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ABSTRACT: Dairy cow fertility is a complex trait that depends on the cow's physiological status, the farm's environmental and management conditions, and their interactions. Already the slightest improvement in fertility can positively impact a farm's profitability and sustainability. In research, milk progesterone (P4) has often been used as an accurate and feasible way to identify a dairy cow's reproduction status. Moreover, in Europe and Canada, it has been used to improve fertility management on commercial farms as it allows to accurately identify reproduction issues, pregnancy, and the optimal insemination window. An on-farm P4 device (OPD) automatically samples, measures, and monitors the milk P4 concentration of individual cows. To this end, the P4 data are smoothed to be robust for measurement errors and outliers, and fixed thresholds are used to estimate the time of luteolysis preceding ovulation, thereby generating a luteolysis alert (LA). By smoothing the P4 data, the OPD introduces a time lag on the LA. Variation in this time lag is not considered in the estimation of the optimal insemination window that is advised to the farmer. Ignoring this variation might decrease the accuracy of the optimal insemination window and, therefore, decreases the likelihood of conception. We hypothesize that considering the length of the time lag and adapting the advice accordingly improves the conception rate. This observational retrospective study uses an extensive dataset from 17 commercial dairy farms that are equipped with an OPD. We estimated the time lag on the alerts and evaluated their relationship with the interval from LA to insemination for successful (n = 3,721) and unsuccessful inseminations (n = 3,896) separately. Results showed that the probability of conception increases when a longer LA time lag is compensated with a shorter interval from LA to insemination and vice versa. In addition, for successful inseminations, we found a clear negative relation between the time lag and the interval from LA to insemination and the interval was significantly shorter when the time lag of the LA was longer. This negative relation between time lag and interval from LA to insemination was less pronounced for unsuccessful inseminations. Additionally, we evaluated the conception rates for inseminations that are performed too early, in time, or too late with respect to the optimal insemination window advised by the OPD, in function of their associated time lags. We found that, for inseminations that were preceded by a short time lag (

Background A coronary function test (CFT) is the recommended diagnostic test to identify coronary vasomotor dysfunction as a cause of symptoms in patients with angina and nonobstructive coronary arteries (ANOCA). Acetylcholine is the commonly used pharmacological agent for spasm provocation. We aimed to investigate an association between severity of symptoms and provocative acetylcholine dose. Methods and Results We included ANOCA patients undergoing clinically indicated CFT from the Netherlands Registry of Invasive Coronary Vasomotor Function Testing: NL‐CFT. Patients with epicardial spasm (n=251) were divided according to acetylcholine spasm triggering dose: low (2–20 mcg, EpiLOW), middle (100 mcg, EpiMIDDLE) or high (200 mcg, EpiHIGH). Patients with microvascular spasm (n=157) were analyzed irrespective of triggering dose. The patient groups were compared to each other and to a control group with negative CFT results (n=101). We assessed mean Seattle Angina Questionnaire angina frequency and summary scores at baseline and follow‐up and the proportion of patients improving or deteriorating. An inverse relationship between provocation dosage and angina frequency at baseline was found in epicardial spasm: the lower the triggering dose, the more frequently patients experienced angina (EpiLOW 48±20, EpiMIDDLE 53±21, EpiHIGH 57±19, microvascular spasm 61±21, controls 64±21, overall P=0.003). A trend was seen toward most patients improving in the high triggering dose group, and most patients deteriorating in the low triggering dose group. Conclusions A significant dose‐dependent relationship between spasm provocation and anginal complaints exists. Acetylcholine provocation dose could be incorporated as a risk stratification factor or surrogate outcome in future clinical trials. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT06083155.

This article is one of the first attempts to study the mechanisms of foreign language learning by children with DLD. We test the effectiveness of a cognate intervention aiming to enhance cross-linguistic awareness of Dutch-speaking primary-school pupils with DLD, as part of their English as a Foreign Language (EFL) curriculum. The participants were learning English as a school subject in the last three years of special primary education in the Netherlands (ages 8;11-13;8). The intervention group (n = 41) received 12 short lessons on cognate relationships over the course of 14 weeks. The control group (n = 46), matched to the intervention group on the amount and intensity of foreign language instruction, received their regular English lessons that were mainly implicit and skill-based. The study used a pre-test--post-test design and compared the development of English word recognition in the two groups, at the same time controlling for the amount of prior EFL instruction and out-of-school exposure to English. The performance at pre-test was already high, particularly on cognates. Word recognition in the control group did not improve over the course of the 14 weeks. The performance of the intervention group showed significant improvement from pre-test to post-test. After the intervention, they recognized not only more of the words practised in the lessons but also more nontreated cognates, which demonstrates that the intervention participants developed a cognate strategy that allowed them to recognize more English words based on similarity to Dutch. We conclude that explicit cognate instruction implemented in a regular classroom setting facilitates the development of EFL vocabulary in special primary education.

Yuedonghei (YDH) is the only local pig breed with full black hair among the four well-known local pig breeds originated and distributed in Guangdong province, China, which caters to the consumers’ preference of the local market of 127 million residents and thus brings a significantly above-average price. However, considerable genetic introgression (GI) has been reported for the YDH population, i.e., gene flow into YDH from other pig breeds, which is mainly due to the recent crossbreeding with several mainstream breeds for upgrading reasons. Therefore, this study aimed to evaluate the GI as well as the conservation status in the current YDH population and test the feasibility of advanced optimum contribution selection (aOCS) in alleviating GI in YDH. We first analysed the genetic diversity, ancestral structure, population structure, and phylogeny of 360 YDH relative to 782 publicly downloaded pigs of 42 Eurasian or American breeds and wild boars, based on single nucleotide polymorphism chip data. Then, we selected 304 initial YDH and stochastically simulated a practical conservation programme that spanned 10 discrete generations and implemented haplotype segment-based aOCS in every generation. The expected and observed heterozygosity of 360 YDH were 0.344 and 0.336. The linkage disequilibrium-based recent effective population size (Ne) was 32.89. Considerable GI amounting to 32.9% foreign ancestry was found in 28 lowly related YDH individuals using admixture analysis. In the simulated YDH conservation programme, the average native genomic contribution was increased from 50.4 to 71.4% while maintaining a Ne of 100 by controlling classic kinship and native kinship. Our study showed that segment-based aOCS that required only genomic data can be used to alleviate GI in the current YDH population and meanwhile increase its Ne, which provided strategic insights into the sustainable conservation of local genetic resources of livestock.

Non-culprit coronary artery lesions are commonly present in patients presenting with an acute coronary syndrome (ACS). Additional stenting of non-culprit lesions in addition to the culprit lesion intends to prevent secondary events caused by these lesions. At the same time, multiple trials have demonstrated the potential of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in reducing plaque size and changing plaque composition of non-culprit lesions. Whether intensive low-density lipoprotein cholesterol (LDL-C) reduction with PCSK9 inhibitor evolocumab improves non-culprit vessel hemodynamics, reduces the risk of plaque rupture of important non-culprit lesions, and might obviate the need for additional stenting has not been investigated. The “Functional Improvement of non‐infarcT related coronary artery stenosis by Extensive LDL‐C Reduction with a PCSK9 Antibody” (FITTER) trial is a multi-center, randomized, double-blind, placebo-controlled clinical trial for patients presenting with ACS and multivessel disease (MVD). After treatment of the culprit lesion, fractional flow reserve (FFR) is performed in non-culprit vessels amenable for percutaneous coronary intervention (PCI). Coronary intervention in patients with hemodynamically important non-critical lesions (FFR: 0.67–0.85) is staged after baseline imaging using near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS). Eligible patients are randomized and treated for 12 weeks with either evolocumab or placebo, in addition to high-intensity statin therapy. Follow-up angiography with repeat FFR and IVUS-NIRS is scheduled at 12 weeks. Staged PCI is performed at the operator's discretion.The FITTER trial is the first study to evaluate the effect of maximal LDL-C reduction by the PCSK9 inhibitor evolocumab on invasively measured FFR, plaque size, and plaque composition in hemodynamically important non-culprit lesions, during a treatment period of just 12 weeks after an ACS. Currently, all patients have been included (August 2023) and data analysis is ongoing. Trial registration number: clinicaltrials.gov NCT04141579.

Chronic low back pain (CLBP) is one of the most common chronic musculoskeletal disorders worldwide. Guidelines recommend exercise therapy (ET) in CLBP management, but more research is needed to investigate specific ET modalities and their underlying mechanisms. The primary goal of this study is to evaluate the short-term and long-term effectiveness of a time-contingent individualised high-intensity training (HIT) protocol on disability compared with a time-contingent moderate-intensity training (MIT) as used in usual care, in persons with severely disabling CLBP. Additionally, the effectiveness on central effects, the added value of prolonged training at home and technology support, and the cost-effectiveness are evaluated. In this randomised controlled trial, CLBP patients will be randomly divided into three groups of 56 participants. Group 1, ‘TechnoHIT’, receives HIT with technology-support in the home-phase. Group 2, ‘HIT’, receives HIT without technology support. Group 3, ‘MIT’, receives MIT, reflecting training intensity as used in usual care. The primary outcome is patient-reported disability, measured by the Modified Oswestry Disability Index. Secondary outcomes include quantitative sensory testing, psychosocial factors, broad physical fitness, quality of life, cost-effectiveness, adherence and usability of technology. Trial registration number NCT06491121.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

In deze bijdrage combineren we kwantitatieve en kwalitatieve inzichten over virtueel teamwerk in het accountantsberoep. We illustreren dat hoewel meer virtueel werk de prestaties van controleteams kan verminderen, de controlekwaliteit als hoog wordt ervaren – ook bij een toegenomen mate van virtueel teamwerk.1 Verder tonen we dat virtueel teamwerk niet intrinsiek goed of slecht is, maar om een afweging vraagt tussen flexibiliteit en structurele nadelen, zoals beperkte leermomenten. Ook tonen we hoe accountantskantoren optimale omstandigheden kunnen scheppen voor virtuele auditteams door het bevorderen van leergedrag en empowerend leiderschap.

Abstract Imerslund-Gräsbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by vitamin B12 malabsorption. Most patients present with non-specific symptoms attributed to vitamin B12 deficiency, and proteinuria. Patients may if untreated, develop severe neurocognitive manifestations. If recognized and treated with sufficient doses of vitamin B12, patients recover completely. We provide, for the first time, an overview of all previously reported cases of IGS. In addition, we provide a complete review of IGS and describe two new patients.

Background The EXPLORE (Evaluating Xience and Left Ventricular Function in PCI on Occlusions After STEMI) trial was the first and only randomized trial investigating chronic total occlusion (CTO) percutaneous coronary intervention (PCI) early after primary PCI for ST‐segment–elevation myocardial infarction, compared with medical therapy for the CTO. We performed a 10‐year follow‐up of EXPLORE to investigate long‐term safety and clinical impact of CTO PCI after ST‐segment–elevation myocardial infarction, compared with no‐CTO PCI. Methods and Results In EXPLORE, 302 patients post‐ST‐segment–elevation myocardial infarction with concurrent CTO were randomized to CTO PCI within ≈1 week or no‐CTO PCI. We performed an extended clinical follow‐up for the primary end point of major adverse cardiac events, consisting of cardiovascular death, coronary artery bypass grafting, or myocardial infarction. Secondary end points included all‐cause death, angina, and dyspnea. Median follow‐up was 10 years (interquartile range, 8–11 years). The primary end point occurred in 25% of patients with CTO PCI and in 24% of patients with no‐CTO PCI (hazard ratio [HR], 1.11 [95% CI, 0.70–1.76]). Cardiovascular mortality was higher in the CTO PCI group (HR, 2.09 [95% CI, 1.10–2.50]), but all‐cause death was similar (HR, 1.53 [95% CI, 0.93–2.50]). Dyspnea relief was more frequent after CTO PCI (83% versus 65%, P=0.005), with no significant difference in angina. Conclusions This 10‐year follow‐up of patients post‐ST‐segment–elevation myocardial infarction randomized to CTO PCI or no‐CTO PCI demonstrated no clinical benefit of CTO PCI in major adverse cardiac events or overall mortality. However, CTO PCI was associated with a higher cardiovascular mortality compared with no‐CTO PCI. Our long‐term data support a careful weighing of effective symptom relief against an elevated cardiovascular mortality risk in CTO PCI decisions. Registration URL: https://www.trialregister.nl; Unique identifier: NTR1108.

Relevance. Coaches and athletes across a variety of sports commonly perform abdominal exercises to promote core strength and endurance. However, the precise influence of abdominal strength and endurance on cycling performance remains elusive. Purpose. Determine whether abdominal fatigue affects anaerobic sprint and aerobic time- trial (TT) cycling performance. Methods. Twenty-three untrained young adults (age: 19,2 ± 1,0 years, height: 170,4 ± 7,5 cm, and weight: 74,5 ± 14,1 kg) participated in this study. Twelve of the participants completed two Wingate anaerobic power tests on a Monark 834 E ergometer set at 7,5 % of body mass and the remaining 11 participants completed two 3,2 km cycling TTs on an Expresso S3U virtual reality bike; tests were separated by 96 hours. All participants performed abdominal crunches to fatigue prior to the second test. Dependent t-tests were used to assess differences between the cycling trials for the two groups. Results. Abdominal muscle fatigue decreased mean anaerobic power (Pre: 486,75 vs. Post: 408,83 Watts (W, p < 0,001), increased the rate of fatigue (Pre: 42,01 vs. Post: 50,32 %, p = 0,004), and tended to decrease peak anaerobic power (Pre: 643,17 vs. Post: 607,27 W, p = 0,088). However, abdominal muscle fatigue did not affect TT mean power (Pre: 228,18 vs. Post: 220,09 W, p = 0,127) or TT performance (Pre: 382,7 vs. Post: 388,0 seconds, p = 0,222). Conclusion. Abdominal fatigue negatively affects anaerobic cycling performance in untrained young adults. Future studies should evaluate the impact of abdominal fatigue on cycling performance in trained cyclists.

Sea louse (Lepeophtheirus salmonis) infestation of Atlantic salmon (Salmo salar) is a significant challenge in aquaculture. Over the years, this parasite has developed immunity to medicinal control compounds, and non-medicinal control methods have been proven to be stressful, hence the need to study the genomic architecture of salmon resistance to sea lice. Thus, this research used whole-genome sequence (WGS) data to study the genetic basis of the trait since most research using fewer SNPs did not identify significant quantitative trait loci. Mowi Genetics AS provided the genotype (50 k SNPs) and phenotype data for this research after conducting a sea lice challenge test on 3,185 salmon smolts belonging to 191 full-sib families. The 50 k SNP genotype was imputed to WGS using the information from 197 closely related individuals with sequence data. The WGS and 50 k SNPs of the challenged population were then used to estimate genetic parameters, perform a genome-wide association study (GWAS), predict genomic breeding values, and estimate its accuracy for host resistance to sea lice. The heritability of host resistance to sea lice was estimated to be 0.21 and 0.22, while the accuracy of genomic prediction was estimated to be 0.65 and 0.64 for array and WGS data, respectively. In addition, the association test using both array and WGS data did not identify any marker associated with sea lice resistance at the genome-wide level. We conclude that sea lice resistance is a polygenic trait that is moderately heritable. The genomic predictions using medium-density SNP genotyping array were equally good or better than those based on WGS data.

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.