Health service changes to address diabetes in pregnancy in a complex setting: perspectives of health professionals

Background: Australian Aboriginal and Torres Strait Islander women have high rates of gestational and pre-existing type 2 diabetes in pregnancy. The Northern Territory (NT) Diabetes in Pregnancy Partnership was established to enhance systems and services to improve health outcomes. It has three arms: a clinical register, developing models of care and a longitudinal birth cohort. This study used a process evaluation to report on health professional's perceptions of models of care and related quality improvement activities since the implementation of the Partnership. Methods: Changes to models of care were documented according to goals and aims of the Partnership and reviewed annually by the Partnership Steering group. A 'systems assessment tool' was used to guide six focus groups (49 healthcare professionals). Transcripts were coded and analysed according to pre-identified themes of orientation and guidelines, education, communication, logistics and access, and information technology. Results: Key improvements since implementation of the Partnership include: health professional relationships, communication and education; and integration of quality improvement activities. Focus groups with 49 health professionals provided in depth information about how these activities have impacted their practice and models of care for diabetes in pregnancy. Co-ordination of care was reported to have improved, however it was also identified as an opportunity for further development. Recommendations included a central care coordinator, better integration of information technology systems and ongoing comprehensive quality improvement processes. Conclusions: The Partnership has facilitated quality improvement through supporting the development of improved systems that enhance models of care. Persisting challenges exist for delivering care to a high risk population however improvements in formal processes and structures, as demonstrated in this work thus far, play an important role in work towards improving health outcomes.R. Kirkham, J.A. Boyle, C. Whitbread, M. Dowden, C. Connors, S. Corpus, L. McCarthy, J. Oats, H.D. McIntyre, E. Moore, K. O’Dea, A. Brown, L. Maple-Brown (On behalf of the NT Diabetes in Pregnancy Partnership

Resistance of Dynamin-related Protein 1 Oligomers to Disassembly Impairs Mitophagy, Resulting in Myocardial Inflammation and Heart Failure

We have reported previously that a missense mutation in the mitochondrial fission gene Dynamin-related protein 1 (Drp1) underlies the Python mouse model of monogenic dilated cardiomyopathy. The aim of this study was to investigate the consequences of the C452F mutation on Drp1 protein function and to define the cellular sequelae leading to heart failure in the Python monogenic dilated cardiomyopathy model. We found that the C452F mutation increased Drp1 GTPase activity. The mutation also conferred resistance to oligomer disassembly by guanine nucleotides and high ionic strength solutions. In a mouse embryonic fibroblast model, Drp1 C452F cells exhibited abnormal mitochondrial morphology and defective mitophagy. Mitochondria in C452F mouse embryonic fibroblasts were depolarized and had reduced calcium uptake with impaired ATP production by oxidative phosphorylation. In the Python heart, we found a corresponding progressive decline in oxidative phosphorylation with age and activation of sterile inflammation. As a corollary, enhancing autophagy by exposure to a prolonged low-protein diet improved cardiac function in Python mice. In conclusion, failure of Drp1 disassembly impairs mitophagy, leading to a downstream cascade of mitochondrial depolarization, aberrant calcium handling, impaired ATP synthesis, and activation of sterile myocardial inflammation, resulting in heart failure

A counterbalanced cross-over study of the effects of visual, auditory and no feedback on performance measures in a simulated cardiopulmonary resuscitation

<p>Abstract</p> <p>Background</p> <p>Previous research has demonstrated that trained rescuers have difficulties achieving and maintaining the correct depth and rate of chest compressions during both in and out of hospital cardiopulmonary resuscitation (CPR). Feedback on rate and depth mitigate decline in performance quality but not completely with the residual performance decline attributed to rescuer fatigue. The purpose of this study was to examine the effects of feedback (none, auditory only and visual only) on the quality of CPR and rescuer fatigue.</p> <p>Methods</p> <p>Fifteen female volunteers performed 10 minutes of 30:2 CPR in each of three feedback conditions: none, auditory only, and visual only. Visual feedback was displayed continuously in graphic form. Auditory feedback was error correcting and provided by a voice assisted CPR manikin. CPR quality measures were collected using SkillReporter^®software. Blood lactate (mmol/dl) and perceived exertion served as indices of fatigue. One-way and two way repeated measures analyses of variance were used with alpha set <it>a priori </it>at 0.05.</p> <p>Results</p> <p>Visual feedback yielded a greater percentage of correct compressions (78.1 ± 8.2%) than did auditory (65.4 ± 7.6%) or no feedback (44.5 ± 8.1%). Compression rate with auditory feedback (87.9 ± 0.5 compressions per minute) was less than it was with both visual and no feedback (p < 0.05). CPR performed with no feedback (39.2 ± 0.5 mm) yielded a shallower average depth of compression and a lower percentage (55 ± 8.9%) of compressions within the accepted 38-50 mm range than did auditory or visual feedback (p < 0.05). The duty cycle for auditory feedback (39.4 ± 1.6%) was less than it was with no feedback (p < 0.05). Auditory feedback produced lower lactate concentrations than did visual feedback (p < 0.05) but there were no differences in perceived exertion.</p> <p>Conclusions</p> <p>In this study feedback mitigated the negative effects of fatigue on CPR performance and visual feedback yielded better CPR performance than did no feedback or auditory feedback. The perfect confounding of sensory modality and periodicity of feedback (visual feedback provided continuously and auditory feedback provided to correct error) leaves unanswered the question of optimal form and timing of feedback.</p

Endothelial IGF‐1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota

A novel treatment of cystic fibrosis acting on-target:cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts ‘on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Association between the age of solid food introduction and eczema; a systematic review and a meta-analysis

INTRODUCTION: Eczema is a common childhood ailment responsible for a considerable disease burden. Both timing of introduction to solid food and allergenic food are believed to be related to childhood eczema. Despite the growing body of evidence, the relationship between timing of any solid food introduction (allergenic and/or non-allergenic) and development of eczema has not previously been systematically reviewed. METHODS: PubMed and EMBASE databases were searched using food and eczema terms. Two authors selected papers according to the inclusion criteria and extracted information on study characteristics and measures of association. Meta-analyses were performed after grouping studies according to the age and type of exposure. RESULTS: A total of 17 papers met the inclusion criteria, reporting results from 16 study populations. Of these, 11 were cohort studies, two case controls, one cross sectional study and, 2 randomised controlled trials. Limited meta-analyses were performed due to heterogeneity between studies. Timing of solid food introduction was not associated with eczema. One randomized controlled trial provided weak evidence of an association between early allergenic (around 4 months) food introduction and reduced risk of eczema. CONCLUSIONS: The available evidence is currently insufficient to determine whether the timing of introduction of any solid food influences the risk of eczema. This article is protected by copyright. All rights reserved

Stress-induced in vivo recruitment of human cytotoxic natural killer cells favors subsets with distinct receptor profiles and associates with increased epinephrine levels

Acute stress drives a 'high-alert' response in the immune system. Psychoactive drugs induce distinct stress hormone profiles, offering a sought-after opportunity to dissect the in vivo immunological effects of acute stress in humans. 3,4-methylenedioxymethamphetamine (MDMA), methylphenidate (MPH), or both, were administered to healthy volunteers in a randomized, double-blind, placebo-controlled crossover-study. Lymphocyte subset frequencies, natural killer (NK) cell immune-phenotypes, and changes in effector function were assessed, and linked to stress hormone levels and expression of CD62L, CX3CR1, CD18, and stress hormone receptors on NK cells. MDMA/MPH > MDMA > MPH robustly induced an epinephrine-dominant stress response. Immunologically, rapid redistribution of peripheral blood lymphocyte-subsets towards phenotypically mature NK cells occurred. NK cytotoxicity was unaltered, but they expressed slightly reduced levels of the activating receptor NKG2D. Preferential circulation of mature NK cells was associated with high epinephrine receptor expression among this subset, as well as expression of integrin ligands previously linked to epinephrine-induced endothelial detachment. The acute epinephrine-induced stress response was characterized by rapid accumulation of mature and functional NK cells in the peripheral circulation. This is in line with studies using other acute stressors and supports the role of the acute stress response in rapidly mobilizing the innate immune system to counteract incoming threats