Occurrence of Gastrointestinal Adverse Events Upon GLP-1 Receptor Agonist Initiation With Concomitant Metformin Use: A Post Hoc Analysis of LEADER, STEP 2, SUSTAIN-6, and PIONEER 6.

OBJECTIVE: To assess the impact of concomitant metformin use on gastrointestinal adverse events during the initiation and titration of a glucagon-like peptide 1 receptor agonist (GLP-1RA). RESEARCH DESIGN AND METHODS: Using data from four clinical trials of liraglutide and semaglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER], Semaglutide Treatment Effect in People with Obesity [STEP 2], Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6], and Peptide Innovation for Early Diabetes Treatment [PIONEER] 6), we compared the incidence of gastrointestinal adverse events during GLP-1RA initiation and titration in participants with and without concomitant metformin use. RESULTS: Of 16,996 participants, 12,928 (76%) were treated with metformin. Concomitant metformin use did not increase the percentage of participants who developed gastrointestinal adverse events or their severity during the observation window. Among participants experiencing gastrointestinal adverse events, metformin use did not increase study product discontinuation. Within treatment arms (GLP-1RA and placebo), a numerically higher percentage of metformin nonusers experienced gastrointestinal adverse events and discontinued the study product compared with metformin users. CONCLUSIONS: Concomitant metformin use does not increase occurrence of gastrointestinal symptoms during GLP-1RA initiation or impact GLP-1RA discontinuation.

Promoting insect farming and household consumption through agricultural training and nutrition education in Africa: A study protocol for a multisite cluster-randomized controlled trial.

BACKGROUND: Edible insects are a sustainable source of high-quality animal protein. Insect farming is gaining interest globally, particularly in low-income countries, where it may provide substantial nutritional and economic benefits. To enhance insect farming practices in Africa, new farming systems are being developed. However, knowledge on how to best promote uptake of these systems is lacking. This study aims to fill this gap by investigating the effectiveness of educational interventions in promoting insect farming for household consumption in Africa. METHOD: The study is designed as a multi-site randomized controlled trial to evaluate the impacts of agricultural training alone or in combination with nutrition education on the adoption of insect farming in Ghana, Kenya and Uganda. In each of the three countries, ninety-nine villages are randomly assigned to one of three arms: two intervention arms and a control arm with no interventions. Focusing on production (P), the first intervention arm covers agricultural training on insect farming combined with provision of insect production starter kits. Focusing on both production and consumption (PC), the second intervention arm involves the same intervention components as treatment P plus additional nutrition education. The impacts of the interventions are measured by comparing baseline and endline data collected one year apart. Primary outcomes are adoption of insect farming and consumption of the farmed insects. DISCUSSION: Understanding the drivers and impacts of novel agricultural practices is crucial for transitioning to sustainable food systems. The current project is the first to investigate how educational interventions promote insect farming for household consumption in low-income countries. The results will contribute evidence-based knowledge to support sustainable development through insect farming in Africa. TRIAL REGISTRATION: The protocol is registered in the American Economic Association registry for randomized control trials with registration number AEARCTR-0009996. Initial registration date: 02 September 2022, last updated 17 May 2023.

Health versus environmental benefits: Does additional information influence consumer acceptance of pulse-based spreads?

Despite the known health benefits and the potential for substituting less environmentally sustainable consumed foods such as meat, the current intake of pulses in developed countries remains less than recommended. Barriers are related to sensory characteristics and lack of knowledge about preparation, while drivers of environmental benefits are intangible. The aim of this study was to investigate the effect of additional information about health or environmental benefits of pulses on the acceptance of novel pulse-based products from chickpeas, black beans, and faba beans. Perceptions of these pulse-based spreads in a blind and informed stage were assessed with 202 consumers in urban and suburban areas of Denmark. In general, the familiar chickpea spread followed by the relatively most unfamiliar black bean spread was liked the most. Only for these two products, additional information increased hedonic perception, regardless of the context (health or environmental benefits). If consumers did not like the spread, as found for the faba bean spread, providing additional information did not significantly alter this perception. Participants' preferences and willingness to pay (WTP) in a discrete choice experiment corresponded to hedonic scores, whereas providing additional information increased the WTP. These findings suggest that extrinsic cues such as health or environmental benefits may only be useful in products with an acceptable baseline taste profile. Moreover, black beans might be investigated as a promising source for further product development due to their acceptance by consumers besides being the comparably most unfamiliar pulse type.

Willingness to replace animal-based products with pulses among consumers in different European countries.

The growing world population and increased meat consumption pose a challenge for current food production systems. While pulses present a promising position in terms of low impacts in primary production and high nutritional quality, it is unclear whether consumers are willing to consume pulses instead of meat. Based on an online survey answered by 4,322 respondents across five European countries, this study examined consumers' willingness to utilize pulses as a plant-based alternative to animal-based products. More than a third of pulse consumers (42%) were, to some extent, already using pulses as an alternative to animal-based foods. Beef was noted as the most frequently replaced type of food, mainly driven by arguments relating to health, environment, and sustainability, especially relevant for German and Danish consumers. Respondents who did not indicate a current replacement of animal-based foods stated a relatively low willingness to change in the future (40%). German pulse consumers were likely to be part of the low willingness segment. In contrast, Polish consumers possessed a relatively higher incidence of using pulses instead of meat, especially pork and poultry. Respondents with a low replacement willingness indicated a high importance of future pulse-based products to be natural, while respondents already using pulses instead of animal-based foods expected convenient and minimally processed foods. Respondents, who already replaced meat with pulses or expressed a low future willingness, stated to prefer plain pulses over processed pulse-based products, and meat-resembling forms considering the former segment, alternatively to meat. These preferences and expectations should be considered for future product development, especially if aiming to attract unwilling consumers to shift to pulse-based foods.

Caretakers' perceptions and willingness-to-pay for complementary food in urban and rural Cambodia.

Inadequate child nutrition during the first '1000 days' is widespread in Cambodia, resulting in a high prevalence of child malnutrition. Access to processed complementary food in packages (PCFP) may support caretakers in improving diet of young children. This study aimed to evaluate the caretakers' preferences and willingness-to-pay (WTP) for PCFP in Cambodia. The study was conducted in urban and rural settings, involving 520 caretakers with children aged 7-24 months in Phnom Penh (urban) and Prey Veng (rural). Four PCFPs were included: a commercial brand, a social-commercial brand, a worldwide distributed fortified complementary food aid product (CSB++) and an experimental fortified rice-and-fish-based PCFP developed in Cambodia (WF-L). Sensory analysis was conducted for all products, stated WTP was assessed for three products (excluding CSB++) and actual WTP experiment was conducted on WF-L only. Our results show that overall, WF-L was preferred by the rural participants over food aid CSB++. Further improvements in the organoleptic qualities of WF-L should focus on consistency and taste. The participants were, on average, willing to pay 1,667 Cambodian riel (KHR, $0.4) and 1,192 KHR ($0.3) in urban and rural settings, respectively, for 35 g of WF-L. We also found that despite being nutritionally inadequate, most participants considered homemade porridge to be healthier, more practical and preferred by the children. Therefore improving the quality of homemade foods merits urgent consideration. When applying PCFP in nutrition programmes as a supplementary option to homemade complementary foods, locally produced products could be a more viable supplementary option than global food aid.

Nutrient mitigation under the impact of climate and land-use changes: A hydro-economic approach to participatory catchment management.

Excessive nutrient loadings into rivers are a well-known ecological problem. Implemented mitigation measures should ideally be cost-effective, but perfectly ranking alternative nutrient mitigation measures according to cost-effectiveness is a difficult methodological challenge. Furthermore, a particularly practical challenge is that cost-effective measures are not necessarily favoured by local stakeholders, and this may impede their successful implementation in practice. The objective of this study was to evaluate the cost-effectiveness of mitigation measures using a methodology that includes a participatory process and social learning to ensure their successful implementation. By combining cost data, hydrological modelling and a bottom-up approach for three different European catchment areas (the Latvian Berze, the Swedish Helge and the German Selke rivers), the cost-effectiveness of 16 nutrient mitigation measures were analysed under current conditions as well as under selected scenarios for future climate and land-use changes. Fertiliser reduction, wetlands, contour ploughing and municipal wastewater treatment plants are the measures that remove nutrients with the highest cost-effectiveness in the respective case study context. However, the results suggest that the cost-effectiveness of measures not only depends on their design, specific location and the conditions of the surrounding area, but is also affected by the future changes the area may be exposed to. Climate and land-use changes do not only affect the cost-effectiveness of measures, but also shape the overall nutrient loads and potential target levels in a catchment.

MRI of the sacroiliac joints in athletes: recognition of non-specific bone marrow oedema by semi-axial added to standard semi-coronal scans.

OBJECTIVE: Assessment of combined semi-axial and semi-coronal SI joint MRI in two cohorts of young athletes to explore frequency and topography of non-specific bone marrow oedema (BMO), its association with four constitutional SI joint features, and potential restriction of false-positive assignments of Assessment of SpondyloArthritis International Society-defined sacroiliitis on standard semi-coronal scans alone. METHODS: Combined semi-axial and semi-coronal SI joint MRI scans of 20 recreational runners before/after running and 22 elite ice-hockey players were evaluated by three blinded readers for BMO and its association with four constitutional SI joint features: vascular partial volume effect, deep iliac ligament insertion, fluid-filled bone cyst and lumbosacral transitional anomaly. Scans of TNF-treated spondyloarthritis patients served to mask readers. We analysed distribution and topography of BMO and SI joint features across eight anatomical SI joint regions (upper/lower ilium/sacrum, subdivided in anterior/posterior slices) descriptively, as concordantly recorded by ⩾2/3 readers on both MRI planes. BMO confirmed on both scans was compared with previous evaluation of semi-coronal MRI alone, which met the Assessment of SpondyloArthritis International Society definition for active sacroiliitis. RESULTS: Perpendicular semi-axial and semi-coronal MRI scans confirmed BMO in the SI joint of every fourth young athlete, preferentially in the anterior upper sacrum. BMO associated with four constitutional SI joint features was observed in 20-36% of athletes, clustering in the posterior lower ilium. The proportion of Assessment of SpondyloArthritis International Society-positive sacroiliitis recorded on the semi-coronal plane alone decreased by 33-56% upon amending semi-axial scans. CONCLUSION: Semi-axial combined with standard semi-coronal scans in MRI protocols for sacroiliitis facilitated recognition of non-specific BMO, which clustered in posterior lower ilium/anterior upper sacrum.

Public preferences for co-benefits of riparian buffer strips in Denmark: An economic valuation study.

Riparian buffer strips are an extensively used measure to combat the transfer of nutrients and sediment into waterbodies. However, benefits from riparian buffer strips are not limited to improvements in the aquatic environment, as buffer strips per se can provide various societal co-benefits, such as recreational and aesthetic benefits, to name a few. The values of these co-benefits are likely to depend on the design and physical features of the buffer strips. In this paper, we use a stated choice experiment survey to assess the values of different characteristics of riparian buffer strips in Denmark. Comparing different regions of Denmark, we find that public preferences for buffer strip characteristics are largely homogenous across geographical regions, but heterogeneous within the regions. Thus, differentiating the buffer strip regulation between regions to maximize the value of the co-benefits does not lead to a large difference in welfare, compared to a uniform national regulation. However, differentiation at a more localized geographical level could potentially improve societal welfare. Overall, the results show that buffer strips can provide large societal co-benefits in addition to the benefits of improving water quality. The results may provide important information for optimizing the future design and management of buffer strips to ensure that all types of societal welfare impacts are taken into account.

Frequency and Anatomic Distribution of Magnetic Resonance Imaging Features in the Sacroiliac Joints of Young Athletes: Exploring "Background Noise" Toward a Data-Driven Definition of Sacroiliitis in Early Spondyloarthritis.

OBJECTIVE: Low-grade bone marrow edema (BME) has been reported in the sacroiliac (SI) joints of 25% of healthy individuals and patients with nonspecific mechanical back pain, thus challenging the specificity and predictive value of magnetic resonance imaging (MRI) for the discrimination of early spondyloarthritis (SpA). It is unknown whether stress injury in competition sports may trigger BME. This study sought to explore the frequency and anatomic distribution of SI joint MRI lesions in recreational and elite athletes. METHODS: After pretest calibration, semicoronal MRI scans of the SI joints of 20 recreational runners before and after running and 22 elite ice hockey players were assessed for BME and structural lesions. Three readers assessed the MRI scans in a blinded manner, using an SI joint quadrant-based module; scans from tumor necrosis factor inhibitor-treated patients with SpA served for masking. The readers recorded subjects who met the Assessment of SpondyloArthritis international Society (ASAS) definition of active sacroiliitis. For descriptive analysis, the frequency of SI joint quadrants exhibiting BME and structural lesions, as concordantly recorded by ≥2 of 3 readers, and their distribution in 8 anatomic SI joint regions (the upper and lower ilium and sacrum, subdivided in anterior and posterior slices) were determined. RESULTS: The proportions of recreational runners and elite ice hockey players fulfilling the ASAS definition of active sacroiliitis, as recorded concordantly by ≥2 of 3 readers, were 30-35% and 41%, respectively. In recreational runners before and after running, the mean ± SD number of SI joint quadrants showing BME was 3.1 ± 4.2 and 3.1 ± 4.5, respectively, while in elite ice hockey players, it was 3.6 ± 3.0. The posterior lower ilium was the single most affected SI joint region, followed by the anterior upper sacrum. Erosion was virtually absent. CONCLUSION: In recreational and elite athletes, MRI revealed BME in an average of 3-4 SI joint quadrants, meeting the ASAS definition of active sacroiliitis in 30-41% of subjects. The posterior lower ilium was the single most affected SI joint region. These findings in athletes could help refine data-driven thresholds for defining sacroiliitis in early SpA.

Accounting protesting and warm glow bidding in Contingent Valuation surveys considering the management of environmental goods--an empirical case study assessing the value of protecting a Natura 2000 wetland area in Greece.

Based on a Contingent Valuation survey aiming to reveal the willingness to pay (WTP) for conservation of a wetland area in Greece, we show how protest and warm glow motives can be taken into account when modeling WTP. In a sample of more than 300 respondents, we find that 54% of the positive bids are rooted to some extent in warm glow reasoning while 29% of the zero bids can be classified as expressions of protest rather than preferences. In previous studies, warm glow bidders are only rarely identified while protesters are typically identified and excluded from further analysis. We test for selection bias associated with simple removal of both protesters and warm glow bidders in our data. Our findings show that removal of warm glow bidders does not significantly distort WTP whereas we find strong evidence of selection bias associated with removal of protesters. We show how to correct for such selection bias by using a sample selection model. In our empirical sample, using the typical approach of removing protesters from the analysis, the value of protecting the wetland is significantly underestimated by as much as 46% unless correcting for selection bias.

Product inhibition of five Hypocrea jecorina cellulases.

Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information on individual cellulases hydrolyzing insoluble cellulose remains insufficient. Such knowledge is necessary to pinpoint and quantify inhibitory weak-links in cellulose hydrolysis, but has proven challenging to come by. Here we show that product inhibition of mono-component cellulases hydrolyzing unmodified cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly CBH1), Cel6A (CBH2), Cel7B (EG1), Cel5A (EG2) and Cel12A (EG3), for their sensitivity to the products glucose and cellobiose. The strongest inhibition was found for Cel7A, which showed a 50% activity-loss in 19 mM cellobiose (IC(50)=19 mM). The other exoglucanase, Cel6A, was much less inhibited by cellobiose, but showed the highest sensitivity to glucose among all investigated enzymes. The endoglucanases Cel12A and Cel7B were moderately inhibited by cellobiose (IC(50)=60-80 mM), and weakly inhibited by glucose (IC(50)=350-380 mM). The highest resistance to both products was found for Cel5A, which retained about 75% of its activity at the highest investigated concentrations (respectively 65 mM cellobiose and 1000 mM glucose).

Origin of initial burst in activity for Trichoderma reesei endo-glucanases hydrolyzing insoluble cellulose.

The kinetics of cellulose hydrolysis have long been described by an initial fast hydrolysis rate, tapering rapidly off, leading to a process that takes days rather than hours to complete. This behavior has been mainly attributed to the action of cellobiohydrolases and often linked to the processive mechanism of this exo-acting group of enzymes. The initial kinetics of endo-glucanases (EGs) is far less investigated, partly due to a limited availability of quantitative assay technologies. We have used isothermal calorimetry to monitor the early time course of the hydrolysis of insoluble cellulose by the three main EGs from Trichoderma reesei (Tr): TrCel7B (formerly EG I), TrCel5A (EG II), and TrCel12A (EG III). These endo-glucanases show a distinctive initial burst with a maximal rate that is about 5-fold higher than the rate after 5 min of hydrolysis. The burst is particularly conspicuous for TrCel7B, which reaches a maximal turnover of about 20 s(-1) at 30 °C and conducts about 1200 catalytic cycles per enzyme molecule in the initial fast phase. For TrCel5A and TrCel12A the extent of the burst is 2-300 cycles per enzyme molecule. The availability of continuous data on EG activity allows an analysis of the mechanisms underlying the initial kinetics, and it is suggested that the slowdown is linked to transient inactivation of enzyme on the cellulose surface. We propose, therefore, that the frequency of structures on the substrate surface that cause transient inactivation determine the extent of the burst phase.

Kinetics of enzymatic high-solid hydrolysis of lignocellulosic biomass studied by calorimetry.

Enzymatic hydrolysis of high-solid biomass (>10% w/w dry mass) has become increasingly important as a key step in the production of second-generation bioethanol. To this end, development of quantitative real-time assays is desirable both for empirical optimization and for detailed kinetic analysis. In the current work, we have investigated the application of isothermal calorimetry to study the kinetics of enzymatic hydrolysis of two substrates (pretreated corn stover and Avicel) at high-solid contents (up to 29% w/w). It was found that the calorimetric heat flow provided a true measure of the hydrolysis rate with a detection limit of about 500 pmol glucose s(-1). Hence, calorimetry is shown to be a highly sensitive real-time method, applicable for high solids, and independent on the complexity of the substrate. Dose-response experiments with a typical cellulase cocktail enabled a multidimensional analysis of the interrelationships of enzyme load and the rate, time, and extent of the reaction. The results suggest that the hydrolysis rate of pretreated corn stover is limited initially by available attack points on the substrate surface (<10% conversion) but becomes proportional to enzyme dosage (excess of attack points) at later stages (>10% conversion). This kinetic profile is interpreted as an increase in polymer end concentration (substrate for CBH) as the hydrolysis progresses, probably due to EG activity in the enzyme cocktail. Finally, irreversible enzyme inactivation did not appear to be the source of reduced hydrolysis rate over time.

A comparative study of activity and apparent inhibition of fungal ß-glucosidases.

ß-Glucosidases (BGs) from Aspergillus fumigates, Aspergillus niger, Aspergillus oryzae, Chaetomium globosum, Emericella nidulans, Magnaporthe grisea, Neurospora crassa, and Penicillium brasilianum were purified to homogeneity, and analyzed by isothermal titration calorimetry with respect to their hydrolytic activity and its sensitivity to glucose (product) using cellobiose as substrate. Global non-linear regression of several reactions, with or without added glucose, to a product inhibition equation enabled the concurrent derivation of the kinetic parameters k(cat), K(m), and the apparent product inhibition constant (app)K(i) for each of the enzymes. A more simple fit is not advisable to use as the determined (app)K(i) are in the same range as their K(m) for some of the tested BGs and produced glucose would in these cases interfere. The highest value for k(cat) was determined for A. fumigatus (768 s(-1)) and the lowest was a factor 9 less. K(m) varied by a factor of 3 with the lowest value determined for C. globosum (0.95 mM). The measured (app)K(i) varied a factor of 15; the hydrolytic activity of N. crassa being the most resistant to glucose with an apparent product inhibition constant of 10.1 mM. Determination of (app)K(i) using cellobiose as substrate is important as it reflects to what extent the different BGs are hydrolytically active under industrial conditions where natural substrates are hydrolyzed and the final glucose concentrations are high.

Role of electrostatic repulsion on colloidal stability of Bacillus halmapalus alpha-amylase.

The colloidal stability of charged particles in suspension is often controlled by electrostatic repulsion, which can be rationalized in a semi-quantitative way by the DLVO theory. In the current study, we investigate this approach towards understanding irreversible protein aggregation, using Bacillus halmapalus alpha-amylase (BHA) as a model protein. Repulsive forces between partly unfolded monomers were shown to strongly affect aggregation. Adding salt, increasing valence of counter ions or decreasing pH in the direction of pI resulted in a shift in the rate-limiting step from association to unfolding as evidenced by a change in aggregation kinetics from second to first-order in protein concentration. Charge screening effects by salts resulted in increased average size of protein aggregates but only moderately affected the secondary structure of protein within the aggregates. Salt and pH effects could be explained within the DLVO framework, indicating that partially unfolded BHA monomers can be modelled realistically as colloids with a random charge distribution.

Resection of cancer of the body and tail of the pancreas.

BACKGROUND/AIMS: To report our results of resection of cancer in the body and tail of the pancreas and review the literature. METHODOLOGY: Thirteen patients with a median age of 62 years with cancer of the body and/or tail of the pancreas. The diagnosis was made by ultrasonography, computed tomography, endoscopic retrograde cholangiopancreatography and angiography. Eleven patients had distal or subtotal pancreatectomy and two patients total pancreatectomy. The surgical procedure included extensive dissection of lymph nodes and the connective tissue in the peripancreatic region. Main outcome measures were postoperative morbidity and mortality, median and 5-year survival rates. RESULTS: Ten of the resections were considered to be curative. Postoperative complications occurred in seven patients and one patient died in the postoperative period. The median survival time of operative survivors was 392 days. Two patients survived five years, and one was alive ten years after surgery. Eight patients died of recurrence. CONCLUSIONS: Long-term survival may be achieved in a quarter of the resectable patients.