The acute effects of rumen pulse-dosing of hydrogen acceptors during methane inhibition with nitrate or 3-nitrooxypropanol in dairy cows.

Dietary methane (CH4) mitigation is in some cases associated with an increased hydrogen (H2) emission. The objective of the present study was to investigate the acute and short-term effects of acceptors for H2 (fumaric acid, acrylic acid or phloroglucinol) supplemented via pulse-dosing to dairy cows fed CH4 mitigating diets (using nitrate or 3-nitrooxypropanol), on gas exchange, rumen gas and VFA composition. For this purpose, 2 individual 4 × 4 Latin square experiments were conducted with 4 periods of 3 d (nitrate supplementation) and 7 d (3-nitrooxypropanol supplementation), respectively. In each study, 4 rumen cannulated Danish Holstein cows were used. Each additive for CH4 mitigation was included in the ad libitum fed diet within the 2 experiments, to which the cows were adapted for at least 14 d. Acceptors for H2 were administered twice daily in equal portions through the rumen fistula immediately after feeding of the individual cow. In Exp. 1 (nitrate), the treatments were CON-1 (no H2-acceptor), FUM-1 (fumaric acid), ACR-1 (acrylic acid) and FUM+ACR-1 (50% FUM-1 + 50% ACR-1). In Exp. 2 (3-nitrooxypropanol), the 3 treatments, CON-2, FUM-2, and ACR-2, were similar to CON-1, FUM-1 and ACR-1 treatments, however the fourth treatment was PHL-2 (phloroglucinol). Gas exchanges were measured in respiration chambers, while samples of rumen liquid and headspace gas were taken in time series relative to feeding and dosing on specific days. Headspace gas was analyzed for gas composition and rumen liquid was analyzed for volatile fatty acid composition and dissolved gas concentrations. Headspace gas composition and dissolved gas concentration were only measured in Exp. 2. Dry matter intake was reduced upon acrylic acid supplementation. There were no significant effects of any treatments in any experiments on H2 emission, except for a decrease in hourly H2 emission rate (g/h) at 1 h after feeding in both experiments. In Exp. 2, H2 headspace proportions increased by ACR-2 supplementation, whereas dissolved concentrations were unaffected. In Exp. 1, cows on ACR-1 increased propionate proportion at 1 h after feeding. In Exp. 2, both FUM-2 and ACR-2 increased rumen propionate proportion in the hours after feeding and dosing. There was no effect on rumen acetate for cows on PHL-2. There was a strong positive correlation between rumen dissolved CH4 and headspace CH4 (r = 0.84), whereas the equivalent correlation was weaker for H2 (r = 0.41). For the relationship between dissolved concentrations and emissions of CH4 and of H2, there was a moderate positive correlation for CH4 (r = 0.54), whereas it was weak for H2 (r = 0.28) with zero slope. In conclusion, the results suggested that fumaric acid and acrylic acid to some extent was reduced to propionate without associative effects on measures for H2 redirection. Furthermore, phloroglucinol seemed not to be metabolized in the rumen in the present study, as no effects on rumen acetate or measures of H2 were observed. Changes in H2 headspace and emission may be a poor proxy for actual changes in the rumen fluid concentration of H2.

Association between travel distance and face-to-face consultations with general practitioners before an incident acute myocardial infarction: a nationwide register-based spatial epidemiological study.

OBJECTIVES: This study examined the association between travel distance to the general practitioner's (GP) office and no face-to-face GP consultation within 1 year before an incident acute myocardial infarction (AMI). DESIGN: A prospective cohort study using multilevel spatial logistic regression analysis of nationwide register data. SETTING: Nationwide study including contacts to GPs in Denmark prior to an incident AMI in 2005-2017. PARTICIPANTS: 121 232 adults (≥30 years) with incident AMI were included in the study. PRIMARY AND SECONDARY OUTCOMES MEASURES: The primary outcome was odds of not having a face-to-face GP consultation within 1 year before an incident AMI. RESULTS: In total, 13 108 (10.8%) of the 121 232 individuals with incident AMI had no face-to-face consultation with the GP within 1 year before the AMI. Population density modified the association between travel distance and no face-to-face GP consultation. Increased odds of no face-to-face GP consultation was observed for medium (25th-75th percentile/1123-5449 m) and long (>75th percentile/5449 m) compared with short travel distance (<25th percentile/1123 m) among individuals living in small cities (OR (95% credible intervals) of 1.19 (1.10 to 1.29) and 1.19 (1.06 to 1.33), respectively) and rural areas (1.46 (1.26 to 1.68) and 1.48 (1.29 to 1.68), respectively). No association was observed for individuals living in large cities and the capital. CONCLUSIONS: Travel distance above approximately 1 km was significantly associated with no face-to-face GP consultation before an incident AMI among individuals living in small cities and rural areas. The structure of the healthcare system should consider the importance of geographical distance between citizens and the GP in remote areas.

Gas exchange, rumen hydrogen sinks, and nutrient digestibility and metabolism in lactating dairy cows fed 3-nitrooxypropanol and cracked rapeseed.

Fat in the form of cracked rapeseed and 3-nitrooxypropanol (3-NOP, market as Bovaer) were fed alone or in combination to 4 Danish Holstein multicannulated dairy cows, with the objective to investigate effects on gas exchange, dry matter intake (DMI), nutrient digestion, and nutrient metabolism. The study design was a 4 × 4 Latin square with a 2 × 2 factorial treatment arrangement with 2 levels of fat supplementation; 33 g of crude fat per kg of dry matter (DM) or 64 g of crude fat per kg of DM for low and high fat diets, respectively, and 2 levels of 3-NOP; 0 mg/kg DM or 80 mg/kg DM. In total, 4 diets were formulated: low fat (LF), high fat (HF), 3-NOP and low fat (3LF), and 3-NOP and high fat (3HF). Cows were fed ad libitum and milked twice daily. The adaptation period lasted 11 d, followed by 5 d with 12 diurnal sampling times of digesta and ruminal fluid. Thereafter, gas exchange was measured for 5 d in respiration chambers. Chromic oxide and titanium dioxide were used as external flow markers to determine intestinal nutrient flow. No interactions between fat supplementation and 3-NOP were observed for methane yield (g/kg DM), total-tract digestibility of nutrients or total volatile fatty acid (VFA) concentration in the rumen. Methane yield (g/kg DMI) was decreased by 24% when cows were fed 3-NOP. In addition, 3-NOP increased carbon dioxide and hydrogen yield (g/kg DM) by 6% and 3,500%, respectively. However, carbon dioxide production was decreased when expressed on a daily basis. Fat supplementation did not affect methane yield but tended to reduce methane in percent of gross energy intake. A decrease (11%) in DMI was observed, when cows were fed 3-NOP. Likely, the lower DMI mediated a lower passage rate causing the tendency to higher rumen and total-tract neutral detergent fiber digestibility, when the cows were fed 3-NOP. Total VFA concentrations in the rumen were negatively affected both by 3-NOP and fat supplementation. Furthermore, 3-NOP caused a shift in the VFA fermentation profile, with decreased acetate proportion and increased butyrate proportion, whereas propionate proportion was unaffected. Increased concentrations of the alcohols methanol, ethanol, propanol, butanol, and 2-butanol were observed in the ruminal fluid when cows were fed 3-NOP. These changes in rumen metabolites indicate partial re-direction of hydrogen into other hydrogen sinks, when methanogenesis is inhibited by 3-NOP. In conclusion, fat supplementation did not reduce methane yield, whereas 3-NOP reduced methane yield, irrespective of fat level. However, the concentration of 3-NOP and diet composition and resulting desired mitigation effect must be considered before implementation. The observed reduction in DMI with 80 mg 3-NOP/kg DM was intriguing and may indicate that a lower dose should be applied in a Northern European context; however, the mechanism behind needs further investigation.

Effects of feed energy density, daily milking frequency, and a single injection of cabergoline on behavior and welfare in dairy cows at dry-off.

Drying off dairy cows may challenge animal welfare due to high milk yields. A total of 111 loose-housed Holstein cows yielding >15 kg/d of milk were included in a 2 × 2 × 2 factorial design during dry-off to investigate the effects of reduced feeding level (normal vs. reduced energy density), reduced milking frequency (twice vs. once daily), and administration of a dopamine agonist (saline i.m. injection vs. cabergoline i.m. injection) on behavior in the home pen. During the 7 d before dry-off, cows were fed and milked according to 1 of the 4 feeding level and milking frequency combinations. Within 3 h after the last milking, cows were injected i.m. with 5 mL of either saline or a dopamine agonist (5.6 mg of cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, i.e., no preceding reduction in feeding level or milking frequency before last milking). Cows' behavior during d -1, 0, and +1 relative to the last milking was recorded via video and leg-attached sensors. Cows on the reduced energy density diet spent more time feeding and showed more attempts to feed from other cows' bins on d -1. Throughout the period of observations, cows on the reduced diet spent a lower percentage of lying time with their head raised, a higher percentage of lying time with their legs bent, and less time standing in a vigilant posture than did cows on the normal lactation diet. Reducing the daily milking frequency from 2 to 1 did not result in any clear behavioral signs of discomfort. On d 0, cows injected with cabergoline lay down longer but had their head raised for a shorter percentage of time while lying, compared with cows injected with saline. Cows injected with cabergoline also spent less time feeding than cows injected with saline on d 0, and reduced the time spent drinking from d -1 to d 0. Finally, fewer cabergoline-injected cows used the brush for self-grooming, and, among cows that did use the brush, the cows injected with cabergoline reduced the time spent using the brush from d -1 to d 0. In conclusion, cows injected with cabergoline showed several behavioral changes compared with control cows injected with saline. The behavioral changes shown by cows injected with cabergoline may be indicative of malaise during the first 24 h after injection, raising concern for animal welfare. No behavioral evidence for reduced udder pain in cows injected with cabergoline compared with control cows injected with saline was found. Drying off by reducing the energy density of the diet caused behavioral changes indicative of hunger before dry-off, whereas reducing the milking frequency had no clear effects on behavior.

Effect of nitrate supplementation, dietary protein supply, and genetic yield index on performance, methane emission, and nitrogen efficiency in dairy cows.

The objective was to investigate the effect of nonprotein nitrogen source, dietary protein supply, and genetic yield index on methane emission, N metabolism, and ruminal fermentation in dairy cows. Forty-eight Danish Holstein dairy cows (24 primiparous cows and 24 multiparous cows) were used in a 6 × 4 incomplete Latin square design with 4 periods of 21-d duration. Cows were fed ad libitum with the following 6 experimental diets: diets with low, medium, or high rumen degradable protein (RDP):rumen undegradable protein (RUP) ratio (manipulated by changing the proportion of corn meal, corn gluten meal, and corn gluten feed) combined with either urea or nitrate (10 g NO3-/kg of dry matter) as nonprotein nitrogen source. Samples of ruminal fluid and feces were collected from multiparous cows, and total-tract nutrient digestibility was estimated using TiO2 as flow marker. Milk samples were collected from all 48 cows. Gas emission (CH4, CO2, and H2) was measured by 4 GreenFeed units. We observed no significant interaction between dietary RDP:RUP ratio and nitrate supplementation, and between nitrate supplementation and genetic yield index on CH4 emission (production, yield, intensity). As dietary RDP:RUP ratio increased, intake of crude protein, RDP, and neutral detergent fiber and total-tract digestibility of crude protein linearly increased, and RUP intake linearly decreased. Yield of milk, energy-corrected milk, and milk protein and lactose linearly decreased, whereas milk fat and milk urea nitrogen concentrations linearly increased as dietary RDP:RUP ratio increased. The increase in dietary RDP:RUP ratio resulted in a linear increase in the excretion of total purine derivatives and N in urine, but a linear decrease in N efficiency (milk N in % of N intake). Nitrate supplementation reduced dry matter intake (DMI) and increased total-tract organic matter digestibility compared with urea supplementation. Nitrate supplementation resulted in a greater reduction in DMI and daily CH4 production and a greater increase in daily H2 production in multiparous cows compared with primiparous cows. Nitrate supplementation also showed a greater reduction in milk protein and lactose yield in multiparous cows than in primiparous cows. Milk protein and lactose concentrations were lower for cows receiving nitrate diets compared with cows receiving urea diets. Nitrate supplementation reduced urinary purine derivatives excretion from the rumen, whereas N efficiency tended to increase. Nitrate supplementation reduced proportion of acetate and propionate in ruminal volatile fatty acids. In conclusion, no interaction was observed between dietary RDP:RUP ratio and nitrate supplementation, and no interaction between nitrate supplementation and genetic yield index on CH4 emission (production, yield, intensity) was noted. Nitrate supplementation resulted in a greater reduction in DMI and CH4 production, and a greater increase in H2 production in multiparous cows than in primiparous cows. As the dietary RDP:RUP ratio increased, CH4 emission was unaffected and RDP intake increased, but RUP intake and milk yield decreased. Genetic yield index did not affect CH4 production, yield, or intensity.

Trends in low-density lipoprotein cholesterol goal achievement and changes in lipid-lowering therapy after incident atherosclerotic cardiovascular disease: Danish cohort study.

BACKGROUND: We aimed to investigate trends in low-density lipoprotein cholesterol (LDL-C) goal achievement (LDL-C<1.8 mmol/L, equivalent to 70 mg/dL), initiation of lipid-lowering therapy (LLT) and changes in LLT intensity in individuals with atherosclerotic cardiovascular disease (ASCVD) at very high risk of recurrent cardiovascular disease. METHODS: A cohort study design was used including individuals with incident ASCVD and LDL-C≥1.8 mmol/L in 2010-2015. Data were obtained from national, population-based registers (patient, prescription, income, and laboratory). RESULTS: We included 11,997 individuals. Acute myocardial infarction, ischemic stroke and stable angina pectoris accounted for 79.6% of the qualifying ASCVD events. At inclusion, 37.2% were in LLT. Mean LDL-C before or during ASCVD hospitalization was 3.1 mmol/L (120 mg/dL). LDL-C goal achievement increased within the first two years after inclusion from 40.5% to 50.6%. LLT initiation within the first 90 days increased from 48.6% to 56.0%. Initiation of intensive LLT increased from 9.6% to 32.8%. The largest change in LLT intensity was seen in the period 180 days before to 90 days after discharge with 2.2% in 2010 to 12.1% in 2015. CONCLUSION: LDL-C goal achievement within the first 2 years after inclusion increased from 40.5% in 2010 to 50.6% in 2015. LLT initiation within the first year after inclusion increased, especially for intensive LLT, although only one third initiated intensive LLT in 2015. Despite trends show improvements in LDL-C goal achievement, 49.4% of individuals at very high risk of a CV event did not achieve the LDL-C goal within 2 years after ASCVD hospitalization.

Effects of feeding level, milking frequency, and single injection of cabergoline on blood metabolites, hormones, and minerals around dry-off in dairy cows.

This study aimed to investigate the effect of the different dry-off strategies based on reducing feeding level (normal vs. reduced energy density), reducing milking frequency (twice vs. once daily), and administration of a dopamine agonist after last milking (i.e. saline vs. cabergoline injection) on blood metabolites, hormones, and minerals around dry-off. In this experiment, 119 Holstein dairy cows were used in a 2 × 2 × 2 factorial arrangement. In the last week before dry-off, cows were allocated to 1 of the 4 possible dry-off strategies based on feeding level and milking frequency. Within 3 h after last milking, cows were injected with either saline or a D2 dopamine agonist (cabergoline; Velactis, Ceva Santé Animale, Libourne, France; labeled for use only with abrupt dry-off, e.g., no preceding reduction in feeding level or milking frequency before last milking). After dry-off, all cows were fed the same dry cow diet and data collection continued for a week. Blood samples were collected from the coccygeal vein on d -9, -6, -5, -2, 1, 2, 5, and 7 relative to dry-off. Additionally, blood was sampled at 0, 3, and 6 h relative to injection of either cabergoline or saline, equivalent to d 0.125, 0.250, and 0.375 relative to last milking (dry-off). The reduced feeding level before dry-off caused reduced glucose and insulin concentrations as well as increased free fatty acid concentrations, particularly when reduced feeding level was combined with milking the cows 2× daily. The intramuscular injection of cabergoline caused the expected reduction in circulating prolactin concentrations. In addition, dopamine-agonist cabergoline induced an atypical simultaneous pattern of plasma metabolites (i.e., increased glucose and free fatty acid concentrations), hormones (i.e., reduced insulin and increased cortisol concentrations), and minerals (i.e., reduced calcium concentration), indicating that normal metabolic and mineral homeostatic regulations were hindered after the injection of ergot alkaloid cabergoline. In conclusion, reducing milking frequency seems the best management strategy to reduce milk production at dry-off among those tested in this study.

Effects of feeding level and milking frequency on behavior of dairy cows before dry-off.

Drying-off may challenge the welfare of especially high-yielding dairy cows. In this study, 119 loose-housed Holstein cows yielding ≥20 kg milk/d were enrolled in a 2 × 2 factorial design aiming to investigate effects of changes in diet energy density and daily milking frequency on behavior. The last 7 d before the dry-off day, cows were milked either twice or once daily, and were fed either a lactation diet or the same diet diluted with 30% barley straw, both offered in individual bins for ad libitum intake. All cows were fitted with sensors to record lying time and activity, and data from 109 of these cows were used together with behavioral observations obtained from video recordings of 52 of the cows. Data from activity sensors and video recordings were obtained during 24 h on d -6, -3, and -1 relative to the dry-off day (i.e., the day of the last milking). Across all days of observation, cows milked once daily spent more time feeding (149 vs. 130 min/d) than cows milked twice daily. Cows on the reduced diet and milked twice daily had a shorter lying time compared with cows on the normal diet and milked twice (759 vs. 837 min/d), whereas lying times of cows on the remaining 2 treatments were intermediate. Among cows on the lactation diet, reduced milking frequency increased time spent perching (from 11.1 to 28.7 min/d). Cows fed the energy-reduced diet spent more time feeding (154 vs. 124 min/d), showed more attempts to feed from unassigned feed bins (31.7 vs. 15.4 attempts daily), and spent less time using a mechanical brush (6.5 vs. 9.2 min/d) than cows fed the lactation diet. These results show that several aspects of cows' behavior, including main activities such as lying and feeding, but also behaviors of low resilience such as brush use, and to some extent more subtle and complex behaviors such as perching and attempts to feed from unassigned feed bins, are sensitive to management changes typically applied during the days before dry-off. The behavioral effects of the reduced feed energy level support earlier findings suggesting that qualitative feed restriction renders cows hungry. The effects of the reduced milking frequency on behavior were generally less pronounced, but 2 noteworthy interactions between milking frequency and diet were seen. First, cows milked twice daily and fed the energy-reduced diet spent less time lying, which is possibly related to increased energy demand and hunger. Second, cows milked once daily and fed the lactation diet spent more time perching, which may be related to udder discomfort. However, these more complex findings warrant further study. Taken together, the results of this study show that a dry-off procedure involving reduced energy supply induces behavioral changes indicating a higher degree of compromised welfare compared with reduced milking frequency.

Childhood adversity and cardiovascular disease in early adulthood: a Danish cohort study.

AIMS: To examine the effect of childhood adversity on the development of cardiovascular disease (CVD) between ages 16 and 38, specifically focusing on ischaemic heart disease and cerebrovascular disease. METHODS AND RESULTS: Register data on all children born in Denmark between 1 January 1980 and 31 December 2001, who were alive and resident in Denmark without a diagnosis of CVD or congenital heart disease until age 16 were used, totalling 1 263 013 individuals. Cox proportional hazards and Aalen additive hazards models were used to estimate adjusted hazard ratios (HRs) and adjusted hazard differences of CVD from ages 16 to 38 in five trajectory groups of adversity experienced between ages 0 and 15. In total, 4118 individuals developed CVD between their 16th birthday and 31 December 2018. Compared with those who experienced low levels of adversity, those who experienced severe somatic illness and death in the family (men: adjusted HR: 1.6, 95% confidence interval: 1.4-1.8, women: 1.4, 1.2-1.6) and those who experienced very high rates of adversity across childhood and adolescence (men: 1.6, 1.3-2.0, women: 1.6, 1.3-2.0) had a higher risk of developing CVD, corresponding to 10-18 extra cases of CVD per 100 000 person-years in these groups. CONCLUSIONS: Individuals who have been exposed to childhood adversity are at higher risk of developing CVD in young adulthood compared to individuals with low adversity exposure. These findings suggest that interventions targeting the social origins of adversity and providing support for affected families may have long-term cardio-protective effects.

Effects of the density of extruded pellets on starch digestion kinetics, rumen fermentation, fiber digestibility and enteric methane production in dairy cows.

Dynamics of starch digestion in dairy cows fed extruded pellets differing in physical functional properties were investigated by measuring starch digestibility, post-prandial rumen fermentation patterns, and post-prandial duodenal starch appearance. Additionally, starch digestion effects on neutral detergent fiber (NDF) digestibility and methane (CH4 ) emission were studied. Pure barley was extruded to produce three treatments having pellets of either low-density (LD), medium-density (MD) or high-density (HD). The experiment was conducted in a 3 × 3 Latin square design using three lactating Danish Holstein cows fitted with ruminal, duodenal and ileal cannulas. After the allocation of experimental concentrate directly into the rumen through the rumen cannula, cows were fed a basal diet low in starch. Eight samples were collected on equal time intervals (9 h) from duodenal digesta, ileal digesta and feces (grab sample) to determine digestibility. For post-prandial rumen fermentation patterns, four sample sets of rumen dorsal, medial and ventral fluid were taken from each cow, whereas for post-prandial duodenal starch appearance, 14 samples of duodenal chyme were obtained from each cow relative to morning feeding of experimental concentrate at 07:00 h. Ruminal, small intestinal, hindgut and total tract digestibility of starch did not differ among treatments. Similarly, NDF digestibility and CH4 emission also remained unaffected by treatments. However, compared with the LD and MD treatments, the HD treatment showed higher acetate: propionate ratio at all positions in the rumen and a higher post-prandial duodenal starch appearance. This indicates lower ruminal starch degradation (RSD) and higher starch flow into the small intestine for HD treatment. In conclusion, the current study indicates that pellets' physical properties can manipulate RSD, where pellets with high density and fluid stability can partly shift starch digestion from the rumen to the small intestine. Indeed, further investigations are needed.

Socioeconomic and ethnical disparity in coronary heart disease outcomes in Denmark and the effect of cardiac rehabilitation-A nationwide registry study.

AIMS: Cardiovascular patients with low socioeconomic status and non-western ethnic background have worse prognostic outcomes. The aim of this nationwide study was first to address whether short-term effects of hospital-based outpatient cardiac rehabilitation (CR) are similar across educational level and ethnic background, and secondly to study whether known disparity in long-term prognosis in patients with cardiovascular disese is diminished by CR participation. METHODS: All patients with myocardial infarction and/or coronary revascularization from August 2015 until March 2018 in the Danish national patient registry or the Danish cardiac rehabilitation database (DHRD) were included. We used descriptive statistics to address disparity in achievement of quality indicators in CR, and Cox proportional hazard regression to examine the association between the disparity measures and MACE (cardiovascular hospitalization and all-cause mortality) with adjustment for age, gender, index-diagnose and co-morbidity. RESULTS: We identified 34,511 patients of whom 19,383 had participated in CR and 9,882 provided information on CR outcomes from the DHRD. We demonstrated a socioeconomic gradient in improvements in VO2peak, and non-western patients were less often screened for depression or receive dietary consulting. We found a strong socioeconomic gradient in MACE irrespective of CR participation, medication, and risk factor control (adjusted HR 0.65 (95% CI 0.56-0.77) for high versus low education). Non-western origin was associated with higher risk of MACE (adjusted HR 1.2 (1.1-1.4)). CONCLUSION: We found only minor socioeconomic and ethnic differences in achievement of CR quality indicators but strong differences in CHD prognosis indication that conventional risk factor control and medical treatment following CR do not diminish the socioeconomic and ethnical disparity in CHD prognosis.

Discovery of an Oral, Rule of 5 Compliant, Interleukin 17A Protein-Protein Interaction Modulator for the Potential Treatment of Psoriasis and Other Inflammatory Diseases.

Interleukin 17A (IL-17A) is an interleukin cytokine whose dysregulation is implicated in autoimmune disorders such as psoriasis, and monoclonal antibodies against the IL-17A pathway are now well-established and very effective treatments. This article outlines the work that led to the identification of 23 as an oral, small-molecule protein-protein interaction modulator (PPIm) clinical development candidate. Protein crystallography provided knowledge of the key binding interactions between small-molecule ligands and the IL-17A dimer, and this helped in the multiparameter optimization toward identifying an orally bioavailable, Rule of 5 compliant PPIm of IL-17A. Overlap of early ligands led to a series of benzhydrylglycine-containing compounds that allowed the identification of dimethylpyrazole as a key substituent that gave PPIm with oral bioavailability. Exploration of the amino acid portion of the structure then led to dicyclopropylalanine as a group that gave potent and metabolically stable compounds, including the development candidate 23.

Perception of pharmacological prevention and subsequent non-adherence to medication in patients with ischaemic heart disease: a population-based cohort study.

OBJECTIVE: A patient-focused approach is advocated to embody risk of non-adherence to medication and subsequent adverse clinical outcomes following ischaemic heart disease (IHD). This study aimed to explore how patient perceived information on pharmacological prevention was associated with subsequent non-adherence to medication (measured by non-initiation, non-implementation and non-persistence) in patients with incident IHD. DESIGN: Cohort study. SETTING: Denmark. PARTICIPANTS: Register-based cohort of 829 patients with incident IHD in 2013. MEASURES: Perception covered whether patients' experienced being adequately informed about their pharmacological prevention. Information on such was obtained from a survey and divided into 'Well informed', 'Moderately informed' and 'Poorly informed'. Information on baseline characteristics, and reimbursed prescriptions of medication (antiplatelets, statins, ACE-inhibitors/angiotensin receptor blockers and ß-blockers) during follow-up were obtained by linkage to nationwide public registers. Non-initiation and non-implementation of medication, measured as proportion of days covered, were analysed by Poisson regression. Non-persistence to medication, measured as risk of discontinuation, was analysed by multivariable Cox proportional hazard regression. PRIMARY AND SECONDARY OUTCOME MEASURES: Non-implementation and non-persistence to medication up to 365 days of follow-up were primary outcomes. Secondary outcomes included non-initiation as well as non-implementation and non-persistence to medication at 180 days of follow-up. RESULTS: A dose-response association was in general found between perception of pharmacological prevention and risk of non-implementation and non-persistence. For example, the hazard of non-persistence to antiplatelets was 1.18 (95% CI 0.71 to 1.96) times higher for patients reporting 'Moderately informed' and 1.89 (95% CI 1.10 to 3.25) times higher for patients reporting 'Poorly informed', compared with patients reporting 'Well informed of perception of pharmacological prevention' up to 365 days of follow-up. CONCLUSION: Lower levels of perception of pharmacological prevention were associated with subsequent non-implementation and non-persistence to medication in patients with incident IHD.

Association Between Newly Diagnosed Atrial Fibrillation and Work Disability (from a Nationwide Danish Cohort Study).

It is previously shown that cardiovascular conditions have a negative effect on the ability to work. However, it is unknown if incident atrial fibrillation (AF) influences the ability to work. We examined the association between AF and the risk of work disability and the influence of socioeconomic factors. All Danish residents with a hospital diagnosis of AF and aged ≥30 and ≤63 years in the period January 1, 2000, to September 31, 2014, were included and matched 1:10 with an AF-free gender and age-matched random person from the general population. Permanent social security benefit was used as a marker of work disability. Risk difference (RD) and 95% confidence interval (95% CI) of work disability were calculated over 15 months. The analyses were furthermore stratified in low, medium, and high levels of socioeconomic factors. In total, 28,059 patients with AF and 312,667 matched reference persons were included. The risk of receiving permanent social security benefits within 15 months was 4.5% (4.3% to 4.8%) for the AF cohort and 1.3% (95% CI 1.3% to 1.4%) for the matched reference cohort. Adjusted RD (95% CI) was 2.3% (2.0% to 2.5%). Stratified on income, RDs were higher in low-income groups (adjusted RD 3.7% [95% CI 3.1% to 4.3%]) versus high-income groups (RD 1.3% [1.0% to 1.5%]). In conclusion, the risk of work disability within 15 months after incident AF was more than 3 times as high in patients with AF compared with the general population, especially when comparing individuals in lower socioeconomic strata.

Association between magnesium in drinking water and atrial fibrillation incidence: a nationwide population-based cohort study, 2002-2015.

BACKGROUND: Atrial fibrillation (AF) is a common heart rhythm disorder and a risk factor of adverse cardiovascular diseases. Established causes do not fully explain the risk of AF and unexplained risk factors might be related to the environment, e.g. magnesium in drinking water. Low magnesium levels in drinking water might be associated with higher risk of cardiovascular diseases including AF. With detailed individual data from nationwide registries and long-term magnesium exposure time series, we had a unique opportunity to investigate the association between magnesium in drinking water and AF. OBJECTIVE: We evaluated the association between magnesium concentration in drinking water and AF risk. METHODS: A nationwide register-based cohort study (2002-2015) was used including individuals aged ≥30 years. Addresses were linked with water supply areas (n = 2418) to obtain time-varying drinking water magnesium exposure at each address. Five exposure groups were defined based on a 5-year rolling time-weighted average magnesium concentration. AF incidence rate ratios (IRRs) between exposure groups were calculated using a Poisson regression of incidence rates, adjusted for sex, age, and socioeconomic position. Robustness of results was investigated with different exposure definitions. RESULTS: The study included 4,264,809 individuals (44,731,694 person-years) whereof 222,998 experienced an incident AF. Magnesium exposure ranged from 0.5 to 62.0 mg/L (mean = 13.9 mg/L). Estimated IRR (95% CI) compared to the referent exposure group (< 5 mg/L) was 0.98 (0.97-1.00) for the second lowest exposure group (5-10 mg/L), and 1.07 (1.05-1.08) for the two highest exposure groups (15-62 mg/L). Strongest positive associations were observed among those aged ≥80 years and with lowest education group. An inverse association was found among individuals with highest education group. CONCLUSION: There might be a small beneficial effect on AF of an increase in magnesium level in drinking water up to 10 mg/L, though an overall positive association was observed. The unexpected positive association and different associations observed for subgroups suggest a potential influence of unaccounted factors, particularly in vulnerable populations. Future research on magnesium in drinking water and cardiovascular diseases needs to focus on contextual risk factors, especially those potentially correlating with magnesium in drinking water.

Non-Persistence with Medication as a Mediator for the Social Inequality in Risk of Major Adverse Cardiovascular Events in Patients with Incident Acute Coronary Syndrome: A Nationwide Cohort Study.

AIM: Low socioeconomic status is associated with higher risk of major adverse cardiovascular events (MACE) among patients with incident acute coronary syndrome (ACS). We examined whether non-persistence with antiplatelet and statin therapy mediated the income- and educational-related inequality in risk of MACE. METHODS: Using national registers, all Danish patients diagnosed with incident ACS from 2010 to 2017 were identified. The primary outcome (MACE) comprised all-cause death, cardiac death and cardiac readmission. Risk of MACE was handled by discrete time analyses using inverse probability of treatment weights. The mediator variable comprised non-persistence to a combined 2-dimensional measure of statin and antiplatelet treatment. The mediation analysis was evaluated by population average effects. RESULTS: The study population was 45,874 patients, of whom 16,958 (37.0%) were non-persistent with medication and 16,365 (35.7%) suffered MACE during the median follow-up of 3.5 years. Compared to patients with low income, the adjusted hazard ratio of MACE was lowered by 33% (HR: 0.67, 95% CI: 0.61-0.72) in men and by 34% (HR: 0.66, 95% CI: 0.61-0.72) in women with high income, respectively. Similar results were observed according to level of education. A socioeconomic difference in risk of non-persistence was found in men but not women and only in relation to income. The lower risk of non-persistence observed in high-income men mediated the lower risk of MACE by 12.6% (95% CI: 11.1-14.1%) compared with low-income men. CONCLUSION: Non-persistence with medication mediated some of the income-related inequality in risk of MACE in men, but not women, with incident ACS.

Joint mapping of cardiovascular diseases: comparing the geographic patterns in incident acute myocardial infarction, stroke and atrial fibrillation, a Danish register-based cohort study 2014-15.

BACKGROUND: Disease mapping aims at identifying geographic patterns in disease. This may provide a better understanding of disease aetiology and risk factors as well as enable targeted prevention and allocation of resources. Joint mapping of multiple diseases may lead to improved insights since e.g. similarities and differences between geographic patterns may reflect shared and disease-specific determinants of disease. The objective of this study was to compare the geographic patterns in incident acute myocardial infarction (AMI), stroke and atrial fibrillation (AF) using the unique, population-based Danish register data. METHODS: Incident AMI, stroke and AF was modelled by a multivariate Poisson model including a disease-specific random effect of municipality modelled by a multivariate conditionally autoregressive (MCAR) structure. Analyses were adjusted for age, sex and income. RESULTS: The study included 3.5 million adults contributing 6.8 million person-years. In total, 18,349 incident cases of AMI, 28,006 incident cases of stroke, and 39,040 incident cases of AF occurred. Estimated municipality-specific standardized incidence rates ranged from 0.76 to 1.35 for AMI, from 0.79 to 1.38 for stroke, and from 0.85 to 1.24 for AF. In all diseases, geographic variation with clusters of high or low risk of disease after adjustment was seen. The geographic patterns displayed overall similarities between the diseases, with stroke and AF having the strongest resemblances. The most notable difference was observed in Copenhagen (high risk of stroke and AF, low risk of AMI). AF showed the least geographic variation. CONCLUSION: Using multiple-disease mapping, this study adds to the results of previous studies by enabling joint evaluation and comparison of the geographic patterns in AMI, stroke and AF. The simultaneous mapping of diseases displayed similarities and differences in occurrence that are non-assessable in traditional single-disease mapping studies. In addition to reflecting the fact that AF is a strong risk factor for stroke, the results suggested that AMI, stroke and AF share some, but not all environmental risk factors after accounting for age, sex and income (indicator of lifestyle and health behaviour).

Effects of feeding level, milking frequency, and single injection of cabergoline on feed intake, milk yield, milk leakage, and clinical udder characteristics during dry-off in dairy cows.

Abrupt and gradual dry-off strategies by reducing feeding level (normal vs. reduced energy density), reducing milking frequency (twice vs. once daily), and administration of a dopamine agonist after last milking (i.m. saline vs. cabergoline injection) were investigated (2 × 2 × 2 factorial arrangement) for their effects on feed intake, milk yield, energy balance, milk leakage, and clinical udder characteristics in 119 Holstein cows. In the last week before dry-off, cows were assigned to 1 of 4 combinations of feeding level and milking frequency. Within 3 h after last milking, cows were injected with either saline or a dopamine agonist (cabergoline; Velactis, Ceva Santé Animale; labeled for use only with abrupt dry-off, i.e., no preceding reduction in feeding level or milking frequency before last milking). After dry-off, all cows were fed the same diet for dry cows, and data collection continued for a week. Dry matter intake (DMI) was recorded in automated feed bins and milk yield in an automatic milking system where additional concentrate was fed. Clinical udder characteristics and milk leakage were scored 10 times during the week before and the week after dry-off. Before dry-off, total DMI decreased with reduced feeding level compared with normal feeding level, but did not differ between milking frequencies. The combined effect of reduced DMI and diet energy concentration resulted in a 47% lower net energy intake with reduced feeding level compared with normal feeding level during the week before dry-off. Milk yield was approximately 30% lower during the week before dry-off when either feeding level or milking frequency was reduced compared with no change in feeding level or milking frequency, whereas milk yield was 45% lower when both feeding level and milking frequency were reduced. The net energy balance during the week before dry-off was negative with reduced feeding level and more negative when combined with twice-daily milking. After dry-off, udder engorgement was reduced in the 3 gradual dry-off treatments compared with abrupt dry-off. Cabergoline injection after last milking resulted in least udder engorgement and signs of milk leakage for 48 h, but also resulted in abrupt reduction of DMI lasting approximately 24 h irrespective of treatment before dry-off. In conclusion, gradual cessation of lactation by reducing milking frequency to once daily without reducing the feeding level decreased milk yield before dry-off in high-yielding dairy cows and reduced udder engorgement after dry-off without inducing negative energy balance during the period of dry-off. In contrast, reduced feeding level induced negative energy balance, which may compromise welfare due to metabolic stress and hunger. No clear differences in risk of milk leakage after dry-off were observed between abrupt and gradual dry-off management strategies. Use of cabergoline led to fewer signs of milk leakage and reduced udder engorgement during the first days after dry-off, which may positively affect welfare at dry-off. However, the mechanism behind and the welfare consequences of the concomitant abrupt decrease in DMI lasting approximately 24 h needs further investigation to complete our understanding of dopamine agonist use for dry-off.

New onset anxiety and depression in patients with an implantable cardioverter defibrillator during 24 months of follow-up (data from the national DEFIB-WOMEN study).

OBJECTIVE: To examine the cumulative incidence of and covariates' association with new onset anxiety and depression in implantable cardioverter defibrillator (ICD) patients during 24 months of follow-up in patients without depression and anxiety at implant. METHODS: Patients (n = 1040; 155 (14.9%) women; mean age: 64.2 ± 10.6) with a first-time ICD enrolled in the national, multi-center prospective observational DEFIB-WOMEN study comprised the study cohort. We obtained information on demographic and clinical data from the Danish Pacemaker and ICD Register. RESULTS: During 24 months of follow-up, 138 (14.5%) patients developed new onset anxiety and 109 (11.3%) new onset depression. Age ≥ 60 [HR:0.60;95%CI:0.40-0.90] and an anxiety score between 3 and 4 [HR:2.85; 95%CI:1.71-4.75] and 5-7 [HR:5.97; 95%CI:3.77-9.45] on the Hospital Anxiety and Depression Scale (HADS) were associated with different hazards of new onset anxiety during follow-up. Age ≥ 60 [HR:0.62;95%CI:0.42-0.93] and a HADS depression score between 3 and 4 [HR:2.99;95%CI:1.80-4.95] and 5-7 [HR:6.45; 95%CI:4.12-10.10] were associated with different hazards of new onset depression. CONCLUSION: During 24 months of follow-up, respectively 14.5% and 11.3% of patients developed new onset anxiety and depression, suggesting that screening patients at several timepoints, and in particular those with even minimally elevated HADS scores at baseline, may be warranted to identify patients at risk for poor health outcomes.