De-simplifying antiretroviral therapy from a single-tablet to a two-tablet regimen: Acceptance, patient-reported outcomes, and cost savings in a multicentre study.

BACKGROUND: Antiretroviral therapy (ART), which is increasingly used by people with HIV, accounts for significant care costs, particularly because of single-tablet regimens (STRs). This study explored de-simplification to a two-tablet regimen (TTR) for cost reduction. The objectives of this study were: (1) acceptance of de-simplification, (2) patient-reported outcomes, and (3) cost savings. METHODS: All individuals on Triumeq®, Atripla® or Eviplera® in five HIV clinics in the Netherlands were eligible. Healthcare providers informed individuals of this study. After inclusion, individuals were free to de-simplify. An electronic questionnaire was sent to assess study acceptance, adherence, quality of life (SF12) and treatment satisfaction (HIVTSQ). After 3 and 12 months, questionnaires were repeated. Cost savings were calculated using Dutch drug prices. RESULTS: In total, 283 individuals were included, of whom 55.5% agreed to de-simplify their ART, with a large variability between treatment centres: 41.1-74.2%. Individuals who were willing to de-simplify tended to be older, had a longer history of HIV diagnosis, and used more co-medication than those who preferred to remain on an STR regimen. Patient-reported outcomes, including quality of life and treatment satisfaction, showed no significant difference between people with HIV who switched to a TTR and those who remained on an STR regimen. Furthermore, we observed a 17.8% reduction in drug costs in our cohort of people with HIV who were initially on an STR. CONCLUSIONS: De-simplification from an STR to a TTR within the Dutch healthcare setting has been demonstrated as feasible, leads to significant cost reductions and should be discussed with every eligible person with HIV in the Netherlands.

Evolution of local misorientations in the γ/γ'-microstructure of single crystal superalloys during creep studied with the rotation vector baseline (RVB) EBSD method.

The present work uses the rotation vector baseline electron back scatter orientation imaging method (RVB-EBSD) to study the evolution of small misorientations between the γ- and γ'-phase in Ni-base single crystal superalloys (SXs) during creep. For this purpose, two material states of the SX ERBO1 (CMSX4 type) were characterized after creep deformation at 850°C and 600 MPa to final strains of 1% and 2%. Obtaining reliable phase boundary misorientation (PBM), kernel average misorientation (KAM) and orientation spread (OS) data represents a challenge for electron backscatter diffraction (EBSD), not only because the method operates at its limits of lateral and angular resolution, but also because it is difficult to differentiate between the two phases merely based on Kikuchi diffraction. The two phases differ in chemical composition which gives rise to different EBSD background intensities. These can be exploited to differentiate between the two phases. In the present work, crystallographic and chemical information are combined to demonstrate that orientation imaging can be used to document the formation of dislocation networks at γ/γ'-interfaces and the filling of γ-channels by dislocations. These findings are in good agreement with reference results from diffraction contrast scanning transmission electron microscopy. It is also shown that misorientations evolve between small groups of equally oriented γ/γ'-neighborhoods, on a size scale above characteristic γ/γ'-dimensions (>0.5 µm) and below distances associated with dendritic mosaicity (<200 µm). The methodological aspects as well as the new material specific results are discussed in the light of previous work published in the literature. RESEARCH HIGHLIGHTS: Microstructure evolution during [001] tensile creep of Ni-based single-crystalline alloy. Application of RVB-EBSD technique, focused on angular misorientations between γ/γ' phases, with accuracy of 0.01°. Separation of γ/γ' phases using experimental post-processing of raw EBSD data.

GLP-1 agonists for people living with HIV and obesity, is there a potential?

BACKGROUND AND OBJECTIVES: Obesity trends and metabolic dysregulation are rising in people living with HIV using antiretrovirals (ARVs). Underlying causes and preventive strategies are being investigated. Two glucagon like-peptide 1 (GLP-1) agonists, liraglutide and semaglutide, were formerly approved as glucose-lowering drugs and have been recently approved for long-term weight loss in people with obesity. Due to the lack of therapeutic guidelines or clinical trials in people with HIV, we discuss the potential benefits, safety aspects and pharmacological considerations of prescribing liraglutide and semaglutide in people with HIV. RESULTS: Clinical experience is limited to two clinical cases of diabetic people with HIV using liraglutide after which a successful weight loss and glycaemic control were observed. None of the adverse events associated with liraglutide and semaglutide usage indicate an additional risk for people with HIV. Extra caution showed be warranted when initiating GLP-1 agonist therapy in people with HIV taking protease inhibitors who have pre-existing risk factors for heart rate variability to reduce the incidence of RP interval prolongation. GLP-1 agonists are metabolized by endopeptidases, and thus do not generate major drug-drug interactions with most drugs, including ARVs. GLP-s agonists are known to inhibit gastric acid secretion, which warrants caution and close monitoring when combined with atazanavir and oral rilpivirine, two ARVs that require low gastric pH for an optimal absorption. CONCLUSION: Theoretical considerations and a few available clinical observations support semaglutide and liraglutide prescription in people with HIV, with, thus far, no indications of concern regarding efficacy, safety or pharmacological interactions with ARVs.

Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naïve individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA).

To the authors' knowledge, there is currently no literature or guidance recommendation regarding whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and compared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretroviral therapy within <24 h of enrolment: DTG 50 mg BID, DRV/r 800/100 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs thereafter (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration-time profile of 0-24 h (AUC0-24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90-2.55). Total exposure during DTG BID increased but did not double [AUC0-24h GMR 1.65 (90% CI 1.50-1.81) h.mg/L]. DTG glucuronidation MR increased by approximately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads ≤40 copies/mL. The drug-drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.

Outcomes of modern antiretroviral therapy in obese individuals living with HIV.

Obesity is a global epidemic and people living with HIV (PLWH) are showing similar obesity trends to those in the general population. Obesity is manifested by several physiological features that can alter volume of distribution, elimination and metabolism of various medications including ART. Some drugs are increasingly prone to pharmacokinetic alteration during obesity depending on their physicochemical properties and clearance mechanism. These considerations raise concerns of hampered efficacy, development of resistance or increased toxicity of ART in PLWH. Here, we summarize available literature on the exposure and antiviral outcomes of currently available antiretroviral drugs in the context of obesity and provide a panel of recommendations for the clinical management and follow-up in this growing patient population.

Prediction of Maternal and Fetal Doravirine Exposure by Integrating Physiologically Based Pharmacokinetic Modeling and Human Placenta Perfusion Experiments.

BACKGROUND AND OBJECTIVE: Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling. METHODS: Ex vivo placenta perfusions were performed in a closed-closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (Ctrough) values were compared with the target (0.23 mg/L) derived from in vivo exposure-response analysis. RESULTS: A decrease of 55% in maternal doravirine area under the plasma concentration-time curve (AUC)0-24h was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM Ctrough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure. CONCLUSION: Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.

No increase in pregnancy rate of mares after preovulatory deep uterine horn application of misoprostol.

A potential source of fertility loss in mares is oviductal dysfunction, potentially caused by masses or debris in the lumen, that may prevent either sperm from reaching the fertilization site or the embryo from reaching the uterus. Recently a novel therapeutic method leading to increased pregnancy results was described by infusing misoprostol, a synthetic prostaglandin E1, in the uterus of mares with unexplained fertility problems. In this study, we aimed, after examining the compatibility of misoprostol with semen, to evaluate the pregnancy rate after routine preovulatory deep uterine horn application of misoprostol in clinically normal oestrous mares, which were inseminated in the same cycle. In experiment 1, ejaculates of 10 stallions diluted with INRA 96™ were mixed with different concentrations of misoprostol (0.01 mg/mL, 0.001 mg/mL, 0.0001 mg/mL, and 0.00001 mg/mL) and total semen motility was evaluated immediately, 12, 24, 48, and 72 h later, and compared with a control sample (mixed with NaCl 0.9%). In experiments 2 and 3, 33 privately-owned clinically normal oestrous mares were each allocated to a treatment or control group. Ovulation was then induced with intramuscularly 2.25 mg deslorelin acetate. At the moment of ovulation induction (experiment 2) and 24 h earlier (experiment 3), 0.2 mg misoprostol diluted in 2 mL NaCl 0.9% were applied deep in the uterine horn (treatment groups) and pure 2 mL NaCl 0.9% in the mares of the control groups. Mares were then inseminated 24 h after deslorelin administration and prior to ovulation with commercial chilled-warmed or frozen-thawed semen, as well as immediately after ovulation detection (both types of semen) maximally 48 h after ovulation induction. In experiment 1, regardless of time and compared with the control groups, all solutions with different concentrations of misoprostol had a negative effect on total motility of semen, which was significant for the highest concentrations (0.01 mg/mL: 18.0% reduction, CI = 22-13%, p = < 0.01). We found no beneficial effect of preovulatory uterine treatment with misoprostol on pregnancy rate (OR = 0.45, CI = 0.15-1.31, p = 0.14): in experiment 2, 2/11 (18.2%) mares of the treatment group became pregnant vs. 12/22 (54.5%) mares in the control group (OR = 0.19, CI = 0.03-1.06, p = 0.07), in experiment 3, 5/14 (35.7%) mares in the treatment group vs. 7/19 (36.8%) mares in the control group (OR = 0.95, CI = 0.23-4.02, p = 0.95), respectively. In conclusion, pregnancy rate was not increased in reproductively normal mares with routine preovulatory deep uterine horn application of misoprostol.

Assessment of anti-Müllerian hormone in mares' transitional period and in relation to fertility in elderly mares.

Anti-Müllerian Hormone (AMH) has been linked to reproductive tract abnormalities in mares and stallions. This study aimed at evaluating AMH as a biomarker for two reproductive conditions in mares. In the first part of this study, plasma AMH was evaluated as an early indicator of the onset of cyclicity in mares in the transitional period from the anovulatory phase during winter anoestrus to the cyclic phase during the breeding season. Ten mares between 8 and 17 years old were included in the experiment which lasted from mid-February until the end of April. Ovarian activity was monitored with ultrasonography three times per week, the detection of a corpus haemorrhagicum/luteum was documented and antral follicle counts (AFC) were recorded. Blood samples were collected weekly by jugular venipuncture during the whole study period to compare AMH concentrations before and after the first ovulation of the year. The second objective was to evaluate if plasma AMH concentrations in middle-aged mares are linked to fertility and could serve as a prognostic marker in that age group. A total of 41 privately-owned clinically sound mares aged between 12 and 21 years of various breeds were inseminated with fresh or frozen semen. Mares were scanned between day 14 and 20 and the "early pregnancy rate" included only positive pregnancy examinations after the first observed cycle in the season of each mare. Potential associations between the early pregnancy rate in the first cycle and the explanatory factors AMH concentrations, age, status of the mare, stud, development of post-breeding endometritis, number of inseminations and semen type were analysed using logistic regression models. In the first part of the study, correlation between AMH and AFC for the whole study period (P = 0.0002, ρ = 0.55) as well as prior to (P = 0.008, ρ = 0.58) and after the first ovulation (P = 0.0007, ρ = 0.69) were observed. However, AMH concentrations before and after the first ovulation of the year were not statistically different. The second part of the study revealed no association between early pregnancy rate and AMH concentrations or any of the other mentioned factors. In conclusion, this study showed no evidence of a difference between AMH concentrations before and after the first ovulation of the year thus not supporting the use of AMH as a biomarker to predict the onset of cyclicity in mares. We could furthermore not show a relationship between plasma AMH concentrations and early pregnancy rates in this cohort of animals.

[Prevalence of health problems in midlife Swiss warm-blooded horses]. / Auftreten gesundheitlicher Probleme beim Schweizer Warmblutpferd ­mittleren Alters.

INTRODUCTION: The breeding of a healthy horse is the basic requirement for optimal performance. This is also specifically stated in the breeding goal of the Swiss warmblood horse and should be achieved through a strict selection of the stallions. The aim of this retrospective study was to assess the current state of the population to optimize breeding. Data on the health status of Swiss warmblood horses in the age between 6 and 16 years (midlife) were collected by a telephone survey and analyzed descriptively. Following the heritability of the most common health problems were estimated. Data on 1,861 horses were collected between 2016 and 2018. Lameness (34%), colic (22%), sarcoids (19%), and pastern dermatitis (16%) were among the most common health problems, followed by back problems (13%), cough (10%), urticaria (10%), free fecal water syndrome (9%), nasal discharge (8%) and sweet itch (4%). Lameness was observed in 49% of the cases in the forelimbs, in 25% in the hindlimbs and in 26% in both. 27% of horses with colic have been hospitalized once and 8% have undergone colic surgery. Sarcoids became fewer or smaller in 89% of the treated and in 58% of the untreated horses. A significant relationship between treatment and the status of the sarcoids was demonstrated (p .

INTRODUCTION: L'élevage d'un cheval en bonne santé représente une condition de base pour une performance optimale. Ceci est également spécifiquement mentionné dans l'objectif d'élevage du cheval de sang suisse et doit être atteint par une sélection stricte des étalons. Afin d'optimiser l'élevage, il faut connaître l'état actuel de la population, ce qui était le but de cette étude rétrospective. Au moyen d'une enquête téléphonique, des données sur l'état de santé des chevaux de sang suisses âgés de 6 à 16 ans (âge moyen) ont été collectées et traitées de manière descriptive. Les héritabilités des problèmes de santé les plus courants ont ensuite été estimées. Au total, les données de1861 chevaux ont été collectés entre 2016 et 2018. Les boiteries (34%), les coliques (22%), les sarcoïdes (19%) et les crevasses (16%) figuraient parmi les problèmes de santé les plus courants, suivis des problèmes de dos (13%), de la toux (10%), des urticaires (10%), d'écoulements anaux (« Kotwasser ¼) (9%), d'écoulements nasaux (8%) et de dermite estivale (4%). Chez 49% des chevaux boiteux, il s'agissait d'une boiterie antérieure, chez 25% d'une boiterie postérieure et chez 26% d'une boiterie impliquant antérieurs et postérieurs. 27% des chevaux présentant des coliques avaient été hospitalisés et 8% avaient subi une chirurgie de coliques. Les sarcoïdes sont devenus moins nombreux ou plus petits chez 89% des chevaux traités mais également chez 58% des chevaux non traités. Une relation significative entre le traitement et l'état des sarcoïdes a pu être démontrée (p .

The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement.

OBJECTIVES: The dolutegravir/valproic acid drug-drug interaction (DDI) is suggested to be caused by protein displacement. Here, we assess the underlying mechanism. METHODS: Participants in a randomized controlled trial investigating valproic acid as an HIV latency reversing agent were recruited in a predefined pharmacokinetic substudy if they were on once-daily 50 mg dolutegravir-containing combination ART (cART) for >12 months with a plasma HIV-RNA <50 copies/mL (trial registration: ClinicalTrials.gov NCT03525730). Participants were randomized to receive 30 mg/kg/day valproic acid orally (divided into two equal doses) for 14 days or not. Total and unbound dolutegravir concentrations were measured on day 0 (before intake of valproic acid and 6 h after intake of valproic acid) and on days 1, 7, 14 and 42. Intra- and inter-subject dolutegravir concentrations and geometric means (GMs) were evaluated. RESULTS: Six of 10 participants on dolutegravir were randomized to receive valproic acid. During 14 days of valproic acid treatment, the GM total dolutegravir concentration decreased sharply from 1.36 mg/L on day 0 to 0.85, 0.31 and 0.20 mg/L on days 0, 1, 7 and 14, respectively, while total dolutegravir concentrations in the controls remained comparable during the same period: 1.27-1.49 mg/L. We observed a parallel increase in unbound dolutegravir fractions ranging from 0.39% to 0.58% during valproic acid administration, compared with 0.25% to 0.28% without valproic acid. Unbound dolutegravir concentrations were above the established in vitro EC90 value for unbound dolutegravir in 85% of the tested samples. CONCLUSIONS: This study confirms protein displacement as the main mechanism for this DDI, although additional mechanisms might be involved too. If dolutegravir is taken with food, this DDI is probably not clinically relevant.

Spatial orientation in virtual environment compared to real-world.

Virtual reality (VR) is popular across many disciplines and has been increasingly used in sports as a training tool lately. However, it is not clear whether the spatial orientation of humans works equally within VR and in the real-world. In this paper, two studies are presented, in which natural body movements were allowed and demanded. Firstly, a series of verbal and walking distance estimation tests were conducted in both the virtual and the real environment. The non-parametric Friedman test with pairwise comparisons showed no significant differences neither in verbal nor in walking distance estimations between the conditions (all p > 0.05). However, shorter distances (0.9-1.5 m) were estimated more precisely than larger distances (2.6-2.8 m) in both environments. Secondly, a self-developed route recall test to examine the spatial orientation was performed in the virtual and the real environment. The participants visually perceived the predefined route and were instructed to follow these routes with their eyes blindfolded and afterward to return to their starting position. Between the ending and the starting position, no difference between the two environments was observed (p > 0.05). Based on these two studies, the performance of the human spatial orientation preliminarily verified the same in a virtual and real environment.

Cumulative pemetrexed dose increases the risk of nephrotoxicity.

INTRODUCTION: Pemetrexed is a pharmacotherapeutic cornerstone in the treatment of non-small cell lung cancer. As it is primarily eliminated by renal excretion, adequate renal function is essential to prevent toxic exposure. There is growing evidence for the nephrotoxic potential of pemetrexed, which even becomes a greater issue now combined immuno-chemotherapy prolongs survival. Therefore, the aim of this study was to describe the incidence of nephrotoxicity and related treatment consequences during pemetrexed-based treatment. METHODS: A retrospective cohort study was conducted in the Jeroen Bosch Hospital, Den Bosch, the Netherlands. All patients that received at least 1 cycle of pemetrexed based therapy were included in the dataset. The primary outcome was defined as a ≥25 % reduction in eGFR. Additionally, the treatment consequences of decreased renal function were assessed. Logistic regression was used to identify risk factors for nephrotoxicity during treatment with pemetrexed. RESULTS: Of the 359 patients included in this analysis, 21 % patients had a clinically relevant decline in renal function after treatment and 8.1 % of patients discontinued treatment due to nephrotoxicity. Cumulative dose (≥10 cycles of pemetrexed based therapy) was identified as a risk factor for the primary outcome measure (adjusted OR 5.66 (CI 1.73-18.54)). CONCLUSION: This study shows that patients on pemetrexed-based treatment are at risk of developing renal impairment. Risk significantly increases with prolonged treatment. Renal impairment is expected to become an even greater issue now that pemetrexed-based immuno-chemotherapy results in longer survival and thus longer treatment duration.

Editor's Choice - Nationwide Analysis of Patients Undergoing Iliac Artery Aneurysm Repair in the Netherlands.

OBJECTIVE: The new 2019 guideline of the European Society for Vascular Surgery (ESVS) recommends consideration for elective iliac artery aneurysm (eIAA) repair when the iliac diameter exceeds 3.5 cm, as opposed to 3.0 cm previously. The current study assessed diameters at time of eIAA repair and ruptured IAA (rIAA) repair and compared clinical outcomes after open surgical repair (OSR) and endovascular aneurysm repair (EVAR). METHODS: This retrospective observational study used the nationwide Dutch Surgical Aneurysm Audit (DSAA) registry that includes all patients who undergo aorto-iliac aneurysm repair in the Netherlands. All patients who underwent primary IAA repair between 1 January 2014 and 1 January 2018 were included. Diameters at time of eIAA and rIAA repair were compared in a descriptive fashion. The anatomical location of the IAA was not registered in the registry. Patient characteristics and outcomes of OSR and EVAR were compared with appropriate statistical tests. RESULTS: The DSAA registry comprised 974 patients who underwent IAA repair. A total of 851 patients were included after exclusion of patients undergoing revision surgery and patients with missing essential variables. eIAA repair was carried out in 713 patients, rIAA repair in 102, and symptomatic IAA repair in 36. OSR was performed in 205, EVAR in 618, and hybrid repairs and conversions in 28. The median maximum IAA diameter at the time of eIAA and rIAA repair was 43 (IQR 38-50) mm and 68 (IQR 58-85) mm, respectively. Mortality was 1.3% (95% CI 0.7-2.4) after eIAA repair and 25.5% (95% CI 18.0-34.7) after rIAA repair. Mortality was not significantly different between the OSR and EVAR subgroups. Elective OSR was associated with significantly more complications than EVAR (intra-operative: 9.8% vs. 3.6%, post-operative: 34.0% vs. 13.8%, respectively). CONCLUSION: In the Netherlands, most eIAA repairs are performed at diameters larger than recommended by the ESVS guideline. These findings appear to support the recent increase in the threshold diameter for eIAA repair.

Serum acylcarnitine profile in endurance horses with and without metabolic dysfunction.

Mitochondrial ß-oxidation is essential in fat metabolism and can be monitored with blood acylcarnitine profiling, as partly degraded fatty acids accumulate as their carnitine esters. To guarantee continuous energy supply during long-distance exercise, endurance horses oxidise considerable amounts of fat in the mitochondrion. In endurance races over 80 km, glycogen depletion is evident in equine slow-twitch high oxidative muscle fibres and as a consequence, horses participating in endurance races over 80 km rely almost entirely on ß-oxidation of fatty acids. This study investigated mitochondrial fatty acid ß-oxidation in endurance horses exposed to long-distance exercise. Electrospray tandem mass spectrometry analysis of serum acylcarnitine profiles from 10 Arab horses was performed before and after a 160 km endurance race. Results were analysed statistically using ANOVA. Mean speed over the entire race in finishing horses was 16.7 ± 1.2 km/h. Endurance exercise increased mitochondrial ß-oxidation approximately eight-fold (pre-race, 5648.62 ± 1508.52 nmol/L; post-race, 44,243.17 ± 11,504.45 nmol/L; P = 0.001). In these horses, there was an approximately 17-fold increased lipolysis, as demonstrated by elevated serum concentrations of non-esterified fatty acids (NEFA; pre-race, 0.08 ± 0.08 mmol/L; post-race, 1.32 ± 0.36 mmol/L; P < 0.001). In comparison, four Arab horses with poor performance showed an approximately five-fold increase in mitochondrial ß-oxidation (pre-race, 5286.17 ± 3355.16 nmol/L; post-race, 26,660.57 ± 10,064.27 nmol/L; P = 0.009); there was a 29-fold increase in NEFA (pre-race, 0.02 ± 0.01 mmol/L; post-race, 0.58 ± 0.07 mmol/L; P = 0.006) in these horses. Similar post-exercise free carnitine:acetylcarnitine ratios in both groups suggest that the availability of carnitine in long-distance endurance horses might limit performance.

Embryo survival in the oviduct not significantly influenced by major histocompatibility complex social signaling in the horse.

The major histocompatibility complex (MHC) influences sexual selection in various vertebrates. Recently, MHC-linked social signaling was also shown to influence female fertility in horses (Equus caballus) diagnosed 17 days after fertilization. However, it remained unclear at which stage the pregnancy was terminated. Here we test if MHC-linked cryptic female choice in horses happens during the first days of pregnancy, i.e., until shortly after embryonic entrance into the uterus and before fixation in the endometrium. We exposed estrous mares to one of several unrelated stallions, instrumentally inseminated them with semen of another stallion, and flushed the uterus 8 days later to test for the presence of embryos. In total 68 embryos could be collected from 97 experimental trials. This success rate of 70.1% was significantly different from the mean pregnancy rate of 45.7% observed 17 days after fertilization using the same experimental protocol but without embryo flushing. Embryo recovery rate was not significantly dependent on whether the mares had been socially exposed to an MHC-dissimilar or an MHC-similar stallion. These observations suggest that MHC-linked maternal strategies affect embryo survival mainly (or only) during the time of fixation in the uterus.

Retrieval of chronic hepatitis C patients. A manifesto for action to eliminate hepatitis C in the Netherlands: the CELINE project.

Chronic hepatitis C virus (HCV) infection is a global public health issue, which is associated with high rates of morbidity and mortality. The development of direct acting antivirals (DAAs) has transformed treatment: they offer us highly-effective therapy with superior tolerability compared to interferon-containing regimens. In 2016, the World Health Organization (WHO) therefore adopted several ambitious viral hepatitis elimination targets, aiming for a 90% reduction in new infections and a 65% reduction in mortality by 2030. The ultimate goal is to eliminate HCV completely. It is reasonable that these goals may be achieved in the Netherlands due to the low prevalence of chronic HCV, the availability of DAAs, and excellent healthcare infrastructure. This paper describes a national effort to curtail the HCV epidemic in the Netherlands through an HCV retrieval and linkage to care project (CELINE: Hepatitis C Elimination in the Netherlands).

Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis.

OBJECTIVES: Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment. METHODS: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg·h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated. RESULTS: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg·h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed. CONCLUSION: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.