The association between time-series milk ß-hydroxybutyrate dynamics and early reproductive performance of dairy cows.

The DeLaval Herd Navigator is an on-farm sensor system that measures on a frequent basis milk progesterone (P4) and ß-hydroxybutyrate (BHB) in individual cows to closely monitor reproductive performance and energy balance. This information provides the opportunity to investigate the dynamics of BHB measured in milk (mBHB) and study the association between mBHB and early reproductive performance. The objectives of the study were (1) to describe mBHB dynamics within the first 20 d in milk (DIM), and (2) to evaluate the association between mBHB dynamics and early reproductive performance at cow-level. Two-year time-series data from 4,133 dairy cows in 38 Dutch dairy farms were available for analysis. Data included information on mBHB, daily milk yield and the indicators of early reproductive performance, days from calving to resumption of cyclicity, days from calving to first estrus, and days from calving to first insemination. The following mBHB dynamic parameters were defined based on the first 20 DIM for each individual cow: average mBHB (AvgBHB), DIM when mBHB was for the first time ≥80 µmol/L (OnsetKeto), the total number of consecutive days a cow had mBHB concentration ≥80 µmol/L, and the number of measurements mBHB concentration was ≥80 µmol/L. Three Cox proportional hazard regression models with random herd effect were developed to evaluate the association between cow level mBHB dynamics and days from calving to resumption of cyclicity, first estrus, and first insemination. Results showed that the mean AvgBHB within 20 DIM among all cows was 73 µmol/L. The mean OnsetKeto within 20 DIM, was 8 DIM. Among all cows having hyperketolactia, 55.8% (1,350/2,419) had OnsetKeto in the first week of lactation. In total, 41.5% (1,714/4,133) of the cows did not have OnsetKeto in the first 20 DIM. An early onset of hyperketolactia was associated with delayed fertility events. Cows with higher AvgBHB have a prolonged time interval from calving to resumption of cyclicity and first estrus. Information on mBHB dynamics and the association with early reproductive performance provides insights that might be helpful to improve reproductive performance of individual dairy cows.

SINGLE-DOSE, MULTIPLE-DOSE, AND THERAPEUTIC DRUG MONITORING PHARMACOKINETICS OF FIROCOXIB IN ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Firocoxib is a COX-2-selective nonsteroidal anti-inflammatory drug (NSAID) with limited effects on COX-1, which means it likely has fewer side effects than typically associated with other NSAIDs. This study determined possible doses of firocoxib based on single- and multidose pharmacokinetic trials conducted in 10 Asian elephants (Elephas maximus). Initially, two single oral dose trials (0.01 and 0.1 mg/kg) of a commercially available tablet (n = 6) and paste (n = 4) formulation were used to determine a preferred dose. The 0.1 mg/kg dose was further evaluated via IV single dose (n = 3) and oral multidose trials (tablets n = 6; paste n = 4). Serum peak and trough firocoxib concentrations were also evaluated in Asian elephants (n = 4) that had been being treated for a minimum of 90 consecutive days. Key pharmacokinetic parameters for the 0.1 mg/kg single-dose trials included mean peak serum concentrations of 49 ± 3.3 ng/ml for tablets and 62 ± 14.8 ng/ml for paste, area under the curve (AUC) of 1,332 ± 878 h*mg/ml for tablets and 1,455 ± 634 h*mg/ml for paste, and half-life (T1/2) of 34.3 ± 30.3 h for tablets and 19.9 ± 12.8 h for paste. After 8 d of dosing at 0.1 mg/kg every 24 h, pharmacokinetic parameters stabilized to an AUC of 6,341 ± 3,003 h*mg/ml for tablets and 5,613 ± 2,262 for paste, and T1/2 of 84.4 ± 32.2 h for tablets and 62.9 ± 2.3 h for paste. Serum COX inhibition was evaluated in vitro and ex vivo in untreated elephant plasma, where firocoxib demonstrated preferential inhibition of COX-2. No adverse effects from firocoxib administration were identified in this study. Results suggest administering firocoxib to Asian elephants at a dose of 0.1 mg/kg orally, using either tablet or paste formulations, every 24 h.

Using a digital platform to establish odontometric variation based on race, gender and Angle classification.

Orthodontists often encounter significant clinical challenges in the finishing stages of treatment due to a disproportion in interarch tooth size relationships. Despite the increasing presence of digital technology and concomitant focus on customized treatment approaches, there is a gap in the knowledge of how generating tooth size data using digital versus traditional methods may impact our treatment regime. OBJECTIVE: This study aimed to compare the prevalence of tooth size discrepancies using digital models and a digitally based cast analysis in our cohort based on (i) Angle's Classification; (ii) gender and (iii) race. MATERIALS AND METHODS: The mesiodistal widths of teeth in 101 digital models were assessed using computerized odontometric software. A Chi-square test was used to determine the prevalence of tooth size disproportions among the study groups. The differences between all three groups of the cohort were analysed using a three-way analysis of variance (ANOVA). RESULTS: An overall Bolton tooth size discrepancy (TSD) prevalence of 36.6% was observed in our study cohort; 26.7% had an anterior Bolton TSD. No differences existed in the prevalence of tooth size discrepancies between male and female subjects as well as between the different malocclusion groups (P > .05). Caucasian subjects had a statistically significant smaller prevalence of TSD compared to Black and Hispanic patients (P < .05). CONCLUSION: The prevalence results in this study illuminate how relatively common TSD is and underscores the importance of proper diagnosis. Our findings also suggest that racial background may be an influential factor in the presence of TSD.

SERUM DISPOSITION OF A SINGLE DOSE OF ORALLY ADMINISTERED FIROCOXIB IN AFRICAN ELEPHANTS (LOXODONTA AFRICANA).

The time course of serum firocoxib concentrations was described after administration of two single oral doses (0.01 and 0.1 mg/kg) of commercially available firocoxib tablet (n = 4) and paste (n = 2) formulations to six healthy adult female African (Loxodonta africana) elephants. Firocoxib was quantitated by high-performance liquid chromatography. Firocoxib serum concentrations were below detectable levels after administration of 0.01 mg/kg of both formulations. A dose of 0.1 mg/kg (n = 4) of the tablet formulation had the following mean ± SD of pharmacokinetic parameters: area under the curve (AUC) 1,588 ± 362 h × ng/ml, maximum plasma concentration (Cmax) 31 ± 6.6 ng/ml at 6.4 ± 1.8 h, and disappearance half-life (T1/2) 66 ± 59 h, Elephant compliance to oral administration of the paste formulation was challenging, with only two elephants accepting administration of the paste at 0.1 mg/kg. Pharmacokinetic parameters determined included AUC of 814 h × ng/ml, Cmax of 44 ng/ml at Tmax of 7.0 h, and T1/2 of 36.4 h. Based on mean AUC, the relative bioavailability of paste compared to tablet formulations was 50%. Limitations of this study were the small number of participants and elephant compliance with the paste formulation. This study supports an oral dose of 0.1 mg/kg every 24 h. Multidose and IV trials are indicated to confirm firocoxib dosing requirements for African elephants.

The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

Incidence and prevalence of rheumatoid arthritis in Denmark from 1998 to 2018: a nationwide register-based study.

OBJECTIVE: To investigate the incidence and prevalence of rheumatoid arthritis (RA) in the adult Danish population. METHOD: In this nationwide register-based cohort study, patients with incident RA between 1998 and the end of 2018 were identified using Danish administrative registries. The age- and sex-standardized incidence rate (IR), incidence proportion (IP), lifetime risk (LR), and point prevalence (PP) of RA were calculated. RA was defined as a first-time RA diagnosis registered in the Danish National Patient Registry combined with a redeemed prescription of a conventional synthetic disease-modifying anti-rheumatic drug in the following year. In addition, three different case definitions of RA were explored. RESULTS: The overall age- and sex-standardized IR of RA from 1998 to 2018 was 35.5 [95% confidence interval (CI) 35.1-35.9] per 100 000 person-years while the IP was 35.2 (95% CI 34.8-35.5) per 100 000 individuals. The IR was two-fold higher for women than for men. The LR of RA ranged from 2.3% to 3.4% for women and from 1.1% to 1.5% for men, depending on the RA case definition used. The overall PP of RA was 0.6% (95% CI 0.5-0.6%) in 2018: 0.8% (95% CI 0.7-0.8%) for women and 0.3% (95% CI 0.3-0.4%) for men. The prevalence increased about 1.5-fold from 2000 to 2018. CONCLUSION: The IR and PP were approximately two-fold higher for women than for men. The prevalence of RA in Denmark increased significantly from 2000 to 2018. The RA case definition had more impact on the results than the choice of denominator.

Impact of comorbidity on renal cell carcinoma prognosis: a nationwide cohort study.

BACKGROUND: Presence of comorbid diseases at time of cancer diagnosis may affect prognosis. We evaluated the impact of comorbidity on survival of patients diagnosed with renal cell carcinoma (RCC), overall and among younger (<70 years) and older (≥70 years) patients. METHODS: We established a nationwide register-based cohort of 7894 patients aged ≥18 years diagnosed with RCC in Denmark between 2006 and 2017. We computed 1- and 5-year overall survival and hazard ratios (HRs) for death according to the Charlson Comorbidity Index (CCI) score. RESULTS: Survival decreased with increasing CCI score despite an overall increase in survival over time. The 5-year survival rate of patients with no comorbidity increased from 57% among those diagnosed in 2006-2008 to 69% among those diagnosed in 2012-2014. During the same periods, the survival rate increased from 46% to 62% among patients with a CCI score of 1-2 and from 39% to 44% for those with a CCI score of ≥3. Patients with CCI scores of 1-2 and ≥3 had higher mortality rates than patients with no registered comorbidity (HR 1.15, 95% CI 1.06-1.24 and HR 1.56, 95% CI 1.40-1.73). Patterns were similar for older and younger patients. Particularly, diagnoses of liver disease (HR 2.09, 95% CI 1.53-2.84 and HR 4.01, 95% CI 2.44-6.56) and dementia (HR 2.16, 95% CI 1.34-3.48) increased mortality. CONCLUSION: Comorbidity decreased the survival of patients with RCC, irrespective of age, despite an overall increasing survival over time. These results highlight the importance of focusing on comorbidity in this group of patients.

The relationships between early lactation energy status indicators and endocrine fertility traits in dairy cows.

The relationships between dairy cow milk-based energy status (ES) indicators and fertility traits were studied during periods 8 to 21, 22 to 35, 36 to 49, and 50 to 63 d in milk. Commencement of luteal activity (C-LA) and interval from calving to the first heat (CFH), based on frequent measurements of progesterone by the management tool Herd Navigator (DeLaval), were used as fertility traits. Energy status indicator traits were milk ß-hydroxybutyrate (BHB) concentration provided by Herd Navigator and milk fat:protein ratio, concentration of C18:1 cis-9, the ratio of fatty acids (FA) C18:1 cis-9 and C10:0 in test-day milk samples, and predicted plasma concentration of nonesterified fatty acids (NEFA) on test days. Plasma NEFA predictions were based either directly on milk mid-infrared spectra (MIR) or on milk fatty acids based on MIR spectra (NEFAmir and NEFAfa, respectively). The average (standard deviation) C-LA was 39.3 (±16.6) days, and the average CFH was 50.7 (±17.2) days. The correlations between fertility traits and ES indicators tended to be higher for multiparous (r < 0.28) than for primiparous (r < 0.16) cows. All correlations were lower in the last period than in the other periods. In period 1, correlations of C-LA with NEFAfa and BHB, respectively, were 0.15 and 0.14 for primiparous and 0.26 and 0.22 for multiparous cows. The associations between fertility traits and ES indicators indicated that negative ES during the first weeks postpartum may delay the onset of luteal activity. Milk FPR was not as good an indicator for cow ES as other indicators. According to these findings, predictions of plasma NEFA and milk FA based on milk MIR spectra of routine test-day samples and the frequent measurement of milk BHB by Herd Navigator gave equally good predictions of cow ES during the first weeks of lactation. Our results indicate that routinely measured milk traits can be used for ES evaluation in early lactation.

Maternal use of hormonal contraception and epilepsy in offspring.

STUDY QUESTION: Is maternal use of hormonal contraception associated with the development of epilepsy in the offspring? SUMMARY ANSWER: We found that maternal use of hormonal contraception was associated with a slightly increased risk of epilepsy in the offspring. WHAT IS KNOWN ALREADY: Foetal exposure to exogenous hormones has been associated with changes in brain development. However, little is known about maternal hormonal contraception use and development of epilepsy in the offspring. STUDY DESIGN, SIZE, DURATION: A nationwide cohort of all live born children born in Denmark between 1 January 1998 and 31 December 2014, was followed from day 29 after birth for epilepsy (first diagnosis of epilepsy or first redeemed prescription for anti-epileptic medication) to censoring (emigration, death) or 31 December 2015, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Diagnoses of epilepsy were obtained from the National Patient Registry. The Danish National Prescription Registry supplied information on redeemed prescriptions for hormonal contraception and anti-epileptic medication. Maternal hormonal contraception use was categorized as never use (reference group), previous use (prescriptions redeemed >3 months before pregnancy start) and recent use (prescriptions redeemed ≤3 months before or during pregnancy). MAIN RESULTS AND THE ROLE OF CHANCE: The data show that 17 585 children developed epilepsy during a median follow-up of 9.2 years (9 732 635 person-years). The hazard ratio (HR) for epilepsy was 1.07 (95% CI 1.02-1.13) in children of mothers who had used any type of hormonal contraception recently, compared with children of mothers who had not used hormonal contraception. The HR was similar for recent use of oral combined products, while the HRs for recent or previous use of non-oral combined products were 1.32 (95% CI 0.98-1.77) and 1.16 (95% CI 1.02-1.32), respectively. For non-oral progestin-only products, the HRs were 1.19 (95% CI 1.04-1.38) and 1.53 (95% CI 1.31-1.80), respectively, for recent and previous use. LIMITATIONS, REASONS FOR CAUTION: There may be some misclassification of maternal hormonal contraception use, as some women may not have used the redeemed prescriptions or used them at a different point in time; potentially leading to an attenuation of the estimates. In addition, although we were able to account for known risk factors for epilepsy, unknown or residual confounding cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are based on nationwide population-based data and can therefore be applied to other similar populations. However, as this is the first study in this field, further studies are needed to confirm our findings. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study, which was supported by internal funding at the Unit of Virus, Lifestyle and Genes. All authors report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Comprehensive lipid and metabolite profiling in healthy adults with low and high consumption of fatty fish: a cross-sectional study.

Fish consumption is associated with reduced risk of CVD, which may be partly mediated by alterations in plasma lipids, such as HDL-cholesterol. However, comprehensive analyses of associations between fatty fish consumption and lipoprotein subclass profile are limited and show inconsistent results. Therefore, the aim of the present exploratory study was to investigate the association between fatty fish consumption and lipoprotein subclass particle concentrations and composition, with an emphasis on HDL. We performed a comprehensive plasma metabolite profiling in 517 healthy adults, using a targeted high-throughput NMR spectroscopy platform. The participants were divided into tertiles based on consumption of fatty fish, reported through a validated FFQ. We compared the concentration of metabolites between the participants in the lowest and highest tertiles of fatty fish consumption. We show that high consumers of fatty fish (>223 g/week, median intake 294 g/week) had higher particle concentrations and content of total lipids, free cholesterol and phospholipids in large and extra-large HDL particles and higher content of total cholesterol, cholesteryl esters and TAG in large HDL particles than low consumers (<107 g/week, median intake 58 g/week). Using fatty fish consumption as a continuous variable, we found that fatty fish consumption was associated with lower levels of the inflammation marker glycoprotein acetyls. In conclusion, high consumers of fatty fish seem to have a more favourable HDL-cholesterol-related lipoprotein profile and anti-inflammatory phenotype than low consumers of fatty fish. Thus, these data support the current Norwegian dietary recommendations for fish consumption regarding CVD risk.

Genetic parameters for reproductive losses estimated from in-line milk progesterone profiles in Swedish dairy cattle.

This study assessed the extent of reproductive losses and associated genetic parameters in dairy cattle, using in-line milk progesterone records for 14 Swedish herds collected by DeLaval's Herd Navigator. A total of 330,071 progesterone samples were linked to 10,219 inseminations (AI) from 5,238 lactations in 1,457 Swedish Red and 1,847 Swedish Holstein cows. Pregnancy loss traits were defined as early embryonic loss (1-24 d after AI), late embryonic loss (25-41 d after AI), fetal loss (42 d after AI until calving), and total pregnancy loss (from d 1 after AI until calving). The following classical fertility traits were also analyzed: interval from calving to first service, interval from calving to last service, interval between first and last service, calving interval, and number of inseminations per service period. Least squares means with standard error (LSM ± SE), heritabilities, and genetic correlations were estimated in a mixed linear model. Fixed effects included breed, parity (1, 2, ≥3), estrus cycle number when the AI took place, and a linear regression on 305-d milk yield. Herd by year and season of AI, cow, and permanent environmental effect were considered random effects. Extensive (approximately 45%) early embryonic loss was found, but with no difference between the breeds. Swedish Red was superior to Swedish Holstein in the remaining pregnancy loss traits with, respectively: late embryonic loss of 6.1 ± 1.2% compared with 13.3 ± 1.1%, fetal loss of 7.0 ± 1.2% compared with 12.3 ± 1.2%, and total pregnancy loss of 54.4 ± 1.4% compared with 60.6 ± 1.4%. Swedish Red also had shorter calving to first service and calving to last service than Swedish Holstein. Estimated heritability was 0.03, 0.06, and 0.02 for early embryonic, late embryonic, and total pregnancy loss, respectively. Milk yield was moderately genetically correlated with both early and late embryonic loss (0.52 and 0.39, respectively). The pregnancy loss traits were also correlated with several classical fertility traits (-0.46 to 0.92). In conclusion, Swedish Red cows had lower reproductive loss during late embryonic stage, fetal stage, and in total, and better fertility than Swedish Holstein cows. The heritability estimates for pregnancy loss traits were of the same order of magnitude as previously reported for classical fertility traits. These findings could be valuable in work to determine genetic variation in reproductive loss and its potential usefulness as an alternative fertility trait to be considered in genetic or genomic evaluations.

Shift work, inflammation and musculoskeletal pain-The HUNT Study.

BACKGROUND: Studies have indicated that shift work, in particular night work, is associated with chronic musculoskeletal pain but the mechanisms are unclear. It has been suggested that sleep disturbance, a common complaint among shift and night workers, may induce low-grade inflammation as well as heightened pain sensitivity. AIMS: Firstly, this study was aimed to examine the cross-sectional associations between shift work, C-reactive protein (CRP) level and chronic musculoskeletal pain, and secondly, to analyse CRP as a mediator between shift work and chronic musculoskeletal pain. METHODS: The study included 23 223 vocationally active women and men who participated in the HUNT4 Survey of the Trøndelag Health Study (HUNT). Information was collected by questionnaires, interviews, biological samples and clinical examination. RESULTS: Regression analyses adjusted for sex, age and education revealed significant associations between shift work and odds of any chronic musculoskeletal pain (odd ratio [OR] 1.11, 95% confidence interval [CI] 1.04-1.19), between shift work and CRP level (OR 1.09, 95% CI 1.03-1.16) and between CRP level 3.00-10 mg/L and any chronic musculoskeletal pain (OR 1.38, 95% CI 1.27-1.51). Shift work and CRP were also associated with number of chronic pain sites. Mediation analysis indicated that shift work was indirectly associated with any chronic musculoskeletal pain through CRP (OR 1.03, 95% CI 1.01-1.06). CONCLUSIONS: The results support the hypothesis that shift work is associated with chronic musculoskeletal pain, and that systemic inflammation may be a biological mechanism linking shift work to chronic pain.

Modeling Anthropogenic and Environmental Influences on Freshwater Harmful Algal Bloom Development Detected by MERIS Over the Central United States.

Human and ecological health have been threatened by the increase of cyanobacteria harmful algal blooms (cyanoHABs) in freshwater systems. Successful mitigation of this risk requires understanding the factors driving cyanoHABs at a broad scale. To inform management priorities and decisions, we employed random forest modeling to identify major cyanoHAB drivers in 369 freshwater lakes distributed across 15 upper Midwest states during the 2011 bloom season (July-October). We used Cyanobacteria Index (CI_cyano)-A remotely sensed product derived from the MEdium Resolution Imaging Spectrometer (MERIS) aboard the European Space Agency's Envisat satellite-as the response variable to obtain variable importance metrics for 75 landscape and lake physiographic predictor variables. Lakes were stratified into high and low elevation categories to further focus CI_cyano variable importance identification by anthropogenic and natural influences. "High elevation" watershed land cover (LC) was primarily forest or natural vegetation, compared with "low elevation" watersheds LC dominated by anthropogenic landscapes (e.g., agriculture and municipalities). We used the top ranked 25 Random Forest variables to create a classification and regression tree (CART) for both low and high elevation lake designations to identify variable thresholds for possible management mitigation. Mean CI_cyano was 3 times larger for "low elevation" lakes than for "high elevation" lakes, with both mean values exceeding the "High" World Health Organization recreational guidance/action level threshold for cyanobacteria (100,000 cells/mL). Agrarian-related variables were prominent across all 369 lakes and low elevation lakes. High elevation lakes showed more influence of lakeside LC than for the low elevation lakes.

PHARMACOKINETICS OF ORALLY ADMINISTERED FLUNIXIN MEGLUMINE IN AFRICAN (LOXODONTA AFRICANA) AND ASIAN (ELEPHAS MAXIMUS) ELEPHANTS.

Flunixin meglumine is the most commonly used nonsteroidal anti-inflammatory drug used to treat elephants; however, no pharmacokinetic study for flunixin has yet been conducted in these species, and dosages used range widely. Pharmacokinetic parameters of flunixin were determined in African (Loxodonta africana) and Asian (Elephas maximus) elephants after single-dose oral administration of 0.8 and 1.5 mg/kg flunixin paste in each species. Elephant compliance to oral administration of banamine was occasionally challenging, especially among older, female African elephants. After administration of 0.8 mg/kg flunixin, mean serum concentrations peaked in approximately 1.3 hr at 2.1 ± 0.8 µg/ml for Asian (n = 8) and 2.8 hr at 2.5 ± 0.7 µg/ml for African (n = 8) elephants. Dosages of 1.5 mg/kg flunixin resulted in mean serum concentration peaks of 7.2 ± 1.5 µg/ml in Asian elephants (n = 7) and 4.4 ± 0.7 µg/ml in African elephants (n = 6). However, multiple-dose trials using 1.1 mg/kg flunixin resulted in peak serum concentrations that were again less in Asian than African elephants (2.7 µg/ml versus 4.4 µg/ml, respectively). Asian elephants consistently had lower time to maximal concentration, greater area under the curve, and longer mean residence times compared with African elephants. In other species, flunixin is excreted unchanged primarily via hepatic routes with small amounts in the urine. Asian elephants may engage in some level of enterohepatic recycling of flunixin, as was previously reported for phenylbutazone. This study supports that different oral dosing regimens should be used for Asian (1.0 mg/kg SID) and African (1.2 mg/kg SID) elephants, and oral administration techniques used should ensure complete dosage delivery.

Targeting Krasg12c -mutant cancer with a mutation-specific inhibitor.

The RAS genes, which include H, N, and KRAS, comprise the most frequently mutated family of oncogenes in cancer. Mutations in KRAS - such as the G12C mutation - are found in most pancreatic, half of colorectal and a third of lung cancer cases and is thus responsible for a substantial proportion of cancer deaths. Consequently, KRAS has been the subject of exhaustive drug-targeting efforts over the past 3-4 decades. These efforts have included targeting the KRAS protein itself but also its posttranslational modifications, membrane localization, protein-protein interactions and downstream signalling pathways. Most of these strategies have failed and no KRAS-specific drugs have yet been approved. However, for one specific mutation, KRASG12C , there is light on the horizon. MRTX849 was recently identified as a potent, selective and covalent KRASG12C inhibitor that possesses favourable drug-like properties. MRTX849 selectively modifies the mutant cysteine residue in GDP-bound KRASG12C and inhibits GTP-loading and downstream KRAS-dependent signalling. The drug inhibits the in vivo growth of multiple KRASG12C -mutant cell line xenografts, causes tumour regression in patient-derived xenograft models and shows striking responses in combination with other agents. It has also produced objective responses in patients with mutant-specific lung and colorectal cancer. In this review, we discuss the history of RAS drug-targeting efforts, the discovery of MRTX849, and how this drug provides an exciting and long-awaited opportunity to selectively target mutant KRAS in patients.

Profiling of immune-related gene expression in children with familial hypercholesterolaemia.

BACKGROUND: Innate and adaptive immune responses are pivotal in atherosclerosis, but their association with early-stage atherosclerosis in humans is incompletely understood. In this regard, untreated children with familial hypercholesterolaemia may serve as a human model to investigate the effect of elevated low-density lipoprotein (LDL)-cholesterol. OBJECTIVES: We aimed to study the immunological and inflammatory pathways involved in early atherosclerosis by examining mRNA molecules in peripheral blood mononuclear cells (PBMCs) from children with FH. METHODS: We analysed the level of 587 immune-related mRNA molecules using state-of-the-art Nanostring technology in PBMCs from children with (n = 30) and without (n = 21) FH, and from FH children before and after statin therapy (n = 10). RESULTS: 176 genes (30%) were differentially expressed between the FH and healthy children at P < 0.05. Compared to healthy children, the dysregulated pathways in FH children included the following: T cells (18/19); B cells (5/6); tumour necrosis factor super family (TNFSF) (6/8); cell growth, proliferation and differentiation (5/7); interleukins (5/9); toll-like receptors (2/5); apoptosis (3/7) and antigen presentation (1/7), where the ratio denotes higher expressed genes to total number of genes. Statin therapy reversed expression of thirteen of these mRNAs in FH children. CONCLUSION: FH children display higher PBMC expression of immune-related genes mapped to several pathways, including T and B cells, and TNFSF than healthy children. Our results suggest that LDL-C plays an important role in modulating expression of different immune-related genes, and novel data on the involvement of these pathways in the early atherosclerosis may represent future therapeutic targets for prevention of atherosclerotic progression.

Epidemiology and outcome of idiopathic generalized epilepsy in adults.

BACKGROUND AND PURPOSE: Drug-resistant idiopathic generalized epilepsy (IGE) remains challenging despite a favourable overall prognosis of IGE, and little is known about basic epidemiology and long-term outcome of drug-resistant IGE. The aim of the study was to describe the incidence, prevalence and outcome of IGE in an unbiased, population-based cohort. METHODS: In 2014-2018, all patients (≥17 years) with IGE inhabiting the island of Funen (496 000 inhabitants) were recruited. The socioeconomic and clinical information available for 406 individuals was assessed. Median follow-up was 15 years. RESULTS: The average IGE incidence (2008-2017) was 2.9/100 000 inhabitants/year. The point prevalence of identifiable IGE patients was 1.0/1000 adults (juvenile myoclonic epilepsy 0.4/1000; absence epilepsy 0.3/1000, epilepsy with generalized tonic-clonic seizures alone 0.3/1000); 92.1% of the patients were diagnosed before 25 years of age. When correcting for unequal age distribution in the cohort, 1102 people on the island of Funen fulfilled the diagnostic criteria for IGE at the age of 25 (estimated prevalence 2.7/1000 adults). In the year before data closure, 121 patients reported seizures. Fifty patients met the definition of drug-resistant IGE (12.1% of the cohort, 4.5% of the estimated 1102 IGE patients). The average seizure burden of all patients with drug-resistant IGE was 2.2 generalized tonic-clonic seizures per year; only 14 patients suffered more than two generalized tonic-clonic seizures per year. Drug-resistant IGE was associated with an increased risk of requiring treatment for affective disorders and a reduced probability of working full time. CONCLUSION: Idiopathic generalized epilepsy was associated with a low risk of persistent drug-resistant seizures requiring specialist medical attention. Drug resistance was associated with a negative socioeconomic outcome.

Tau positron emission tomography imaging in C9orf72 repeat expansion carriers.

BACKGROUND AND PURPOSE: AV-1451 (18 F-AV-1451, flortaucipir) positron emission tomography was performed in C9orf72 expansion carriers to assess tau accumulation and disease manifestation. METHODS: Nine clinically characterized C9orf72 expansion carriers and 18 age- and gender- matched cognitively normal individuals were psychometrically evaluated and underwent tau positron emission tomography imaging. The regional AV-1451 standard uptake value ratios from multiple brain regions were analyzed. Spearman correlation was performed to relate the AV-1451 standard uptake value ratio to clinical, psychometric and cerebrospinal fluid measures. RESULTS: C9orf72 expansion carriers had increased AV-1451 binding in the entorhinal cortex compared to controls. Primary age-related tauopathy was observed postmortem in one patient. AV-1451 uptake did not correlate with clinical severity, disease duration, psychometric performance or cerebrospinal fluid markers. CONCLUSION: C9orf72 expansion carriers exhibited increased AV-1451 uptake in entorhinal cortex compared to cognitively normal controls, suggesting a propensity for primary age-related tauopathy. However, AV-1451 accumulation was not associated with psychometric performance in our cohort.

Does losing a parent early influence the education you obtain? A nationwide cohort study in Denmark.

BACKGROUND: Health inequalities are rooted in education and we investigate the association between early parental death and attainment across the educational spectrum. METHODS: Using total population data on Danes born between 1982 and 2000 (n = 1 043 813), we assess incidence rate ratios (RRs) by gender for attainment of each educational level (basic school, high school or vocational training, bachelor degree or professional programme, and university graduate degree) according to loss of a parent before the age of 18 years. We adjust for family income, education and psychiatric illness and examine parent's gender, cause of death and child's age at time of death as potential moderators. RESULTS: Bereaved people had significantly lower attainment rates than non-bereaved people: basic school (RR = 0.95; 95% CI: 0.93-0.97 for men and 0.96; 0.94-0.98 for women), high school or vocational training (0.78; 0.76-0.80 for men and 0.82; 0.80-0.84 for women), bachelor degree or professional programme (0.74; 0.70-0.79 for men and 0.83; 0.79-0.86 for women) and university graduate degree (0.77; 0.68-0.86 for men and 0.77; 0.69-0.86 for women). Parent's gender, cause of death and child's age at the death did not modify the associations. CONCLUSIONS: As education impacts population health, support for bereaved school children may be more important than realized.

Effects of psychosocial work factors on number of pain sites: The role of sleep quality as mediator.

BACKGROUND: Objective of the current study was to determine which of thirteen specific psychosocial work factors were related to number of musculoskeletal pain sites (NPS) prospectively over a two-year time span. Furthermore, the study aimed to explore possible mediation of these prospective relationships through sleep problems. METHODS: The study was a two-wave full panel study. Participants included 6277 employees of Norwegian companies, representing a wide range of occupations. Structural equation modelling was employed to analyze direct and indirect effects of thirteen specific psychological- and social work factors on sleep problems and NPS. RESULTS: Out of the thirteen work factors studied, positive challenges at work, role conflict, decision control, superior support, coworker support, empowering leadership, and social climate were statistically significantly related to subsequent NPS, both directly and indirectly through sleep quality. Sleep quality was related to NPS in all analyses. Most psychosocial work factors exhibited direct effects on either sleep or number of pain sites. Decision demands and control over work pacing were not statistically significantly related to sleep or pain. CONCLUSION: In conclusion, the results suggested sleep quality to be involved in the mechanisms by which work affects the number of pain complaints employees experience. SIGNIFICANCE: Findings from this study suggest sleep may play a role in the complex mechanism from work stressors to musculoskeletal pain. Workplace interventions aiming to reduce musculoskeletal pain may wish to target work factors described in this study, as they affect sleep and may thereby increase number of musculoskeletal pain sites.