Sleep studies in children on long-term non-invasive respiratory support

Purpose

The aim of this study was to assess the impact of changes in respiratory support (RS) settings recommended after a titration polysomnography (PSG), in terms of daytime symptoms and quality of life.

Methods

A retrospective chart review of all RS (CPAP and bi-level ventilation) titration studies was carried out at our tertiary paediatric sleep laboratory in the past 5 years. All patients with at least two studies in the past 5 years were included in the analysis. Parents completed the obstructive sleep apnoea (OSA)-18 and Paediatric Daytime Sleepiness Scale (PDSS) questionnaires on the night of each PSG. Results are presented as means (SD).

Results

A total of 42 patients (25 on CPAP and 17 on bi-level ventilation, age 11 (6)?years) had 71 pairs of titration studies (41 CPAP and 30 bi-level). Changes in RS settings were recommended in 27 of 41 (65 %) CPAP studies and 11 of 30 (36 %) bi-level studies. Overall, changes were fully implemented by the treating physician in 55 % of cases. There was an improvement in total OSA-18 score between studies in 48 % of the paired CPAP studies and 65 % of bi-level studies. OSA-18 scores improved in 47 % of the studies where any recommended change had been implemented versus 0 % of those where none of the recommended changes had been made (p?=?0.1).

Conclusions

Titration studies frequently led to recommendations for a change in RS settings in these patients on long-term RS. Symptom scores were more likely to improve if recommendations for change were implemented by the time of the follow-up study.     

Antecedent hypoglycaemia does not diminish the glycaemia-increasing effect and glucoregulatory responses of a 10 s sprint in people with type 1 diabetes

Aims/hypothesis

A 10 s sprint has been reported to provide a means to prevent acute post-exercise hypoglycaemia in young adults with type 1 diabetes because of its glycaemia-raising effect, but it is unclear whether this effect is impaired by antecedent hypoglycaemia. The purpose of this study was to investigate whether antecedent hypoglycaemia impairs the glycaemia-raising effect of a 10 s sprint in individuals with type 1 diabetes.

Methods

Eight individuals underwent a hyperinsulinaemic–hypoglycaemic or hyperinsulinaemic–euglycaemic clamp on two separate mornings. Thereafter, the participants underwent a basal insulin–euglycaemic clamp before performing a 10 s sprint on a cycle ergometer. The levels of blood glucose and glucoregulatory hormones and rates of glucose appearance (Ra) and disappearance (Rd) were compared between conditions.

Results

During the morning clamps, blood glucose levels were significantly different between conditions of hypoglycaemia (2.8?±?0.1 mmol/l) and euglycaemia (5.4?±?0.2 mmol/l; p?<?0.001). Mean glycaemia prior to sprinting was similar (5.6?±?0.4 and 5.5?±?0.3 mmol/l for hypoglycaemic and euglycaemic conditions, respectively; p?=?0.83). In response to the afternoon sprint, the pattern of increase in blood glucose levels did not differ between conditions, reaching similar maximal levels 45 min after exercise (6.5?±?0.4 and 6.6?±?0.3 mmol/l, respectively; p?=?0.43). The early post-exercise patterns in glucose Ra and Rd and increases in plasma adrenaline (epinephrine), growth hormone and cortisol levels did not differ between conditions.

Conclusions/interpretation

Hypoglycaemia in the morning does not diminish the glycaemia-raising effect of an afternoon 10 s sprint in young adults with type 1 diabetes, suggesting that sprinting is a useful strategy for opposing hypoglycaemia, regardless of prior hypoglycaemia.     

Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor whose function can be allosterically modulated in a positive or negative manner by calcimimetics or calcilytics, respectively. Indeed, the second-generation calcimimetic, cinacalcet, has proven clinically useful in the treatment of chronic kidney disease patients with secondary hyperparathyroidism but is not widely used in earlier stages of renal disease due to the potential to predispose such patients to hypocalcaemia and hyperphosphatemia. The development of a biased CaSR ligand that is more selective for specific signaling pathway(s) leading only to beneficial effects may overcome this limitation. The detection of such stimulus-bias at a G protein-coupled receptor requires investigation across multiple signaling pathways and the development of methods to quantify the effects of allosteric ligands on orthosteric ligand affinity and cooperativity at each pathway. In the current study, we determined the effects of the calcimimetics, NPS-R568 or cinacalcet, and the calcilytic, NPS-2143, on Ca(o)(2+)-mediated intracellular Ca(2+) mobilization, ERK1/2 phosphorylation, and plasma membrane ruffling in a stably transfected human embryonic kidney 293-TREx c-myc-CaSR cell line and applied a novel analytical model to quantify these modulator effects. We present quantitative evidence for the generation of stimulus bias by both positive and negative allosteric modulators of the CaSR, manifested as greater allosteric modulation of intracellular Ca(2+) mobilization relative to ERK1/2 phosphorylation, and a higher affinity of the modulators for the state of the CaSR mediating plasma membrane ruffling relative to the other two pathways. Our findings provide the first evidence that an allosteric modulator used in clinical practice exhibits stimulus bias.     

The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: a meta-analysis

Aims/hypothesis  

It is well established that diabetes mellitus increases the risk of cardiovascular disease (CVD) and all-cause mortality. Observational studies suggest that a history of diabetic foot ulceration (DFU) may increase this risk further still. We sought to determine to what extent DFU is associated with excess risk over and above diabetes.     

The Association of Beliefs About Heredity with Preventive and Interpersonal Behaviors in Communities Affected by Podoconiosis in Rural Ethiopia

Little is known about how beliefs about heredity as a cause of health conditions might influence preventive and interpersonal behaviors among those individuals with low genetic and health literacy. We explored causal beliefs about podoconiosis, a neglected tropical disease (NTD) endemic in Ethiopia. Podoconiosis clusters in families but can be prevented if individuals at genetically high risk wear shoes consistently. Adults (N = 242) from four rural Ethiopian communities participated in qualitative assessments of beliefs about the causes of podoconiosis. Heredity was commonly mentioned, with heredity being perceived as (1) the sole cause of podoconiosis, (2) not a causal factor, or (3) one of multiple causes. These beliefs influenced the perceived controllability of podoconiosis and in turn, whether individuals endorsed preventive and interpersonal stigmatizing behaviors. Culturally informed education programs that increase the perceived controllability of stigmatized hereditary health conditions like podoconiosis have promise for increasing preventive behaviors and reducing interpersonal stigma.     

USING MENDELIAN RANDOMISATION TO INFER CAUSALITY IN DEPRESSION AND ANXIETY RESEARCH

Depression and anxiety co‐occur with substance use and abuse at a high rate. Ascertaining whether substance use plays a causal role in depression and anxiety is difficult or impossible with conventional observational epidemiology. Mendelian randomisation uses genetic variants as a proxy for environmental exposures, such as substance use, which can address problems of reverse causation and residual confounding, providing stronger evidence about causality. Genetic variants can be used instead of directly measuring exposure levels, in order to gain an unbiased estimate of the effect of various exposures on depression and anxiety. The suitability of the genetic variant as a proxy can be ascertained by confirming that there is no relationship between variant and outcome in those who do not use the substance. At present, there are suitable instruments for tobacco use, so we use that as a case study. Proof‐of‐principle Mendelian randomisation studies using these variants have found evidence for a causal effect of smoking on body mass index. Two studies have investigated tobacco and depression using this method, but neither found strong evidence that smoking causes depression or anxiety; evidence is more consistent with a self‐medication hypothesis. Mendelian randomisation represents a technique that can aid understanding of exposures that may or may not be causally related to depression and anxiety. As more suitable instruments emerge (including the use of allelic risk scores rather than individual single nucleotide polymorphisms), the effect of other substances can be investigated. Linkage disequilibrium, pleiotropy, and population stratification, which can distort Mendelian randomisation studies, are also discussed.