Community empowerment and mental wellbeing: longitudinal findings from a survey of people actively involved in the big local place-based initiative in England.

BACKGROUND: Community empowerment initiatives are receiving increased interest as ways of improving health and reducing health inequalities. PURPOSE: Longitudinally examine associations between collective control, social-cohesion and mental wellbeing amongst participants in the Big Local community empowerment initiative across 150 disadvantaged areas of England. METHODS: As part of the independent Communities in Control study, we analysed nested cohort survey data on mental wellbeing (Short Warwick Edinburgh Mental Wellbeing Scale-SWEMWBS) and perceptions of collective control and social-cohesion. Data were obtained in 2016, 2018 and 2020 for 217 residents involved in the 150 Big Local areas in England. Adjusted linear mixed effect models were utilized to examine changes in SWEMWBS over the three waves. Subgroup analysis by gender and educational level was conducted. RESULTS: There was a significant 1.46 (0.14, 2.77) unit increase in mental wellbeing score at wave 2 (2018) but not in wave 3 (2020) (0.06 [-1.41, 1.53]). Across all waves, collective control was associated with a significantly higher mental wellbeing score (3.36 [1.51, 5.21]) as was social cohesion (1.09 [0.19, 2.00]). Higher educated participants (1.99 [0.14, 3.84]) and men (2.41 [0.55, 4.28]) experienced significant increases in mental wellbeing in 2018, but lower educated participants and women did not. CONCLUSION: Collective control and social cohesion are associated with better mental wellbeing amongst residents engaged with the Big Local initiative. These health benefits were greater amongst men and participants from higher educational backgrounds. This suggests that additional care must be taken in future interventions to ensure that benefits are distributed equally.

Collective control, social cohesion and health and well-being: baseline survey results from the communities in control study in England.

BACKGROUND: Area-based initiatives (ABIs) are receiving renewed interest as a part of the 'place-based public health' approaches to reducing health inequalities. PURPOSE: Examine associations between collective control, social cohesion and health amongst residents involved in the Big Local (BL) ABI. METHODS: Survey data on general health, mental well-being, perceptions of individual and collective control and social cohesion was obtained in 2016 for 1600 residents involved in the 150 BL ABI areas in England, and 862 responded-a response rate of >50%. Adjusted mean differences and adjusted odds ratios (ORs) were calculated using random effect linear and generalized estimating equation models. Subgroup analysis by gender and educational level was conducted. RESULTS: Mental well-being was positively associated with collective control (mean difference: 3.06 units, 1.23-4.90) and some measures of social cohesion ('people in the area are willing to help each other' [mean difference: 1.77 units, 0.75-2.78]). General health was positively associated with other measures of social cohesion (area-belonging [OR: 4.25, 2.26-7.97]). CONCLUSIONS: Collective control and some aspects of social cohesion were positively associated with better mental well-being and self-rated health amongst residents involved with BL. These positive associations were often greater amongst women and participants with a lower education. Increasing the collective control residents have in ABIs could improve the health effects of ABIs.

Risk factors for non-communicable diseases related to obesity among first- and second-generation Bangladeshi migrants living in north-east or south-east England.

BACKGROUND: Obesity is a global burden, which significantly increases the risk of non-communicable diseases (NCDs). More than a quarter of adults in the United Kingdom are obese, but prevalence varies by ethnicity, and South Asians have the largest burden of NCDs. This paper assesses how sex, generation, and region interplay to vary the predisposition to obesity-related (OR) NCDs among UK Bangladeshis. METHODS: We used National Institute for Health and Care Excellence suggested grading for combining body mass index and waist circumference to define populations at risk of OR-NCDs. Data from 517 adults of Bangladeshi origin from a cross-sectional study (March 2013 to April 2015) were analysed. Male and female participants from London and north-east England were equally sampled including: (1) adult migrants, who came to the UK aged >16 years; (2) child migrants, who came to the UK aged ≤16 years; and (3) second-generation Bangladeshis (who were born and brought up in the UK). A generalised estimating equation using a binomial distribution and a logit link was used to explore the relationship between the binary outcome of being 'at risk of OR-NCDs' and associated factors. RESULTS: Females, married individuals, those living in London, the second-generation, and those of lower self-assessed financial status, with low acculturation status, or who did not walk daily for at least 20 min were more likely to develop OR-NCDs. A striking sex difference was found with more females prone to OR-NCD risk in the north-east than in London. CONCLUSIONS: Our study observed important inter- and intra-regional inequality in OR-NCD risk which worsens the health of ethnic minorities and widens inequality.

Recombinant irisin induces weight loss in high fat DIO mice through increase in energy consumption and thermogenesis.

OBJECTIVE: Irisin is known to be an important metabolic regulator of glucose and lipid metabolism. The aims of the present study are to assess the role of mouse Irisin in obesity and energy metabolism and its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) mice model. METHODS: DIO mice were treated with recombinant murine Irisin or vehicle, and parameters such as body weight, feed intake, glucose, and lipid levels, obesity, energy consumption, and insulin sensitivity were assessed. mRNA and protein levels of UCP1 and different thermogenesis biomarker were evaluated by quantitative real-time PCR and Western blot, respectively, in tissues and major metabolic organs. RESULTS: Irisin decreased body weight and whole-body fat mass in DIO mice in a dose dependent manner due to marked increases in total energy expenditure. It also lowered blood glucose, insulin, and lipid levels and possibly reversed hepatic steatosis. Irisin improved hepatic and peripheral insulin sensitivity in DIO mice along with body weight reduction and adiposity. Gene expression of UCP1 in different organs (adipose tissue and major organs, i.e., liver, kidney, heart, brain, and spleen) have suggested the role of irisin is global. Gene expression profile of different biomarkers in spleen suggest a profound role of Irisin in inflammation. Liver tissue have also shown significant increase of UCP1 expression in dose dependent manner which suggest a role of irisin in liver.

Discovery and evaluation of novel FAAH inhibitors in neuropathic pain model.

Conceptual design and modification of urea moiety in chemotype PF-3845/04457845, the bench marking irreversible inhibitor of fatty acid amide hydrolase (FAAH), led to discovery of a novel nicotinamide-based lead 12a having reversible mechanism of action. Focused SAR around the pyridine heterocycle (Ar) in 12a (Tables 1 and 2) resulted into four shortlisted compounds, (-)-12a, (-)-12i, (-)-12l-m. The required (-)-enantiomers were obtained via diastereomeric resolution of a novel chiral dissymmetric intermediate 15. Based on comparative profile of FAAH potency, metabolic stability in liver microsome, liability of inhibiting major hCYP450 isoforms, rat PK, and brain penetration ability, two SAR optimized compounds, (-)-12l and (-)-12m, were selected for efficacy study in rat model of chemotherapy-induced peripheral neuropathy (CIPN). Both the compounds exhibited dose related antihyperalgesic effects, when treated with 3-30 mg/kg po for 7 days. The effects at 30 mg/kg are comparable to that of PF-04457845 (10 mg/kg) and Tramadol (40 mg/kg).

Discovery and pharmacological evaluation of indole derivatives as potent and selective RORγt inverse agonist for multiple autoimmune conditions.

Targeting nuclear receptor RORγ is recognized to be beneficial in multiple autoimmune disorders. We disclosed new indole analogues as potent RORγ inverse agonists. RO-2 as one of the potent and orally bioavailable compounds was evaluated in various models of autoimmune disorder. It showed potent suppression of downstream markers of RORγt activity in murine and human primary cells, ex vivo PD assay and in multiple animal models of autoimmune diseases. The results indicate the potential of these indole analogues as orally bioavailable small molecule inverse agonists of RORγt, efficacious in various Th17 driven models of autoimmune disorders.

Evaluation of separate role of intestine and liver in first pass metabolism of budesonide in rat.

1. Budesonide, a potent topical corticosteroid, reported to have low oral bioavailability in mice, rat, dog and human due to rapid first pass metabolism. However, there is insufficient information available in literature regarding the role of intestine and or liver responsible for the first pass metabolism of budesonide. 2. Current study in rats investigates the role of intestine and liver in first pass metabolism of budesonide using two in vivo models. Additionally, budesonide was also evaluated in in vitro assays such as thermodynamic solubility, permeability in Caco-2 cells and stability in simulated gastric (SGF), intestinal fluids (SIF) to understand the underlaying cause for low oral bioavailability. 3. Budesonide showed low oral, intra-duodenal and high intra-portal bioavailability in rat. In a dual vein cannulated rat model, intestinal and hepatic extraction ratios calculated based upon intestinal availability (Fa·Fg) and hepatic availability (Fh), suggests hepatic extraction of budesonide is minimal compared to intestinal. 4. In vitro results suggest, solubility and permeability may not be a barrier for the observed low oral bioavailability in rats. 5. Correlating the in vitro and in vivo data together, it can be concluded that, intestine might be playing major role in first pass metabolism of budesonide.

Reliability of repeated arm-crank cardiopulmonary exercise tests in patients with small abdominal aortic aneurysm.

Arm-crank ergometry may be useful in patients unable to pedal, for instance due to peripheral arterial disease. Twenty participants with small abdominal aortic aneurysm undertook two serial arm-crank tests and then a pedal test, four of whom had indeterminate anaerobic thresholds, precluding analysis. The mean (SD) peak arm and leg oxygen consumptions in 16 participants were 13.71 (2.62) ml.kg-1 .min-1 and 16.82 (4.44) ml.kg-1 .min-1 , with mean (SD) individual differences of 3.11 (2.48) ml.kg-1 .min-1 , p = 0.0001. The respective values at the anaerobic thresholds were 7.83 (1.58) ml O2 .kg-1 .min-1 and 10.09 (3.15) ml O2 .kg-1 .min-1 , with mean (SD) individual differences of 2.26 (2.34) ml O2 .kg-1 .min-1 , p = 0.0001. The correlation coefficients (95%CI) for peak oxygen consumption and anaerobic threshold were 0.88 (0.62-1.0) and 0.70 (0.32-1.0). There were no significant differences in serial arm-crank tests, with intracluster correlations (95%CI) of 0.87 (0.86-0.88) and 0.65 (0.61-0.69) for peak oxygen consumption and anaerobic threshold, respectively.

Discovery and evaluation of 1H-pyrrolo[2,3-b]pyridine based selective and reversible small molecule BTK inhibitors for the treatment of rheumatoid arthritis.

In a pursuit to identify reversible and selective BTK inhibitors, two series based on 7H-pyrrolo[2,3-d]pyrimidine and 1H-pyrrolo[2,3-b]pyridine as the hinge binding core, have been identified. Structure activity relationship (SAR) exploration led to identification of two advanced lead molecules, 11 and 13, which demonstrated desired BTK inhibitory potency in different cellular assays, excellent selectivity in a panel of 50 diverse kinases, favorable in vivo PK properties in mice and anti-arthritic effect in a mouse model of CIA.

Modifications of flexible nonyl chain and nucleobase head group of (+)-erythro-9-(2's-hydroxy-3's-nonyl)adenine [(+)-EHNA] as adenosine deaminase inhibitors.

A series of terminal nonyl chain and nucleobase modified analogues of (+)-EHNA (III) were synthesized and evaluated for their ability to inhibit adenosine deaminase (ADA). The constrained carbon analogues of (+)-EHNA, 7a-7h, 10a-c, 12, 13, 14 and 17a-c appeared very potent with Ki values in the low nanomolar range. Thio-analogues of (+)-EHNA 24a-e wherein 5'C of nonyl chain replaced by sulfur atom found to be less potent compared to (+)-EHNA. Docking of the representative compounds into the active site of ADA was performed to understand structure-activity relationships. Compounds 7a (Ki: 1.1nM) 7b (Ki: 5.2nM) and 26a (Ki: 5.9nM) showed suitable balance of potency, microsomal stability and demonstrated better pharmacokinetic properties as compared to (+)-EHNA and therefore may have therapeutic potential for various inflammatory diseases, hypertension and cancer.

Design and synthesis of novel, potent and selective hypoxanthine analogs as adenosine A1 receptor antagonists and their biological evaluation.

Multipronged approach was used to synthesize a library of diverse C-8 cyclopentyl hypoxanthine analogs from a common intermediate III. Several potent and selective compounds were identified and evaluated for pharmacokinetic (PK) properties in Wistar rats. One of the compounds 14 with acceptable PK parameters was selected for testing in in vivo primary acute diuresis model. The compound demonstrated significant diuretic activity in this model.

A systematic review of the effectiveness of individual, community and societal-level interventions at reducing socio-economic inequalities in obesity among adults.

BACKGROUND: Socioeconomic inequalities in obesity are well established in high-income countries. There is a lack of evidence of the types of intervention that are effective in reducing these inequalities among adults. OBJECTIVES: To systematically review studies of the effectiveness of individual, community and societal interventions in reducing socio-economic inequalities in obesity among adults. METHODS: Nine electronic databases were searched from start date to October 2012 along with website and grey literature searches. The review examined the best available international evidence (both experimental and observational) of interventions at an individual, community and societal level that might reduce inequalities in obesity among adults (aged 18 years or over) in any setting and country. Studies were included if they reported a body fatness-related outcome and if they included a measure of socio-economic status. Data extraction and quality appraisal were conducted using established mechanisms and narrative synthesis was conducted. RESULTS: The 'best available' international evidence was provided by 20 studies. At the individual level, there was evidence of the effectiveness of primary care delivered tailored weight loss programmes among deprived groups. Community based behavioural weight loss interventions and community diet clubs (including workplace ones) also had some evidence of effectiveness-at least in the short term. Societal level evaluations were few, low quality and inconclusive. Further, there was little evidence of long term effectiveness, and few studies of men or outside the USA. However, there was no evidence to suggest that interventions increase inequalities. CONCLUSIONS: The best available international evidence suggests that some individual and community-based interventions may be effective in reducing socio-economic inequalities in obesity among adults in the short term. Further research is required particularly of more complex, multi-faceted and societal-level interventions.

Prospective pilot evaluation of the effectiveness and cost-utility of a 'health first' case management service for long-term Incapacity Benefit recipients.

BACKGROUND: In line with the NICE guidance, an NHS-commissioned case management intervention was provided for individuals receiving Incapacity Benefit payments for ≥3 years in the North East of England. The intervention aimed to improve the health of the participants. METHODS: A total of 131 participants receiving the intervention were compared over 9 months with a (non-equivalent) comparison group of 229 receiving Incapacity Benefit payments and usual care. Health was measured using EQ-5D, EQ-VAS, SF-8, HADS and the Nordic Musculoskeletal questionnaire. Socio-demographic and health behaviour data were also collected. Fixed-effects linear models with correlated errors were used to compare health changes between groups over time. A preliminary cost-utility analysis was also conducted. RESULTS: The comparison group measures of health were stable over time. Starting from comparatively poor initial levels, case-management group generic (EQ5D, EQ-VAS) and mental health (HADS-A, HADS-D and SF8-MCS) measures improved within 6 months to similar levels found in the comparison group. Musculoskeletal (Nordic 2) and health behaviours did not improve. Tentative estimates of cost-utility suggest an intervention cost in the region of £16 700-£23 500 per QALY. CONCLUSIONS: Case management interventions may improve the health of Incapacity Benefit recipients. Further research is required to help confirm these pilot findings.

Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.

Dietary methionine and n-6/n-3 polyunsaturated fatty acid ratio reduce adverse effects of infectious bursal disease in broilers.

This study was carried out to investigate the modulatory effects of dietary methionine and n-6/n-3 polyunsaturated fatty acids (PUFA) ratio on immune response and performance of infectious bursal disease (IBD)-challenged broiler chickens. In total, 350 one-day-old male broiler chicks were assigned to 1 of the 6 dietary treatment groups in a 3 × 2 factorial arrangement. There were 3 n-6/n-3 PUFA ratios (45, 5.5, and 1.5) and 2 levels of methionine (NRC recommendation and twice NRC recommendation). The results showed that birds fed with dietary n-6/n-3 PUFA ratio of 5.5 had higher BW, lower feed intake, and superior FCR than other groups. However, the highest antibody response was observed in birds with dietary n-6/n-3 PUFA ratio of 1.5. Lowering n-6/n-3 PUFA ratio reduced bursa lesion score equally in birds fed with n-6/n-3 PUFA ratio of 5.5 and 1.5. Supplementation of methionine by twice the recommendation also improved FCR and reduced feed intake and bursa lesion score. However, in this study, the optimum performance (as measured by BW, feed intake, and FCR) did not coincide with the optimum immune response (as measured by antibody titer). It seems that dietary n-3 PUFA modulates the broiler chicken performance and immune response in a dose-dependent but nonlinear manner. Therefore, it can be suggested that a balance of moderate level of dietary n-6/n-3 PUFA ratio (5.5) and methionine level (twice recommendation) might enhance immune response together with performance in IBD-challenged broiler chickens.

Discovery of a potent and selective small molecule hGPR91 antagonist.

GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 µM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay.

The Comparative Analysis of the Ruminal Bacterial Population in Reindeer (Rangifer tarandus L.) from the Russian Arctic Zone: Regional and Seasonal Effects.

The reindeer (Rangifer tarandus L.) is a unique animal inhabitant of arctic regions. Low ambient temperatures and scant diets (primarily, lichens) have resulted in different evolutional adaptations, including the composition of the ruminal microbiota. In the study presented here, the effects of seasonal and regional aspects of the composition of the ruminal microbiota in reindeer (Nenets breed, 38 animals) were studied (wooded tundra from the Yamalo-Nenetski Autonomous District (YNAD) vs. from the Nenetski Autonomous District (NAD)). The ruminal content of calves (n = 12) and adult animals (n = 26, 15 males and 11 females) was sampled in the summer (n = 16) and winter seasons (n = 22). The composition of the ruminal microbial population was determined by the V3-V4 16S rRNA gene region sequencing. It was found that the population was dominated by Bacteroidetes and Firmicutes phyla, followed by Spirochaetes and Verrucomicrobia. An analysis of the community using non-metric multidimensional scaling and Bray-Curtis similarity metrics provided evidence that the most influential factors affecting the composition of ruminal microbiota are the region (p = 0.001) and season (p = 0.001); heat map analysis revealed several communities that are strongly affected by these two factors. In the summer season, the following communities were significantly larger compared to in the winter season: Coriobactriaceae, Erysipelothrihaceae, and Mycoplasmataceae. The following communities were significantly larger in the winter season compared to in summer: Paraprevotellaceae, Butyrivibrio spp., Succiniclasticum spp., Coprococcus spp., Ruminococcus spp., and Pseudobutyrivibrio spp. In NAD (tundra), the following communities were significantly larger in comparison to YNAD (wooded tundra): Verrucomicrobia (Verruco-5), Anaerolinaceae, PeHg47 Planctomycetes, cellulolytic Lachnospiraceae, and Succiniclasticum spp. The following bacterial groups were significantly larger in YNAD in comparison to NAD: cellulolytic Ruminococaceae, Dehalobacteriaceae, Veillionelaceae, and Oscilospira spp. The significant differences in the ruminal microbial population were primarily related to the ingredients of diets, affected by region and season. The summer-related increases in the communities of certain pathogens (Mycoplasmataceae, Fusobacterium spp., Porphyromonas endodentalis) were found. Regional differences were primarily related to the ratio of the species involved in ruminal cellulose degradation and ruminal fatty acids metabolism; these differences reflect the regional dissimilarities in botanical diet ingredients.

Ileal endogenous amino acid flow of broiler chickens under high ambient temperature.

High environmental temperature has detrimental effects on the gastrointestinal tract of poultry. An experiment was conducted to determine the effect of acute heat stress on endogenous amino acid (EAA) flow in broiler chickens. A total of 90, day-old broiler chicks were housed in battery cages in an environmentally controlled chamber. Chicks were fed a nitrogen-free diet on day 42 following either no heat exposure (no-heat) or 2 weeks exposure to 35 ± 1 °C for 3 h from days 28 to 42 (2-week heat) or 1 week exposure to 35 ± 1 °C for 3 h from days 35 to 42 (1 week heat). The most abundant amino acid in the ileal flow was glutamic acid, followed by aspartic acid, serine and threonine in non-heat stressed group. The EAA flow in 1-week heat and 2-week heat birds were significantly (p < 0.05) higher than those under no heat exposure (14682, 11161 and 9597 mg/kg of dry matter intake respectively). Moreover, the EAA flow of 2-week heat group was less than 1-week heat group by approximately 36%. These observations suggest that the effect of heat stress on EAA flow is mostly quantitative; however, heat stress may also alter the content of EAA flow qualitatively.

Cancer-associated venous thrombosis in the surgical setting.

OBJECTIVE: Cancer patients are at a relatively high risk of venous thromboembolism (VTE), and this has implications for surgical outcome. DATA SOURCE: English literature search including the keywords cancer, surgery and VTE was undertaken to review the risk, etiology, prevention and treatment of VTE in surgical oncology patients. DATA SYNTHESIS: Malignant disease is highlighted as an important risk factor for VTE with an odds ratio of 6.5. The risk factors include higher age, previous VTE, advanced cancer, length of operation and immobility. CONCLUSIONS: Use of in-hospital thromboprophylaxis with low-molecular-weight heparin (LMWH) or low dose unfractionated heparin with graded stockings has been validated both in terms of safety and efficacy and should be considered for all patients. Subcutaneous LMWH has replaced unfractionated heparin for the initial treatment of VTE. The use of long-term LMWH instead of oral anticoagulants can substantially reduce the risk of recurrent VTE without increased bleeding. Recently, results of few trials have shown that LMWH may improve patient survival.

Crystal structure of trans-bis-[2-(1H-benzotriazol-1-yl)acetato-κO]bis-(ethano-lamine-κ2 N,O)copper(II).

The reaction of 2-(1H-benzotriazol-1-yl)acetic acid (HBTA; C8H7N3O2) and mono-ethano-lamine (MEA; C2H7NO) with CuCl2·2H2O resulted in the formation of the title complex, [Cu(C8H6N3O2)2(C2H7NO)2] or [Cu(BTA)2(MEA)2]. Its asymmetric unit comprises one BTA anion coordin-ating to the Cu2+ cation (site symmetry ) through the carboxyl O atom, and one MEA ligand chelating the metal cation by two heteroatoms (O and N). The equatorial Cu-O and Cu-N bond lengths are similar at 2.029 (1) and 1.980 (2) Å, respectively, while the length of the axial Cu-O bond is considerably greater [2.492 (2) Å], as is typical for Jahn-Teller-distorted systems. An intra-molecular hydrogen bond is present between the hy-droxy group of the MEA ligand and the non-coordinating O atom of the carboxyl-ate group. Inter-molecular hydrogen bonding involving the amino function of the MEA ligand and the carboxyl-ate group results in eight-membered rings with an R 2 2(8) graph-set motif. The mol-ecules are further linked by C-H⋯π inter-actions involving the triazole rings and methyl-ene groups of MEA, thus generating an overall three-dimensional supra-molecular framework.