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Fatty acids (FAs) and other lipid molecules are important for many cellular functions, including vesicle exocytosis. For the pancreatic beta-cell, while the presence of some FAs is essential for glucose-stimulated insulin secretion, FAs have enormous capacity to amplify glucose-stimulated insulin secretion, which is particularly operative in situations of beta-cell compensation for insulin resistance. In this review, we propose that FAs do this via three interdependent processes, which we have assigned to a "trident model" of beta-cell lipid signaling. The first two arms of the model implicate intracellular metabolism of FAs, whereas the third is related to membrane free fatty acid receptor (FFAR) activation. The first arm involves the AMP-activated protein kinase/malonyl-CoA/long-chain acyl-CoA (LC-CoA) signaling network in which glucose, together with other anaplerotic fuels, increases cytosolic malonyl-CoA, which inhibits FA partitioning into oxidation, thus increasing the availability of LC-CoA for signaling purposes. The second involves glucose-responsive triglyceride (TG)/free fatty acid (FFA) cycling. In this pathway, glucose promotes LC-CoA esterification to complex lipids such as TG and diacylglycerol, concomitant with glucose stimulation of lipolysis of the esterification products, with renewal of the intracellular FFA pool for reactivation to LC-CoA. The third arm involves FFA stimulation of the G-protein-coupled receptor GPR40/FFAR1, which results in enhancement of glucose-stimulated accumulation of cytosolic Ca2+ and consequently insulin secretion. It is possible that FFA released by the lipolysis arm of TG/FFA cycling is partly "secreted" and, via an autocrine/paracrine mechanism, is additive to exogenous FFAs in activating the FFAR1 pathway. Glucose-stimulated release of arachidonic acid from phospholipids by calcium-independent phospholipase A2 and/or from TG/FFA cycling may also be involved. Improved knowledge of lipid signaling in the beta-cell will allow a better understanding of the mechanisms of beta-cell compensation and failure in diabetes. [ABSTRACT FROM AUTHOR]

Objective: To identify factors associated with neonatal respiratory distress (NRD) in early Gestational diabetes mellitus (eGDM)., Design: Nested case-control analysis of the TOBOGM trial., Setting: Seventeen hospitals: Australia, Sweden, Austria and India., Population: Pregnant women, <20 weeks' gestation, singleton, GDM risk factors., Methods: Women with GDM risk factors completed an oral glucose tolerance test (OGTT) before 20 weeks: those with eGDM (WHO-2013 criteria) were randomised to immediate or deferred GDM treatment. Logistic regression compared pregnancies with/without NRD, and in pregnancies with NRD, those with/without high-dependency nursery admission for ≤24 h with those admitted for >24 h. Comparisons were adjusted for age, pre-pregnancy body mass index, ethnicity, smoking, primigravity, education and site. Adjusted odds ratios (95% CI) are reported., Main Outcome Measures: NRD definition: ≥4 h of respiratory support (supplemental oxygen or supported ventilation) postpartum. Respiratory distress syndrome (RDS): Supported ventilation and ≥24 h nursery stay., Results: Ninety-nine (12.5%) of 793 infants had NRD; incidence halved (0.50, 0.31-0.79) if GDM treatment was started early. NRD was associated with Caesarean section (2.31, 1.42-3.76), large for gestational age (LGA) (1.83, 1.09-3.08) and shorter gestation (0.95, 0.93-0.97 per day longer). Among NRD infants, >24 h nursery-stay was associated with higher OGTT 1-h glucose (1.38, 1.08-1.76 per mmol/L). Fifteen (2.0%) infants had RDS., Conclusions: Identifying and treating eGDM reduces NRD risk. NRD is more likely with Caesarean section, LGA and shorter gestation. Further studies are needed to understand the mechanisms behind this eGDM complication and any long-term effects., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Rationale: Internally perceived stimuli evoked by morphine administration can form Pavlovian associations such that they can function as occasion setters (OSs) for externally perceived reward cues in rats, coming to modulate reward-seeking behaviour. Though much research has investigated mechanisms underlying opioid-related reinforcement and analgesia, neurotransmitter systems involved in the functioning of opioids as Pavlovian interoceptive discriminative stimuli remain to be disentangled despite documented differences in the development of tolerance to analgesic versus discriminative stimulus effects., Objectives: Dopamine has been implicated in many opioid-related behaviours, so we aimed to investigate the role of this neurotransmitter in expression of morphine occasion setting., Methods: Male and female rats were assigned to positive- (FP) or negative-feature (FN) groups and received an injection of morphine or saline before each training session. A 15-s white noise conditioned stimulus (CS) was presented 8 times during every training session; offset of this stimulus was followed by 4-s access to liquid sucrose on morphine, but not saline, sessions for FP rats. FN rats learned the reverse contingency. Following stable discrimination, rats began generalization testing for expression of morphine-guided sucrose seeking after systemic pretreatment with different doses of the non-selective dopamine receptor antagonist, flupenthixol, and the non-selective dopamine receptor agonist, apomorphine, combined with training doses of morphine or saline in a Latin-square design., Results: The morphine discrimination was acquired under both FP and FN contingencies by males and females. Neither flupenthixol nor apomorphine at any dose substituted for morphine, but both apomorphine and flupenthixol disrupted expression of the morphine OS. This inhibition was specific to sucrose seeking during CS presentations rather than during the period before CS onset and, in the case of apomorphine more so than flupenthixol, to trials on which access to sucrose was anticipated., Conclusions: Our findings lend support to a mechanism of occasion setting involving gating of CS-induced dopamine release rather than by direct dopaminergic modulation by the morphine stimulus., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We evaluated associations between early-pregnancy oral glucose tolerance test (OGTT) glucose and complications in the Treatment of Booking Gestational Diabetes Mellitus (TOBOGM) cohort to inform prognostic OGTT thresholds., Research Design and Methods: Individuals with risk factors for hyperglycemia were recruited for an international, multicenter, randomized controlled gestational diabetes mellitus (GDM) (World Health Organization 2013 criteria) treatment trial. A 2-h 75-g OGTT was performed at <20 weeks' gestation. Individuals with early treated hyperglycemia in pregnancy were excluded from the primary analysis. Early OGTT glucose concentrations were analyzed continuously and in glycemic categories (normal, low band, and high band)., Results: Overall, 3,645 individuals had an OGTT at (mean ± SD) 15.6 ± 2.5 weeks. For each 1-SD increase in fasting, 1-h, and 2-h glucose values, there were continuous positive associations with late GDM: adjusted odds ratio (aOR) 2.04 (95% CI 1.82-2.27), 3.05 (2.72-3.43), and 2.21 (1.99-2.45), respectively. There were continuous positive associations between 1-h and 2-h glucose and the perinatal composite (birth <37 + 0 weeks, birth trauma, birth weight ≥4,500 g, respiratory distress, phototherapy requirement, stillbirth/neonatal death, and shoulder dystocia), with aOR 1.15 (95% CI 1.04-1.26) and 1.14 (1.04-1.25), respectively, and with large-for-gestational-age offspring, with aOR 1.18 (1.06-1.31) and 1.26 (1.01-1.25), respectively. Significant associations were also observed between 1-h glucose and cesarean section and between fasting and 2-h glucose and neonatal hypoglycemia. In categorical analysis, only the high-band 1-h glucose (≥10.6 mmol/L [191 mg/dL]) predicted the perinatal composite., Conclusions: There is a continuous positive association between early-pregnancy OGTT glucose and complications. In individuals with hyperglycemia risk factors, only the high-glycemic-band 1-h glucose corresponded to increased risk of major perinatal complications., (© 2024 by the American Diabetes Association.)

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., Competing Interests: Declaration of interests KB reports research funding and receipt of study devices from Medtronic for the investigator-initiated CRISTAL study; receipt of study devices from Dexcom for the investigator-initiated GLORIA study; receipt of study medication from Novo Nordisk for the investigator-initiated SERENA study; and consulting fees from AstraZeneca and Lilly; and served on the speakers bureau for Novo Nordisk, AstraZeneca, and Mundipharma. DS reports receipt of study devices on loan from Tandem for the CIRCUIT study; and speaker fees from Ascensia and Sanofi. All the other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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., Competing Interests: Declaration of interests KB received research funding and study devices from Medtronic for the investigator-initiated CRISTAL study; study devices from Dexcom for the investigator-initiated GLORIA-study; study medication from Novo Nordisk for the investigator-initiated SERENA study; consulting fees from AstraZeneca and Lilly; and serves on the speakers bureau for Novo Nordisk, AstraZeneca, and Mundipharma. DS received study devices on loan from Tandem for the CIRCUIT study; and speaker fees from Ascensia and Sanofi. M-FH, PC, HB, CJDM, CLM, GD, AJ, JI, CJN, UR, and AS declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Diabetic ketoacidosis (DKA) is a life-threatening acute complication of diabetes characterized by the accumulation of ketone bodies in the blood. Breath acetone, a ketone, directly correlates with blood ketones. Therefore, monitoring breath acetone can significantly enhance the safety and efficacy of diabetes care. In this work, the design and fabrication of an InP/Pt/chitosan nanowire array-based chemiresistive acetone sensor is reported. By incorporation of chitosan as a surface-functional layer and a Pt Schottky contact for efficient charge transfer processes and photovoltaic effect, self-powered, highly selective acetone sensing is achieved. The sensor has exhibited an ultra-wide acetone detection range from sub-ppb to >100 000 ppm level at room temperature, covering those in the exhaled breath from healthy individuals (300-800 ppb) to people at high risk of DKA (>75 ppm). The nanowire sensor has also been successfully integrated into a handheld breath testing prototype, the Ketowhistle, which can successfully detect different ranges of acetone concentrations in simulated breath samples. The Ketowhistle demonstrates the immediate potential for non-invasive ketone monitoring for people living with diabetes, in particular for DKA prevention., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Disentangling which of insulin hypersecretion and insulin resistance is upstream in obesity-related type 2 diabetes (T2D) is challenging. Here, we consider the dynamics of insulin secretion and action in the fetuses of mothers with diabetes. We argue that fetal insulin hypersecretion occurs first, with insulin resistance being an adaptive protective response., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: A recently undertaken multicenter randomized controlled trial (RCT) " Treatment Of BOoking Gestational diabetes Mellitus" (TOBOGM: 2017-2022) found that the diagnosis and treatment of pregnant women with early gestational diabetes mellitus (GDM) improved pregnancy outcomes. Based on data from the trial, this study aimed to assess the cost-effectiveness of diagnosis and treatment of early GDM (from <20 weeks') among women with risk factors for hyperglycemia in pregnancy compared with usual care (no treatment until 24-28 weeks') from a healthcare perspective., Methods: Participants' healthcare resource utilization data were collected from their self-reported questionnaires and hospital records, and valued using the unit costs obtained from standard Australian national sources. Costs were reported in US dollars ($) using the purchasing power parity (PPP) estimates to facilitate comparison of costs across countries. Intention-to-treat (ITT) principle was followed. Missing cost data were replaced using multiple imputations. Bootstrapping method was used to estimate the uncertainty around mean cost difference and cost-effectiveness results. Bootstrapped cost-effect pairs were used to plot the cost-effectiveness (CE) plane and cost-effectiveness acceptability curve (CEAC)., Findings: Diagnosis and treatment of early GDM was more effective and tended to be less costly, i.e., dominant (cost-saving) [-5.6% composite adverse pregnancy outcome (95% CI: -10.1%, -1.2%), -$1373 (95% CI: -$3,749, $642)] compared with usual care. Our findings were confirmed by both the CE plane (88% of the bootstrapped cost-effect pairs fall in the south-west quadrant), and CEAC (the probability of the intervention being cost-effective ranged from 84% at a willingness-to-pay (WTP) threshold value of $10,000-99% at a WTP threshold value of $100,000 per composite adverse pregnancy outcome prevented). Sub-group analyses demonstrated that diagnosis and treatment of early GDM among women in the higher glycemic range (fasting blood glucose 95-109 mg/dl [5.3-6.0 mmol/L], 1-h blood glucose ≥191 mg/dl [10.6 mmol/L] and/or 2-h blood glucose 162-199 mg/dl [9.0-11.0 mmol/L]) was more effective and less costly (dominant) [ - 7.8% composite adverse pregnancy outcome (95% CI: -14.6%, -0.9%), -$2795 (95% CI: -$6,638, -$533)]; the intervention was more effective and tended to be less costly [ - 8.9% composite adverse pregnancy outcome (95% CI: -15.1%, -2.6%), -$5548 (95% CI: -$16,740, $1547)] among women diagnosed before 14 weeks' gestation as well., Interpretation: Our findings highlight the potential health and economic benefits from the diagnosis and treatment of early GDM among women with risk factors for hyperglycemia in pregnancy and supports its implementation. Long-term follow-up studies are recommended as a key future area of research to assess the potential long-term health benefits and economic consequences of the intervention., Funding: National Health and Medical Research Council (grants 1104231 and 2009326), Region O¨rebro Research Committee (grants Dnr OLL-970566 and OLL-942177), Medical Scientific Fund of the Mayor of Vienna (project 15,205 and project 23,026), South Western Sydney Local Health District Academic Unit (grant 2016), and Western Sydney University Ainsworth Trust Grant (2019)., Competing Interests: WHH reports participation on Merck Sharp & Dohme Board and Rivus Pharmaceuticals Board. DS reports Presidency of the Australasian Diabetes in Pregnancy Society. All otherauthor(s) have no potential conflict of interests to report., (© 2024 The Author(s).)

Objective: To compare pregnancy outcomes among women with a normal oral glucose tolerance test (OGTT) before 20 weeks' gestation (early) and at 24-28 weeks' gestation (late) (no gestational diabetes mellitus, or No-GDM), those with early GDM randomized to observation with a subsequent normal OGTT (GDM-Regression), and those with GDM on both occasions (GDM-Maintained)., Research Design and Methods: Women at <20 weeks' gestation with GDM risk factors who were recruited for a randomized controlled early GDM treatment trial were included. Women with treated early GDM and late GDM (according to the World Health Organization's 2013 criteria) were excluded from this analysis. Logistic regression compared pregnancy outcomes., Results: GDM-Regression (n = 121) group risk factor profiles and OGTT results generally fell between the No-GDM (n = 2,218) and GDM-Maintained (n = 254) groups, with adjusted incidences of pregnancy complications similar between the GDM-Regression and No-GDM groups., Conclusions: Women with early GDM but normal OGTT at 24-28 weeks' gestation had pregnancy outcomes that were similar to those of individuals without GDM. Identifying early GDM likely to regress would allow treatment to be avoided., (© 2024 by the American Diabetes Association.)

Objective: In most gestational diabetes mellitus (GDM) studies, cohorts have included women combined into study populations without regard to whether hyperglycemia was present earlier in pregnancy. In this study we sought to compare perinatal outcomes between groups: women with early GDM (EGDM group: diagnosis before 20 weeks but no treatment until 24-28 weeks if GDM still present), with late GDM (LGDM group: present only at 24-28 weeks), and with normoglycemia at 24-28 weeks (control subjects)., Research Design and Methods: This is a secondary analysis of a randomized controlled treatment trial where we studied, among women with risk factors, early (<20 weeks' gestation) GDM defined according to World Health Organization 2013 criteria. Those receiving early treatment for GDM treatment were excluded. GDM was treated if present at 24-28 weeks. The primary outcome was a composite of birth before 37 weeks' gestation, birth weight ≥4,500 g, birth trauma, neonatal respiratory distress, phototherapy, stillbirth/neonatal death, and shoulder dystocia. Comparisons included adjustment for age, ethnicity, BMI, site, smoking, primigravity, and education., Results: Women with EGDM (n = 254) and LGDM (n = 467) had shorter pregnancy duration than control subjects (n = 2,339). BMI was lowest with LGDM. The composite was increased with EGDM (odds ratio [OR] 1.59, 95% CI 1.18-2.12)) but not LGDM (OR 1.19, 95% CI 0.94-1.50). Induction of labor was higher in both GDM groups. In comparisons with control subjects there were higher birth centile, higher preterm birth rate, and higher rate of neonatal jaundice for the EGDM group (but not the LGDM group). The greatest need for insulin and/or metformin was with EGDM., Conclusions: Adverse perinatal outcomes were increased with EGDM despite treatment from 24-28 weeks' gestation, suggesting the need to initiate treatment early, and more aggressively, to reduce the effects of exposure to the more severe maternal hyperglycemia from early pregnancy., (© 2024 by the American Diabetes Association.)

Introduction: To prevent progression of early-stage diabetic retinopathy, we need functional tests that can distinguish multiple levels of neural damage before classical vasculopathy. To that end, we compared multifocal pupillographic objective perimetry (mfPOP), and two types of subjective automated perimetry (SAP), in persons with type 2 diabetes (PwT2D) with either no retinopathy (noDR) or mild to-moderate non-proliferative retinopathy (mmDR)., Methods: Both eyes were assessed by two mfPOP test methods that present stimuli within either the central ±15° (OFA15) or ±30° (OFA30), each producing per-region sensitivities and response delays. The SAP tests were 24-2 Short Wavelength Automated Perimetry and 24-2 Matrix perimetry., Results: Five of eight mfPOP global indices were significantly different between noDR and mmDR eyes, but none of the equivalent measures differed for SAP. Per-region mfPOP identified significant hypersensitivity and longer delays in the peripheral visual field, verifying earlier findings. Diagnostic power for discrimination of noDR vs. mmDR, and normal controls vs. PwT2D, was much higher for mfPOP than SAP. The mfPOP per-region delays provided the best discrimination. The presence of localized rather than global changes in delay ruled out iris neuropathy as a major factor., Discussion: mfPOP response delays may provide new surrogate endpoints for studies of interventions for early-stage diabetic eye damage., Competing Interests: TM, JK, CC and FS could earn royalty income from the sale of the OFA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sabeti, van Kleef, Iyer, Carle, Nolan, Chia and Maddess.)

Pancreas agenesis is a rare condition underlying a variant of permanent neonatal diabetes mellitus. Neonates with this condition are born small for gestational age, but less is known about which components of growth are impacted, the timing of the growth restriction and potential sex differences. Our objective was to assess in which periods in gestation complete pancreas agenesis restricts fetal growth and possible sex differences in susceptibility. Published cases (n=49) with pancreas agenesis providing relevant data (gestational age, fetal sex, birth weight, birth length, head circumference, placental weight) were identified by MEDLINE and secondary literature search covering the years 1950-January 2023. Semi-quantitative analysis of these case reports used centiles based on Intergrowth-21 reference charts. Neonates with pancreas agenesis were severely growth restricted, however, median centiles for birth weight, length and head circumference of those born before week 36 were significantly higher compared to those born from 36 weeks. Similar results were found when data were separated by before and from 38 weeks. Head circumference was less affected than birth weight or length. No sex differences were found. In conclusion, pancreas agenesis severely restricts fetal length and head circumference in addition to weight growth, with stronger effects evident from 36 weeks of gestation. In addition to the well-known effects of insulin on growth of fetal fat mass, the pronounced effect on birth length and head circumference indicates effects of insulin on fetal lean body growth as well. Lack of power may account for failure to find sex differences.

Background: The compounding effects of climate change catastrophes such as bushfires and pandemics impose significant burden on individuals, societies, and their economies. The enduring effects of such syndemics on mental health remain poorly understood, particularly for at-risk populations (e.g., pregnant women and newborns). The aim of this study was to investigate the impact of direct and indirect exposure to the 2019/20 Australian Capital Territory and South-Eastern New South Wales bushfires followed by COVID-19 on the mental health and wellbeing of pregnant women and mothers with newborn babies., Methods: All women who were pregnant, had given birth, or were within three months of conceiving during the 2019/2020 bushfires, lived within the catchment area, and provided consent were invited to participate. Those who consented were asked to complete three online surveys. Mental health was assessed with the DASS-21 and the WHO-5. Bushfire, smoke, and COVID-19 exposures were assessed by self-report. Cross-sectional associations between exposures and mental health measures were tested with hierarchical regression models., Results: Of the women who participated, and had minimum data ( n = 919), most (>75%) reported at least one acute bushfire exposure and 63% reported severe smoke exposure. Compared to Australian norms, participants had higher depression (+12%), anxiety (+35%), and stress (+43%) scores. Women with greater exposure to bushfires/smoke but not COVID-19 had poorer scores on all mental health measures., Conclusions: These findings provide novel evidence that the mental health of pregnant women and mothers of newborn babies is vulnerable to major climate catastrophes such as bushfires.

The prevailing COVID-19 pandemic and climate change-mediated wildfires can combine to impact maternal-child health, yet this connection remains understudied. To shape policies and design interventions to mitigate the combined effects of future global catastrophes, it is vital to holistically evaluate the impact of syndemics on maternal-child health., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Schizophrenia is a severe neuropsychiatric disorder with significant differences in the incidence and symptomology between cisgender men and women. In recent years, considerably more attention has been on the inclusion of sex and gender in schizophrenia research. However, the majority of this research has failed to consider gender outside of the socially constructed binary of men and women. As a result, little is known about schizophrenia in transgender and gender-nonconforming populations. In this review, we present evidence showing that transgender and gender-nonconforming individuals have elevated risk of developing schizophrenia, and we discuss minority stress theory and other potential factors that may contribute to this risk. The need for inclusion of transgender and gender-nonconforming communities in schizophrenia research is emphasized, alongside a discussion on considerations and challenges associated with this type of research. Finally, we offer specific strategies to make research on schizophrenia, and research on other neuropsychiatric disorders, more inclusive of those populations that do not fall within the socially constructed gender binary. If we are to succeed in the development of more personalized therapeutic approaches for all, a better understanding of the variability of the human brain is needed., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: The dopamine D5 receptor (D5R) shows high expression in cortical regions, yet the role of the receptor in learning and memory remains poorly understood. This study evaluated the impact of prefrontal cortical (PFC) D5R knockdown in rats on learning and memory and assessed the role of the D5R in the regulation of neuronal oscillatory activity and glycogen synthase kinase-3 (GSK-3β), processes integral to cognitive function., Materials and Methods: Using an adeno-associated viral (AAV) vector, male rats were infused with shRNA to the D5R bilaterally into the PFC. Local field potential recordings were taken from freely moving animals and spectral power and coherence were evaluated in, and between, the PFC, orbitofrontal cortex (OFC), hippocampus (HIP), and thalamus. Animals were then assessed in object recognition, object location, and object in place tasks. The activity of PFC GSK-3β, a downstream effector of the D5R, was evaluated., Results: AAV-mediated knockdown of the D5R in the PFC induced learning and memory deficits. These changes were accompanied by elevations in PFC, OFC, and HIP theta spectral power and PFC-OFC coherence, reduced PFC-thalamus gamma coherence, and increased PFC GSK-3β activity., Conclusion: This work demonstrates a role for PFC D5Rs in the regulation of neuronal oscillatory activity and learning and memory. As elevated GSK-3β activity has been implicated in numerous disorders of cognitive dysfunction, this work also highlights the potential of the D5R as a novel therapeutic target via suppression of GSK-3β., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Adverse environmental exposures in utero and early childhood are known to programme long-term health. Climate change, by contributing to severe heatwaves, wildfires, and other natural disasters, is plausibly associated with adverse pregnancy outcomes and an increase in the future burden of chronic diseases in both mothers and their babies. In this Personal View, we highlight the limitations of existing evidence, specifically on the effects of severe heatwave and wildfire events, and compounding syndemic events such as the COVID-19 pandemic, on the short-term and long-term physical and mental health of pregnant women and their babies, taking into account the interactions with individual and community vulnerabilities. We highlight a need for an international, interdisciplinary collaborative effort to systematically study the effects of severe climate-related environmental crises on maternal and child health. This will enable informed changes to public health policy and clinical practice necessary to safeguard the health and wellbeing of current and future generations., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The development of continuous glucose monitoring (CGM) systems has enabled people with type 1 diabetes mellitus (T1DM) to track their glucose trajectory in real-time and inspired research in personalised glucose prediction. In this paper, our aim is to predict postprandial abnormal-glycemia events. Different from prior research which focuses on hypoglycemia only, we make the first attempt to establish our problem as the joint prediction of hyperglycemia and hypoglycemia. On this basis, we propose a machine learning model that learns from the pattern of 1 hour past glucose and makes predictions for the two tasks simultaneously using a unified backbone. Key benefits of our methodology include 1) requiring only the CGM sequence as the input, thus making it more widely applicable than other counterparts using extra inputs such as the nutrition details, and 2) minimising the computational cost as the two tasks are unified into a single model. Our experiments on the openly available OhioT1DM dataset achieve state-of-the-art performance (Matthew's correlation coefficient of 0.61 for hyperglycemia and 0.48 for hypoglycemia). To encourage further study, we release our codes at https://github.com/r-cui/PostprandialHyperHypoPrediction under the MIT license.

Background: Both obesity and sleep disorders are common among women during pregnancy. Although prior research has identified a relationship between obesity and sleep disorders, those findings are from women later in pregnancy., Objective: To explore the relationships between self-reported sleep duration, insufficient sleep and snoring with body mass index (BMI) among multiethnic women at risk of gestational diabetes mellitus (GDM)in early pregnancy., Methods: Cross-sectional study of baseline data from women at risk of GDM enrolled in the Treatment of BOoking Gestational diabetes Mellitus (TOBOGM) multicentre trial across 12 Australian/Austrian sites. Participants completed a questionnaire before 20 weeks' gestation to evaluate sleep. BMI <25 kg/m 2 served as the reference group in multivariable logistic regression., Results: Among the 2865 women included, the prevalence of overweight and obesity classes I-III was 28%, 19%, 11% and 12%, respectively. There was no relationship between sleep duration and BMI. The risk of insufficient sleep >5 days/month was higher in class II and class III obesity (1.38 (1.03-1.85) and 1.34 (1.01-1.80), respectively), and the risk of snoring increased as BMI increased (1.59 (1.25-2.02), 2.68 (2.07-3.48), 4.35 (3.21-5.88) to 4.96 (3.65-6.74), respectively))., Conclusions: Obesity is associated with insufficient sleep among pregnant women at risk of GDM. Snoring is more prevalent with increasing BMI., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Purpose: Retinal function beyond foveal vision is not routinely examined in the clinical screening and management of diabetic retinopathy although growing evidence suggests it may precede structural changes. In this study we compare optical coherence tomography (OCT) based macular structure with function measured objectively with the ObjectiveFIELD Analyzer (OFA), and with Matrix perimetry. We did that longitudinally in Type 2 diabetes (T2D) patients with mild Diabetic Macular Oedema (DMO) with good vision and a similar number of T2D patients without DMO, to evaluate changes in retinal function more peripherally over the natural course of retinopathy., Methods: Both eyes of 16 T2D patients (65.0 ± 10.1, 10 females), 10 with baseline DMO, were followed for up longitudinally for 27 months providing 94 data sets. Vasculopathy was assessed by fundus photography. Retinopathy was graded using to Early Treatment of Diabetic Retinopathy Study (ETDRS) guidelines. Posterior-pole OCT quantified a 64-region/eye thickness grid. Retinal function was measured with 10-2 Matrix perimetry, and the FDA-cleared OFA. Two multifocal pupillographic objective perimetry (mfPOP) variants presented 44 stimuli/eye within either the central 30° or 60° of the visual field, providing sensitivities and delays for each test-region. OCT, Matrix and 30° OFA data were mapped to a common 44 region/eye grid allowing change over time to be compared at the same retinal regions., Results: In eyes that presented with DMO at baseline, mean retinal thickness reduced from 237 ± 25 μm to 234.2 ± 26.7 μm, while the initially non-DMO eyes significantly increased their mean thickness from 250.7 ± 24.4 μm to 255.7 ± 20.6 μm (both p<0.05). Eyes that reduced in retinal thickness over time recovered to more normal OFA sensitivities and delays (all p<0.021). Matrix perimetry quantified fewer regions that changed significantly over the 27 months, mostly presenting in the central 8 degrees., Conclusions: Changes in retinal function measured by OFA possibly offer greater power to monitor DMO over time than Matrix perimetry data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sabeti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.)., (Copyright © 2023 Massachusetts Medical Society.)

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., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To improve birth outcomes, all pregnant women without known diabetes are recommended for an oral glucose tolerance test (OGTT) to screen for hyperglycaemia in pregnancy (diabetes in pregnancy or gestational diabetes mellitus (GDM)). This narrative review presents contemporary approaches to minimise preanalytical glycolysis in OGTT samples with a focus on GDM diagnosis using criteria derived from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. The challenges of implementing each approach across a diverse Australian healthcare setting were explored. Many Australian sites currently collect and transport OGTT samples at ambient temperature in sodium fluoride (NaF) tubes which is likely to lead to missed diagnosis of GDM in a significant proportion of cases. Alternative preanalytical solutions should be pragmatic and tailored to individual settings and as close as possible to the preanalytical conditions of the HAPO study for correct interpretation of OGTT results. Rapid centrifugation of barrier tubes to separate plasma could be suitable in urban settings provided time to centrifugation is strictly controlled. Tubes containing NaF and citrate could be useful for remote or resource poor settings with long delays to analysis but the impact on the interpretation of OGTT results should be carefully considered. Testing venous blood glucose at the point-of-care bypasses the need for glycolytic inhibition but requires careful selection of devices with robust analytical performance. Studies to evaluate the potential error of each solution compared to the HAPO protocol are required to assess the magnitude of misdiagnosis and inform clinicians regarding the potential impact on patient safety and healthcare costs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Since the 1930s, California's Sierra Nevada has warmed by an average of 1.2 ∘ C. Warming directly primes forests for easier wildfire ignition, but the change in climate also affects vegetation species composition. Different types of vegetation support unique fire regimes with distinct probabilities of catastrophic wildfire, and anticipating vegetation transitions is an important but undervalued component of long-term wildfire management and adaptation. Vegetation transitions are more likely where the climate has become unsuitable but the species composition remains static. This vegetation climate mismatch (VCM) can result in vegetation conversions, particularly after a disturbance like wildfire. Here we produce estimates of VCM within conifer-dominated forests in the Sierra Nevada. Observations from the 1930s Wieslander Survey provide a foundation for characterizing the historical relationship between Sierra Nevada vegetation and climate before the onset of recent, rapid climate change. Based on comparing the historical climatic niche to the modern distribution of conifers and climate, ∼19.5% of modern Sierra Nevada coniferous forests are experiencing VCM, 95% of which is below an elevation of 2356 m. We found that these VCM estimates carry empirical consequences: likelihood of type-conversion increased by 9.2% for every 10% decrease in habitat suitability. Maps of Sierra Nevada VCM can help guide long-term land management decisions by distinguishing areas likely to transition from those expected to remain stable in the near future. This can help direct limited resources to their most effective uses-whether it be protecting land or managing vegetation transitions-in the effort to maintain biodiversity, ecosystem services, and public health in the Sierra Nevada., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Background: An important strategy to understand young people's needs regarding technologies for type 1 diabetes mellitus (T1DM) management is to examine their day-to-day experiences with these technologies., Objective: This study aimed to examine young people's and their caregivers' experiences with diabetes technologies in an exploratory way and relate the findings to the existing technology acceptance and technology design theories. On the basis of this procedure, we aimed to develop device characteristics that meet young people's needs., Methods: Overall, 16 in-person and web-based face-to-face interviews were conducted with 7 female and 9 male young people with T1DM (aged between 12 and 17 years) and their parents between December 2019 and July 2020. The participants were recruited through a pediatric diabetes clinic based at Canberra Hospital. Data-driven thematic analysis was performed before theory-driven analysis to incorporate empirical data results into the unified theory of acceptance and use of technology (UTAUT) and value-sensitive design (VSD). We used the COREQ (Consolidated Criteria for Reporting Qualitative Research) checklist for reporting our research procedure and findings. In this paper, we summarize the key device characteristics that meet young people's needs., Results: Summarized interview themes from the data-driven analysis included aspects of self-management, device use, technological characteristics, and feelings associated with device types. In the subsequent theory-driven analysis, the interview themes aligned with all UTAUT and VSD factors except for one (privacy). Privacy concerns or related aspects were not reported throughout the interviews, and none of the participants made any mention of data privacy. Discussions around ideal device characteristics focused on reliability, flexibility, and automated closed loop systems that enable young people with T1DM to lead an independent life and alleviate parental anxiety. However, in line with a previous systematic review by Brew-Sam et al, the analysis showed that reality deviated from these expectations, with inaccuracy problems reported in continuous glucose monitoring devices and technical failures occurring in both continuous glucose monitoring devices and insulin pumps., Conclusions: Our research highlights the benefits of the transdisciplinary use of exploratory and theory-informed methods for designing improved technologies. Technologies for diabetes self-management require continual advancement to meet the needs and expectations of young people with T1DM and their caregivers. The UTAUT and VSD approaches were found useful as a combined foundation for structuring the findings of our study., (©Nicola Brew-Sam, Anne Parkinson, Madhur Chhabra, Adam Henschke, Ellen Brown, Lachlan Pedley, Elizabeth Pedley, Kristal Hannan, Karen Brown, Kristine Wright, Christine Phillips, Antonio Tricoli, Christopher J Nolan, Hanna Suominen, Jane Desborough. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 25.01.2023.)

Introduction: The terms 'precision medicine' and 'personalised medicine' have become key terms in health-related research and in science-related public communication. However, the application of these two concepts and their interpretation in various disciplines are heterogeneous, which also affects research translation and public awareness. This leads to confusion regarding the use and distinction of the two concepts. Our aim is to provide a snapshot of the current understanding of these concepts., Methods and Analysis: Our study will use Rodgers' evolutionary concept analysis to systematically examine the current understanding of the concepts 'precision medicine' and 'personalised medicine' in clinical medicine, biomedicine (incorporating genomics and bioinformatics), health services research, physics, chemistry, engineering, machine learning and artificial intelligence, and to identify their respective attributes (clusters of characteristics) and surrogate and related terms. A systematic search of the literature will be conducted for 2016-2022 using databases relevant to each of these disciplines: ACM Digital Library, CINAHL, Cochrane Library, F1000Research, IEEE Xplore, PubMed/Medline, Science Direct, Scopus and Web of Science. These are among the most representative databases for the included disciplines. We will examine similarities and differences in definitions of 'precision medicine' and 'personalised medicine' in the respective disciplines and across (sub)disciplines, including attributes of each term. This will enable us to determine how these two concepts are distinguished., Ethics and Dissemination: Following ethical and research standards, we will comprehensively report the methodology for a systematic analysis following Rodgers' concept analysis method. Our systematic concept analysis will contribute to the clarification of the two concepts and distinction in their application in given settings and circumstances. Such a broad concept analysis will contribute to non-systematic syntheses of the concepts, or occasional systematic reviews on one of the concepts that have been published in specific disciplines, in order to facilitate interdisciplinary communication, translational medical research and implementation science., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Background: Portable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however, the design features preferred by users have not been studied. We aimed to elucidate breath sensor design preferences of young people with T1DM (age 12 to 16) and their parents to inform the development of a breath ketone sensor prototype that would best suit their diabetes management needs., Research Designs and Methods: To elicit foundational experiences from which design preference ideas could be generated, two commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM. Participants interacted with the breath ketone sensing devices, and undertook blood ketone testing, at least twice daily for five days to simulate use within a real life and ambulatory care setting. Semi-structured interviews were conducted post-testing with the ten young participants and their caregivers (n = 10) to elicit preferences related to breath sensor design and use, and to inform the co-design of a breath ketone sensor prototype for use in T1DM self-management. We triangulated our data collection with key informant interviews with two diabetes educators working in pediatric care about their perspectives related to young people using breath ketone sensors., Results: Participants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people who tended to under-test using blood ketone strips., Conclusions: Breath ketone sensors for diabetes management have potential that may facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Nicotine and alcohol-containing products are some of the most commonly used substances of abuse and are both leading causes of preventable death. These substances also have significant interactions that have additive and, in some cases, multiplicative effects on the health consequences of their use. Thus, to reduce these negative consequences, it is important to understand the abuse liability of nicotine and alcohol in combination, especially in the most relevant use cases among those who are most vulnerable. Specifically, as tobacco cigarette use is continually decreasing, vaping is quickly replacing cigarettes as the primary mode of nicotine use. This pattern is especially true in adolescent populations in which vaping has grown considerably. Particularly concerning is that adolescents are more vulnerable than adults to the negative consequences of substance use. It is therefore imperative to revisit the literature as it relates to the rising state of co-use of vaping products with alcohol. Here, we review the clinical outcomes of nicotine and alcohol co-use as they relate to the abuse liability of each individually. Special attention is paid to adolescent findings, where available, as well as investigations that use nontobacco nicotine products as these may more accurately reflect the more recent trends of co-use., Implications: Though nicotine alone has previously been considered a proxy for tobacco and tobacco cigarette use, combustible routes of administration have been decreasing. They are, instead, being replaced by e-cigarettes that do not involve other tobacco constituents and contain additional nonnicotine constituents of their own. Unfortunately, the literature remains limited with regard to e-cigarettes and their interactions with other substances, especially their prevalent co-use with alcohol. This review attempts to discuss the current literature on nicotine and alcohol co-use in the context of the vaping epidemic, predominantly focusing on addiction-related outcomes and why e-cigarette use may be unique., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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., (©Elena Daskalaki, Anne Parkinson, Nicola Brew-Sam, Md Zakir Hossain, David O'Neal, Christopher J Nolan, Hanna Suominen. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.04.2022.)

Background: Type 1 diabetes (T1D) is a chronic autoimmune disease in which a deficiency in insulin production impairs the glucose homeostasis of the body. Continuous subcutaneous infusion of insulin is a commonly used treatment method. Artificial pancreas systems (APS) use continuous glucose level monitoring and continuous subcutaneous infusion of insulin in a closed-loop mode incorporating a controller (or control algorithm). However, the operation of APS is challenging because of complexities arising during meals, exercise, stress, sleep, illnesses, glucose sensing and insulin action delays, and the cognitive burden. To overcome these challenges, options to augment APS through integration of additional inputs, creating multi-input APS (MAPS), are being investigated., Objective: The aim of this survey is to identify and analyze input data, control architectures, and validation methods of MAPS to better understand the complexities and current state of such systems. This is expected to be valuable in developing improved systems to enhance the quality of life of people with T1D., Methods: A literature survey was conducted using the Scopus, PubMed, and IEEE Xplore databases for the period January 1, 2005, to February 10, 2020. On the basis of the search criteria, 1092 articles were initially shortlisted, of which 11 (1.01%) were selected for an in-depth narrative analysis. In addition, 6 clinical studies associated with the selected studies were also analyzed., Results: Signals such as heart rate, accelerometer readings, energy expenditure, and galvanic skin response captured by wearable devices were the most frequently used additional inputs. The use of invasive (blood or other body fluid analytes) inputs such as lactate and adrenaline were also simulated. These inputs were incorporated to switch the mode of the controller through activity detection, directly incorporated for decision-making and for the development of intermediate modules for the controller. The validation of the MAPS was carried out through the use of simulators based on different physiological models and clinical trials., Conclusions: The integration of additional physiological signals with continuous glucose level monitoring has the potential to optimize glucose control in people with T1D through addressing the identified limitations of APS. Most of the identified additional inputs are related to wearable devices. The rapid growth in wearable technologies can be seen as a key motivator regarding MAPS. However, it is important to further evaluate the practical complexities and psychosocial aspects associated with such systems in real life., (©Chirath Hettiarachchi, Elena Daskalaki, Jane Desborough, Christopher J Nolan, David O’Neal, Hanna Suominen. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 24.02.2022.)