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Multiple system atrophy (MSA) and pure autonomic failure (PAF) represent distinct pathological models of autonomic failure in humans. We have investigated the neuroendocrine, behavioural and autonomic cardiovascular responses to the 35% CO2 challenge. Nine patients with MSA, nine with PAF and five control subjects received a single breath of 35% CO2. Peripheral autonomic failure (i.e., PAF) was associated with significantly lower resting noradrenaline levels. All groups demonstrated a significant pressor response to CO2. In controls, the mean pressor response was +60.2 mm Hg, which was significantly smaller in both the PAF (+26.8 mm Hg, P < 0.01) and MSA (+18.3 mm Hg, P < 0.001) patients. In addition, the onset of the response was significantly delayed in both MSA (140.2 s) and PAF (154.2 s) patients compared with controls (32.4 s, P = 0.04 and P = 0.03, respectively). Noradrenaline levels increased only in controls. Central autonomic impairment (i.e., MSA) was associated with lower cortisol release (+8.8% in MSA compared with +35.2% in control and +23.7% in PAF) and fewer somatic symptoms of emotional arousal. Both MSA and PAF exhibit marked sympathetic autonomic impairment, however, residual (albeit differing) sympathetic pathways can still maintain a partial cardiovascular response. A central autonomic lesion, however, also appears to be associated with blunting of both cortisol and emotional responses to this stress paradigm. [ABSTRACT FROM AUTHOR]

Lactation has been associated with suppression of some components of the neuroendocrine stress response. In humans, suppression of the hypothalamo–pituitary–adrenal (HPA) axis has been demonstrated in response to both a psychological and an exercise challenge, but appears to be limited to a short period of time following suckling. Information regarding other components of the stress response and to other challenges in humans is limited. We have evaluated the endocrine, autonomic and psychological response to a single breath of 35% CO2 during lactation. The 35% CO2 challenge is a safe and simple test that has been shown to stimulate the HPA axis, produce autonomic activation and emotional arousal. Eight breastfeeding and six bottle-feeding mothers, 6 weeks’ postpartum, and eight control women were studied. Twenty minutes following the cessation of feeding, plasma cortisol levels were significantly reduced in the breastfeeding women (P = 0·002 compared with control andP = 0·003 compared with bottle-feeders). Despite this, cortisol, blood pressure, heart rate and psychological responses to the challenge were no different in the breastfeeding group compared to either the control or bottle feeding groups. These results confirm that suckling is associated with short-term suppression of cortisol, but this has no effect on the ability of the mother to mount a normal hormonal, autonomic and psychological response to the 35% CO2 challenge. [ABSTRACT FROM AUTHOR]

Reports on a case of a 38-year-old man with Erdheim-Chester disease, a non-Langerhans cell histiocytosis. Medical history of the patient; Cutaneous manifestations of the disease; Histological diagnosis on the patient's retroperitoneal tissue.

Less than 20% of Australians with type 1 diabetes (T1D) meet recommended glucose targets. Technology use is associated with better glycaemia, with the most advanced being automated insulin delivery (AID) systems, which are now recommended as gold‐standard T1D care. Our Australian AID trial shows a wide spectrum of adults with T1D can achieve recommended targets. Other studies, including lived experience data, are supportive. Insulin pumps are not subsidised for most Australian adults with T1D. We advocate change. [ABSTRACT FROM AUTHOR]

AIM To assess relationships between continuous glucose monitoring (CGM) time in 70-180mg/dL range (TIR), time below range (TBR), <70mg/dL, time above range (TAR), >180mg/dL and glucose coefficient of variation (CV) in relation to currently recommended clinical CGM targets for older people, which recommend reduced TIR and TBR targets relative to the general type 1 diabetes population. METHODS We conducted a post-hoc analysis using the JDRF Australia Adult Hybrid Closed Loop trial database examining correlations in 120 adults with type 1 diabetes of 3-weeks masked CGM (Guardian Sensor 3; Medtronic) metrics (n=61 on multiple daily injections, 59 on non-CGM augmented pumps) using manual insulin dosing at baseline and at 26-weeks, with 50% randomized to automated insulin dosing (AID). RESULTS Correlations between baseline TIR and TAR were strong (r= -0.966; p<0.0001), weak for TBR (r=0.363; p<0.0001) and glucose CV (r=0.037; p=0.687) while moderate between CV and TBR (r=0.726; p<0.0001). Associations were similar for participants aged >60 years (n=15) vs. younger subjects. Correlations of changes in (∆) TIR with ∆TAR over 26-weeks were strong (r=-0.945; p<0.001) and for ∆TBR were weak (r=0.025; p=0.802). ∆CV did not significantly correlate with ∆TAR (r=-0.064; p=0.526) but did with ∆TBR (r=0.770; p=<0.001) CONCLUSIONS Changes in TIR are not associated with changes in TBR. We therefore suggest that, particularly with AID, while TBR targets in older adults may be prioritized to ensure safety that they should not be linked to TIR but addressed independently. [ABSTRACT FROM AUTHOR]

Abstract: Background: Abnormal glucose regulation (AGR) is common and an adverse risk factor in patients presenting with acute coronary syndromes (ACS). Methods: We prospectively evaluated the prevalence of AGR in 300 ACS patients. Fasting blood glucose (BGL), glycated haemoglobin (HbA1c) and urinary albumin creatinine ratio (ACR) were performed. Patients without diabetes completed an oral glucose tolerance test (OGTT) ≥4 weeks post-discharge. Results: On admission, AGR prevalence was 60%; 32% (n =94) with diabetes and 28% (n =83) with IFG. OGTT completed in 157 patients, detected new diabetes in 5% (n =8), IGT in 24% (n =37), and IFG in 6% (n =10). In 91 patients with normal admission fasting BGL, 25% (n =23) had AGR on OGTT. Conversely, in 62 patients with admission IFG, 50% (n =31) had a normal OGTT. Patients with versus those without AGR on OGTT had higher adjusted geometric mean HbA1c (5.92; 95% CI 5.81–6.02 vs. 5.66; 95% CI, 5.59–5.74, P =0.001) and urinary ACR (1.38; 95% CI, 0.99–1.91 vs. 0.74; 95% CI, 0.58–0.94, P =0.003) levels. Conclusions: AGR is present in the majority of ACS patients and unrecognised in up to half of cases. OGTT improves the detection of AGR. [Copyright &y& Elsevier]

There is limited evidence supporting the recommendation that drivers with insulin-treated diabetes need to start journeys with glucose >90 mg/dL. Glucose levels of drivers with type 1 diabetes were monitored for 3 weeks using masked continuous glucose monitoring (CGM). Eighteen drivers (median [IQR] age 40 [35, 51] years; 11 men) undertook 475 trips (duration 15 [13, 21] min). Hypoglycemia did not occur in any trip starting with glucose >90 mg/dL (92%; n = 436). Thirteen drivers recorded at least one trip (total n = 39) starting with glucose <90 mg/dL. Among these, driving glucose was <70 mg/dL in five drivers (38%) during 10 trips (26%). Among five drivers (28%), a ≥ 36 mg/dL drop was observed within 20 min of starting their journey. Journey duration was positively associated with maximum glucose change. These findings support current guidelines to start driving with glucose >90 mg/dL, and to be aware that glucose levels may change significantly within 20 min. A CGM-based, in-vehicle display could provide glucose information and alerts that are compatible with safe driving. Clinical Trial Registration number: ACTRN12617000520336. [ABSTRACT FROM AUTHOR]

Background: This prerandomization analysis from the Australian HCL-Adult trial (registration number: ACTRN12617000520336) compared masked continuous glucose monitoring (CGM) metrics among adults using insulin pumps versus multiple daily injections (MDIs), who were all self-monitoring blood glucose (SMBG). Methods: Adults with type 1 diabetes, using an insulin pump or MDIs without real-time CGM (and entering a trial of closed-loop technology), were eligible. MDI users were given an insulin dosage calculator. All participants received diabetes and carbohydrate-counting education, then wore masked CGM sensors for 3 weeks. Ethics Approval: HREC-D 088/16 Results: Adults using MDIs (n = 61) versus pump (n = 59) did not differ by age, sex, diabetes duration, insulin total daily dose, or HbA1c at baseline. After education, median (interquartile range) CGM time in range (TIR) 70-180 mg/dL (3.9-10.0 mmol/L) was 54% (47, 62) for those using MDIs and 56% (48, 66) for those using pump (P = 0.40). All CGM metrics were equivalent for 24 h/day for MDI and pump users. Overnight, those using MDIs (vs. pump) spent more time with glucose <54 mg/dL (<3.0 mmol/L): 1.4% (0.1, 5.1) versus 0.5% (0.0, 2.0), respectively (P = 0.012). They also had more CGM hypoglycemia episodes (121 vs. 54, respectively; incidence rate ratio [95% confidence interval] 2.48 [1.51, 4.06]; P < 0.001). Conclusions: Adults with type 1 diabetes using pumps versus MDIs in conjunction with SMBG experienced less nocturnal hypoglycemia, measured by masked CGM, after equivalent diabetes and dietary education in conjunction with insulin dosage calculator provision to all. However, both groups had equivalent TIR. This observation may reflect advantages afforded by flexibility in basal insulin delivery provided by pumps. [ABSTRACT FROM AUTHOR]

Objective: To investigate glycemic and psychosocial outcomes with hybrid closed-loop (HCL) versus user-determined insulin dosing with multiple daily injections (MDI) or insulin pump (i.e., standard therapy for most adults with type 1 diabetes).Research Design and Methods: Adults with type 1 diabetes using MDI or insulin pump without continuous glucose monitoring (CGM) were randomized to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was masked CGM time in range (TIR; 70-180 mg/dL) during the final 3 weeks.Results: Participants were randomized to HCL (n = 61) or control (n = 59). Baseline mean (SD) age was 44.2 (11.7) years, HbA1c was 7.4% (0.9%) (57 [10] mmol/mol), 53% were women, and 51% used MDI. HCL TIR increased from (baseline) 55% (13%) to (26 weeks) 70% (10%) with the control group unchanged: (baseline) 55% (12%) and (26 weeks) 55% (13%) (difference 15% [95% CI 11, 19]; P < 0.0001). For HCL, HbA1c was lower (median [95% CI] difference -0.4% [-0.6, -0.2]; -4 mmol/mol [-7, -2]; P < 0.0001) and diabetes-specific positive well-being was higher (difference 1.2 [95% CI 0.4, 1.9]; P < 0.0048) without a deterioration in diabetes distress, perceived sleep quality, or cognition. Seventeen (9 device-related) versus 13 serious adverse events occurred in the HCL and control groups, respectively.Conclusions: In adults with type 1 diabetes, 26 weeks of HCL improved TIR, HbA1c, and their sense of satisfaction from managing their diabetes compared with those continuing with user-determined insulin dosing and self-monitoring of blood glucose. For most people living with type 1 diabetes globally, this trial demonstrates that HCL is feasible, acceptable, and advantageous. [ABSTRACT FROM AUTHOR]

Summary: Acute tryptophan depletion (ATD) is a technique that has been used to evaluate the effects on humans of acutely reducing serotonin neurotransmission. We have developed a model using a single breath of 35% CO2 that activates the hormonal axis and produces autonomic and behavioural arousal, thus modelling a stress response. This study combines ATD and single breath 35% CO2 inhalation to study stress responses in volunteers. A randomised, double-blinded, placebo-controlled, cross-over trial involving 14 healthy adult volunteers aged between 18 and 65 years was undertaken. Subjects underwent double-blind tryptophan depletion over 2 days and were then crossed over 1 week later. During each study day, at the time of peak depletion, participants were single blinded to receive a single breath of 35% CO2 or air. This was followed 40min later by the other gas. Psychological outcomes were assessed with the Spielberger State Anxiety Inventory (SSAI), Visual Analogue Scales (VAS), Panic Inventory (PI), Panic and Agoraphobia Scale (PSI) and Beck Depression Inventory (BDI). Physiological outcome was measured by serial plasma cortisol, prolactin and tryptophan levels, pulse and blood pressure. Tryptophan depletion did not exacerbate 35% CO2 inhalation effects on anxiety symptoms. Single breath CO2 robustly increased plasma cortisol levels in comparison to an air inhalation; this was less certain for prolactin levels. ATD influenced the HPA axis (associated with higher cortisol levels), apparently independent of CO2 or air inhalation stressors. ATD and 35% CO2 inhalation both induced a pressor response and bradycardia in these normal volunteers. Thirty-five percent CO2 inhalation and ATD independently activate the human stress response, but do not appear to produce synergistic effects when combined, at least for the conditions produced in this study. [Copyright &y& Elsevier]

Summary: Background: Hypercapnia is a threat to homeostasis and results in neuroendocrine, autonomic and anxiogenic responses. The inhalation of carbon dioxide (CO2) may, therefore, provide a good paradigm for exploring the pathways by which stress can lead to increased susceptibility to ill-health through physiological and psychological stress reactivity. The current study was designed, therefore, to assess the psychological and physiological responses to the inhalation of CO2. Methods: Healthy participants (N=24) inhaled a single vital capacity breath of a mixture of CO2 (35%) and oxygen (65%). Blood pressure and heart rate were recorded for 5min before and after the test and blood and saliva samples were taken immediately before and 2, 10, 20 and 30min post-inhalation for the measurement of noradrenaline, salivary and serum cortisol and salivary α amylase. In addition, psychosomatic symptoms were recorded immediately before and after the test. The same protocol was repeated 4–6 weeks later at the same time of day. Results: A single inhalation of CO2 increased blood pressure, noradrenaline, salivary α amylase and psychosomatic symptoms, but decreased heart rate at both testing sessions. Analyses of salivary cortisol data revealed that 70% of the sample could be reliably classified as either responders (i.e. demonstrated a post-CO2 cortisol increase) or non-responders (i.e. responded with a decrease or no change in cortisol following CO2) at both test sessions. Responders also perceived the test to be more aversive than non-responders. Conclusions: Inhalation of 35% CO2 reliably stimulated the key mechanisms involved in the human stress response. The inter-individual differences in the reactivity of the hypothalamic–pituitary–adrenal axis were also related to differences in the perception of the test. [Copyright &y& Elsevier]

Objective Overt or subclinical thyroid dysfunction is common within the community, yet the significance of subtle anomalies in thyroid function tests remains contentious. The aims of this study were to: (a) establish reference intervals for serum-free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid antibodies (antithyroperoxidase, TPOAb and antithyroglobulin, TgAb) in the Busselton community of south-western Western Australia; and (b) determine the prevalence of thyroid hormone anomalies in this community. Subjects and design In 1981, 2115 adults residing in Busselton participated in a cross-sectional health survey that involved blood collection and a questionnaire on lifestyle and general health history. Measurements Serum samples were analysed for FT4, TSH, TPOAb and TgAb by immunochemiluminescent assays. Results Based on standard statistical approaches and using guidelines recommended by the National Academy of Clinical Biochemistry (NACB), reference intervals were derived for each analyte: 9–23 pmol/l for FT4, 0·4–4·0 mIU/l (TSH), < 35 KIU/l (TPOAb) and < 55 KIU/l (TgAb). The prevalence of elevated thyroid antibodies was 12·4% among subjects without a history of thyroid disease and is more common in women than in men. Elevated thyroid antibody levels were observed at both extremes of TSH abnormality, but were more commonly increased when TSH levels were above 4·0 mIU/l (63% subjects) than for those with TSH levels 0·4–4·0mIU/l (7·8% subjects). Conclusions This study establishes the prevalence of antibodies to thyroperoxidase and thyroglobulin in a community-based sample and reference intervals for free T4 and TSH. When the NACB decision limits are applied to older men or women, there is a markedly increased number with ‘elevated’ autoantibody levels compared to sex- and age-specific reference intervals. [ABSTRACT FROM AUTHOR]

Aims: To compare meal-time glycaemia in adults with type 1 diabetes mellitus (T1D) managed with multiple daily injections (MDI) vs. insulin pump therapy (IPT), using self-monitoring blood glucose (SMBG), following diabetes education.Methods: Adults with T1D received carbohydrate-counting education and a bolus calculator: MDI (Roche Aviva Expert) and IPT (pump bolus calculator). All then wore 3-weeks of masked-CGM (Enlite, Medtronic). Meal-times were assessed by two approaches: 1) Set time-blocks (breakfast 06:00-10:00hrs; lunch 11:00-15:00hrs; dinner 17:00-21:00hrs) and 2) Bolus-calculator carbohydrate entries signalling meal commencement. Post-meal masked-CGM time-in-range (TIR) 3.9-10.0 mmol/L was the primary outcome.Results: MDI(n = 61) and IPT (n = 59) participants were equivalent in age, sex, diabetes duration and HbA1c. Median (IQR) education time provided did not differ (MDI: 1.1 h (0.75, 1.5) vs. IPT: 1.1 h (1.0, 2.0); p = 0.86). Overall, daytime (06:00-24:00hrs), lunch and dinner TIR did not differ for MDI vs. IPT participants but was greater for breakfast with IPT in both analyses with a mean difference of 12.8%, (95 CI 4.8, 20.9); p = 0.002 (time-block analysis).Conclusion: After diabetes education, MDI and IPT use were associated with similar day-time glycemia, though IPT users had significantly greater TIR during the breakfast period. With education, meal-time glucose levels are comparable with use of MDI vs. pumps. [ABSTRACT FROM AUTHOR]

Background: Few long-term RCTs compare Hybrid Closed Loop (HCL) insulin delivery to manual (non-HCL) insulin dosing in type 1 diabetes (T1D). Objective: To examine glycemic and psychosocial outcomes in adults with T1D using HCL vs. manual insulin dosing with self-monitoring of blood glucose (SMBG) for 6 months. Methods: Adults using multiple daily injections or pumps with SMBG were randomized 1:1 after insulin dose optimization to 26 weeks of HCL (Medtronic 670G) or continuation of current therapy. The primary outcome was time in target range (70-180mg/dL) with masked CGM during the final 3 weeks. Secondary outcomes included other CGM metrics, HbA1c, treatment satisfaction (DTSQs) and diabetes distress (PAID). Intention to treat analysis was performed with ANCOVA or rank sum test. Results: HCL and control groups were well balanced at baseline (Table). At 26 weeks, mean (95% CI) CGM time in range with HCL was greater by 14.8% (11.1, 18.5), with reduced high and low glucose time, and lower HbA1c. There were no between-group differences in treatment satisfaction or diabetes distress (Table). Conclusions: HCL provided a significant and sustained glycemic benefit compared with standard therapy. Results will inform potential users and health professionals and a cost-benefit analysis may facilitate HCL access. Disclosure: S.A. McAuley: Advisory Panel; Self; Medtronic. Research Support; Self; Medtronic, Roche Diabetes Care. Speaker's Bureau; Self; Lilly Diabetes, Roche Diabetes Care. M.H. Lee: Research Support; Self; Medtronic. Speaker's Bureau; Self; AstraZeneca, Medtronic. B. Paldus: Research Support; Self; JDRF. Speaker's Bureau; Self; Australian Diabetes Society, Medtronic. S. Vogrin: None. M.B. Abraham: Speaker's Bureau; Self; Lilly Diabetes. L. Bach: None. M. Burt: None. N. Cohen: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes. Research Support; Self; Ypsomed AG. Speaker's Bureau; Self; Novo Nordisk A/S. P.G. Colman: None. E.A. Davis: None. C. Hendrieckx: None. M. de Bock: None. J. Holmes-Walker: None. J. Kaye: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk Inc. K. Kumareswaran: None. R. MacIsaac: None. R.W. McCallum: None. C.M. Sims: Stock/Shareholder; Self; Medtronic. J. Speight: Research Support; Self; Abbott, AstraZeneca, Medtronic, Sanofi-Aventis. Speaker's Bureau; Self; American Diabetes Association, Australian Diabetes Society, Roche Diabetes Care. S. Stranks: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Sanofi-Aventis. S. Trawley: None. V. Sundararajan: None. G. Ward: None. A.C. Keech: Advisory Panel; Self; Amgen, Kowa Research Institute, Inc. Consultant; Self; Sanofi-Aventis. Speaker's Bureau; Self; Abbott, Amgen. A. Jenkins: Advisory Panel; Self; Abbott, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Sanofi-Aventis. T. Jones: Other Relationship; Self; Medtronic. D.N. ONeal: None. [ABSTRACT FROM AUTHOR]

Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear. The receptor for advanced-glycation-end-products (RAGE) regulates immune responses and inflammation and has been linked to diabetes and possibly CF. We performed a pilot study to determine if CF and CF-related diabetes (CFRD) are associated with enhanced RAGE expression. Full length (fl)RAGE, soluble (s)RAGE, endogenous soluble (es)RAGE, S100A12 (enRAGE) and advanced-glycation-end-products (AGE) expression was assessed in serum, white blood cells and sputum of patients with CF; diabetes; CFRD and healthy subjects. Sputum enRAGE/sRAGE ratios were high in CF but particularly in CFRD which negatively correlated with % predicted FEV1. Serum AGE and AGE/sRAGE ratios were high in diabetics but not in CF. A complex, multifaceted approach was used to assess the role of RAGE and its ligands which is fundamental to determining their impact on airway inflammation. There is a clear association between RAGE activity in the airways of CF and CFRD patients that is not evident in the vascular compartment and correlates with lung function, in contrast to diabetes. This strongly suggests a role for RAGE in contributing to the inflammatory overdrive seen in CF and to a greater extent in CFRD. [ABSTRACT FROM AUTHOR]

Abstract: We assessed urine albumin in 180 diabetics by conventional immunonephelometry (IN) and HPLC methods. Those with HPLC but not IN detectable albuminuria had higher BP, worse glycaemic control and more vascular events (p <0.05 for all) but received fewer vascular risk reduction treatments. [Copyright &y& Elsevier]