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Glacial terminations are marked by a re-organisation of the different components of the climate system. In particular, rapid ice sheet disintegration leads to multiple complex feedback loops that are still poorly understood. To further investigate this aspect, we use here a fully coupled Northern Hemisphere ice sheet–climate model to perform numerical experiments of the last two glacial terminations. We show that even if the first-order climate trajectory is similar for the two terminations, the difference in terms of solar insolation leads to important changes for the ice sheet–climate system. Warmer temperatures during the penultimate termination are compatible with higher sea level during the last interglacial period with respect to the Holocene. We simulate a last interglacial Greenland contribution to sea level rise of about 2 m of sea level equivalent. We also simulate warmer subsurface Southern Ocean, compatible with an additional contribution from the Antarctic ice sheet. In addition, even without considering freshwater flux to the ocean resulting from ice sheet melting, the two terminations display different Atlantic overturning circulation sensitivity, this circulation being more prone to collapses during the penultimate termination. Finally, with additional sensitivity experiments we show that, for the two terminations, the Northern Hemisphere insolation is the main driver for the ice sheet retreat even if vegetation changes have also to be taken into account to simulate the full deglaciation. Conversely, even though it impacts the temperature, greenhouse gas concentration change alone does not explain the amplitude of ice sheet retreat and only modulates its timing.

Abstract As part of the R2D2 (Rare Decays with Radial Detector) R &D, the use of a gas detector with a spherical or cylindrical cathode, equipped with a single anode and operating at high pressure, was studied for the search of rare phenomena such as neutrinoless double-beta decay. The presented measurements were obtained with a cylindrical detector, covering gas pressures ranging from 1 to 10 bar in argon and 1 to 6 bar in xenon, using both a point-like source of $$^{210} $$ 210 Po (5.3 MeV $$\alpha $$ α ) and a diffuse source of $$^{222}$$ 222 Rn (5.5 MeV $$\alpha $$ α ). Analysis and interpretation of the data were developed using the anodic current waveform. Similar detection performances were achieved with both gases, and comparable energy resolutions were measured with both sources. As long as the purity of the gas was sufficient, no significant degradation of the measured energy was observed by increasing the pressure. At the highest operating pressure, an energy resolution better than 1.5% full-width at half-maximum (FWHM) was obtained for both gaseous media, although optimal noise conditions were not reached.

Stable water isotopes are used to infer changes in the hydrological cycle for different climate periods and various climatic archives. Following previous developments of δ18O in the coupled climate model of intermediate complexity, iLOVECLIM, we present here the implementation of the 1H2H16O and 1H217O water isotopes in the different components of this model and calculate the associated secondary markers deuterium excess (d-excess) and oxygen-17 excess (17O-excess) in the atmosphere and ocean. So far, the latter has only been modelled by the atmospheric model LMDZ4. Results of a 5000-year equilibrium simulation under preindustrial conditions are analysed and compared to observations and several isotope-enabled models for the atmosphere and ocean components. In the atmospheric component, the model correctly reproduces the first-order global distribution of the δ2H and d-excess as observed in the data (R=0.56 for δ2H and 0.36 for d-excess), even if local differences are observed. The model–data correlation is within the range of other water-isotope-enabled general circulation models. The main isotopic effects and the latitudinal gradient are properly modelled, similarly to previous water-isotope-enabled general circulation model simulations, despite a simplified atmospheric component in iLOVECLIM. One exception is observed in Antarctica where the model does not correctly estimate the water isotope composition, a consequence of the non-conservative behaviour of the advection scheme at a very low moisture content. The modelled 17O-excess presents a too-important dispersion of the values in comparison to the observations and is not correctly reproduced in the model, mainly because of the complex processes involved in the 17O-excess isotopic value. For the ocean, the model simulates an adequate isotopic ratio in comparison to the observations, except for local areas such as the surface of the Arabian Sea, a part of the Arctic and the western equatorial Indian Ocean. Data–model evaluation also presents a good match for the δ2H over the entire water column in the Atlantic Ocean, reflecting the influence of the different water masses.

ABSTRACT: Improving health and welfare outcomes for replacement and surplus dairy calves is important for the sustainability of the dairy industry. Dairy farmers and veterinarians hold expertise in calf management and have valuable perspectives on how to practically motivate improvements. The objective of this study was to determine strategies that could improve the care calves receive on dairy farms from the perspective of dairy farmers and their herd veterinarians. Two veterinary clinics specializing in dairy practice in British Columbia, Canada, and 21 of their client dairy farms participated in the project. Following a meeting in which calf colostrum management was discussed between farmers and their herd veterinarian, participant interviews were conducted. Separate interviews were conducted for the farmers (n = 27 farmers from 21 farms) and their herd veterinarians (n = 7, with 1 to 5 farms that each vet worked with enrolled in the study) using tailored semi-structured question guides. Interviews (n = 42) were transcribed and coded following inductive thematic analysis methodology. The themes identified included strategies for farmers, veterinarians, and calf buyers, as well as contexts that influenced the dairy farmers' internal motivation to provide good calf care. Results indicated that farmers could optimize their calf management through fostering engagement of calf care personnel or by enlisting technology. Veterinarians could provide support to farms by being actively involved in calf monitoring, assisting in developing operating protocols, and setting goals, and especially by using farm-specific data to guide their management recommendations. Calf buyers could communicate with and provide accountability to farmers and improve their purchasing strategies to encourage farms to raise more vigorous surplus calves. Farmers' personal values, social networks, and relationships with different dairy industry stakeholders influenced their concern about the standards of their calf care practices. These findings provide guidance on how dairy farmers could achieve or be prompted to achieve improvements in their calf care practices.

California is the largest agricultural economy in the United States; however, its current and projected climate risks pose significant challenges. Farmers will need to adapt to climate change in their farming practices. The goal of this needs assessment was to understand farmers' perceptions and experiences with climate change exposures; the risk management practices they currently use; and what tools and resources would assist them in making strategic decisions. A statewide survey was conducted through Qualtrics with farmers (n = 341). Results showed that 67% of the farmers agree (agree + strongly agree) that climate change is happening, and 53.1% agreed that actions are required. Moreover, historically underrepresented farmers were very concerned about climate change-related impacts related to water, temperatures, and natural disasters. Farmers are currently implementing adaptation practices related to water management, soil health, and renewable energy and are also seeking insurance and government assistance programs to increase agricultural resilience. They also expressed interest and a high need for information on those adaptation practices to acquire skills and knowledge to manage various challenges of farming in variable climates. Also, the assessment established that farmers (47.5%) use decision-support tools, mostly weather stations (22.4%); and 51.9% indicated their interest in using online tools designed to translate climate information into forms that support production decision-making. Farmers (60.8%) responded that they would or may attend workshops to learn about adaptation practices. The findings of this needs assessment will inform the development of extension education programs on climate-smart agriculture for farmers in California and elsewhere.

ABSTRACT: This study used realistic evaluation to determine how, and in which circumstances, providing dairy farmers with benchmarked data on their calves can motivate improved colostrum management practices. Dairy farmers from British Columbia, Canada, were recruited through 2 veterinary clinics that offered benchmarking of calf data as part of their services. For approximately 8 wk, blood samples were collected from newborn calves to evaluate serum total protein concentrations as an indicator of the effectiveness of the farmer's colostrum management. These data were analyzed separately for heifer calves (“replacement calves”) and non-replacement calves, including males and beef crossbred females (“surplus calves”). The results of these analyses were benchmarked against other participating herds and presented to dairy farmers (n = 27) by their herd veterinarian (n = 7). Follow-up interviews were conducted separately with the farmers and veterinarians after each meeting to determine their perspectives on the utility of this benchmarking strategy. Therefore, a total of 42 interviews were coded, and realistic evaluation was used to determine common contexts and mechanisms that contributed to the success or failure of the benchmark meeting, with success characterized by farmers' expressed intention to improve their colostrum management practices. Four important contexts were identified that influenced the outcome of the benchmark meetings: (1) farm resources (e.g., facility limitations), (2) the farmer's perception of their calf performance, (3) management strategies, and (4) the farmer's personal values. Depending on these contexts, some farmers intended to improve their calf care practices based on resources the benchmark meeting provided, which included illustrative data and veterinary advice. These resources motivated change through influencing farmer decision-making, which depended on the value they saw in the data as a decision-making tool. The economic or moral interest farmers expressed in their surplus calves also influenced whether farmers intended to implement management changes. Recommendations for future implementation of benchmarking include targeting producers who are motivated to improve and who value the future performance of their calves, those who have engaged calf care personnel, and those who prefer data-driven decision-making. This study supports the important role veterinarians can play in motivating improved calf care practices through providing benchmarking services.

Abstract Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. First, the QT interval is corrected for the influence of rate and then statistical significance is tested. There is renewed interest in improving the sensitivity of nonclinical corrected QT interval (QTc) assessment with modern studies having greater data density than previously utilized. The current analyses examine the effects of moxifloxacin or vehicle on the QT interval in nonhuman primates (NHPs) using a previously described one‐step method. The primary end point is the statistical sensitivity of the assessment. Publications suggest that for a four animal crossover (4 × 4) in NHPs the minimal detectable difference (MDD) is greater than or equal to 10 ms, whereas in an eight animal crossover the MDD is ~6.5 ms. Using the one‐step method, the MDD for the four animal NHP assessments was 3 ms. In addition, the one‐step model accounted for day‐to‐day differences in the heart rate and QT‐rate slope as well as drug‐induced changes in these parameters. This method provides an increase in the sensitivity and reduces the number of animals necessary for detecting potential QT change and represents “best practice” in nonclinical QTc assessment in safety pharmacology studies.

The primary objective of this study was to demonstrate the non-inferiority between lidocaine-impregnated ligation bands (LLBs) and control bands (CBs) with respect to the efficacy of castration and tail docking. Secondary objectives were to compare castration and tail-docking success, evaluate local site reactions, and compare average daily gain (ADG) between the treatment groups. A total of 238 male lambs were enrolled and randomly assigned to receive LLBs or CBs on their tail and scrotum. Lambs were weighed, had a health assessment, and the band site was observed on −3, 7, 14, 21, 28, 35, and 42 days after the bands were applied. A linear regression model was built to assess average daily gain, whereas a repeated measures model was used to evaluate body weight differences at each of the measured timepoints. Furthermore, logistic regression models were used to evaluate associations with casting outcomes. Few differences were noted between treatment groups with respect to casting success for the scrotum and tail and ADG over the entire experimental period. Non-inferiority calculations demonstrated no differences in tail docking and scrotal casting success, with casting occurring for the majority of animals by d 21 and d 42 for castration and tail docking, respectively. However, lambs receiving LLBs gained more weight from d −3 to 7 (+0.03 kg/d; 95% CI: 0 to 0.07), which may be an indication of effective pain control during the first week following band application. Overall, the use of an LLB does not affect the time to successful casting of the tail and could improve short-term growth when compared to a control band. Further studies are needed to compare LLBs to multimodal methods of pain relief.

During the last deglaciation, the climate evolves from a cold state at the Last Glacial Maximum (LGM) at 21 ka (thousand years ago) with large ice sheets to the warm Holocene at ∼9 ka with reduced ice sheets. The deglacial ice sheet melt can impact the climate through multiple ways: changes of topography and albedo, bathymetry and coastlines, and freshwater fluxes (FWFs). In the PMIP4 (Paleoclimate Modelling Intercomparison Project – Phase 4) protocol for deglacial simulations, these changes can be accounted for or not depending on the modelling group choices. In addition, two ice sheet reconstructions are available (ICE-6G_C and GLAC-1D). In this study, we evaluate all these effects related to ice sheet changes on the climate using the iLOVECLIM model of intermediate complexity. We show that the two reconstructions yield the same warming to a first order but with a different amplitude (global mean temperature of 3.9 ∘C with ICE-6G_C and 3.8 ∘C with GLAC-1D) and evolution. We obtain a stalling of temperature rise during the Antarctic Cold Reversal (ACR, from ∼14 to ∼12 ka) similar to proxy data only with the GLAC-1D ice sheet reconstruction. Accounting for changes in bathymetry in the simulations results in a cooling due to a larger sea ice extent and higher surface albedo. Finally, freshwater fluxes result in Atlantic meridional overturning circulation (AMOC) drawdown, but the timing in the simulations disagrees with proxy data of ocean circulation changes. This questions the causal link between reconstructed freshwater fluxes from ice sheet melt and recorded AMOC weakening.

IntroductionSocio-indexical cues to gender and vocal affect often interact and sometimes lead listeners to make differential judgements of affective intent based on the gender of the speaker. Previous research suggests that rising intonation is a common cue that both women and men produce to communicate lack of confidence, but listeners are more sensitive to this cue when it is produced by women. Some speech perception theories assume that listeners will track conditional statistics of speech and language cues (e.g., frequency of the socio-indexical cues to gender and affect) in their listening and communication environments during speech perception. It is currently less clear if these conditional statistics will impact listener ratings when context varies (e.g., number of talkers).MethodsTo test this, we presented listeners with vocal utterances from one female and one male-pitched voice (single talker condition) or many female/male-pitched voices (4 female voices; 4 female voices pitch-shifted to a male range) to examine how they impacted perceptions of talker confidence.ResultsResults indicated that when one voice was evaluated, listeners defaulted to the gender stereotype that the female voice using rising intonation (a cue to lack of confidence) was less confident than the male-pitched voice (using the same cue). However, in the multi-talker condition, this effect went away and listeners equally rated the confidence of the female and male-pitched voices.DiscussionFindings support dual process theories of information processing, such that listeners may rely on heuristics when speech perception is devoid of context, but when there are no differentiating qualities across talkers (regardless of gender), listeners may be ideal adapters who focus on only the relevant cues.

ABSTRACTSalmonella is the only bacterium able to enter a host cell by the two known mechanisms: trigger and zipper. The trigger mechanism relies on the injection of bacterial effectors into the host cell through the Salmonella type III secretion system 1. In the zipper mechanism, mediated by the invasins Rck and PagN, the bacterium takes advantage of a cellular receptor for invasion. This study describes the transcriptomic reprogramming of the IEC-6 intestinal epithelial cell line to Salmonella Typhimurium strains that invaded cells by a trigger, a zipper, or both mechanisms. Using S. Typhimurium strains invalidated for one or other entry mechanism, we have shown that IEC-6 cells could support both entries. Comparison of the gene expression profiles of exposed cells showed that irrespective of the mechanism used for entry, the transcriptomic reprogramming of the cell was nearly the same. On the other hand, when gene expression was compared between cells unexposed or exposed to the bacterium, the transcriptomic reprogramming of exposed cells was significantly different. It is particularly interesting to note the modulation of expression of numerous target genes of the aryl hydrocarbon receptor showing that this transcription factor was activated by S. Typhimurium infection. Numerous genes associated with the extracellular matrix were also modified. This was confirmed at the protein level by western-blotting showing a dramatic modification in some extracellular matrix proteins. Analysis of a selected set of modulated genes showed that the expression of the majority of these genes was modulated during the intracellular life of S. Typhimurium.

This study presents the application of an interactive downscaling in Europe using iLOVECLIM (a model of intermediate complexity), increasing its atmospheric resolution from 5.56 to 0.25∘ kilometric. A transient simulation using the appropriate climate forcings for the entire Holocene (11.5–0 ka BP) was done for both the standard version of the model and with an interactive downscaling applied. Our results show that simulations from downscaling present spatial variability that agrees better with proxy-based reconstructions and other climate models as compared to the standard model. The downscaling scheme simulates much higher (by at least a factor of 2) precipitation maxima and provides detailed information in mountainous regions. We focus on examples from the Scandes mountains, the Alps, the Scottish Highlands, and the Mediterranean. The higher spatial resolution of the downscaling provides a more realistic overview of the topography and gives local climate information, such as precipitation and temperature gradient, that is important for paleoclimate studies. With downscaling, we simulate similar trends and spatial patterns of the precipitation changes reconstructed by other proxy studies (for example in the Alps) as compared to the standard version. Our downscaling tool is numerically cheap, implying that our model can perform kilometric, multi-millennial simulations and is suitable for future studies.

This study aimed to assess the effective tissue concentrations of the current standard of care for pain mitigation in calves during castration (injectable lidocaine) and to assess the ability of a lidocaine-loaded elastration band (LLB) to deliver effective concentrations into the scrotal tissue over time. This study comprised two different trials: (1) effective concentrations of injectable lidocaine in the scrotal tissue; and (2) the in vivo delivery of effective concentrations of lidocaine from LLBs placed on the calf scrotums. Sensation in the scrotal tissue was assessed by electrocutaneous stimulation. Injectable lidocaine allowed for short-term anesthesia for up to 60 min, highlighting the importance of finding additional strategies to mitigate long-term pain. An elastomeric ligation band impregnated with lidocaine could provide a suitable alternative, as it yielded tissue levels of lidocaine that approached EC50 and exceeded EC95 at 2 and 72 h following application, respectively, and remained above those levels for at least 28 days after application. Further studies are warranted to compare the use of LLBs to injectable local anesthetics.

The development of novel antimicrobial technologies for the food industry represents an important strategy to improve food safety. Antimicrobial photodynamic disinfection (aPDD) is a method that can inactivate microbes without the use of harsh chemicals. aPDD involves the administration of a non-toxic, light-sensitive substance, known as a photosensitizer, followed by exposure to visible light at a specific wavelength. The objective of this study was to screen the antimicrobial photodynamic efficacy of 32 food-safe pigments tested as candidate photosensitizers (PSs) against pathogenic and food-spoilage bacterial suspensions as well as biofilms grown on relevant food contact surfaces. This screening evaluated the minimum bactericidal concentration (MBC), minimum biofilm eradication concentration (MBEC), and colony forming unit (CFU) reduction against Salmonella enterica, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas fragi, and Brochothrix thermosphacta. Based on multiple characteristics, including solubility and the ability to reduce the biofilms by at least 3 log10 CFU/sample, 4 out of the 32 PSs were selected for further optimization against S. enterica and MRSA, including sunset yellow, curcumin, riboflavin-5′-phosphate (R-5-P), and erythrosin B. Optimized factors included the PS concentration, irradiance, and time of light exposure. Finally, 0.1% w/v R-5-P, irradiated with a 445 nm LED at 55.5 J/cm2, yielded a “max kill” (upwards of 3 to 7 log10 CFU/sample) against S. enterica and MRSA biofilms grown on metallic food contact surfaces, proving its potential for industrial applications. Overall, the aPDD method shows substantial promise as an alternative to existing disinfection technologies used in the food processing industry.

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and colorectal cancer. Importantly, not all obese phenotypes are equal. Obese adipose tissue heterogeneity depends on the location, structure, cellular profile (including resident immune cell populations), and dietary fatty acid intake. We discuss whether adipose heterogeneity impacts the tumorigenic environment. Dietary fat quality, in particular saturated fatty acids, promotes a hypertrophic, pro-inflammatory adipose profile, in contrast to monounsaturated fatty acids, resulting in a hyperplastic, less inflammatory adipose phenotype. The purpose of this review is to examine the impact of obesity, including dietary fat quality, on adipose tissue biology and oncogenesis, specifically focusing on lipid metabolism and inflammatory mechanisms. This is achieved with a particular focus on gastrointestinal cancers as exemplar models of obesity-associated cancers.

The objectives of this study were to assess the pharmacokinetics and pharmacodynamics of the current standard-of-care for pain mitigation in lambs during castration and tail docking (injectable lidocaine) and assess the ability of Lidocaine-Loaded Bands (LLBs) to deliver therapeutic concentrations into the contacted tissues over time. The study was comprised of four different trials: (1) investigation of in vitro release of lidocaine from LLBs; (2) pharmacokinetics and pharmacodynamics of injectable lidocaine in scrotal and tail tissue; (3) pharmacokinetics and pharmacodynamics of in vivo delivery of lidocaine with LLBs placed on the tail and scrotum of lambs; and (4) a “proof-of-concept” study comparing the sensation of control- versus LLB-banded tail tissue over time. The use of injectable lidocaine provides effective short-term anesthesia for 120 to 180 min following the injection; however, additional strategies are needed to manage long-term pain. The use of an LLB could provide an alternative where tissue lidocaine concentrations meet or exceed the EC50 for at least 21–28 days and, based on electrostimulation data, provides local anesthesia for at least 3 days when compared to a control band. Further studies are needed to compare the use of an injectable local anesthetic to the LLBs.

The spatio-temporal structure of natural climate variability has to be taken into account when unravelling observed climatic changes and simulating future climate change. However, based on the comparison of temperature reconstructions and climate model simulations covering the past 2 millennia, it has been argued that climate models are biased. They would simulate too little temporal temperature variability and too high correlations between temperature time series from different continents. One of the proposed causes is the lack of internal climate variability in climate models on centennial timescales, for instance variability related to the Atlantic meridional overturning circulation (AMOC). We present a perturbed-parameter ensemble with the iLOVECLIM Earth system model containing various levels of AMOC-related internal climate variability to investigate the effect on the spatio-temporal temperature variability structure. The model ensemble shows that enhanced AMOC variability indeed leads to more continental-scale temperature variability, but it also increases the spatio-temporal temperature correlations between different continents. However, combining the iLOVECLIM results with CMIP5 model results and various PAGES-2k temperature field reconstructions, we show overall agreement for the magnitude of continental temperature variability in models and reconstructions, but both the simulated and the reconstructed ranges are large. This is even more true when considering higher-order metrics like inter-continental temperature correlations or temperature variability land–sea contrasts. For such metrics, uncertainties in both model results and temperature reconstructions are so large that they hamper our ability to constrain simulated spatio-temporal structure of centennial temperature variability. As a result, we cannot determine the importance of AMOC variability for the climatic evolution over the past 2 millennia.

Background: This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. Summary: It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients’ lived experiences; move beyond simplistic approaches of “eat less, move more” and address the root drivers of obesity. Key Messages: People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay.

The desertification and vegetation feedbacks of the “green Sahara” during the last interglacial (LIG) and the Holocene have been investigated by many studies. Yet the abruptness of climate and vegetation changes and their interactions are still under discussion. In this study, we apply an Earth system model of intermediate complexity (iLOVECLIM) in combination with two dynamical vegetation models (VECODE and LPJ-GUESS) to simulate climate–vegetation changes during the Holocene and the LIG to compare the patterns of North African vegetation evolutions and mechanisms of their feedbacks during these two interglacials. Our results confirmed the existence of the green Sahara during the early LIG, which is as an analogue to the green Sahara during the Holocene. During both interglacials, an overall consistent transition from vegetated Sahara to desert is shown in our results, but the amplitudes of these transitions vary. These simulated Sahara vegetation transitions are nearly linearly related to the summer insolation declines at 20∘ N, resulting in faster declines of vegetation cover during the LIG than in the Holocene. The decline of vegetation cover peaks at 25% kyr−1 at around 122 ka, while during the Holocene the steepest vegetation cover decline is 10 % kyr−1 at around 6 ka. Our results suggest net positive vegetation feedbacks to climate during the two interglacials. During the early LIG and Holocene, vegetation strengthens precipitation by a factor of 2 to 3 through the vegetation–albedo feedback when the vegetation cover is greater than 60 %. Vegetation cover decreases with declines of the incoming moisture transport by the atmosphere due to the reduced summer insolation at 20∘ N, weakening the summer monsoon during both interglacials. This desertification is accelerated when the positive vegetation–albedo feedback cannot offset the reduction of precipitation due to a weaker summer monsoon. The impacts of this positive vegetation feedback on precipitation decrease with decreased vegetation cover, during which the impacts of negative vegetation–evaporation feedbacks increase, accelerating the loss of soil moisture and vegetation cover. Overall, the net positive vegetation feedback is strong during the early phases of both interglacials, but the vegetation transition is more abrupt during the LIG than during the Holocene due to the more rapid changes in summer insolation during the LIG. The main difference between the two interglacials is the rate of precipitation change, which is relatively gradual during the Holocene, leading to a more gradual vegetation transition in comparison to the LIG.

Milk-derived peptides are known to confer anti-inflammatory effects. We hypothesised that milk-derived cell-penetrating peptides might modulate inflammation in useful ways. Using computational techniques, we identified and synthesised peptides from the milk protein Alpha-S1-casein that were predicted to be cell-penetrating using a machine learning predictor. We modified the interpretation of the prediction results to consider the effects of histidine. Peptides were then selected for testing to determine their cell penetrability and anti-inflammatory effects using HeLa cells and J774.2 mouse macrophage cell lines. The selected peptides all showed cell penetrating behaviour, as judged using confocal microscopy of fluorescently labelled peptides. None of the peptides had an effect on either the NF-κB transcription factor or TNFα and IL-1β secretion. Thus, the identified milk-derived sequences have the ability to be internalised into the cell without affecting cell homeostatic mechanisms such as NF-κB activation. These peptides are worthy of further investigation for other potential bioactivities or as a naturally derived carrier to promote the cellular internalisation of other active peptides.

Abstract Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.

Abstract Background Nowadays, more people are treating dogs as family members. This reflects their increased attention towards their nutrition, with renewed interest for non-conventional diets such as Biologically Appropriate Raw Food/ Bones and Raw Food in United States (BARF) or homemade. In previous studies, owners feeding their dog non-conventional diets reported lower levels of trust in veterinary advice. The aim of the study was to identify differences in lifestyle between owners feeding dogs non-conventional diets and those feeding conventional diets (i.e., dry/wet pet food) to give further insight for improving communication between veterinarians and owners. Results A total of 426 surveys were usable. Fifteen percent of the participants lived in the metropole of Paris and had more than one dog (mean 1.72 dogs). Thirty-eight percent of the survey respondents stated that their dogs were fed exclusively with non-conventional diets, while 55% declared using conventional diets alone (not considering treats). The study canine population was for the most part neutered (63%) and purebred (68%). Amongst owners feeding conventional diets exclusively, 47% determined how much food to feed by consulting the feeding guidelines on the packaging, and only 28% said that the amount of food was prescribed by their veterinarian or veterinary nurse. Out of the participants feeding non-conventional diets, 65% declared that the information for formulating the recipes was gathered on the internet or in non-veterinary books. When compared with owners feeding exclusively conventional diets, those feeding non-conventional diets were living more frequently outside the metropole of Paris, had fewer children (0.23 ± 0.57 vs 0.37 ± 0.78; p = 0.03) and had more frequently other animals. They also dewormed less often their pets, walked their dog more each day (91 vs 78%; p

Abstract Background Precision nutrition is highly topical. However, no studies have explored the interindividual variability in response to nutrition interventions for sarcopenia. The purpose of this study was to determine the magnitude of interindividual variability in response to two nutrition supplementation interventions for sarcopenia and metabolic health, after accounting for sources of variability not attributable to supplementation. Methods A 24 week, randomized, double‐blind, placebo‐controlled trial tested the impact of leucine‐enriched protein (LEU‐PRO), LEU‐PRO plus long‐chain n‐3 PUFA (LEU‐PRO+n‐3) or control (CON) supplementation in older adults (n = 83, 71 ± 6 years) at risk of sarcopenia. To estimate the true interindividual variability in response to supplementation (free of the variability due to measurement error and within‐subject variation), the standard deviation of individual responses (SDR) was computed and compared with the minimally clinically important difference (MCID) for appendicular lean mass (ALM), leg strength, timed up‐and‐go (TUG), and serum triacylglycerol (TG) concentration. Clinically meaningful interindividual variability in response to supplementation was deemed to be present when the SDR positively exceeded the MCID. The probability that individual responses were clinically meaningful, and the phenotypic, dietary, and behavioural determinants of response to supplementation were examined. Results The SDR was below the MCID for ALM (LEU‐PRO: −0.12 kg [90% CI: −0.38, 0.35], LEU‐PRO+n‐3: −0.32 kg [−0.45, 0.03], MCID: 0.21 kg), TUG (LEU‐PRO: 0.58 s [0.18, 0.80], LEU‐PRO+n‐3: 0.73 s [0.41, 0.95], MCID: 0.9 s) and TG (LEU‐PRO: −0.38 mmol/L [−0.80, 0.25], LEU‐PRO+n‐3: −0.44 mmol/L [−0.63, 0.06], MCID: 0.1 mmol/L), indicating no meaningful interindividual variability in response to either supplement. The SDR exceeded the MCID (19 Nm) for strength in response to LEU‐PRO (25 Nm [−29, 45]) and LEU‐PRO+n‐3 (23 Nm [−29, 43]) supplementation but the effect was uncertain, evidenced by wide confidence intervals. In the next stage of analysis, similar proportions of participant responses were identified as very likely, likely, possibly, unlikely, and very unlikely to represent clinically meaningful improvements across the LEU‐PRO, LEU‐PRO+n‐3, and CON groups (P > 0.05). Baseline LC n‐3 PUFA status, habitual protein intake, and numerous other phenotypic and behavioural factors were not determinants of response to LEU‐PRO or LEU‐PRO+n‐3 supplementation. Conclusions Applying a novel, robust methodological approach to precision nutrition, we show that there was minimal interindividual variability in changes in ALM, muscle function, and TG in response to LEU‐PRO and LEU‐PRO+n‐3 supplementation in older adults at risk of sarcopenia.

Abstract Numerous studies have demonstrated the key role of the Salmonella Pathogenicity Island 1-encoded type III secretion system (T3SS1) apparatus as well as its associated effectors in the invasion and intracellular fate of Salmonella in the host cell. Several T3SS1 effectors work together to control cytoskeleton networks and induce massive membrane ruffles, allowing pathogen internalization. Salmonella resides in a vacuole whose maturation requires that the activity of T3SS1 subverts early stages of cell signaling. Recently, we identified five cell lines in which Salmonella Typhimurium enters without using its three known invasion factors: T3SS1, Rck and PagN. The present study investigated the intracellular fate of Salmonella Typhimurium in one of these models, the murine hepatocyte cell line AML12. We demonstrated that both wild-type Salmonella and T3SS1-invalidated Salmonella followed a common pathway leading to the formation of a Salmonella containing vacuole (SCV) without classical recruitment of Rho-GTPases. Maturation of the SCV continued through an acidified phase that led to Salmonella multiplication as well as the formation of a tubular network resembling Salmonella induced filaments (SIF). The fact that in the murine AML12 hepatocyte, the T3SS1 mutant induced an intracellular fate resembling to the wild-type strain highlights the fact that Salmonella Typhimurium invasion and intracellular survival can be completely independent of T3SS1.

The last deglaciation offers an unique opportunity to understand the climate–ice-sheet interactions in a global warming context. In this paper, to tackle this question, we use an Earth system model of intermediate complexity coupled to an ice sheet model covering the Northern Hemisphere to simulate the last deglaciation and the Holocene (26–0 ka). We use a synchronous coupling every year between the ice sheet and the rest of the climate system and we ensure a closed water cycle considering the release of freshwater flux to the ocean due to ice sheet melting. Our reference experiment displays a gradual warming in response to the forcings, with no abrupt changes. In this case, while the amplitude of the freshwater flux to the ocean induced by ice sheet retreat is realistic, it is sufficient to shut down the Atlantic meridional overturning circulation from which the model does not recover within the time period simulated. However, with reduced freshwater flux we are nonetheless able to obtain different oceanic circulation evolutions, including some abrupt transitions between shut-down and active circulation states in the course of the deglaciation. The inclusion of a parameterisation for the sinking of brines around Antarctica also produces an abrupt recovery of the Atlantic meridional overturning circulation, absent in the reference experiment. The fast oceanic circulation recoveries lead to abrupt warming phases in Greenland. Our simulated ice sheet geometry evolution is in overall good agreement with available global reconstructions, even though the abrupt sea level rise at 14.6 ka is underestimated, possibly because the climate model underestimates the millennial-scale temperature variability. In the course of the deglaciation, large-scale grounding line instabilities are simulated both for the Eurasian and North American ice sheets. The first instability occurs in the Barents–Kara seas for the Eurasian ice sheet at 14.5 ka. A second grounding line instability occurs ca. 12 ka in the proglacial lake that formed at the southern margin of the North American ice sheet. With additional asynchronously coupled experiments, we assess the sensitivity of our results to different ice sheet model choices related to surface and sub-shelf mass balance, ice deformation and grounding line representation. While the ice sheet evolutions differ within this ensemble, the global climate trajectory is only weakly affected by these choices. In our experiments, only the abrupt shifts in the oceanic circulation due to freshwater fluxes are able to produce some millennial-scale variability since no self-generating abrupt transitions are simulated without these fluxes.

In 2016-17, shellfish harvesting closed for the first time in Narragansett Bay, Rhode Island, USA, from domoic acid (DA), a neurotoxin produced by diatoms of the Pseudo-nitzschia genus. Pseudo-nitzschia have occurred frequently for over 60 years in Narragansett Bay’s Long-Term Plankton Time Series (NBPTS), therefore it is surprising that the first closure only recently occurred. Pseudo-nitzschia species are known to vary in their toxin production, thus species identification is critical for understanding the underlying ecological causes of these harmful algal blooms (HABs). DNA in plankton biomass can be preserved for many years, so molecular barcoding of archived samples is useful for delineation of taxa over time. This study used amplification of the Pseudo-nitzschia-specific 18S-5.8S rDNA internal transcribed spacer region 1 (ITS1) in plankton samples and high throughput sequencing to characterize Pseudo-nitzschia species composition over a decade in Narragansett Bay, including eight years before the 2016-17 closures and two years following. This metabarcoding method can discriminate nearly all known Pseudo-nitzschia species. Several species recur as year-round residents in Narragansett Bay (P. pungens var. pungens, P. americana, P. multiseries, and P. calliantha). Various other species increased in frequency after 2015, and some appeared for the first time during the closure period. Notably, P. australis, a species prevalent in US West Coast HABs and known for high DA production, was not observed in Narragansett Bay until the 2017 closure but has been present in several years after the closures. Annual differences in Pseudo-nitzschia composition were correlated with physical and chemical conditions, predominantly water temperature. The long-term composition trends of Pseudo-nitzschia in Narragansett Bay serve as a baseline for identifying the introduction of new species, understanding shifting assemblages that contributed to the 2016-17 closures, and monitoring species that may be cause for future concern.

Abstract Background Rapid spread of SARS-CoV-2 has led to a global pandemic, resulting in the need for rapid assays to allow diagnosis and prevention of transmission. Reverse transcription-polymerase chain reaction (RT-PCR) provides a gold standard assay for SARS-CoV-2 RNA, but instrument costs are high and supply chains are potentially fragile, motivating interest in additional assay methods. Reverse transcription and loop-mediated isothermal amplification (RT-LAMP) provides an alternative that uses orthogonal and often less expensive reagents without the need for thermocyclers. The presence of SARS-CoV-2 RNA is typically detected using dyes to report bulk amplification of DNA; however, a common artifact is nonspecific DNA amplification, which complicates detection. Results Here we describe the design and testing of molecular beacons, which allow sequence-specific detection of SARS-CoV-2 genomes with improved discrimination in simple reaction mixtures. To optimize beacons for RT-LAMP, multiple locked nucleic acid monomers were incorporated to elevate melting temperatures. We also show how beacons with different fluorescent labels can allow convenient multiplex detection of several amplicons in “single pot” reactions, including incorporation of a human RNA LAMP-BEAC assay to confirm sample integrity. Comparison of LAMP-BEAC and RT-qPCR on clinical saliva samples showed good concordance between assays. To facilitate implementation, we developed custom polymerases for LAMP-BEAC and inexpensive purification procedures, which also facilitates increasing sensitivity by increasing reaction volumes. Conclusions LAMP-BEAC thus provides an affordable and simple SARS-CoV-2 RNA assay suitable for population screening; implementation of the assay has allowed robust screening of thousands of saliva samples per week.

Changes in water mass distribution are considered to be a significant contributor to the atmospheric CO2 concentration drop to around 186 ppm recorded during the Last Glacial Maximum (LGM). Yet simulating a glacial Atlantic Meridional Overturning Circulation (AMOC) in agreement with paleotracer data remains a challenge, with most models from previous Paleoclimate Modelling Intercomparison Project (PMIP) phases showing a tendency to simulate a strong and deep North Atlantic Deep Water (NADW) instead of the shoaling inferred from proxy records of water mass distribution. Conversely, the simulated Antarctic Bottom Water (AABW) is often reduced compared to its pre-industrial volume, and the Atlantic Ocean stratification is underestimated with respect to paleoproxy data. Inadequate representation of surface conditions, driving deep convection around Antarctica, may explain inaccurately simulated bottom water properties in the Southern Ocean. We investigate here the impact of a range of surface conditions in the Southern Ocean in the iLOVECLIM model using nine simulations obtained with different LGM boundary conditions associated with the ice sheet reconstruction (e.g., changes of elevation, bathymetry, and land–sea mask) and/or modeling choices related to sea-ice export, formation of salty brines, and freshwater input. Based on model–data comparison of sea-surface temperatures and sea ice, we find that only simulations with a cold Southern Ocean and a quite extensive sea-ice cover show an improved agreement with proxy records of sea ice, despite systematic model biases in the seasonal and regional patterns. We then show that the only simulation which does not display a much deeper NADW is obtained by parameterizing the sinking of brines along Antarctica, a modeling choice reducing the open-ocean convection in the Southern Ocean. These results highlight the importance of the representation of convection processes, which have a large impact on the water mass properties, while the choice of boundary conditions appears secondary for the model resolution and variables considered in this study.

The Last Glacial Maximum (LGM, ∼ 21 000 years ago) has been a major focus for evaluating how well state-of-the-art climate models simulate climate changes as large as those expected in the future using paleoclimate reconstructions. A new generation of climate models has been used to generate LGM simulations as part of the Paleoclimate Modelling Intercomparison Project (PMIP) contribution to the Coupled Model Intercomparison Project (CMIP). Here, we provide a preliminary analysis and evaluation of the results of these LGM experiments (PMIP4, most of which are PMIP4-CMIP6) and compare them with the previous generation of simulations (PMIP3, most of which are PMIP3-CMIP5). We show that the global averages of the PMIP4 simulations span a larger range in terms of mean annual surface air temperature and mean annual precipitation compared to the PMIP3-CMIP5 simulations, with some PMIP4 simulations reaching a globally colder and drier state. However, the multi-model global cooling average is similar for the PMIP4 and PMIP3 ensembles, while the multi-model PMIP4 mean annual precipitation average is drier than the PMIP3 one. There are important differences in both atmospheric and oceanic circulations between the two sets of experiments, with the northern and southern jet streams being more poleward and the changes in the Atlantic Meridional Overturning Circulation being less pronounced in the PMIP4-CMIP6 simulations than in the PMIP3-CMIP5 simulations. Changes in simulated precipitation patterns are influenced by both temperature and circulation changes. Differences in simulated climate between individual models remain large. Therefore, although there are differences in the average behaviour across the two ensembles, the new simulation results are not fundamentally different from the PMIP3-CMIP5 results. Evaluation of large-scale climate features, such as land–sea contrast and polar amplification, confirms that the models capture these well and within the uncertainty of the paleoclimate reconstructions. Nevertheless, regional climate changes are less well simulated: the models underestimate extratropical cooling, particularly in winter, and precipitation changes. These results point to the utility of using paleoclimate simulations to understand the mechanisms of climate change and evaluate model performance.

Predictions begin with an extrapolation of the properties of their underlying representations to forecast a future state not presently in evidence. For numerical predictions, sets of numbers are summarized and the result forms the basis of and constrains numerical predictions. One open question is how the accuracy of underlying representations influences predictions, particularly numerical predictions. It is possible that inaccuracies in individual number representations are randomly distributed and averaged over during summarization (e.g., wisdom of crowds). It is also possible that inaccuracies are not random and lead to errors in predictions. We investigated this question by measuring the accuracy of individual number representations of 279 children ages 8–12 years, using a 0–1,000 number line, and numerical predictions, measured using a home run derby task. Consistent with prior research, our results from mixed random effects models evaluating percent absolute error (PAE; prediction error) demonstrated that third graders’ representations of individual numbers were less accurate, characterized by overestimation errors, and were associated with overpredictions (i.e., predictions above the set mean). Older children had more accurate individual number representations and a slight tendency to underpredict (i.e., predictions below the set mean). The results suggest that large, systematic inaccuracies appear to skew predictions while small, random errors appear to be averaged over during summarization. These findings add to our understanding of summarization and its role in numerical predictions.

Extreme precipitation poses a major challenge for local governments, including the City and County of San Francisco, California, as flooding can damage and destroy infrastructure and property. As the climate continues to warm, reliable future precipitation projections are needed to provide the best possible information to decision makers. However, future changes in the magnitude of extreme precipitation are uncertain, as current state-of-the-art global climate models are typically run at relatively coarse horizontal resolutions that require the use of convective parameterization and have difficulty simulating observed extreme rainfall rates. Here, we performed ensembles of convection-permitting regional climate model simulations to investigate how five historically impactful extreme precipitation events over the San Francisco Bay Area could change if similar events occurred in future climates. We found that changes in storm-total precipitation depend strongly on storm type. Precipitation associated with an atmospheric river (AR) accompanied by an extratropical cyclone (ETC) is projected to increase at a rate exceeding (by up to 1.5 times) the theoretical Clausius Clapeyron scaling of 6–7% per °C warming. On the other hand, future precipitation changes are weak or negative for events characterized by an AR only, despite increases in precipitable water and integrated vapor transport that are similar to those of the co-occurring AR and ETC events. The differences in the sign of future precipitation change between AR-only events and co-occurring AR and ETC events is instead linked with changes in mid-tropospheric vertical velocity. Given that the majority of observed ARs are associated with an ETC, this research has important implications for future precipitation impacts over the Bay Area, as it indicates that storm-total precipitation associated with the most common type of storm event may increase by up to 26–37% in 2100 relative to historical.

Background: Globally, reverse shoulder arthroplasty (RSA) has moved away from the Grammont design to modern prosthesis designs. The purpose of this study was to provide a focused, updated systematic review for each of the most common complications of RSA by limiting each search to publications after 2010. In this part II, the following were examined: (1) instability, (2) humerus/glenoid fracture, (3) acromial/scapular spine fractures (AF/SSF), and (4) problems/miscellaneous. Methods: Four separate PubMed database searches were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Overall, 137 studies for instability, 94 for humerus/glenoid fracture, 120 for AF/SSF, and 74 for problems/miscellaneous were included in each review, respectively. Univariate analysis was performed with chi-square and Fisher exact tests. Results: The Grammont design had a higher instability rate vs. all other designs combined (4.0%, 1.3%; P < .001), and the onlay humerus design had a lower rate than the lateralized glenoid design (0.9%, 2.0%; P = .02). The rate for intraoperative humerus fracture was 1.8%; intraoperative glenoid fracture, 0.3%; postoperative humerus fracture, 1.2%; and postoperative glenoid fracture, 0.1%. The rate of AF/SSF was 2.6% (371/14235). The rate for complex regional pain syndrome was 0.4%; deltoid injury, 0.1%; hematoma, 0.3%; and heterotopic ossification, 0.8%. Conclusions: Focused systematic reviews of recent literature with a large volume of shoulders demonstrate that using non-Grammont modern prosthesis designs, complications including instability, intraoperative humerus and glenoid fractures, and hematoma are significantly reduced compared with previous studies. As the indications continue to expand for RSA, it is imperative to accurately track the rate and types of complications in order to justify its cost and increased indications.

Oesophageal adenocarcinoma (OAC) is a poor prognosis cancer with limited response rates to current treatment modalities and has a strong link to obesity. To better elucidate the role of visceral adiposity in this disease state, a full metabolic profile combined with analysis of secreted pro-inflammatory cytokines, metabolites, and lipid profiles were assessed in human ex vivo adipose tissue explants from obese and non-obese OAC patients. These data were then related to extensive clinical data including obesity status, metabolic dysfunction, previous treatment exposure, and tumour regression grades. Real-time energy metabolism profiles were assessed using the seahorse technology. Adipose explant conditioned media was screened using multiplex ELISA to assess secreted levels of 54 pro-inflammatory mediators. Targeted secreted metabolite and lipid profiles were analysed using Ultra-High-Performance Liquid Chromatography coupled with Mass Spectrometry. Adipose tissue explants and matched clinical data were collected from OAC patients (n = 32). Compared to visceral fat from non-obese patients (n = 16), visceral fat explants from obese OAC patients (n = 16) had significantly elevated oxidative phosphorylation metabolism profiles and an increase in Eotaxin-3, IL-17A, IL-17D, IL-3, MCP-1, and MDC and altered secretions of glutamine associated metabolites. Adipose explants from patients with metabolic dysfunction correlated with increased oxidative phosphorylation metabolism, and increases in IL-5, IL-7, SAA, VEGF-C, triacylglycerides, and metabolites compared with metabolically healthy patients. Adipose explants generated from patients who had previously received neo-adjuvant chemotherapy (n = 14) showed elevated secretions of pro-inflammatory mediators, IL-12p40, IL-1α, IL-22, and TNF-β and a decreased expression of triacylglycerides. Furthermore, decreased secreted levels of triacylglycerides were also observed in the adipose secretome of patients who received the chemotherapy-only regimen FLOT compared with patients who received no neo-adjuvant treatment or chemo-radiotherapy regimen CROSS. For those patients who showed the poorest response to currently available treatments, their adipose tissue was associated with higher glycolytic metabolism compared to patients who had good treatment responses. This study demonstrates that the adipose secretome in OAC patients is enriched with mediators that could prime the tumour microenvironment to aid tumour progression and attenuate responses to conventional cancer treatments, an effect which appears to be augmented by obesity and metabolic dysfunction and exposure to different treatment regimes.

Climate model simulations are inherently biased. It is a notably difficult problem when dealing with climate impact assessments and model-data integration. This is especially true when looking at derived quantities such as biomes, where not only climate but also vegetation dynamics biases come into play. To overcome such difficulties, we evaluate the performance of an existing methodology to correct climate model outputs, applied here for the first time to long past climate conditions. The proposed methodology relies on the ‘Cumulative Distribution Function-transform’ (CDF-t) technique, which allows to account for climate change within the bias-correction procedure. The results are evaluated in two independent ways: (i) using forward modelling, so that model results are directly comparable to reconstructed vegetation distribution; (ii) using climatic reconstructions based on an inverse modelling approach. The modelling is performed using the intermediate complexity model iLOVECLIM in the standard global and interactively downscaled over the Europe version. The combined effects of dynamical downscaling and bias correction resulted in significantly stronger agreement between the simulated results and pollen-based biome reconstructions (BIOME6000) for the pre-industrial (0.18 versus 0.44) and mid-Holocene (MH) (0.31 versus 0.40). Higher correlation is also observed between statistically modelled global gridded potential natural distribution and modelled biomes (0.36 versus 0.41). Similarly, we find higher correlation between the reconstructed and the modelled temperatures for the MH (0.02 versus 0.21). No significant difference is found for the Last Glacial Maximum when using temperature reconstructions, due to the low number of data points available. Our findings show that the application of the CDF-t method on simulated climate variables enables us to simulate palaeoclimate and vegetation distribution in better agreement with independent reconstructions.

This study investigated the effects of dystocia on milk production, somatic cell count, reproductivity, disease, and milk production. A total of 2159 cows across 21 dairy farms in Alberta, Canada were enrolled in this study. Multivariable models were created to explore associations between outcome variables and calving ease score. In total, 89.5% of calvings were unassisted, 6.1% were an easy pull, and 4.3% were a moderate–hard pull. Cows that had a moderate–hard pull produced 4.01 kg less milk, 0.12 kg less volume of milk fat, and 0.12 kg less milk protein per day than those that had an unassisted calving. No difference was found between calving ease groups with respect to SCC. Cows with a moderate or hard pull produced 510 kg less milk per lactation than unassisted cows. Cows with a moderate to high level of assistance at birth had a higher hazard of being culled over the duration of their lactation. Cows with an easy pull had increased odds of developing a retained placenta. It is evident that assistance at calving, particularly a moderate–hard pull, is associated with significant impacts on future milk production and risk of being culled; therefore, efforts should be made to minimize dystocia and prevent these impacts.

Background: Globally, reverse shoulder arthroplasty (RSA) has moved away from the Grammont design to modern prosthesis designs. The purpose of this 2-part study was to systematically review each of the most common complications of RSA, limiting each search to publications in 2010 or later. In this part (part I), we examined (1) scapular notching (SN), (2) periprosthetic infection (PJI), (3) mechanical failure (glenoid or humeral component), and (4) neurologic injury (NI). Methods: Four separate PubMed database searches were performed following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Overall, 113 studies on SN, 62 on PJI, 34 on mechanical failure, and 48 on NI were included in our reviews. Univariate analysis was performed with the χ2 or Fisher exact test. Results: The Grammont design had a higher SN rate vs. all other designs combined (42.5% vs. 12.3%, P < .001). The onlay humeral design had a lower rate than the lateralized glenoid design (10.5% vs. 14.8%, P < .001). The PJI rate was 2.4% for primary RSA and 2.6% for revision RSA. The incidence of glenoid and humeral component loosening was 2.3% and 1.4%, respectively. The Grammont design had an increased NI rate vs. all other designs combined (0.9% vs. 0.1%, P = .04). Conclusions: Focused systematic reviews of the recent literature with a large volume of RSAs demonstrate that with the use of non-Grammont modern prosthesis designs, complications including SN, PJI, glenoid component loosening, and NI are significantly reduced compared with previous studies. As the indications for RSA continue to expand, it is imperative to accurately track the rates and types of complications to justify its cost and increased indications.

Purpose: In the first quarter of 2020, World Health Organization (WHO) declared COVID-19 as a public health emergency around the globe. Therefore, different users from all over the world shared their thoughts about COVID-19 on social media platforms i.e., Twitter, Facebook etc. So, it is important to analyze public opinions about COVID-19 from different regions over different period of time. To fulfill the spatial analysis issue, a previous work called H-TF-IDF (Hierarchy-based measure for tweet analysis) for term extraction from tweet data has been proposed. In this work, we focus on the sentiment analysis performed on terms selected by H-TF-IDF for spatial tweets groups to know local situations during the ongoing epidemic COVID-19 over different time frames. Methods & Materials: The primary step is to extract terms from tweets using H-TF-IDF approach. Moreover, these terms are utilized in two ways i.e., 1) select tweets containing terms, 2) terms used as features for sentiment analysis. Thereafter, data preprocessing is performed to clean the text. Afterwards, Vectorization models i.e., bag-of-words (BOW) and term frequency-inverse document frequency (TF-IDF) are used to extract features with the help of n-gram techniques. These features are extracted to train the prediction models for sentiment analysis. Lastly, different statistical and machine learning models i.e., Logistic regression, support vector machine (SVM), etc. are applied to classify the spatial tweets groups. For preliminary results, experiments are conducted on H-TF-IDF tweets corpus having geocoded spatial information for the period of January, 2020. These tweets are extracted from the dataset collected by E.Chen (https://github.com/echen102/COVID-19-TweetIDs) that focuses on the early beginning of the outbreak. A uniform experiment setup of train-test (80% and 20%) split scheme is used for each prediction model. Results: The results illustrate that specific terms highlighted by H-TF-IDF provide useful information that would not have been identified without this spatial analysis. The classification results spatial location tweet groups into positive, negative and neutral by subjectivity and polarity measures. Conclusion: The current work is applied on English language-based Twitter information. A following work is to incorporate other languages to perform sentiment analysis. Furthermore, BERT will be used to extend these features.

Purpose: Event Based Surveillance (EBS) systems detect and monitor diseases by analysing articles from online newspapers and reports from health organizations (e.g. FAO, OIE, etc.). However, they partially integrate data from social networks, even though these data are present in large quantities on the web. The purpose of this study is to exploit social network data, such as Twitter and YouTube, to provide epidemiological and additional information for Avian Influenza surveillance. Methods & Materials: In this context, we propose new text-mining approaches combining lexical rules and statistical approaches, in order to normalise textual data from Social Network(’h5 n8’→’H5N8’) and to correct errors from YouTube transcriptions (e.g. ’birth flu’→’bird flu’). Another challenge consists of extracting epidemiological events automatically by identifying spatial entities (Where?), thematic entities (What?), and temporal information (When?). For this, we extended Named Entity Recognition (NER) tools like spaCy. Results: We collected 100 automatic transcripts of YouTube videos and 268 tweets, in English, dealing with avian influenza, thanks to dedicated API. We obtain encouraging results (i.e. accuracy around 0.6) in order to recognise automatically epidemiological information (e.g. hosts, symptoms etc.) in textual data contents. Extraction of spatial information obtains better results (i.e. accuracy around 0.8). Conclusion: The final objective of the study consists of linking social media data based on these entities with official information from health organisations, for the improvement of epidemiological monitoring.

Introduction: High-fat diet (HFD)-induced obesity impairs clearance of cholesterol through the Reverse Cholesterol Transport (RCT) pathway, with downregulation in hepatic expression of cholesterol and bile acid transporters, namely ABCG5/8 and ABCB11, and reduced high-density lipoprotein (HDL) cholesterol efflux capacity (CEC). In the current study, we hypothesized that the development of hepatosteatosis, secondary to adipose-tissue dysfunction, contributes to obesity-impaired RCT and that such effects could be mitigated using the anti-inflammatory drug sodium salicylate (NaS). Materials and methods: C57BL/6J mice, fed HFD ± NaS or low-fat diet (LFD) for 24 weeks, underwent glucose and insulin tolerance testing. The 3H-cholesterol movement from macrophage-to-feces was assessed in vivo. HDL-CEC was determined ex vivo. Cytokine secretion from adipose-derived stromal vascular fraction (SVF) cells was measured ex vivo. Liver and HDL proteins were determined by mass spectrometry and analyzed using Ingenuity Pathway Analysis. Results: NaS delayed HFD-induced weight gain, abrogated priming of pro-IL-1β in SVFs, attenuated insulin resistance, and prevented steatohepatitis (ectopic fat accumulation in the liver). Prevention of hepatosteatosis coincided with increased expression of PPAR-alpha/beta-oxidation proteins with NaS and reduced expression of LXR/RXR-induced proteins including apolipoproteins. The latter effects were mirrored within the HDL proteome in circulation. Despite remarkable protection shown against steatosis, HFD-induced hypercholesterolemia and repression of the liver-to-bile cholesterol transporter, ABCG5/8, could not be rescued with NaS. Discussions and conclusions: The cardiometabolic health benefits of NaS may be attributed to the reprogramming of hepatic metabolic pathways to increase fatty acid utilization in the settings of nutritional overabundance. Reduced hepatic cholesterol levels, coupled with reduced LXR/RXR-induced proteins, may underlie the lack of rescue of ABCG5/8 expression with NaS. This remarkable protection against HFD-induced hepatosteatosis did not translate to improvements in cholesterol homeostasis.

ABSTRACT The severe acute respiratory coronavirus-2 (SARS-CoV-2) is the cause of the global outbreak of COVID-19. Evidence suggests that the virus is evolving to allow efficient spread through the human population, including vaccinated individuals. Here, we report a study of viral variants from surveillance of the Delaware Valley, including the city of Philadelphia, and variants infecting vaccinated subjects. We sequenced and analyzed complete viral genomes from 2621 surveillance samples from March 2020 to September 2021 and compared them to genome sequences from 159 vaccine breakthroughs. In the early spring of 2020, all detected variants were of the B.1 and closely related lineages. A mixture of lineages followed, notably including B.1.243 followed by B.1.1.7 (alpha), with other lineages present at lower levels. Later isolations were dominated by B.1.617.2 (delta) and other delta lineages; delta was the exclusive variant present by the last time sampled. To investigate whether any variants appeared preferentially in vaccine breakthroughs, we devised a model based on Bayesian autoregressive moving average logistic multinomial regression to allow rigorous comparison. This revealed that B.1.617.2 (delta) showed 3-fold enrichment in vaccine breakthrough cases (odds ratio of 3; 95% credible interval 0.89-11). Viral point substitutions could also be associated with vaccine breakthroughs, notably the N501Y substitution found in the alpha, beta and gamma variants (odds ratio 2.04; 95% credible interval of1.25–3.18). This study thus overviews viral evolution and vaccine breakthroughs in the Delaware Valley and introduces a rigorous statistical approach to interrogating enrichment of breakthrough variants against a changing background. IMPORTANCE SARS-CoV-2 vaccination is highly effective at reducing viral infection, hospitalization and death. However, vaccine breakthrough infections have been widely observed, raising the question of whether particular viral variants or viral mutations are associated with breakthrough. Here, we report analysis of 2621 surveillance isolates from people diagnosed with COVID-19 in the Delaware Valley in southeastern Pennsylvania, allowing rigorous comparison to 159 vaccine breakthrough case specimens. Our best estimate is a 3-fold enrichment for some lineages of delta among breakthroughs, and enrichment of a notable spike substitution, N501Y. We introduce statistical methods that should be widely useful for evaluating vaccine breakthroughs and other viral phenotypes.

Abstract Background Targeted nutrition is defined as dietary advice tailored at a group level. Groups known as metabotypes can be identified based on individual metabolic profiles. Metabotypes have been associated with differential responses to diet, which support their use to deliver dietary advice. We aimed to optimise a metabotype approach to deliver targeted dietary advice by encompassing more specific recommendations on nutrient and food intakes and dietary behaviours. Methods Participants (n = 207) were classified into three metabotypes based on four biomarkers (triacylglycerol, total cholesterol, HDL-cholesterol and glucose) and using a k-means cluster model. Participants in metabotype-1 had the highest average HDL-cholesterol, in metabotype-2 the lowest triacylglycerol and total cholesterol, and in metabotype-3 the highest triacylglycerol and total cholesterol. For each participant, dietary advice was assigned using decision trees for both metabotype (group level) and personalised (individual level) approaches. Agreement between methods was compared at the message level and the metabotype approach was optimised to incorporate messages exclusively assigned by the personalised approach and current dietary guidelines. The optimised metabotype approach was subsequently compared with individualised advice manually compiled. Results The metabotype approach comprised advice for improving the intake of saturated fat (69% of participants), fibre (66%) and salt (18%), while the personalised approach assigned advice for improving the intake of folate (63%), fibre (63%), saturated fat (61%), calcium (34%), monounsaturated fat (24%) and salt (14%). Following the optimisation of the metabotype approach, the most frequent messages assigned to address intake of key nutrients were to increase the intake of fruit and vegetables, beans and pulses, dark green vegetables, and oily fish, to limit processed meats and high-fat food products and to choose fibre-rich carbohydrates, low-fat dairy and lean meats (60–69%). An average agreement of 82.8% between metabotype and manual approaches was revealed, with excellent agreements in metabotype-1 (94.4%) and metabotype-3 (92.3%). Conclusions The optimised metabotype approach proved capable of delivering targeted dietary advice for healthy adults, being highly comparable with individualised advice. The next step is to ascertain whether the optimised metabotype approach is effective in changing diet quality.

Understanding the ocean circulation changes associated with abrupt climate events is key to better assessing climate variability and understanding its different natural modes. Sedimentary Pa∕Th, benthic δ13C and Δ14C are common proxies used to reconstruct past circulation flow rate and ventilation. To overcome the limitations of each proxy taken separately, a better approach is to produce multiproxy measurements on a single sediment core. Yet, different proxies can provide conflicting information about past ocean circulation. Thus, modelling them in a consistent physical framework has become necessary to assess the geographical pattern and the timing and sequence of the multiproxy response to abrupt circulation changes. We have implemented a representation of the 231Pa and 230Th tracers into the model of intermediate complexity iLOVECLIM, which already included δ13C and Δ14C. We have further evaluated the response of these three ocean circulation proxies to a classical abrupt circulation reduction obtained by freshwater addition in the Nordic Seas under preindustrial boundary conditions. The proxy response is shown to cluster in modes that resemble the modern Atlantic water masses. The clearest and most coherent response is obtained in the deep (> 2000 m) northwest Atlantic, where δ13C and Δ14C significantly decrease, while Pa∕Th increases. This is consistent with observational data across millennial-scale events of the last glacial. Interestingly, while in marine records, except in rare instances, the phase relationship between these proxies remains unclear due to large dating uncertainties, in the model the bottom water carbon isotope (δ13C and Δ14C) response lags behind the sedimentary Pa∕Th response by a few hundred years.

A complete understanding of past El Niño–Southern Oscillation (ENSO) fluctuations is important for the future predictions of regional climate using climate models. One approach to reconstructing past ENSO dynamics uses planktonic foraminifera as recorders of past climate to assess past spatio-temporal changes in upper ocean conditions. In this paper, we utilise a model of planktonic foraminifera populations, Foraminifera as Modelled Entities (FAME), to forward model the potential monthly average δ18Oc and temperature signal proxy values for Globigerinoides ruber, Globigerinoides sacculifer, and Neogloboquadrina dutertrei from input variables covering the period of the instrumental record. We test whether the modelled foraminifera population δ18Oc and Tc associated with El Niño events statistically differ from the values associated with other climate states. Provided the assumptions of the model are correct, our results indicate that the values of El Niño events can be differentiated from other climate states using these species. Our model computes the proxy values of foraminifera in the water, suggesting that, in theory, water locations for a large portion of the tropical Pacific should be suitable for differentiating El Niño events from other climate states. However, in practice it may not be possible to differentiate climate states in the sediment record. Specifically, comparison of our model results with the sedimentological features of the Pacific Ocean shows that a large portion of the hydrographically/ecologically suitable water regions coincide with low sediment accumulation rate at the sea floor and/or of sea floor that lie below threshold water depths for calcite preservation.

The Global Land and Marine Observations Database aims to produce a comprehensive land-based meteorological data archive and inventory. This requires the compilation of available information on data from land-based meteorological stations from all known available in situ meteorological data repositories/sources at multiple timescales (e.g. sub-daily, daily, and monthly). During this process the service team members have identified that many of the data sources contain stations with incorrect location coordinates. These stations cannot be included in the processing to be served via the Copernicus Climate Change Service until the issues are satisfactorily resolved. Many of these stations are in regions of the world where a sparsity of climate data currently exists, such as Southeast Asia and South America. As such, resolving these issues would provide important additional climate data, but this is a very labour-intensive task. Therefore, we have developed the Geo-locate project – that enrols the help of undergraduate geography students at Maynooth University, Ireland – to resolve some of the land-based station geolocation issues. To date, we have run two Geo-locate projects: the first in the 2017/2018 academic year and the second in the 2018/2019 academic year. Both iterations have been very successful with 1926 of the 2168 total candidate stations ostensibly resolved, which equates to an 88 % success rate. At the same time, students have gained critical skills that helped to meet the expected pedagogical outcomes of the second-year curriculum, while producing a lasting scientific legacy. We asked the class of 2018/2019 to reflect critically upon the outcomes, and we present the results herein; these results provide important feedback on what students felt that they gained from their participation and how we may improve the experience and learning outcomes in future. We will be continuing to run Geo-locate projects over the next few years. We encourage other organizations to investigate the potential for engaging university students to help resolve similar data issues while enriching the student experience and aiding in the delivery of learning outcomes. This paper provides details of the project, and all supporting information such as project guidelines and templates to enable other organizations to instigate similar programmes.

Poultry are the main source of human infection by Salmonella. As infected poultry are asymptomatic, identifying infected poultry farms is difficult, thus controlling animal infections is of primary importance. As cell tropism is known to govern disease, our aim was therefore to identify infected host–cell types in the organs of chicks known to be involved in Salmonella infection and investigate the role of the three known invasion factors in this process (T3SS-1, Rck and PagN). Chicks were inoculated with wild-type or isogenic fluorescent Salmonella Typhimurium mutants via the intracoelomic route. Our results show that liver, spleen, gall bladder and aortic vessels could be foci of infection, and that phagocytic and non-phagocytic cells, including immune, epithelial and endothelial cells, are invaded in vivo in each organ. Moreover, a mutant defective for the T3SS-1, Rck and PagN remained able to colonize organs like the wild-type strain and invaded non-phagocytic cells in each organ studied. As the infection of the gall bladder had not previously been described in chicks, invasion of gall bladder cells was confirmed by immunohistochemistry and infection was shown to last several weeks after inoculation. Altogether, for the first time these findings provide insights into cell tropism of Salmonella in relevant organs involved in Salmonella infection in chicks and also demonstrate that the known invasion factors are not required for entry into these cell types.

Plant-based proteins are generally characterised by lower Indispensable Amino Acid (IAA) content, digestibility, and anabolic properties, compared to animal-based proteins. However, they are environmentally friendlier, and wider consumption is advocated. Older adults have higher dietary protein needs to prevent sarcopenia, a disease marked by an accelerated loss of muscle mass and function. Given the lower environmental footprint of plant-based proteins and the importance of optimising dietary protein quality among older adults, this paper aims to assess the net peripheral Amino Acid (AA) appearance after ingestion of three different plant protein and fibre (PPF) products, compared to whey protein with added fibre (WPF), in healthy older adults. In a randomised, single-blind, crossover design, nine healthy men and women aged ≥65 years consumed four test meals balanced in AA according to the FAO reference protein for humans, matched for leucine, to optimally stimulate muscle protein synthesis in older adults. A fasted blood sample was drawn at each visit before consuming the test meal, followed by postprandial arterialise blood sampling every 30 min for 3 h. The test meal was composed of a soup containing either WPF or PPF 1–3. The PPF blends comprised pea proteins with varying additional rice, pumpkin, soy, oat, and/or almond protein. PPF product ingestion resulted in a lower maximal increase of postprandial leucine concentration and the sum of branched-chain AA (BCAA) and IAA concentrations, compared to WPF, with no effect on their incremental area under the curve. Plasma methionine and cysteine, and to a lesser extent threonine, appearance were limited after consuming the PPF products, but not WPF. Despite equal leucine doses, the WPF induced greater postprandial insulin concentrations than the PPF products. In conclusion, the postprandial appearance of AA is highly dependent on the protein source in older adults, despite providing equivalent IAA levels and dietary fibre. Coupled with lower insulin concentrations, this could imply less anabolic potential. Further investigation is required to understand the applicability of plant-based proteins in healthy older adults.

As part of broader actions to combat antimicrobial resistance (AMR), health authorities have promoted the reduction of antimicrobial use (AMU) in food animals. Farmers' attitudes and receptivity to reduction of AMU appear to be variable and context specific. Our research objectives were to gain insight into Canadian dairy farmers' attitudes toward AMU, AMR, and AMU-reduction in the dairy industry, and to explore drivers and barriers to change AMU, including the influence of social referents. We conducted seven focus groups with 42 farmers in two provinces of Canada (New Brunswick and Ontario) and used thematic analysis to identify, analyze, and report patterns in the data. Our results indicate that farmers usually rely on their previous experience and judgement of individual cases of disease when making decisions related to AMU. External referents included other farmers, family members, and veterinarians. However, veterinarians were generally only consulted for unusual cases. Participants in this study expressed that maintaining cattle welfare is their responsibility, and that they were not willing to jeopardize animal welfare in order to reduce AMU. In addition, farmers regarded the cost of investment in improved facilities to prevent disease as an important barrier to reduce AMU. Finally, the majority of participants considered themselves to be low users of antimicrobials and perceived a small role of AMU on dairy farms in AMR. In conclusion, farmers from this study showed self-reliance to decide about AMU on their farms and considered animal-related and economic factors in these decisions. There was a general lack of knowledge of how to reduce AMU without investing in facilities, and there is an opportunity to motivate increased involvement of the veterinarian in AMU-related decisions. These results should be considered to design and refine antimicrobial stewardship programs for dairy farms.

Sarcopenia is characterised by the presence of diminished skeletal muscle mass and strength. It is relatively common in older adults as ageing is associated with anabolic resistance (a blunted muscle protein synthesis response to dietary protein consumption and resistance exercise). Therefore, interventions to counteract anabolic resistance may benefit sarcopenia prevention and are of utmost importance in the present ageing population. There is growing speculation that the gut microbiota may contribute to sarcopenia, as ageing is also associated with [1) dysbiosis, whereby the gut microbiota becomes less diverse, lacking in healthy butyrate-producing microorganisms and higher in pathogenic bacteria, and [2) loss of epithelial tight junction integrity in the lining of the gut, leading to increased gut permeability and higher metabolic endotoxemia. Animal data suggest that both elements may impact muscle physiology, but human data corroborating the causality of the association between gut microbiota and muscle mass and strength are lacking. Mechanisms wherein the gut microbiota may alter anabolic resistance include an attenuation of gut-derived low-grade inflammation and/or the increased digestibility of protein-containing foods and consequent higher aminoacidemia, both in favour of muscle protein synthesis. This review focuses on the putative links between the gut microbiota and skeletal muscle in the context of sarcopenia. We also address the issue of plant protein digestibility because plant proteins are increasingly important from an environmental sustainability perspective, yet they are less efficient at stimulating muscle protein synthesis than animal proteins.