An assessment of the Hua Oranga outcome instrument and comparison to other outcome measures in an intervention study with Maori and Pacific people following stroke

The Hua Oranga instrument, developed for Maori people with mental illness, showed good responsiveness and adequate psychometric properties in Maori and Pacific people after stroke. Its simplicity, relative brevity, minimal cost and adequate psychometric properties should favour its use in future studies with both Maori and Pacific people. Suggestions are made for refinements to the measure. These should be tested in a new population before Hua Oranga is recommended for general use in a clinical setting. Abstract Aim Health outcomes research for Maori has been hampered by the lack of adequately validated instruments that directly address outcomes of importance to Maori, framed by a Maori perspective of health. Hua Oranga is an outcome instrument developed for Maori with mental illness that uses a holistic view of Maori health to determine improvements in physical, mental, spiritual and family domains of health. Basic psychometric work for Hua Oranga is lacking. We sought to explore the psychometric properties of the instrument and compare its responsiveness alongside other, more established tools in an intervention study involving Maori and Pacific people following acute stroke. Method Randomised 2x2 controlled trial of Maori and Pacific people following acute stroke with two interventions aimed at facilitating self-directed rehabilitation, and with follow-up at 12 months after randomisation. Primary outcome measures were the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the Short Form 36 (SF36) at 12 months. Hua Oranga was used as a secondary outcome measure for participants at 12 months and for carers and whanau (extended family). Psychometric properties of Hua Oranga were explored using plots and correlation coefficients, principal factors analysis and scree plots. Results 172 participants were randomised, of whom 139 (80.8%) completed follow-up. Of these, 135 (97%) completed the Hua Oranga and 117 (84.2%) completed the PCS and MCS of the SF36. Eighty-nine carers completed the Hua Oranga. Total Hua Oranga scores and PCS improved significantly for one intervention group but not the other. Total Hua Oranga scores for carers improved significantly for both interventions. Total Hua Oranga score correlated moderately with the PCS (correlation coefficient 0.55, p<0.001). Factor analysis suggested that Hua Oranga measures two and not four factors; one 'physical-mental' and one 'spiritual-family'. Conclusion The Hua Oranga instrument, developed for Maori people with mental illness, showed good responsiveness and adequate psychometric properties in Maori and Pacific people after stroke. Its simplicity, relative brevity, minimal cost and adequate psychometric properties should favour its use in future studies with both Maori and Pacific people. Suggestions are made for refinements to the measure. These should be tested in a new population before Hua Oranga is recommended for general use in a clinical setting

Regulation of nucleosome positioning by a CHD Type III chromatin remodeler and its relationship to developmental gene expression in Dictyostelium

Nucleosome placement and repositioning can direct transcription of individual genes; however, the precise interactions of these events are complex and largely unresolved at the whole-genome level. The Chromodomain-Helicase-DNA binding (CHD) Type III proteins are a subfamily of SWI2/SNF2 proteins that control nucleosome positioning and are associated with several complex human disorders, including CHARGE syndrome and autism. Type III CHDs are required for multicellular development of animals and Dictyostelium but are absent in plants and yeast. These CHDs can mediate nucleosome translocation in vitro, but their in vivo mechanism is unknown. Here, we use genome-wide analysis of nucleosome positioning and transcription profiling to investigate the in vivo relationship between nucleosome positioning and gene expression during development of wild-type (WT) Dictyostelium and mutant cells lacking ChdC, a Type III CHD protein ortholog. We demonstrate major nucleosome positional changes associated with developmental gene regulation in WT. Loss of chdC caused an increase of intragenic nucleosome spacing and misregulation of gene expression, affecting ∼50% of the genes that are repositioned during WT development. These analyses demonstrate active nucleosome repositioning during Dictyostelium multicellular development, establish an in vivo function of CHD Type III chromatin remodeling proteins in this process, and reveal the detailed relationship between nucleosome positioning and gene regulation, as cells transition between developmental states

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology

The BASES Expert Statement on Exercise Training for People with Intermittent Claudication due to Peripheral Arterial Disease

Lower-limb peripheral arterial disease (PAD) is a type of cardiovascular disease in which the blood vessels (arteries) that carry blood to the legs and feet are hardened and narrowed or blocked by the build-up of fatty plaques (called atheroma). It affects around 13% of adults over 50 years old, and major risk factors for its development include smoking, diabetes mellitus, and dyslipidaemia (Morley, Sharma, Horsch & Hinchliffe, 2018). The presence of PAD itself is also a risk factor for other cardiovascular problems, such as angina, heart attack and stroke. This is because the underlying disease process, atherosclerosis, is a systemic process, meaning that blood vessels elsewhere in the body may also be affected.The most common symptom of PAD is intermittent claudication (IC), which is muscle pain or discomfort in the legs and/or buttocks brought on by walking and relieved within minutes on rest (Figure 1). It occurs due to an inability to increase blood flow (and oxygen delivery) sufficiently to match the metabolic demands of the lower-limb muscles during exercise. The walking distance or speed at which symptoms occur depends on multiple factors including the severity and site of the arterial disease, walking pace, terrain, incline and footwear. Nevertheless, IC can cause marked reductions in functional capacity and quality of life (Morley et al., 2018).Treatments for IC, aimed at relieving symptoms and reducing the risk of further cardiovascular disease, include lifestyle changes (e.g., stopping smoking, exercising more), vasoactive drugs (e.g. naftidrofuryl oxalate), and revascularisation (i.e. angioplasty or bypass surgery). In 2012, the United Kingdom’s National Institute of Health and Care Excellence (NICE) published a clinical guideline on the management of PAD, which stated that a supervised exercise programme should be offered as a first-line therapy for IC (NICE, 2012). This statement provides an overview of the evidence on exercise training and recommendations for people delivering exercise programmes to this population

Norspermidine is not a self-produced trigger for biofilm disassembly

SummaryFormation of Bacillus subtilis biofilms, consisting of cells encapsulated within an extracellular matrix of exopolysaccharide and protein, requires the polyamine spermidine. A recent study reported that (1) related polyamine norspermidine is synthesized by B. subtilis using the equivalent of the Vibrio cholerae biosynthetic pathway, (2) exogenous norspermidine at 25 μM prevents B. subtilis biofilm formation, (3) endogenous norspermidine is present in biofilms at 50–80 μM, and (4) norspermidine prevents biofilm formation by condensing biofilm exopolysaccharide. In contrast, we find that, at concentrations up to 200 μM, exogenous norspermidine promotes biofilm formation. We find that norspermidine is absent in wild-type B. subtilis biofilms at all stages, and higher concentrations of exogenous norspermidine eventually inhibit planktonic growth and biofilm formation in an exopolysaccharide-independent manner. Moreover, orthologs of the V. cholerae norspermidine biosynthetic pathway are absent from B. subtilis, confirming that norspermidine is not physiologically relevant to biofilm function in this species

Different CHD chromatin remodelers are required for expression of distinct gene sets and specific stages during development of Dictyostelium discoideum

Control of chromatin structure is crucial for multicellular development and regulation of cell differentiation. The CHD (chromodomain-helicase-DNA binding) protein family is one of the major ATP-dependent, chromatin remodeling factors that regulate nucleosome positioning and access of transcription factors and RNA polymerase to the eukaryotic genome. There are three mammalian CHD subfamilies and their impaired functions are associated with several human diseases. Here, we identify three CHD orthologs (ChdA, ChdB and ChdC) in Dictyostelium discoideum. These CHDs are expressed throughout development, but with unique patterns. Null mutants lacking each CHD have distinct phenotypes that reflect their expression patterns and suggest functional specificity. Accordingly, using genome-wide (RNA-seq) transcriptome profiling for each null strain, we show that the different CHDs regulate distinct gene sets during both growth and development. ChdC is an apparent ortholog of the mammalian Class III CHD group that is associated with the human CHARGE syndrome, and GO analyses of aberrant gene expression in chdC nulls suggest defects in both cell-autonomous and non-autonomous signaling, which have been confirmed through analyses of chdC nulls developed in pure populations or with low levels of wild-type cells. This study provides novel insight into the broad function of CHDs in the regulation development and disease, through chromatin-mediated changes in directed gene expression

The ‘T-Shaped Buyer’: a transactional perspective on supply chain relationships

This paper challenges the normative view of interdependent buyer-seller relationships and provides a more holistic perspective of the contextual reality that shapes buyer behaviour. By proposing an innovative qualitative methodology, which focusses on boundary-spanning, pre-sales interactions, the research penetrates complex and commercially sensitive buyer-seller relationships. The longitudinal research design uses web-based diaries and follow-up interviews to explore conditions of power based interdependence between buyers and sellers. The ensuing data is mapped using qualitative content analysis and the results are aggregated graphically for assessment. Using this approach the study develops a nuanced view of the dominant patterns of buyer behaviour, and challenges the opinion that a search for competitive advantage will strengthen cooperative relationships in conditions of power based interdependence. The paper introduces the metaphor of the 'T-Shaped Buyer' to explain the empirical findings and, while acknowledging the contextual limits of the study, suggests that this metaphor may cause both academics and practitioners to reflect on normative thinking

A method for successful collection of multicores and gravity cores from Antarctic subglacial lakes

During the 2018–2019 Antarctic field season, the Subglacial Antarctic Lakes Scientific Access project team cleanly accessed Mercer Subglacial Lake, West Antarctica, to sample water and sediments beneath 1087 m of overlying ice. A multicorer was successful in sampling the sediment–water interface, with 4 deployments retrieving 10 cores between 0.3 and 0.4 m in length. Gravity coring was also successful, retrieving cores of 0.97 and 1.78 m in glacial diamict. However, sediment cores retrieved by the gravity cores were shorter than the core barrel penetration (as measured by mud streaks on the outside of the coring system), indicating that the system can likely be improved. This manuscript describes the design, implementation, successes, and lessons learned while coring sediments in a subglacial lake