. Historically, gestational diabetes was considered a pregnancy complication involving treatment of rising glycaemia late in the second trimester. However, recent evidence challenges this view. Pre-pregnancy and pregnancy-specific factors influence gestational glycaemia, with open questions regarding roles of non-glycaemic factors in the aetiology and consequences of gestational diabetes. Varying patterns of insulin secretion and resistance in early and late pregnancy underlie a heterogeneity of gestational diabetes in the timing and pathophysiological subtypes with clinical implications: early gestational diabetes and insulin resistant gestational diabetes subtypes are associated with a higher risk of pregnancy complications. Metabolic perturbations of early gestational diabetes can affect early placental development, affecting maternal metabolism and fetal development. Fetal hyperinsulinaemia can affect the development of multiple fetal tissues, with short-term and long-term consequences. Pregnancy complications are prevented by managing glycaemia in early and late pregnancy in some, but not all women with gestational diabetes. A better understanding of the pathophysiology and heterogeneity of gestational diabetes will help to develop novel management approaches with focus on improved prevention of maternal and offspring short-term and long-term complications, from pre-conception, throughout pregnancy, and beyond.

Epidemiology and management of gestational diabetes.

Gestational diabetes is defined as hyperglycaemia first detected during pregnancy at glucose concentrations that are less than those of overt diabetes. Around 14% of pregnancies globally are affected by gestational diabetes; its prevalence varies with differences in risk factors and approaches to screening and diagnosis; and it is increasing in parallel with obesity and type 2 diabetes. Gestational diabetes direct costs are US$1·6 billion in the USA alone, largely due to complications including hypertensive disorders, preterm delivery, and neonatal metabolic and respiratory consequences. Between 30% and 70% of gestational diabetes is diagnosed in early pregnancy (ie, early gestational diabetes defined by hyperglycaemia before 20 weeks of gestation). Early gestational diabetes is associated with worse pregnancy outcomes compared with women diagnosed with late gestational diabetes (hyperglycaemia from 24 weeks to 28 weeks of gestation). Randomised controlled trials show benefits of treating gestational diabetes from 24 weeks to 28 weeks of gestation. The WHO 2013 recommendations for diagnosing gestational diabetes (one-step 75 gm 2-h oral glucose tolerance test at 24-28 weeks of gestation) are largely based on the Hyperglycemia and Adverse Pregnancy Outcomes Study, which confirmed the linear association between pregnancy complications and late-pregnancy maternal glycaemia: a phenomenon that has now also been shown in early pregnancy. Recently, the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) trial showed benefit in diagnosis and treatment of early gestational diabetes for women with risk factors. Given the diabesity epidemic, evidence for gestational diabetes heterogeneity by timing and subtype, and advances in technology, a life course precision medicine approach is urgently needed, using evidence-based prevention, diagnostic, and treatment strategies.

Expression of Cathepsin D in early-stage breast cancer and its prognostic and predictive value.

PURPOSE: Cathepsin D is a proteolytic enzyme that is normally localized in the lysosomes and is involved in the malignant progression of breast cancer. There are conflicting results regarding Cathepsin D significance as prognostic and predictor marker in breast cancer. This study aimed to evaluate the expression and prognostic significance of Cathepsin D in early-stage breast cancer. METHODS: Expression of Cathepsin D was assessed by immunohistochemical staining of tissue microarrays, in a large well-characterized series of early-stage operable breast cancer (n = 954) from Nottingham Primary Breast Carcinoma Series between the period of 1988 and 1998 who underwent primary surgery. Correlation of Cathepsin D expression with clinicopathological parameters and prognosis was evaluated. RESULTS: Cathepsin D expression was positive in 71.2% (679/954) of breast cancer tumours. Positive expression of Cathepsin D was significantly associated with high histological grade (p = 0.007), pleomorphism (p = 0.002), poor Nottingham Prognostic Index (NPI) score (p < 0.002), recurrence (p = 0.005) and distant metastasis (p < 0.0001). Kaplan-Meier analysis showed that Cathepsin D expression was significantly associated with shorter breast cancer-specific survival (p = 0.001), higher risk of recurrence (p = 0.001) and distant metastasis (p < 0.0001). ER-positive tumours expressing Cathepsin D and treated with tamoxifen demonstrated a significantly higher risk of distant metastasis. CONCLUSION: Cathepsin D expression significantly predicts poor prognosis in breast cancer and is associated with variables of poor prognosis and shorter outcome. The strong association of Cathepsin D with aggressive tumour characteristics and poor outcomes warrants further research of its potential as a therapeutic target The results also suggest a possible interaction between Cathepsin D and tamoxifen therapy in ER-positive breast cancer which needs further investigation to elucidate the underlying mechanisms.

Assessing the influence of dopamine and mindfulness on the formation of routines in visual search.

Given experience in cluttered but stable visual environments, our eye-movements form stereotyped routines that sample task-relevant locations, while not mixing-up routines between similar task-settings. Both dopamine signaling and mindfulness have been posited as factors that influence the formation of such routines, yet quantification of their impact remains to be tested in healthy humans. Over two sessions, participants searched through grids of doors to find hidden targets, using a gaze-contingent display. Within each session, door scenes appeared in either one of two colors, with each color signaling a differing set of likely target locations. We derived measures for how well target locations were learned (target-accuracy), how routine were sets of eye-movements (stereotypy), and the extent of interference between the two scenes (setting-accuracy). Participants completed two sessions, where they were administered either levodopa (dopamine precursor) or placebo (vitamin C), under double-blind counterbalanced conditions. Dopamine and trait mindfulness (assessed by questionnaire) interacted to influence both target-accuracy and stereotypy. Increasing dopamine improved accuracy and reduced stereotypy for high mindfulness scorers, but induced the opposite pattern for low mindfulness scorers. Dopamine also disrupted setting-accuracy invariant to mindfulness. Our findings show that mindfulness modulates the impact of dopamine on the target-accuracy and stereotypy of eye-movement routines, whereas increasing dopamine promotes interference between task-settings, regardless of mindfulness. These findings provide a link between non-human and human models regarding the influence of dopamine on the formation of task-relevant eye-movement routines and provide novel insights into behavior-trait factors that modulate the use of experience when building adaptive repertoires.

High Dietary Iron in Western Diet-Fed Male Rats Causes Pancreatic Islet Injury and Acute Pancreatitis.

BACKGROUND: High dietary iron has been linked to an increased type 2 diabetes risk. We have previously shown that intrauterine growth restriction (IUGR) and feeding a Western diet (WD) to male Sprague-Dawley rats independently, as well as together, cause pancreatic islet inflammation, fibrosis, and hemosiderosis. OBJECTIVES: To investigate whether iron has a role in the pathogenesis of this inflammatory islet injury caused by IUGR and WD intake. METHODS: Male Sprague-Dawley offspring of bilateral uterine artery ligated (IUGR) and sham-operated (Sham) dams, fostered to nonoperated dams, were fed a WD [45% sucrose, 19.4% protein and 23% fat (w/w)] containing low iron (LI, 20 mg/kg) or high iron (HI, 500 mg/kg) from weaning. Four groups were studied: Sham-LI, Sham-HI, IUGR-LI, and IUGR-HI. Serial measurements of rat body weight, blood glucose, lipids and insulin, an intraperitoneal glucose tolerance test (age 13 wk), and histological analysis of pancreas and liver (age 14 wk) were recorded. The effects of iron, IUGR, and their interaction, on these measurements have been analyzed. RESULTS: WD with HI compared with LI caused an 11% greater weight gain by age 14 wk (P < 0.001), impaired glucose tolerance [AUC for glucose (G-AUC) 17% higher; P < 0.001), acute pancreatitis (17/18, HI; 6/17, LI; P < 0.001), pancreas-associated fat necrosis and saponification (7/18, HI; 0/17 LI; P < 0.01), and a trend to islet fibrotic injury (7/18, HI; 1/17 LI; P = 0.051). Although pancreatic and hepatic steatosis was evident in almost all WD-fed rats, pancreatic and hepatic iron accumulation was prevalent only in HI-fed rats (P < 0.0001 for both), being only mild in the livers. IUGR, independent of dietary iron, also caused impairment in glucose tolerance (G-AUC: 17% higher; P < 0.05). CONCLUSIONS: A postweaning WD containing HI, independent of IUGR, causes acute pancreatitis and islet injury in Sprague-Dawley rats suggesting a role of dietary iron in the development of steatopancreatitis.

Opportunities for primary health care: a qualitative study of perinatal health and wellbeing during bushfire crises.

BACKGROUND: During the summer of 2019/2020, Australia experienced a catastrophic wildfire season that affected nearly 80% of Australians either directly or indirectly. The impacts of climate crisis on perinatal health have only recently begun to receive attention. The objective of this study was to understand experiences of perinatal women during the bushfire and smoke events of 2019-2020 regarding health, health care, and public health messaging. METHODS: Semistructured interviews were conducted by phone or web conferencing platforms with 43 participants living in the south-east of Australia who were either pregnant or who had recently had a baby during the 2019/2020 fires. RESULTS: The health impacts on participants of the fires, associated smoke, and evacuations for some, were both physical and psychological. Many participants sought information regarding how to protect their own health and that of their unborn/recently born children, but reported this difficult to find. CONCLUSIONS: Pregnant women and new mothers exposed to bushfire events are a risk group for adverse physical and psychological outcomes. At the time of the 2019/2020 Australian bushfires, exposed women could not easily access evidence-based information to mitigate this risk. Family practitioners are well placed to provide pregnant women and new mothers with this sought-after information, but they need to be prepared well in advance of future similar events.

XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and protects against diabetic beta cell failure during metabolic stress in mice.

AIMS/HYPOTHESIS: Pancreatic beta cell dedifferentiation, transdifferentiation into other islet cells and apoptosis have been implicated in beta cell failure in type 2 diabetes, although the mechanisms are poorly defined. The endoplasmic reticulum stress response factor X-box binding protein 1 (XBP1) is a major regulator of the unfolded protein response. XBP1 expression is reduced in islets of people with type 2 diabetes, but its role in adult differentiated beta cells is unclear. Here, we assessed the effects of Xbp1 deletion in adult beta cells and tested whether XBP1-mediated unfolded protein response makes a necessary contribution to beta cell compensation in insulin resistance states. METHODS: Mice with inducible beta cell-specific Xbp1 deletion were studied under normal (chow diet) or metabolic stress (high-fat diet or obesity) conditions. Glucose tolerance, insulin secretion, islet gene expression, alpha cell mass, beta cell mass and apoptosis were assessed. Lineage tracing was used to determine beta cell fate. RESULTS: Deletion of Xbp1 in adult mouse beta cells led to beta cell dedifferentiation, beta-to-alpha cell transdifferentiation and increased alpha cell mass. Cell lineage-specific analyses revealed that Xbp1 deletion deactivated beta cell identity genes (insulin, Pdx1, Nkx6.1, Beta2, Foxo1) and derepressed beta cell dedifferentiation (Aldh1a3) and alpha cell (glucagon, Arx, Irx2) genes. Xbp1 deletion in beta cells of obese ob/ob or high-fat diet-fed mice triggered diabetes and worsened glucose intolerance by disrupting insulin secretory capacity. Furthermore, Xbp1 deletion increased beta cell apoptosis under metabolic stress conditions by attenuating the antioxidant response. CONCLUSIONS/INTERPRETATION: These findings indicate that XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and is required for beta cell compensation and prevention of diabetes in insulin resistance states.

Multifocal pupillographic objective perimetry for assessment of early diabetic retinopathy and generalised diabetes-related tissue injury in persons with type 1 diabetes.

BACKGROUND: To examine the potential utility of five multifocal pupillographic objective perimetry (mfPOP) protocols, in the assessment of early diabetic retinopathy (DR) and generalised diabetes-related tissue injury in subjects with type 1 diabetes (T1D). METHODS: Twenty-five T1D subjects (age 41.8 ± 12.1 (SD) years, 13 male) with either no DR (n = 13) or non-proliferative DR (n = 12), and 23 age and gender-matched control subjects (age 39.7 ± 12.9 years, 9 male) were examined by mfPOP using five different stimulus methods differing in visual field eccentricity (central 30° and 60°), and colour (blue, yellow or green test-stimuli presented on, respectively, a blue, yellow or red background), each assessing 44 test-locations per eye. In the T1D subjects, we assessed 16 metabolic status and diabetes complications variables. These were summarised as three principal component analysis (PCA) factors. DR severity was assessed using Early Treatment of Diabetic Retinopathy Study (ETDRS) scores. Area under the curve (AUC) from receiver operator characteristic analyses quantified the diagnostic power of mfPOP response sensitivity and delay deviations for differentiating: (i) T1D subjects from control subjects, (ii) T1D subjects according to three levels of the identified PCA-factors from control subjects, and (iii) TID subjects with from those without non-proliferative DR. RESULTS: The two largest PCA-factors describing the T1D subjects were associated with metabolic variables (e.g. body mass index, HbA1c), and tissue-injury variables (e.g. serum creatinine, vibration perception). Linear models showed that mfPOP per-region response delays were more strongly associated than sensitivities with the metabolic PCA-factor and ETDRS scores. Combined mfPOP amplitude and delay measures produced AUCs of 90.4 ± 8.9% (mean ± SE) for discriminating T1D subjects with DR from control subjects, and T1D subjects with DR from those without of 85.9 ± 8.8%. The yellow and green stimuli performed better than blue on most measures. CONCLUSIONS/INTERPRETATION: In T1D subjects, mfPOP testing was able to identify localised visual field functional abnormalities (retinal/neural reflex) in the absence or presence of mild DR. mfPOP responses were also associated with T1D metabolic status, but less so with early stages of non-ophthalmic diabetes complications.

The Potential of Current Noninvasive Wearable Technology for the Monitoring of Physiological Signals in the Management of Type 1 Diabetes: Literature Survey.

BACKGROUND: Monitoring glucose and other parameters in persons with type 1 diabetes (T1D) can enhance acute glycemic management and the diagnosis of long-term complications of the disease. For most persons living with T1D, the determination of insulin delivery is based on a single measured parameter-glucose. To date, wearable sensors exist that enable the seamless, noninvasive, and low-cost monitoring of multiple physiological parameters. OBJECTIVE: The objective of this literature survey is to explore whether some of the physiological parameters that can be monitored with noninvasive, wearable sensors may be used to enhance T1D management. METHODS: A list of physiological parameters, which can be monitored by using wearable sensors available in 2020, was compiled by a thorough review of the devices available in the market. A literature survey was performed using search terms related to T1D combined with the identified physiological parameters. The selected publications were restricted to human studies, which had at least their abstracts available. The PubMed and Scopus databases were interrogated. In total, 77 articles were retained and analyzed based on the following two axes: the reported relations between these parameters and T1D, which were found by comparing persons with T1D and healthy control participants, and the potential areas for T1D enhancement via the further analysis of the found relationships in studies working within T1D cohorts. RESULTS: On the basis of our search methodology, 626 articles were returned, and after applying our exclusion criteria, 77 (12.3%) articles were retained. Physiological parameters with potential for monitoring by using noninvasive wearable devices in persons with T1D included those related to cardiac autonomic function, cardiorespiratory control balance and fitness, sudomotor function, and skin temperature. Cardiac autonomic function measures, particularly the indices of heart rate and heart rate variability, have been shown to be valuable in diagnosing and monitoring cardiac autonomic neuropathy and, potentially, predicting and detecting hypoglycemia. All identified physiological parameters were shown to be associated with some aspects of diabetes complications, such as retinopathy, neuropathy, and nephropathy, as well as macrovascular disease, with capacity for early risk prediction. However, although they can be monitored by available wearable sensors, most studies have yet to adopt them, as opposed to using more conventional devices. CONCLUSIONS: Wearable sensors have the potential to augment T1D sensing with additional, informative biomarkers, which can be monitored noninvasively, seamlessly, and continuously. However, significant challenges associated with measurement accuracy, removal of noise and motion artifacts, and smart decision-making exist. Consequently, research should focus on harvesting the information hidden in the complex data generated by wearable sensors and on developing models and smart decision strategies to optimize the incorporation of these novel inputs into T1D interventions.

Aspirin for the prevention of pre-eclampsia in women with pre-existing diabetes: Systematic review.

BACKGROUND: There is a lack of evidence for pre-eclampsia prophylaxis with aspirin in women with pre-existing diabetes mellitus (DM). AIMS: To examine the evidence for aspirin in pre-eclampsia prophylaxis in women with pre-existing DM. MATERIAL AND METHODS: An electronic search using Ovid MEDLINE, Embase, CinicalTrials.gov and the Cochrane CENTRAL register of controlled trials through to February 2021 was performed. Reference lists of identified studies, previous review articles, clinical practice guidelines and government reports were manually searched. Randomised controlled trials (RCTs) of aspirin vs placebo for pre-eclampsia prophylaxis were included. Articles were manually reviewed to determine if cohorts included women with DM. The systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Data from included trials were extracted independently by two authors who also independently assessed risk of bias as per the Cochrane Handbook criteria version 5.1.0. Data were analysed using Rev-Man 5.4. RESULTS: Forty RCTs were identified, of which 11 included a confirmed subset of women with DM; however, data were insufficient for meta-analysis. Meta-analysis of 930 women with DM, from individual patient data included in a systematic review and unpublished data from one of the 11 RCTs, showed a non-significant difference in the outcome of pre-eclampsia in participants treated with aspirin compared to placebo (odds ratio 0.58; 95% CI 0.20-1.71; P = 0.33). CONCLUSIONS: Pre-eclampsia risk reduction with aspirin prophylaxis in women with pre-existing DM may be similar to women without pre-existing DM. However, randomised data within this meta-analysis were insufficient, warranting the need for further studies within this high-risk group of women.

The single-item Self-Rated Mental Health Question in women with gestational diabetes mellitus.

OBJECTIVE: This study aims to explore whether the single-item Self-Rated Mental Health Question (SRMHQ) may be an indicator of the need for further mental health assessment and investigation in women with gestational diabetes mellitus (GDM). METHOD: Women with GDM (n = 159) were recruited from outpatient clinics in the Australian Capital Territory prior to a GDM information session (mean gestational age = 26, SD = 4.5). Participants were aged 20-45 (mean = 33, SD = 4.2) and completed a single-item Self-Rated Health Question (SRHQ), single-item Self-Rated Mental Health Question (SRMHQ), Kessler 10-item Psychological Distress Scale (K-10), and Edinburgh Depression Scale (EDS), as well as demographic, psychiatric, and general health items. Multiple regression was used to explore whether there was an association between SRMHQ responses and K-10 or EDS total scores. RESULTS: Regression analysis revealed that the SRMHQ was a statistically significant predictor of K-10 and EDS total scores, while controlling for key potential confounders. When mental health was rated as "poor" compared to "excellent," this was associated with an additional 12 and 9 points on K-10 and EDS total scores, respectively. CONCLUSION: The SRMHQ may have a role as an indicator of the need for further mental health assessment and investigation in women with gestational diabetes mellitus.

There's no sugar-coating psychological distress and illness perceptions in gestational diabetes mellitus: depression and anxiety are associated with negative illness perceptions.

OBJECTIVE: To gain an understanding of how women with gestational diabetes perceive their illness, and whether depressive/anxiety symptoms and/or psychological distress influence these illness perceptions. METHOD: A cross-sectional study was conducted with 159 pregnant women aged 18-44 attending gestational diabetes clinics. Participants completed a questionnaire, which included the Edinburgh Depression Scale (EDS), Kessler 10-item Psychological Distress Scale (K-10), Brief Illness Perception Questionnaire (BIPQ), and psychiatric/general health items. Multiple regression was used to explore the relationship between EDS (total and anxiety subscale) scores and BIPQ scores, as well as between K-10 (total and anxiety subscale) scores and BIPQ scores. RESULTS: Regression analysis revealed a positive association between EDS total/anxiety subscale scores and BIPQ total score, as well as between K-10 total/anxiety subscale scores and BIPQ total score, controlling for potentially confounding variables. There was a strong positive correlation between EDS total score and K-10 total score. The most frequently expressed concern about GDM was an adverse effect on their baby's health. A poor diet was the most frequently reported perceived 'cause' of GDM. CONCLUSION: Greater severity of depressive and anxiety symptoms, and psychological distress, is associated with more negative illness perceptions of GDM in pregnant women.

Community Health Improvement: Social Care Is Healthcare.

Like many communities across the United States, St. Louis, Missouri, faces stark inequities in health outcomes, including wellness, quality of life, and life expectancy. These inequities are the result of social systems and policies that have robbed generations of St. Louisans of opportunity. BJC HealthCare's (BJC's) commitment to becoming a catalyst for community health by helping to eliminate health disparities led to the launch of its community health improvement strategy. This article details the community-driven and evidence-informed process that BJC used to create a multiyear, proactive approach to addressing the social and economic factors that are the root causes of health inequities. It examines areas of opportunity through which the strategy will drive change and explores lessons learned and promising practices for other healthcare institutions to consider as they advance health equity.

The Effect of Place of Service on Diabetic Screening Adherence in the Homeless Population.

This study examined the association between place of service and adherence to select diabetes screening measures in a homeless population. At a Midwestern metropolitan federally qualified health center (FQHC), 508 participants with diabetes and also experiencing homelessness were studied throughout calendar year 2018. Diabetes measures included controlled blood pressure, diabetic foot exam and hemoglobin A1C screening. Patients were seen at one of three locations: FQHC only, shelter only and both shelter and FQHC. After controlling for primary insurance, insurance status, homeless status, age group, ethnicity, primary language, race, sex and poverty level, a stepwise binary logistic regression demonstrated significant model improvement in A1c screening (p ≤ 0.001) and controlled blood pressure (p = 0.009) when place of service was added as a predictor. Specifically, results showed significant negative associations in screening adherence for shelter as compared to FQHC for both controlled blood pressure (OR = 0.40; 95% CI = 0.20-0.79; p = 0.009) and A1c screening (OR = 0.06; 95% CI = 0.03-0.16; p ≤ 0.001). Our results support the hypothesis that FQHC care results in higher rates of adherence than shelter only or FQHC and shelter combined care. The study addresses the gap in literature surrounding place of service and patient adherence. Recommendations for future research are included.

Antenatal models of care for women with gestational diabetes mellitus: Vignettes from an international meeting.

BACKGROUND: Gestational diabetes (GDM) is one of the commonest pregnancy complications and is placing an increasing burden on diabetes and obstetric resources. AIMS: To describe different antenatal models of care that have developed to address the increasing proportion of pregnancies complicated by GDM. MATERIALS AND METHODS: Narrative review with thematic analysis from 15 volunteer antenatal diabetes in pregnancy services from Australia and New Zealand identified through a national diabetes organisation. Main outcomes were approaches to patient education, medical nutrition therapy (MNT), ongoing management and escalation of therapy for women with GDM. RESULTS: All clinics provided at least one group education and one MNT session within 1-2 weeks of GDM diagnosis. Women from culturally and linguistically diverse communities usually required 1:1 education. Ongoing management of women with GDM was through either all women being seen in the GDM clinic, a step-up approach (ongoing management by the primary antenatal team with diabetes team referral if self-blood glucose monitoring (SBGM) or insulin therapy dosage criteria are reached) or step-down approach (ongoing management by the diabetes team with step-down to the primary antenatal team if SBGM criteria are reached). Telehealth was used to reduce the burden of clinic attendance, particularly in rural areas. CONCLUSIONS: Increasing numbers, earlier diagnoses, the need to provide care to women in rural, remote areas, and cultural/language differences, have generated a range of different antenatal models of care, allowed better workload accommodation and probably reduced costs. Randomised controlled trials of different models of care, with associated health economic analyses, are urgently needed.

SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment.

BACKGROUND: SHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT). METHODS: SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα- early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed. RESULTS: As previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc- [HR (95% CI) = 0.52 (0.34-0.78), p = 0.002]. Meanwhile, in ERα- patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto- [HR (95% CI) = 0.50 (0.34-0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc- or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21 vs 4%; OR (95% CI) = 5.88 (1.28-27.03), p = 0.012], or SHON-Cyto- [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18-25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc- [HR (95% CI) = 0.41 (0.19-0.87), p = 0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto- patients [HR (95% CI) = 4.63 (1.05-20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13-44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc+ (p = 0.005), and between SHON-Nuc+ and tamoxifen therapy (p = 0.007), were both statistically significant. CONCLUSION: SHON-Nuce+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.

Kinesin family member-18A (KIF18A) is a predictive biomarker of poor benefit from endocrine therapy in early ER+ breast cancer.

PURPOSE: Identification of effective and reliable biomarkers that could be used to predict the efficacy of endocrine therapy is of crucial importance to the management of oestrogen receptor positive (ER+) breast cancer (BC). KIF18A, a key regulator of cell cycle, is overexpressed in many human cancers, including BC. In this study, we investigated the role of KIF18A as a biomarker to predict the benefit from endocrine treatment in early ER + BC patients. METHODS: KIF18A expression was assessed at the genomic level using the METABRIC dataset to explore its prognostic and predictive value in ER + BC patients (n = 1506). Predictive significance of KIF18A mRNA was validated using KM-Plot datasets (n = 2061). KIF18A protein expression was assessed using immunohistochemistry in a large annotated series of early-stage ER + BC (n = 1592) with long-term follow-up. RESULTS: High mRNA and protein expression of KIF18A were associated with short recurrence-free survival (RFS), distant-metastasis free survival (DMFS) and BC specific survival (all P < 0.05) in ER + BC in patients who received no adjuvant treatment or adjuvant endocrine therapy. In multivariate analysis, high KIF18A expression was an independent prognostic biomarker for poor RFS (P = 0.027) and DMFS (P = 0.028) in patients treated with adjuvant endocrine therapy. CONCLUSION: KIF18A appears to be a candidate biomarker of a subgroup of ER + BC characterised by poor clinical outcome. High KIF18A expression has prognostic significance to predict poor benefit from endocrine treatment for patients with ER + BC. Therefore, measurement of KIF18A on ER + BC patients prior to treatment could guide clinician decision on benefit from endocrine therapy.

The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer.

PURPOSE: Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5, and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. METHODS: SLC1A5, SLC7A5, and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well-characterised BC cohort (n = 2248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. RESULTS: Clustering analysis of SLC1A5, SLC7A5, and SLC3A2 identified three clusters low SLCs (SLC1A5-/SLC7A5-/SLC3A2-), high SLC1A5 (SLC1A5+/SLC7A5-/SLC3A2-), and high SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p < 0.001). The key regulator of tumour cell metabolism, c-MYC, was significantly expressed in tumours in the high SLC cluster (p < 0.001). When different BC subtypes were considered, the association with the poor outcome was observed in the ER+ high proliferation/luminal B class only (p = 0.003). In multivariate analysis, SLC clusters were independent risk factor for shorter BC-specific survival (p = 0.001). CONCLUSION: The co-operative expression of SLC1A5, SLC7A5, and SLC3A2 appears to play a role in the aggressive subclass of ER+ high proliferation/luminal BC, driven by c-MYC, and therefore have the potential to act as therapeutic targets, particularly in synergism.

Glutamate dehydrogenase (GLUD1) expression in breast cancer.

BACKGROUND: Dysregulated cellular metabolism is one of the hallmarks of cancer with some tumours utilising the glutamine metabolism pathway for their sustained proliferation and survival. Glutamate dehydrogenase (GLUD1) is a key enzyme in glutaminolysis converting glutamate to α-ketoglutarate for entry into the TCA cycle. Breast cancer (BC) comprises a heterogeneous group of tumours in terms of molecular biology and clinical behaviour, and we have previously shown that altered glutamine metabolism varies substantially among the different molecular subtypes. We hypothesise that the prognostic value of GLUD1 expression will differ between the BC molecular subtypes and may act as a potential therapeutic target for BC tumours. METHODS: GLUD1 was assessed at the DNA, mRNA (n = 1980) and protein (n = 1300) levels in large, well-characterised cohorts and correlated with clinicopathological parameters, molecular subtypes, patient outcome, and treatments. RESULTS: There was a correlation between GLUD1 mRNA and GLUD1 protein expression which were highly expressed in low grade luminal/ER + BC (p < 0.01). GLUD1 mRNA and protein was associated with good patient outcome but not in any specific molecular subtypes. However, high GLUD1 protein expression was associated with a better outcome in triple negative (TN) patients treated with chemotherapy (p = 0.03). High GLUD1 mRNA was associated with the glutamine transporter, SLC1A5, and leucine transporter, SLC7A8 as well as mTOR (p < 0.0001). CONCLUSION: We provide comprehensive data indicating GLUD1 plays an important role in luminal/ER + BC. GLUD1 expression predicts a better patient outcome and we show that it has the potential for predicting response to chemotherapy in TNBC patients.