‘Back to Life’—Using knowledge exchange processes to enhance lifestyle interventions for liver transplant recipients: A qualitative study

Interventions to prevent excessive weight gain after liver transplant are needed. The purpose of the present study was to enhance a specialist post-transplant well-being program through knowledge exchange with end-users.The study used an interactive process of knowledge exchange between researchers, clinicians and health system users. Data were collected as focus groups or telephone interviews and underwent applied thematic analysis.There were 28 participants (age 24-68 years; 64% male). The results identified experiences that may influence decisions around health behaviours during the course of transplant recovery. Three over-arching themes were identified that impact on liver transplant recipients post-transplant health behaviours. These include (i) Finding a coping mechanism which highlighted the need to acknowledge the significant emotional burden of transplant prior to addressing long-term physical wellness; (ii) Back to Life encompassing the desire to return to employment and prioritise family, while co-ordinating the burden of ongoing medical monitoring and self-management and (iii) Tailored, Personalised Care with a preference for health care delivery by transplant specialists via a range of flexible eHealth modalities.This person-centred process of knowledge exchange incorporated experiences of recipients into service design and identified life priorities most likely to influence health behaviours post-transplant. Patient co-creation of services has the potential to improve the integration of knowledge into health systems and future directions will require evaluation of effectiveness and sustainability of patient-centred multidisciplinary service development

Risk, Reliability and Resilience: Phytolith Evidence for Alternative 'Neolithization' Pathways at Kharaneh IV in the Azraq Basin, Jordan.

'Neolithization' pathway refers to the development of adaptations that characterized subsequent Neolithic life, sedentary occupations, and agriculture. In the Levant, the origins of these human behaviors are widely argued to have emerged during the Early Epipaleolithic (ca. 23 ka cal BP). Consequently, there has been a pre-occupation with identifying and modeling the dietary shift to cereal and grains during this period, which is considered to have been a key development that facilitated increasing sedentism and, eventually, agriculture. Yet, direct evidence of plant use in the form of macrobotanical remains is extremely limited at Epipaleolithic sites and the expected 'Neolithization' pathway has not been robustly demonstrated. However, new direct microbotanical phytolith evidence from the large aggregation site of Kharaneh IV, in the Azraq Basin, suggests that increasingly settled occupation was not the result of wild grass and cereal use, but rather the result of a typical hunter-gatherer balance, based on the use of mostly reliable resources supplemented by some risky resources. Moreover, and illustrating this balance, the direct botanical evidence emphases the importance of the wetlands as an under-recognized reliable plant resource. Significantly, the use of these reliable wetland plant resources at Kharaneh IV represents an unexpected 'Neolithization' pathway

Amino Acids Are an Ineffective Fertilizer for Dunaliella spp. Growth

Autotrophic microalgae are a promising bioproducts platform. However, the fundamental requirements these organisms have for nitrogen fertilizer severely limit the impact and scale of their cultivation. As an alternative to inorganic fertilizers, we investigated the possibility of using amino acids from deconstructed biomass as a nitrogen source in the genus Dunaliella. We found that only four amino acids (glutamine, histidine, cysteine, and tryptophan) rescue Dunaliella spp. growth in nitrogen depleted media, and that supplementation of these amino acids altered the metabolic profile of Dunaliella cells. Our investigations revealed that histidine is transported across the cell membrane, and that glutamine and cysteine are not transported. Rather, glutamine, cysteine, and tryptophan are degraded in solution by a set of oxidative chemical reactions, releasing ammonium that in turn supports growth. Utilization of biomass-derived amino acids is therefore not a suitable option unless additional amino acid nitrogen uptake is enabled through genetic modifications of these algae

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissue-specific deletion of the mTORC1 regulator Raptor in α cells (αRaptorKO), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptorKO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptorKO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in KATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance

Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans

Context: Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective: To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting: Single-blinded, prospective study of three independent parallel groups. Participants and Interventions: Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/l), euglycemic (6.0 mmol/l) or sham-saline clamp (n=8 for each group). Forty-eight hours later, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main outcome measures: We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results: Hypoglycemia increased total leucocytes (9.98±1.14 x109/l vs euglycemia: 4.38±0.53 x109/l; P<0.001 vs sham-saline: 4.76±0.36 x109/l; P<0.001) (mean±SEM), mobilized proinflammatory intermediate monocytes (42.20±7.52/μl vs euglycemia: 20.66±3.43/μl; P<0.01 vs sham-saline: 26.20±3.86/μl; P<0.05) and non-classical monocytes (36.16±4.66/μl vs euglycemia: 12.72±2.42/μl; P<0.001 vs sham-saline: 19.05±3.81/μl; P<0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (AUC) increased (73.87±7.30 vs 52.50±4.04; P<0.05) and formation of monocyte-platelet aggregates increased (96.05±14.51/μl vs 49.32±6.41/μl; P<0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51±1.42/μl vs euglycemia: 4.19±1.08/μl; P<0.05 vs sham-saline: 3.81±1.42/μl; P<0.05) and non-classical monocytes (9.53±1.08/μl vs euglycemia: 2.86±0.72/μl; P<0.01 vs sham-saline: 3.08±1.01/μl; P<0.05) with platelets compared to controls. Hypoglycemia led to greater leucocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96±0.97 vs euglycemia: 8.21±0.85 x109/l; P<0.05). Conclusions: Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute towards increased cardiovascular risk observed in people with diabetes

Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion

HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion

The environmental setting of Epipalaeolithic aggregation site Kharaneh IV

The archaeological site of Kharaneh IV in Jordan's Azraq Basin, and its relatively near neighbour Jilat 6 show evidence of sustained occupation of substantial size through the Early to Middle Epipalaeolithic (c. 24,000 - 15,000 cal BP). Here we review the geomorphological evidence for the environmental setting in which Kharaneh IV was established. The on-site stratigraphy is clearly differentiated from surrounding sediments, marked visually as well as by higher magnetic susceptibility values. Dating and analysis of off-site sediments show that a significant wetland existed at the site prior to and during early site occupation (~ 23,000 - 19,000 BP). This may explain why such a substantial site existed at this location. This wetland dating to the Last Glacial Maximum also provides important information on the palaeoenvironments and potential palaeoclimatic scenarios for today's eastern Jordanian desert, from where such evidence is scarce

Occupying wide open spaces? Late Pleistocene hunter–gatherer activities in the Eastern Levant

With a specific focus on eastern Jordan, the Epipalaeolithic Foragers in Azraq Project explores changing hunter-gatherer strategies, behaviours and adaptations to this vast area throughout the Late Pleistocene. In particular, we examine how lifeways here (may have) differed from surrounding areas and what circumstances drew human and animal populations to the region. Integrating multiple material cultural and environmental datasets, we explore some of the strategies of these eastern Jordanian groups that resulted in changes in settlement, subsistence and interaction and, in some areas, the occupation of substantial aggregation sites. Five years of excavation at the aggregation site of Kharaneh IV suggest some very intriguing technological and social on-site activities, as well as adaptations to a dynamic landscape unlike that of today. Here we discuss particular aspects of the Kharaneh IV material record within the context of ongoing palaeoenvironmental reconstructions and place these findings in the wider spatial and temporal narratives of the Azraq Basin

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved