Combining Cognitive Mapping and indigenous knowledge to improve food environments in regional New Zealand.

ISSUE ADDRESSED: Hawke's Bay has one of the highest rates of childhood obesity in New Zealand. While several initiatives exist aiming to decrease obesity through physical activity, there are few nutritional interventions. This study adopted a systems science and matauranga Maori approach to identify and target underlying drivers of rising childhood obesity and engage the community to improve the food environment. METHODS: Cognitive mapping interviews (CM) with local stakeholders (school principals, Iwi and district health board representatives, education managers and local councillors) were conducted. The aim was to map participants' mental models of the causes of rising childhood obesity and to identify key principles for engaging with the local community in a meaningful, impactful and culturally appropriate way for future action. RESULTS: Eleven interviews were conducted face-to-face and cognitive maps were constructed. Follow-up interviews were carried out online, due to COVID restrictions, to present the maps and for interviewees to make any adjustments. Four composite themes emerged through centrality and cluster analysis of the resulting cognitive maps: the importance of building in matauranga Maori (Maori knowledge and ways of being), the "hauora" of children, working with the community and integrating existing initiatives. Two contextual factors are also considered: the growing need for food security in our communities and the opportunity to start interventions in the school setting. CONCLUSION: Cognitive mapping can produce useful insights in the early stages of community engagement. The six "pou" (pillars) underscore the importance of incorporating indigenous knowledge when embarking on public health interventions, particularly around obesity and in regional communities. SO WHAT?: When designing a public health initiative with a community with a high indigenous population, indigenous knowledge should be promoted to focus on holistic health, working with the community and creating opportunities for cohesion. These founding principles will be used to structure future community actions to improve children's food environments in regional New Zealand.

Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a prospective, longitudinal cohort study.

BACKGROUND: Worldwide, haemoglobin E ß-thalassaemia is the most common genotype of severe ß-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia. METHODS: In this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality. FINDINGS: 109 patients (54 [50%] male; 55 [50%] female) were recruited and followed up for a median of 18 years (IQR 14-20). Median age at recruitment was 13 years (range 8-21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45-not reached). Median survival was worse among male patients (hazard ratio [HR] 2·51, 95% CI 1·16-5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90-24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01-1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 µg/L (vs concentration ≤1300 µg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival. INTERPRETATION: Patients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival. FUNDING: Wellcome Trust, Medical Research Council, US March of Dimes, Anthony Cerami and Ann Dunne Foundation for World Health, and Hemoglobal.

Oxidative status in the ß-thalassemia syndromes in Sri Lanka; a cross-sectional survey.

In the ß-thalassemias, oxidative stress, resulting from chronic hemolysis, globin chain imbalance, iron overload and depleted antioxidant defences, likely contributes to cell death, organ damage, anemia, hypoxia and inflammation. We assessed variations in these parameters in ß-thalassemia syndromes in Sri Lanka. Between November 2017 and June 2018, we assessed children and adults attending two thalassemia centres in Sri Lanka: 59 patients with HbE ß-thalassemia, 50 ß-thalassemia major, 40 ß-thalassemia intermedia and 13 HbS ß-thalassemia. Median age was 26.0 years (IQR 15.3-38.8), 101 (62.3%) were female and 152 (93.8%) of Sinhalese ethnicity. Methemoglobin, plasma hemoglobin, heme and ferritin were measured as sources of oxidants; plasma total antioxidant capacity, haptoglobin, hemopexin and vitamins C and E assessed antioxidant status; plasma thiobarbituric acid reactive substances and 8-hydroxy-2'-deoxyguanosine assessed oxidative damage; hemoglobin, plasma erythropoietin and transferrin receptor assessed anemia and hypoxia and plasma interleukin-6 and C-reactive protein assessed inflammation. Fruit and vegetable intake was determined by dietary recall. Physical fitness was investigated using the 6-min walk test and measurement of handgrip strength. Oxidant sources were frequently increased and antioxidants depleted, with consequent oxidative damage, anemia, hypoxia and inflammation. Biomarkers were generally most abnormal in HbE ß-thalassemia and least abnormal in ß-thalassemia intermedia but also varied markedly between individuals with the same thalassemia syndrome. Oxidative stress and damage were also more severe in splenectomized patients and/or those receiving iron chelation therapy. Less than 15% of patients ate fresh fruits or raw vegetables frequently, and plasma vitamins C and E were deficient in 132/160 (82.5%) and 140/160 (87.5%) patients respectively. Overall, physical fitness was poor in all syndromes and was likely due to anemic hypoxia. Studies of antioxidant supplements to improve outcomes in patients with thalassemia should consider individual patient variation in oxidative status both between and within the thalassemia syndromes.

Vitamin D deficiency and its correction in children with sickle cell anaemia.

Vitamin D deficiency is common in sickle cell anaemia (SCA, HbSS), although its significance and optimal means of correction are unknown. We conducted an audit to assess the clinical significance of 25-hydroxy vitamin D (25-OHD) deficiency in children with SCA and to evaluate two methods of vitamin D supplementation. We audited 25-OHD levels in 81 children with SCA and looked for statistical associations with biochemical, haematological and clinical parameters. In a separate group of regularly transfused children with SCA, we compared changes in 25-OHD blood concentrations following treatment with either high-dose intramuscular ergocalciferol (n = 15) or 4 days of high-dose oral cholecalciferol (n = 64). Ninety-one percent of children with SCA had 25-OHD levels <20 µg/L. The 25-OHD levels were negatively correlated with increasing age (P < 0.001) but showed no significant relationship to laboratory measurements, transcranial Doppler velocities or hospital attendance. Both intramuscular ergocalciferol and oral cholecalciferol supplementations resulted in increases of 25-OHD blood concentration to normal levels. The mean dose of ergocalciferol was greater than that of cholecalciferol (7,729 versus 5,234 international units (IU)/kg, P < 0.001), but the increment in 25-OHD levels was significantly greater in the oral cholecalciferol group (6.44 versus 2.82 (ng/L)/(IU/kg), P < 0.001). Both approaches resulted in vitamin D sufficiency for about 120 days. Increased 25-OHD concentration was significantly associated with increased serum calcium concentration. Vitamin D deficiency is very common in SCA and can be effectively corrected with high-dose intramuscular ergocalciferol or 4 days of high-dose oral cholecalciferol. Prospective, randomised studies are needed to assess the clinical value of vitamin D supplementation.

Cost-effectiveness analysis of preoperative transfusion in patients with sickle cell disease using evidence from the TAPS trial.

The study's objective was to assess the cost-effectiveness of preoperative transfusion compared with no preoperative transfusion in patients with sickle cell disease undergoing low- or medium-risk surgery. Seventy patients with sickle cell disease (HbSS/Sß(0) thal genotypes) undergoing elective surgery participated in a multicentre randomised trial, Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS). Here, a cost-effectiveness analysis based on evidence from that trial is presented. A decision-analytic model is used to incorporate long-term consequences of transfusions and acute chest syndrome. Costs and health benefits, expressed as quality-adjusted life years (QALYs), are reported from the 'within-trial' analysis and for the decision-analytic model. The probability of cost-effectiveness for each form of management is calculated taking into account the small sample size and other sources of uncertainty. In the range of scenarios considered in the analysis, preoperative transfusion was more effective, with the mean improvement in QALYs ranging from 0.018 to 0.206 per patient, and also less costly in all but one scenario, with the mean cost difference ranging from -£813 to £26. All scenarios suggested preoperative transfusion had a probability of cost-effectiveness >0.79 at a cost-effectiveness threshold of £20 000 per QALY.

Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.

Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.

The rise of fragment-based drug discovery.

The search for new drugs is plagued by high attrition rates at all stages in research and development. Chemists have an opportunity to tackle this problem because attrition can be traced back, in part, to the quality of the chemical leads. Fragment-based drug discovery (FBDD) is a new approach, increasingly used in the pharmaceutical industry, for reducing attrition and providing leads for previously intractable biological targets. FBDD identifies low-molecular-weight ligands (∼150 Da) that bind to biologically important macromolecules. The three-dimensional experimental binding mode of these fragments is determined using X-ray crystallography or NMR spectroscopy, and is used to facilitate their optimization into potent molecules with drug-like properties. Compared with high-throughput-screening, the fragment approach requires fewer compounds to be screened, and, despite the lower initial potency of the screening hits, offers more efficient and fruitful optimization campaigns. Here, we review the rise of FBDD, including its application to discovering clinical candidates against targets for which other chemistry approaches have struggled.

Ethnicity questions and antenatal screening for sickle cell/thalassaemia [EQUANS] in England: a randomised controlled trial of two questionnaires.

UNLABELLED: Concepts allied to ethnicity are increasingly coming under question as legitimate variables for use in health research. A randomised controlled trial of two ethnicity screening questions for ascertaining risk of carrying genes associated with sickle cell and thalassaemia illustrates the challenges and limitations of assessing an association of social constructs and genetic statuses. OBJECTIVES: To evaluate two candidate ethnicity screening questions in antenatal screening programmes in low, mixed and high sickle cell prevalence areas, and to identify time taken in administration of the questions by use of the following measures: (1) Proportions of respondents with missing ethnicity data and/or significant changes in ethnic/family origins upon re-interview. (2) Numbers of carriers of clinically significant haemoglobin disorders missed by ethnicity screening questions. (3) Time taken to explain screening question for sickle cell disease (SCD)/thalassaemia and obtain ethnic/family origins. (4) Proportion of clients providing usable ethnic/family origins data. (5) Reported ethnic/family origins in pregnant women at first booking with midwife. DESIGN: Ten-month (September 2002-June 2003) questionnaire study with random allocation to two self-administered ethnicity questions, comparison with laboratory results and results from re-interview. The settings were antenatal booking clinics in four geographical areas of England of varying expected foetal prevalence of SCD: very high (29.75 per 10,000 pregnancies); high (8.2); mixed high and low (1.29); and low (0.18). The subjects were 4,559 pregnant women at first booking with midwife. RESULTS: Proportions of respondents with missing ethnicity data and/or significant changes in ethnic/family origins upon re-interview were 4.33% (CI 2.63-6.68%) for a category-based question and 9.45% (CI 6.86-12.61%) for a binary plus open-ended question. Proportions of carriers missed were 5.74% (CI 2.34-11.46%) and 9.71% (CI 4.75-17.13%) by category-based and binary plus open-ended questions, respectively. Average time taken to ascertain ethnic/family origins for screening was between 2.17 and 5.12 minutes in different areas, and up to 15 minutes at the 95th centile. Usable ethnicity screening data was missing in 2.94% of instances. Errors in interpretation or missing data were 3.2% for a category-based question and 4.71% for a binary plus open-ended ethnicity question. Ethnicity Question A produces fewer cases of missing or misinterpreted data (p < 0.001). CONCLUSIONS: A category-based ethnicity screening question was more effective than a binary plus open-ended question. Using the more effective question, 5.74% (CI 2.34-11.46%) of significant haemoglobinopathies will be missed in a selective screening programme, and 4.33% (CI 2.63-6.68%) of replies to an ethnicity screening question will be unreliable when compared to information given upon re-interview. In specific carefully circumscribed situations, namely, in antenatal screening for sickle cell and thalassaemia, it is possible to measure the degree of association between social constructs of ethnicity and health status in a manner that may help in effecting policy decisions.

Integrated, collaborative palliative care in heart failure: the St. George Heart Failure Service experience 1999-2002.

BACKGROUND: Chronic heart failure (HF) is the only heart condition increasing in prevalence and is primarily a condition of aging. This condition has outcomes worse than many cancers; however, patients are often denied the benefits of palliative care with its important emphasis on symptom management, spirituality, and emotional health and focus on family issues. AIM: To describe the development of a model of an integrated, consultative, palliative care approach within a comprehensive HF community-focussed disease management program. METHOD: A collaborative model was developed following a systematic needs assessment and documentation of local resources. Principles underpinning this model were based upon fostering of communication, consultancy, and skill development. Within this model a health care system, based upon universal coverage, supported co-management of patients and their families. The place of death, level of social support available at home, and degree of palliative care involvement was documented in 121 consecutive deaths from 1999-2002. FINDINGS: Following a period of skill sharing and program development, only 8.3% of HF patients in the collaborative program required specialized palliative care intervention for complex symptom management, carer support, and issues related to spirituality. Twenty percent of this cohort died in nursing homes underscoring the importance of supporting our nursing colleagues in this setting. CONCLUSIONS: In spite of well-documented difficulties in determining prognosis, it is the St George experience that key principles of a palliative care strategy can be implemented in a HF disease management program with support and consultancy from expert palliative care services.

Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships.

A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.