Chylomicrons Regulate Lacteal Permeability and Intestinal Lipid Absorption.

BACKGROUND: Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood. METHODS: We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries. RESULTS: By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction. CONCLUSIONS: Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier.

Pressure-Induced Dislocations and Their Influence on Ionic Transport in Li+-Conducting Argyrodites.

The influence of the microstructure on the ionic conductivity and cell performance is a topic of broad scientific interest in solid-state batteries. The current understanding is that interfacial decomposition reactions during cycling induce local strain at the interfaces between solid electrolytes and the anode/cathode, as well as within the electrode composites. Characterizing the effects of internal strain on ion transport is particularly important, given the significant local chemomechanical effects caused by volumetric changes of the active materials during cycling. Here, we show the effects of internal strain on the bulk ionic transport of the argyrodite Li6PS5Br. Internal strain is reproducibly induced by applying pressures with values up to 10 GPa. An internal permanent strain is observed in the material, indicating long-range strain fields typical for dislocations. With increasing dislocation densities, an increase in the lithium ionic conductivity can be observed that extends into improved ionic transport in solid-state battery electrode composites. This work shows the potential of strain engineering as an additional approach for tuning ion conductors without changing the composition of the material itself.

Challenges and Alternatives to Evaluation Methods and Regulation Approaches for Medical Apps as Mobile Medical Devices: International and Multidisciplinary Focus Group Discussion.

BACKGROUND: The rapid proliferation of medical apps has transformed the health care landscape by giving patients and health care providers unprecedented access to personalized health information and services. However, concerns regarding the effectiveness and safety of medical apps have raised questions regarding the efficacy of randomized controlled trials (RCTs) in the evaluation of such apps and as a requirement for their regulation as mobile medical devices. OBJECTIVE: This study aims to address this issue by investigating alternative methods, apart from RCTs, for evaluating and regulating medical apps. METHODS: Using a qualitative approach, a focus group study with 46 international and multidisciplinary public health experts was conducted at the 17th World Congress on Public Health in May 2023 in Rome, Italy. The group was split into 3 subgroups to gather in-depth insights into alternative approaches for evaluating and regulating medical apps. We conducted a policy analysis on the current regulation of medical apps as mobile medical devices for the 4 most represented countries in the workshop: Italy, Germany, Canada, and Australia. We developed a logic model that combines the evaluation and regulation domains on the basis of these findings. RESULTS: The focus group discussions explored the strengths and limitations of the current evaluation and regulation methods and identified potential alternatives that could enhance the quality and safety of medical apps. Although RCTs were only explicitly mentioned in the German regulatory system as one of many options, an analysis of chosen evaluation methods for German apps on prescription pointed toward a "scientific reflex" where RCTs are always the chosen evaluation method. However, this method has substantial limitations when used to evaluate digital interventions such as medical apps. Comparable results were observed during the focus group discussions, where participants expressed similar experiences with their own evaluation approaches. In addition, the participants highlighted numerous alternatives to RCTs. These alternatives can be used at different points during the life cycle of a digital intervention to assess its efficacy and potential harm to users. CONCLUSIONS: It is crucial to recognize that unlike analog tools, digital interventions constantly evolve, posing challenges to inflexible evaluation methods such as RCTs. Potential risks include high dropout rates, decreased adherence, and nonsignificant results. However, existing regulations do not explicitly advocate for other evaluation methodologies. Our research highlighted the necessity of overcoming the gap between regulatory demands to demonstrate safety and efficacy of medical apps and evolving scientific practices, ensuring that digital health innovation is evaluated and regulated in a way that considers the unique characteristics of mobile medical devices.

[DNVF Memorandum: Objectives and Methods of Physical Activity-Related Health Services Research]. / DNVF Memorandum ­ Ziele und Methoden bewegungsbezogener Versorgungsforschung.

The DNVF Memorandum: Objectives and Methods of Physical Activity-Related Health Services Research summarizes, for the first time, the highly interdisciplinary and interprofessional field of physical activity-based health care in the German healthcare system. In addition to providing a conceptual framework and definition of key measures and concepts in physical activity-related health care research, existing research gaps and needs are identified, and methods for advancing this relatively young field of research are described. A particular focus of this study is the relevant outcome parameters and their standardized assessment using established and valid measurement tools. The memorandum aims to establish a general understanding of the complex subject of promoting physical activity and sports therapy in the context of healthcare, to give an impulse to new research initiatives, and to integrate the currently available strong evidence on the effectiveness of physical activity and exercise into healthcare.

Exosomes: A New Hope for Angiogenesis-Mediated Bone Regeneration.

Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions. After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future.

Zebrafish mutants in vegfab can affect endothelial cell proliferation without altering ERK phosphorylation and are phenocopied by loss of PI3K signaling.

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa had an impact on endothelial cell (EC) migration and proliferation. Surprisingly, mutations in vegfab more strongly affected EC proliferation in distinct blood vessels, such as intersegmental blood vessels in the zebrafish trunk and central arteries in the head. Analysis of downstream signaling pathways revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutant phenotypes in affected blood vessels. Together, these results suggest that extracellular matrix bound Vegfa might act through PI3K signaling to control EC proliferation in a distinct set of blood vessels during angiogenesis.

Confinement-enhanced Li+ ion dynamics in an ionic liquid-based electrolyte in porous material.

While Ionic Liquids (IL) are promising liquid electrolyte components for Li-ion batteries due to their high electrochemical stability and low volatility and flammability, unfavorable Lithium-anion clusters lead to poor Li+ transport properties such as low transference numbers. A confinement of ILs in nanoporous materials could overcome these problems, based on altered structural and dynamic properties of the confined ILs. We investigate the coordination and the Li+ dynamics in an IL/Li-salt mixture of 1-butyl-1-methylpyrrolidinium bis(trifluormethyl-sulfonyl)imide (Pyr14TFSA) and LiTFSA and reveal in how far the confinement has positive or negative effects on ion clustering in the electrolyte. To this end, the electrolyte is confined in mesoporous silica SBA-15 (pore diameter 8 nm or 4 nm) or the metal-organic framework (MOF) ZIF-8 (pore diameter 1.16 nm). Raman spectra elucidate the Li-anion coordination and the interaction of the ions with the walls. Temperature-dependent 7Li spin relaxation rates, analyzed within the model of Bloembergen, Purcell and Pound (BPP), allow statements on the local Li+ environment, the local Li+ dynamics and its activation. In the SBA-15 materials the Li+ coordination is unchanged with persisting Li-TFSA clusters. Furthermore, the local dynamics of Li+ is reduced upon confinement, as expected due to geometrical restrictions. At the same time, however, both structural and dynamic parameters do not show a pronounced dependence on the pore size. Surprisingly, upon confinement in ZIF-8 Li+ displays faster local dynamics and a more asymmetric environment in comparison to the bulk electrolyte. The enhanced dynamics is accompanied by a reduced coordination to TFSA-, suggesting the breakup of Li-TFSA clusters. Differences between the porous materials are attributed to the nature of the wall surface, as Raman spectra suggest that in SBA-15 the TFSA- ion is preferentially interacting with the pore walls, whereas in ZIF-8 the Pyr14+ ion is immobilized by the pore walls. These results demonstrate a strong influence of internal interfaces on IL structure and dynamics and bear potential for further tailoring ion dynamics.

Investigating the Li+ substructure and ionic transport in Li10GeP2-xSbxS12 (0 ≤ x ≤ 0.25).

Understanding the correlation between ionic motion and crystal structure is crucial for improving solid electrolyte conductivities. Several substitution series in the Li10GeP2S12 structure have shown a favorable impact on the ionic conductivity, e.g. the replacement of P(+V) by Sb(+V) in Li10GeP2S12. However, here the interplay between the structure and ionic motion remains elusive. X-Ray diffraction, high-resolution neutron diffraction, Raman spectroscopy and potentionstatic impedance spectroscopy are employed to explore the impact of Sb(+V) on the Li10GeP2S12 structure. The introduction of antimony elongates the unit cell in the c-direction and increases the M(1)/P(1) and Li(2) polyhedral volume. Over the solid solution range, the Li+ distribution remains similar, an inductive effect seems to be absent and the ionic conductivity is comparable for all compositions. The effect of introducing Sb(+V) in Li10GeP2S12 cannot be corroborated.

Spreading the disease: Protest in times of pandemics.

This study analyzes the impact of large anti-lockdown protests on the spread of SARS-CoV-2 in Germany. Since protesters at such large gatherings are very mobile and largely neglect SARS-CoV-2 containment strategies, they may contribute to the regional transmission of the coronavirus. Employing novel data on bus connections of travel companies specialized in driving protesters to these gatherings, and exploiting the timing of two large-scale demonstrations in November 2020, we estimate the causal impact of these protests on the spread of SARS-CoV-2 using an event study framework. Our findings imply sizable increases in infection rates in protesters' origin regions after these demonstrations. A month after the protests, treated areas face a relative increase in infection rates up to 35% compared to non-treated areas. Our results shed light on public health consequences of behavior that ignores potential externalities for the society during a pandemic.

Workplace health promotion interventions for nurses in Germany: a systematic review based on the RE-AIM framework.

BACKGROUND: The German health care system is faced with a serious shortage of nurses. This is associated, amongst other things, with difficult working conditions and work-related health burdens. Workplace health promotion (WHP) is considered a promising approach to promote the health of nurses. The present review aims to give an overview on existing interventions in different nursing settings (acute care hospitals, long-term care (LTC) facilities and home-based long-term care) in Germany. METHODS: A systematic literature search was conducted in PubMed and PubPsych. Studies were included if published after 2010 and provided data of intervention studies on workplace health promotion among nurses in Germany (RCTs, non-RCTs, non-controlled intervention studies and pilot studies). The setting in which the study was conducted (acute medical care hospital, inpatient LTC facilities, home-based LTC, cross-setting) as well as the health issue assessed (physical health, mental health and/or violence experience) were extracted. The intervention was reported against the background of the quality criteria for prevention measures of the statutory health insurers in Germany. The results of the studies were presented according to the RE-AIM framework. RESULTS: Eleven studies on WHP for nurses were included, whereof seven studies were conducted in acute medical care hospitals and four in LTC facilities. No study reported results on WHP for nurses working in the setting of home-based LTC. Most studies aimed at improving mental health. The intervention contents and forms of implementation were heterogeneous. According to the RE-AIM criteria, the reporting of most studies showed several limitations, especially a lack of reporting on Implementation and Adoption. Most studies showed no statistically significant effect on the respective outcomes (Effectiveness). Four studies reported results on Maintenance indicating a sustained effectiveness. CONCLUSION: Despite the high relevance for health promotion for nurses, our review showed a striking lack of intervention studies in this field. From this we derive a high need of tailored interventions, taking into account the setting-specific development, implementation of WHP interventions for nurses. With regard to the evaluation, the RE-AIM criteria should be taken more into account in order to meet the requirements of evaluating complex interventions and thus contribute to evidence development of WHP in nursing. In terms of content, the topic of violence prevention and dealing with experiences of violence should also be taken into account. Regarding the settings, the working conditions and health burdens in LTC facilities, home-based LTC and acute medical hospitals must be considered. TRIAL REGISTRATION: PROSPERO registration number: CRD42021231891.

Mechanistic insights into cancer cell killing through interaction of phosphodiesterase 3A and schlafen family member 12.

Cytotoxic molecules can kill cancer cells by disrupting critical cellular processes or by inducing novel activities. 6-(4-(Diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (DNMDP) is a small molecule that kills cancer cells by generation of novel activity. DNMDP induces complex formation between phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) and specifically kills cancer cells expressing elevated levels of these two proteins. Here, we examined the characteristics and covariates of the cancer cell response to DNMDP. On average, the sensitivity of human cancer cell lines to DNMDP is correlated with PDE3A expression levels. However, DNMDP could also bind the related protein, PDE3B, and PDE3B supported DNMDP sensitivity in the absence of PDE3A expression. Although inhibition of PDE3A catalytic activity did not account for DNMDP sensitivity, we found that expression of the catalytic domain of PDE3A in cancer cells lacking PDE3A is sufficient to confer sensitivity to DNMDP, and substitutions in the PDE3A active site abolish compound binding. Moreover, a genome-wide CRISPR screen identified the aryl hydrocarbon receptor-interacting protein (AIP), a co-chaperone protein, as required for response to DNMDP. We determined that AIP is also required for PDE3A-SLFN12 complex formation. Our results provide mechanistic insights into how DNMDP induces PDE3A-SLFN12 complex formation, thereby killing cancer cells with high levels of PDE3A and SLFN12 expression.

Health literacy, health status and health behaviors of German students- study protocol for the "Healthy Habits" cohort study.

BACKGROUND: The emerging adulthood is traditionally viewed as a time of optimal health, but also as a critical life span, characterized by changing life circumstances and the establishment of an individual lifestyle. Especially university life seems to hold several challenges impeding the manifestation of a health supporting manner, as many students tend to show a poorer health behavior and a higher amount of health-related problems than comparable age groups. This, along with a steady growth of the higher education sector, brings increased attention to the university setting in the context of prevention. To date, there are few empirical longitudinal and coherent cross-sectional data on the status of students' health literacy, health status, and health behaviors, and on the impact of the study format on students' health. The aim of this prospective cohort study is to reduce this research gap. METHODS: Starting during winter semester 2020/21, the prospective cohort study collects data on health literacy, health status and health behavior on a semester-by-semester basis. All enrolled students of the IST University of Applied Sciences, regardless of study format and discipline, can participate in the study at the beginning of their first semester. The data are collected digitally via a specifically programmed app. A total of 103 items assess the subjectively perceived health status, life and study satisfaction, sleep quality, perceived stress, physical activity, diet, smoking, alcohol consumption, drug addiction and health literacy. Statistical analysis uses (1) multivariate methods to look at changes within the three health dimensions over time and (2) the association between the three health dimensions using multiple regression methods and correlations. DISCUSSION: This cohort study collects comprehensive health data from students on the course of study. It is assumed that gathered data will provide information on how the state of health develops over the study period. Also, different degrees of correlations of health behavior and health literacy will reveal different impacts on the state of students' health. Furthermore, this study will contribute to empirically justified development of target group-specific interventions. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00023397 (registered on October 26, 2020).

Influence of Iron Sulfide Nanoparticle Sizes in Solid-State Batteries*.

Given the inherent performance limitations of intercalation-based lithium-ion batteries, solid-state conversion batteries are promising systems for future energy storage. A high specific capacity and natural abundancy make iron disulfide (FeS2 ) a promising cathode-active material. In this work, FeS2 nanoparticles were prepared solvothermally. By adjusting the synthesis conditions, samples with average particle diameters between 10 nm and 35 nm were synthesized. The electrochemical performance was evaluated in solid-state cells with a Li-argyrodite solid electrolyte. While the reduction of FeS2 was found to be irreversible in the initial discharge, a stable cycling of the reduced species was observed subsequently. A positive effect of smaller particle dimensions on FeS2 utilization was identified, which can be attributed to a higher interfacial contact area and shortened diffusion pathways inside the FeS2 particles. These results highlight the general importance of morphological design to exploit the promising theoretical capacity of conversion electrodes in solid-state batteries.

Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes.

BACKGROUND: Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec. METHODS: We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome. RESULTS: Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups. CONCLUSIONS: Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).

Risk of severe hypoglycaemia and its impact in type 2 diabetes in DEVOTE.

AIMS: To undertake a post-hoc analysis, utilizing a hypoglycaemia risk score based on DEVOTE trial data, to investigate if a high risk of severe hypoglycaemia was associated with an increased risk of cardiovascular events, and whether reduced rates of severe hypoglycaemia in patients identified as having the highest risk affected the risk of cardiovascular outcomes. MATERIALS AND METHODS: The DEVOTE population was divided into quartiles according to patients' individual hypoglycaemia risk scores. For each quartile, the observed incidence and rate of severe hypoglycaemia, major adverse cardiovascular event (MACE) and all-cause mortality were determined to investigate whether those with the highest risk of hypoglycaemia were also at the greatest risk of MACE and all-cause mortality. In addition, treatment differences within each risk quartile [insulin degludec (degludec) vs. insulin glargine 100 units/mL (glargine U100)] in terms of severe hypoglycaemia, MACE and all-cause mortality were investigated. RESULTS: Patients with the highest risk scores had the highest rates of severe hypoglycaemia, MACE and all-cause mortality. Treatment ratios between degludec and glargine U100 in the highest risk quartile were 95% confidence interval (CI) 0.56 (0.39; 0.80) (severe hypoglycaemia), 95% CI 0.76 (0.58; 0.99) (MACE) and 95% CI 0.77 (0.55; 1.07) (all-cause mortality). CONCLUSIONS: The risk score demonstrated that a high risk of severe hypoglycaemia was associated with a high incidence of MACE and all-cause mortality and that, in this high-risk group, those treated with degludec had a lower incidence of MACE. These observations support the hypothesis that hypoglycaemia is a risk factor for cardiovascular events.

Development of a hypoglycaemia risk score to identify high-risk individuals with advanced type 2 diabetes in DEVOTE.

AIMS: The ability to differentiate patient populations with type 2 diabetes at high risk of severe hypoglycaemia could impact clinical decision making. The aim of this study was to develop a risk score, using patient characteristics, that could differentiate between populations with higher and lower 2-year risk of severe hypoglycaemia among individuals at increased risk of cardiovascular disease. MATERIALS AND METHODS: Two models were developed for the risk score based on data from the DEVOTE cardiovascular outcomes trials. The first, a data-driven machine-learning model, used stepwise regression with bidirectional elimination to identify risk factors for severe hypoglycaemia. The second, a risk score based on known clinical risk factors accessible in clinical practice identified from the data-driven model, included: insulin treatment regimen; diabetes duration; sex; age; and glycated haemoglobin, all at baseline. Both the data-driven model and simple risk score were evaluated for discrimination, calibration and generalizability using data from DEVOTE, and were validated against the external LEADER cardiovascular outcomes trial dataset. RESULTS: Both the data-driven model and the simple risk score discriminated between patients at higher and lower hypoglycaemia risk, and performed similarly well based on the time-dependent area under the curve index (0.63 and 0.66, respectively) over a 2-year time horizon. CONCLUSIONS: Both the data-driven model and the simple hypoglycaemia risk score were able to discriminate between patients at higher and lower risk of severe hypoglycaemia, the latter doing so using easily accessible clinical data. The implementation of such a tool (http://www.hyporiskscore.com/) may facilitate improved recognition of, and education about, severe hypoglycaemia risk, potentially improving patient care.

Epidemiology of age-dependent prevalence of Bovine Herpes Virus Type 1 (BoHV-1) in dairy herds with and without vaccination.

Many studies report age as a risk factor for BoHV-1 infection or seropositivity. However, it is unclear whether this pattern reflects true epidemiological causation or is a consequence of study design and other issues. Here, we seek to understand the age-related dynamics of BoHV-1 seroprevalence in seasonal calving Irish dairy herds and provide decision support for the design and implementation of effective BoHV-1 testing strategies. We analysed seroprevalence data from dairy herds taken during two Irish seroprevalence surveys conducted between 2010 and 2017. Age-dependent seroprevalence profiles were constructed for herds that were seropositive and unvaccinated. Some of these profiles revealed a sudden increase in seroprevalence between adjacent age-cohorts, from absent or low to close to 100% of seropositive animals. By coupling the outcome of our data analysis with simulation output of an individual-based model at the herd scale, we have shown that these sudden increases are related to extensive virus circulation within a herd for a limited time, which may then subsequently remain latent over the following years. BoHV-1 outbreaks in dairy cattle herds affect animals independent of age and lead to almost 100% seroconversion in all age groups, or at least in all animals within a single epidemiological unit. In the absence of circulating infection, there is a year-on-year increase in the age-cohort at which seroprevalence changes from low to high. The findings of this study inform recommendations regarding testing regimes in the context of contingency planning or an eradication programme in seasonal calving dairy herds.

Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10).

AIM: To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE). MATERIALS AND METHODS: Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time-varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease. RESULTS: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI ] and all-cause mortality [0.50 (0.29; 0.88)95%CI ]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results. CONCLUSIONS: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin.