Molecular autopsy for fetal structural anomaly: diagnostic and clinical utility of multidisciplinary team approach.

OBJECTIVES: In the West Midlands Regional Genetic Service, cases of perinatal death with a possible genetic diagnosis are evaluated by the Perinatal Pathology Genetic Multidisciplinary Team (MDT). The MDT assessed autopsy findings and considered genomic assessments. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT. This is the first evaluation since the introduction of whole genome and whole exome sequencing in routine clinical care. METHOD: The outcomes for all the perinatal MDT cases from January 2021 to December 2021 were examined. All cases received a full or partial post-mortem examination (PM) and a chromosomal microarray. Demographics, phenotype, MDT recommendations, genetic testing, diagnoses, outcomes, impact of PM and impact of genetic testing were collected from patient case notes. RESULTS: One hundred and twenty-three cases were discussed at the MDT meeting in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were identified in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) of all cases or 45% (29/64) of the cases with a suspected genetic diagnosis who underwent genetic testing. PM examination added clinically actionable phenotype data in 79% of cases. A genetic diagnosis enabled accurate counselling of recurrence risk and provision of appropriate follow-up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions. CONCLUSIONS: Genomic testing was a clinically useful addition to (but not a substitute for) PM examination in perinatal cases associated with structural anomalies. The MDT model helped assess cases and plan appropriate follow-up. Expedited whole genome sequencing or panel-agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand prenatal phenotypes and detect novel disease genes and should be a priority for future research. This article is protected by copyright. All rights reserved.

Lactational performance, enteric methane emission, and nutrient utilization of dairy cows supplemented with botanicals.

The objective of this study was to evaluate lactational performance, enteric gas emissions, ruminal fermentation, nutrient use efficiency, milk fatty acid profile, and energy and inflammatory markers in blood of peak-lactation dairy cows fed diets supplemented with Capsicum oleoresin or a combination of Capsicum oleoresin and clove oil. A 10-wk randomized complete block design experiment was conducted with 18 primiparous and 30 multiparous Holstein cows. Cows were blocked based on parity, days in milk, and milk yield (MY), and randomly assigned to 1 of 3 treatments (16 cows/treatment): (1) basal diet (CON); (2) basal diet supplemented with 300 mg/cow per day of Capsicum oleoresin (CAP); and (3) basal diet supplemented with 300 mg/cow per day of a combination of Capsicum oleoresin and clove oil (CAPCO). Premixes containing ground corn (CON), CAP, or CAPCO were mixed daily with the basal diet at 0.8% of dry matter intake (DMI). Supplementation of the diet with CAP or CAPCO did not affect DMI, MY, milk components, and feed efficiency of the cows. Body weight (BW) was increased during the last 2 wk of the experiment by CAP and CAPCO, compared with CON. The botanicals improved BW gain (0.85 and 0.66 kg/d for CAP and CAPCO, respectively, compared with -0.01 kg/d for CON) and CAP enhanced the efficiency of energy utilization, compared with CON (94.5% vs. 78.4%, respectively). Daily CH4 emission was not affected by treatments, but CH4 emission yield (per kg of DMI) and intensity (per kg of MY) were decreased by up to 11% by CAPCO supplementation, compared with CON and CAP. A treatment × parity interaction indicated that the CH4 mitigation effect was pronounced in primiparous but not in multiparous cows. Ruminal molar proportion of propionate was decreased by botanicals, compared with CON. Concentrations of trans-10 C18:1 and total trans fatty acids in milk fat were decreased by CAP and tended to be decreased by CAPCO, compared with CON. Total-tract apparent digestibility of nutrients was not affected by treatments, except for a tendency for decreased starch digestibility in cows supplemented with botanicals. Blood concentrations of ß-hydroxybutyrate, total fatty acids, and insulin were not affected by botanicals. Blood haptoglobin concentration was increased by CAP in multiparous but not in primiparous cows. Lactational performance of peak-lactation dairy cows was not affected by the botanicals in this study, but they appeared to improve efficiency of energy utilization and partitioned energy toward BW gain. In addition, CH4 yield and intensity were decreased in primiparous cows fed CAPCO, suggesting a potential positive environmental effect of the combination of Capsicum oleoresin and clove oil supplementation.

Effects of phytonutrients and yeast culture supplementation on lactational performance and nutrient use efficiency in dairy cows.

Yeast culture and phytonutrients are dietary supplements with distinct modes of action, and they may have additive effects on the performance of dairy cattle. The objective of this study was to investigate the effects of a preparation of phytonutrients and a yeast culture from Saccharomyces cerevisiae on lactational performance, total-tract digestibility of nutrients, urinary nitrogen losses, energy metabolism markers, and blood cells in dairy cows. Thirty-six mid-lactation Holstein cows (10 primiparous and 26 multiparous) were used in an 8-wk randomized complete block design experiment with a 2-wk covariate period, 2 wk for adaptation to the diets, and a 4-wk experimental period for data and samples collection. Following a 2-wk covariate period, cows were blocked by days in milk, parity, and milk yield and randomly assigned to 1 of 3 treatments (12 cows per treatment): basal diet supplemented with 14 g/cow per day yeast culture (YC; S. cerevisiae), basal diet supplemented with 1.0 g/cow per day phytonutrients (PN; 5.5% cinnamaldehyde, 9.5% eugenol, and 3.5% capsicum oleoresin), or basal diet supplemented with a combination of YC and PN (YCPN). Treatments were top-dressed once daily on the total mixed ration at time of feeding. Dry matter intake, milk yield, and feed efficiency were not affected by treatments. Milk composition and energy-corrected milk yield were also not affected by supplementation of YC, PN, and YCPN. There were no differences in intake or total-tract digestibility of dietary nutrients among treatments. Compared with YC, the PN and YCPN treatments tended to decrease the proportion of short-chain fatty acids in milk fat. There was an additive effect of YC and PN supplementation on urinary urea nitrogen (UUN) excretion relative to total nitrogen intake. Cows fed a diet supplemented with YCPN had lower UUN excretion than cows in YC and tended to have lower UUN excretion compared with PN. Blood monocytes count and percentage were decreased in cows fed PN and YCPN diets compared with YC. Treatments did not affect concentrations of blood ß-hydroxybutyrate and total fatty acids. Overall, lactational performance, digestibility of nutrients, energy metabolism markers, and blood cells were not affected by YC, PN, or YCPN supplementation. A combination of PN and YC had an additive effect on nitrogen excretion in dairy cows.

Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study).

BACKGROUND: Up to 60% of breast cancer patients treated with chemotherapy is confronted with cognitive problems, which can have a significant impact on daily activities and quality of life (QoL). We investigated whether exercise training improves cognition in chemotherapy-exposed breast cancer patients 2-4 years after diagnosis. METHODS: Chemotherapy-exposed breast cancer patients, with both self-reported cognitive problems and lower than expected performance on neuropsychological tests, were randomized to an exercise or control group. The 6-month exercise intervention consisted of supervised aerobic and strength training (2 h/week), and Nordic/power walking (2 h/week). Our primary outcome was memory functioning (Hopkins Verbal Learning Test-Revised; HVLT-R). Secondary outcomes included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognition (MD Anderson Symptom Inventory for multiple myeloma; MDASI-MM), physical fitness (relative maximum oxygen uptake; VO2peak), fatigue (Multidimensional Fatigue Inventory), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ C-30), depression (Patient Health Questionnaire-9, Hospital Anxiety and Depression Scale; HADS), and anxiety (HADS). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement (≥ 5 words). Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. RESULTS: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise sessions, and physical fitness significantly improved compared to control patients (B VO2peak 1.4 ml/min/kg, 95%CI:0.6;2.2). No difference in favor of the intervention group was seen on the primary outcome. Significant beneficial intervention effects were found for self-reported cognitive functioning [MDASI-MM severity (B-0.7, 95% CI - 1.2; - 0.1)], fatigue, QoL, and depression. A hypothesis-driven analysis in highly fatigued patients showed positive exercise effects on tested cognitive functioning [ACS Reaction Time (B-26.8, 95% CI - 52.9; - 0.6) and ACS Wordlist Learning (B4.4, 95% CI 0.5; 8.3)]. CONCLUSIONS: A 6-month exercise intervention improved self-reported cognitive functioning, physical fitness, fatigue, QoL, and depression in chemotherapy-exposed breast cancer patients with cognitive problems. Tested cognitive functioning was not affected. However, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients. Trial Registration Netherlands Trial Registry: Trial NL5924 (NTR6104). Registered 24 October 2016, https://www.trialregister.nl/trial/5924 .

Population-based estimates of overtreatment with adjuvant systemic therapy in early breast cancer patients with data from the Netherlands and the USA.

PURPOSE: Although adjuvant systemic therapy (AST) helps increase breast cancer-specific survival (BCSS), there is a growing concern for overtreatment. By estimating the expected BCSS of AST using PREDICT, this study aims to quantify the number of patients treated with AST without benefit to provide estimates of overtreatment. METHODS: Data of all non-metastatic unilateral breast cancer patients diagnosed in 2015 were retrieved from cancer registries from The Netherlands and the USA. The PREDICT tool was used to estimate AST survival benefit. Overtreatment was defined as the proportion of patients that would have survived regardless of or died despite AST within 10 years. Three scenarios were evaluated: actual treatment, and recommendations by the Dutch or USA guidelines. RESULTS: 59.5% of Dutch patients were treated with AST. 6.4% (interquartile interval [IQI] = 2.5, 8.2%) was expected to survive at least 10 years due to AST, leaving 93.6% (IQI = 91.8, 97.5%) without AST benefit (overtreatment). The lowest expected amount of overtreatment was in the targeted and chemotherapy subgroup, with 86.5% (IQI = 83.4, 89.6%) overtreatment, and highest in the only endocrine treatment subgroup, with 96.7% (IQI = 96.0, 98.1%) overtreatment. Similar results were obtained using data from the USA, and guideline recommendations. CONCLUSION: Based on PREDICT, AST prevents 10-year breast cancer death in 6.4% of the patients treated with AST. Consequently, AST yields no survival benefit to many treated patients. Especially improved personalization of endocrine therapy is relevant, as this therapy is widely used and is associated with the highest amount of overtreatment.

Prognosis of pregnancy-associated breast cancer: inferior outcome in patients diagnosed during second and third gestational trimesters and lactation.

PURPOSE: Pregnancy-associated breast cancer, although most commonly defined as breast cancer diagnosed during pregnancy or ≤1 year following delivery, knows a variety of definitions, likely related to the diversity of reported clinicopathological features and prognosis. More insight into the different breast cancer subgroups during pregnancy, time after delivery and the postpartum period is therefore warranted. METHODS: Patients with breast cancer diagnosed during pregnancy or ≤6 months postdelivery were included, and subdivided according to gestational trimester, and postpartum patients according to lactational status. Subgroups were compared to matched non-PABC patients, to investigate the influence of pregnancy and lactation on clinical course and outcome. RESULTS: Overall, 662 PABC patients were included (median age 34 years, median follow-up 6.5 years). PABC patients showed an advanced stage at diagnosis and an inferior 5-years-OS (75.4% vs. 83.2%, p = 0.000) compared to 1392 matched non-PABC patients. In subgroup analysis, first trimester PABC patients showed a significantly lower tumor size and stage as compared to other trimesters. Patients diagnosed during the first trimester and postpartum non-lactating patients had a relatively good OS (81.3% and 77.9%, respectively) versus patients diagnosed during the second and third trimesters and during lactation (OS 60.0%, 64.9% and 65.6%, respectively, p = 0.003). CONCLUSION: In this large (uniquely specified) PABC cohort, an inferior outcome was found for patients diagnosed within the second and third gestational trimesters and during lactation. These findings indicate that PABC is clinically a heterogeneous group of breast cancer patients that should be redefined based on trimester of diagnosis and lactational status.

Preferences of European dairy stakeholders in breeding for resilient and efficient cattle: A best-worst scaling approach.

Including resilience in the breeding objective of dairy cattle is gaining increasing attention, primarily as anticipated challenges to production systems, such as climate change, may make some perturbations more difficult to moderate at the farm level. Consequently, the underlying biological mechanisms by which resilience is achieved are likely to become an important part of the system itself, increasing value on the animal's ability to be unperturbed by variable production circumstances, or to quickly return to pre-perturbed levels of productivity and health. However, because the value of improving genetic traits to a system is usually based on known profit functions or bioeconomic models linked to current production conditions, it can be difficult to define longer-term value, especially under uncertain future production circumstances and where nonmonetary values may be progressively more important. We present the novel application of a discrete choice experiment, used to investigate potential antagonisms in the values of genetic improvements for 8 traits to dairy cattle system stakeholders in Europe when the production goal was either efficiency or resilience. A latent class model was used to identify heterogeneous preferences within each production goal, and postestimation was used to identify associations between these preferences and sociodemographic characteristics of respondents. Results suggested 3 distinct latent preference classes for each production goal. For the efficiency goal, yield and feed efficiency traits were generally highly valued, whereas for the resilience goal, health and robustness traits were generally highly valued. In both cases, these traits generally carried a low value in the other production scenario. Overall, in both scenarios, longevity was highly valued; however, the value of this trait in terms of resilience will depend on phenotyping across diverse environments to sufficiently capture performance under various anticipated system challenges. Additionally, results showed significant associations between membership of latent preference classes with education level and profession. In conclusion, as resilience becomes increasingly important, it is likely that a continued reliance on the short-term economic value of traits alone will lead decision makers to misrepresent the importance of some traits, including those with substantial contextual values in terms of resilience.

Correlations of milk and serum element concentrations with production and management traits in dairy cows.

The present study investigated the potential consequences, positive or negative, that selection for favorable production-related traits may have on concentrations of vitamin B12 and key chemical elements in dairy cow milk and serum and the possible impact on milk healthiness, and associated benefits, for the dairy product consumer. Milk and serum samples (950 and 755, respectively) were collected from Holstein-Friesian dairy cows (n = 479) on 19 occasions over a 59-mo period, generating 34,258 individual records, and analyzed for concentrations of key trace and quantity elements, heavy metals, and milk vitamin B12. These data were then matched to economically important production data (milk, fat, and protein yield) and management data (dry matter intake, liveweight, and body condition score). Multivariate animal models, including full pedigree information, were used to analyze data and investigate relationships between traits of interest. Results highlighted negative genetic correlations between many quantity and trace elements in both milk and serum with production and management traits. Milk yield was strongly negatively correlated with the milk quantity elements Mg and Ca (genetic correlation between traits, ra = -0.58 and -0.63, respectively) as well as the trace elements Mn, Fe, Ni, Cu, Zn, and Mo (ra = -0.32, -0.58, -0.52, -0.40, -0.34, and -0.96, respectively); and in serum, Mg, Ca, Co, Fe, and Zn (ra = -0.50, -0.36, -0.68, -0.54, and -0.90, respectively). Strong genetic correlations were noted between dry matter intake with V (ra = 0.97), Fe (ra = -0.69), Ni (ra = -0.81), and Zn (ra = -0.75), and in serum, strong negative genetic correlations were observed between dry matter intake with Ca and Se (ra = -0.95 and -0.88, respectively). Body condition score was negatively correlated with serum P, Cu, Se, and Pb (ra = -0.45, -0.35, -0.51, and -0.64, respectively) and positively correlated with Mn, Fe, and Zn (ra = 0.40, 0.71, and 0.55, respectively). Our results suggest that breeding strategies aimed at improving economically important production-related traits would most likely result in a negative impact on levels of beneficial nutrients within milk for human consumption (such as Mg, Ca, Fe, Zn, and Se).

Effects of a combination of Capsicum oleoresin and clove essential oil on metabolic status, lactational performance, and enteric methane emissions in dairy cows.

Botanical extracts have a potential to modify ruminal fermentation while enhancing metabolism and immunity in dairy cows. The objective of this study was to investigate the effects of a combination of Capsicum oleoresin and clove essential oil (botanicals; BTC) on lactational performance, nutrient utilization, enteric methane (CH4) emissions, and blood parameters in dairy cows. Twenty Holstein cows (12 multiparous and 8 primiparous) averaging (±SD) 77 ± 28 d in milk in the beginning of the study were used in a replicated 4 × 4 Latin square design experiment with 4 periods of 28 d each. Cows were grouped into squares based on parity, milk yield and days in milk, and assigned to 1 of 4 treatments: control (CON), 150, 300, or 600 mg/cow per day of BTC. Cows received the same basal diet and BTC were top-dressed on the total mixed ration once daily. Dry matter intake, milk production, and milk composition were not affected by BTC supplementation, except for milk fat content that tended to be increased in BTC, compared with CON. Daily CH4 emission (measured using the GreenFeed system) was linearly decreased by up to 7.5% with increasing doses of BTC. Treatment decreased CH4 yield (kg of CH4 ÷ kg of DMI) and tended to decrease CH4 intensity (kg of CH4 ÷ kg of milk or energy-corrected milk yields) by 5% in BTC, compared with CON. Supplementation of BTC resulted in a quadratic decrease of serum ß-hydroxybutyrate in all cows, and a linear decrease of serum insulin concentration in primiparous but not in multiparous cows. Nutrient utilization and other blood parameters (e.g., blood cells count) were not affected by BTC in the current study. The reduction of enteric CH4 emission demonstrates a moderate mitigation effect on carbon footprint of milk by BTC supplementation. These results must be further investigated and confirmed in longer-term experiments.

Pregnancy-associated breast cancer: nationwide Dutch study confirms a discriminatory aggressive histopathologic profile.

PURPOSE: Breast cancer is the most common type of malignancy in pregnant women, occurring approximately once in every 3000 pregnancies. Pregnancy-associated breast cancer (PABC) is commonly defined as breast cancer diagnosed during or within one year after pregnancy, and it accounts for up to 6.9% of all breast cancers in women younger than 45 years old. Whether these cancers arise before or during pregnancy, and whether they are stimulated by the high hormonal environment of pregnancy, is currently unknown. This study assesses the histopathological profile of PABC in a large Dutch population-based cohort. METHODS: We identified 744 patients with PABC (in this cohort defined as breast cancer diagnosed during or within 6 months after pregnancy) diagnosed between 1988 and 2019, in the nationwide Dutch Pathology Registry (PALGA). An age-matched PALGA cohort of unselected breast cancer patients (≤ 45 years), diagnosed between 2013 and 2016, was used as a control. Histopathologic features of both cohorts were compared. RESULTS: The median age of PABC patients was 34.3 years old (range 19-45 years) and most breast cancers were diagnosed during pregnancy (74.2%). As compared to age-matched controls, PABC patients had tumors of higher Bloom-Richardson grade (grade I: 1.5% vs. 12.4%, grade II: 16.9% vs. 31.3%, grade III: 80.3% vs. 39.5%, p < 0.0001). Furthermore, estrogen (ER)- and progesterone (PR)-receptor expression was less frequently reported positive (ER: 38.9% vs. 68.2% and PR: 33.9% vs. 59.0%, p < 0.0001), while a higher percentage of PABC tumors overexpressed HER2 (20.0% vs. 10.0%, p < 0.0001). The most observed intrinsic subtype in PABC was triple-negative breast cancer (38.3% vs. 22.0%, p < 0.0001), whereas hormone-driven cancers were significantly less diagnosed (37.9% vs. 67.3%, p < 0.0001). CONCLUSION: This study, based on a large population-based cohort of 744 PABC Dutch patients, underlines the more aggressive histopathologic profile compared to age-matched breast cancer patients ≤ 45 years. Further in-depth genetic analysis will be performed to unravel the origin of this discriminating phenotype. It definitely calls for timely detection and optimal treatment of this small but delicate subgroup of breast cancer patients.

The increasing importance of histologic grading in tailoring adjuvant systemic therapy in 30,843 breast cancer patients.

PURPOSE: The large variation in histologic grading of invasive breast cancer (IBC) that has been reported likely influences tailoring adjuvant therapy. The role of grading in therapeutic decision-making in daily practice, was evaluated using the Dutch national guidelines for IBC-management. METHODS: Synoptic reports of IBC resection-specimens, obtained between 2013 and 2016, were extracted from the nationwide Dutch Pathology Registry, and linked to treatment-data from the Netherlands Cancer Registry. The relevance of grading for adjuvant chemotherapy (aCT) was quantified by identifying patients for whom grade was the determinative factor. In addition, the relation between grade and aCT-administration was evaluated by multivariate logistic regression for patients with a guideline-aCT-indication. RESULTS: 30,843 patients were included. Applying the guideline that was valid between 2013 and 2016, grade was the determinative factor for the aCT-indication in 7744 (25.1%) patients, a percentage that even increased according to the current guideline where grade would be decisive for aCT in 10,869 (35.2%) patients. Also in current practice, the indication for adjuvant endocrine therapy (aET) would be based on grade in 9173 (29.7%) patients. Finally, as patients with lower-grade tumors receive aCT significantly less often, grade was also decisive in tailoring aCT de-escalation. CONCLUSIONS: In the largest study published so far we illustrate the increasing importance of histologic grade in tailoring adjuvant systemic breast cancer therapy. Next to playing a key-role in aCT-indication and de-escalation, the role of grading has expanded to the indication for aET. Optimizing histologic grading by pathologists is urgently needed to diminish the risk of worse patient outcome due to non-optimal treatment.

Predicting pregnancy status from mid-infrared spectroscopy in dairy cow milk using deep learning.

Accurately identifying pregnancy status is imperative for a profitable dairy enterprise. Mid-infrared (MIR) spectroscopy is routinely used to determine fat and protein concentrations in milk samples. Mid-infrared spectra have successfully been used to predict other economically important traits, including fatty acid content, mineral content, body energy status, lactoferrin, feed intake, and methane emissions. Machine learning has been used in a variety of fields to find patterns in vast quantities of data. This study aims to use deep learning, a sub-branch of machine learning, to establish pregnancy status from routinely collected milk MIR spectral data. Milk spectral data were obtained from National Milk Records (Chippenham, UK), who collect large volumes of data continuously on a monthly basis. Two approaches were followed: using genetic algorithms for feature selection and network design (model 1), and transfer learning with a pretrained DenseNet model (model 2). Feature selection in model 1 showed that the number of wave points in MIR data could be reduced from 1,060 to 196 wave points. The trained model converged after 162 epochs with validation accuracy and loss of 0.89 and 0.18, respectively. Although the accuracy was sufficiently high, the loss (in terms of predicting only 2 labels) was considered too high and suggested that the model would not be robust enough to apply to industry. Model 2 was trained in 2 stages of 100 epochs each with spectral data converted to gray-scale images and resulted in accuracy and loss of 0.97 and 0.08, respectively. Inspection on inference data showed prediction sensitivity of 0.89, specificity of 0.86, and prediction accuracy of 0.88. Results indicate that milk MIR data contains features relating to pregnancy status and the underlying metabolic changes in dairy cows, and such features can be identified by means of deep learning. Prediction equations from trained models can be used to alert farmers of nonviable pregnancies as well as to verify conception dates.

Dietary supplementation with rumen-protected capsicum during the transition period improves the metabolic status of dairy cows.

In ruminants, it has been observed that capsicum oleoresin can alter insulin responses and that high-intensity artificial sweetener can increase glucose absorption from the small intestine. Because glucose metabolism and insulin responses are critical during early lactation, these supplements might have an effect on the metabolic status of dairy cows during the transition period. The objective of this experiment was to evaluate the effects of rumen-protected capsicum oleoresin fed alone or in combination with artificial sweetener during the transition period on lactational performance and susceptibility to subclinical ketosis in dairy cows. Fifteen primiparous and 30 multiparous Holstein cows (a total of 39 cows finished the study) were arranged in a randomized complete block design during d -21 to 60 relative to parturition. Cows within block were randomly assigned to one of the following treatments: no supplement (CON), supplementation with 100 mg of rumen-protected capsicum/cow per day (RPCap), or RPCap plus 2 g of high-intensity artificial sweetener/cow per day (RPCapS). For both the RPCap and RPCapS treatments, only rumen-protected capsicum was fed during the dry period. From d 8 to 11 of lactation, intake was limited to 70% of predicted dry matter intake to induce subclinical ketosis. Production variables were recorded daily, samples for milk composition were collected on wk 2, 4, 6, and 8, and blood samples were collected on wk -2, 1, 2, and 4 of the experiment for analysis of metabolic hormones and blood cell counts. Supplementation with rumen-protected capsicum increased serum insulin and decreased ß-hydroxybutyrate concentrations precalving, indicating a decrease in lipolysis. During the lactation period, RPCap was associated with a trend for increased milk production and feed efficiency following the ketosis challenge. Supplementation with RPCapS appeared to negate the response to rumen-protected capsicum. All cows developed subclinical ketosis during the challenge, and this was not affected by treatment. We conclude that treatments did not decrease susceptibility to subclinical ketosis; however, dietary supplementation with rumen-protected capsicum was effective at improving energy status precalving and tended to increased milk production and feed efficiency. The mechanism underlying these responses is unclear.

Heteropaternal superfecundation frequently occurs in multiple-bearing mob-mated sheep.

Heteropaternal superfecundation may be defined as the fertilisation of two or more ova during the same oestrus cycle as a result of more than one coital act from different males; this results in foetuses being born in the same litter of the same age but different paternity. Heteropaternal superfecundation is more likely to occur in poly-ovulatory species like sheep; moreover, female sheep are often mob-mated with several rams concurrently, thus providing an opportunity for a given female to be served by multiple males during the same oestrus cycle. The objective of the present study was to determine the frequency of heteropaternal superfecundation in six sheep flocks where most of the ewes, lambs and rams were genotyped. A total of 685 multiple-birth litters were available where the sire, dam and all lambs were genotyped. Of the 539 pairs of twins included in the analysis, 160 (i.e. 30%) were sired by two different rams. Of the 137 sets of triplets included in the analysis, 73 (i.e. 53%) were sired by more than one ram. Of the nine sets of quadruplets, eight were sired by two rams with the remaining litter being mono-paternal. The overall incidence of heteropaternal superfecundation among litters was therefore 35%. Given that the incidence of multiple births in these flocks was 65%, heteropaternal superfecundation is expected to be relatively common in sheep; this is especially true as all but two of the litter-mates were polyzygotic. Genotyping of progeny is one practical solution to identity such individuals.

Predicting bovine tuberculosis status of dairy cows from mid-infrared spectral data of milk using deep learning.

Bovine tuberculosis (bTB) is a zoonotic disease in cattle that is transmissible to humans, distributed worldwide, and considered endemic throughout much of England and Wales. Mid-infrared (MIR) analysis of milk is used routinely to predict fat and protein concentration, and is also a robust predictor of several other economically important traits including individual fatty acids and body energy. This study predicted bTB status of UK dairy cows using their MIR spectral profiles collected as part of routine milk recording. Bovine tuberculosis data were collected as part of the national bTB testing program for Scotland, England, and Wales; these data provided information from over 40,500 bTB herd breakdowns. Corresponding individual cow life-history data were also available and provided information on births, movements, and deaths of all cows in the study. Data relating to single intradermal comparative cervical tuberculin (SICCT) skin-test results, culture, slaughter status, and presence of lesions were combined to create a binary bTB phenotype labeled 0 to represent nonresponders (i.e., healthy cows) and 1 to represent responders (i.e., bTB-affected cows). Contemporaneous individual milk MIR spectral data were collected as part of monthly routine milk recording and matched to bTB status of individual animals on the single intradermal comparative cervical tuberculin test date (±15 d). Deep learning, a sub-branch of machine learning, was used to train artificial neural networks and develop a prediction pipeline for subsequent use in national herds as part of routine milk recording. Spectra were first converted to 53 × 20-pixel PNG images, then used to train a deep convolutional neural network. Deep convolutional neural networks resulted in a bTB prediction accuracy (i.e., the number of correct predictions divided by the total number of predictions) of 71% after training for 278 epochs. This was accompanied by both a low validation loss (0.71) and moderate sensitivity and specificity (0.79 and 0.65, respectively). To balance data in each class, additional training data were synthesized using the synthetic minority over sampling technique. Accuracy was further increased to 95% (after 295 epochs), with corresponding validation loss minimized (0.26), when synthesized data were included during training of the network. Sensitivity and specificity also saw a 1.22- and 1.45-fold increase to 0.96 and 0.94, respectively, when synthesized data were included during training. We believe this study to be the first of its kind to predict bTB status from milk MIR spectral data. We also believe it to be the first study to use milk MIR spectral data to predict a disease phenotype, and posit that the automated prediction of bTB status at routine milk recording could provide farmers with a robust tool that enables them to make early management decisions on potential reactor cows, and thus help slow the spread of bTB.

Tamoxifen and pregnancy: an absolute contraindication?

PURPOSE: Breast cancer is the most common malignancy among young women of reproductive age. Adjuvant treatment with tamoxifen reduces the risk of recurrence in hormone-sensitive breast cancer. However, the use of tamoxifen is considered contraindicated during pregnancy, because of a limited number of case reports demonstrating potential adverse effects on the fetus. The objective of this report is to give a more broad overview of the available data on the effect of tamoxifen exposure during pregnancy. METHODS: A literature review was performed using PubMed and the databases of the Netherlands Pharmacovigilance Centre Lareb and of the International Network on Cancer, Infertility, and Pregnancy. RESULTS: A total of 238 cases of tamoxifen use during pregnancy were found. Of the 167 pregnancies with known outcome, 21 were complicated by an abnormal fetal development. The malformations described were non-specific and the majority of cases concerned healthy infants despite exposure to tamoxifen. CONCLUSION: There seems to be an increased risk of fetal abnormalities when taking tamoxifen during pregnancy (12.6% in contrast to 3.9% in the general population), but the evidence is limited and no causal relationship could be established. The possible disadvantage of postponing or discontinuing tamoxifen for the maternal prognosis is unclear. Patients should be counseled about the use of tamoxifen during pregnancy instead of presenting it as being absolutely contraindicated.

The Changing Role of Gene-Expression Profiling in the Era of De-escalating Adjuvant Chemotherapy in Early-Stage Breast Cancer.

PURPOSE: We assessed the recent trends in the administration of adjuvant chemotherapy thereby evaluating the role of the 70-gene signature (70-GS) testing in decision-making in the systemic treatment of patients with lymph node negative (N0) and lymph node positive (N+) breast cancer. METHODS: Patients with a national guideline directed indication for 70-GS use treated between 2013 and 2016 were selected from the Netherlands Cancer Registry. Time trends in the administration of adjuvant chemotherapy were evaluated within guideline- and age-delineated subgroups. The influence of the 70-GS on chemotherapy use was assessed with logistic regression. RESULTS: During the study period, the overall administration of adjuvant chemotherapy decreased from 49 to 23% and 70-GS use increased from 24 to 51%. The 70-GS was not associated with a decreased likelihood for N0 patients to receive chemotherapy (odds ratio [OR] 1.0; 95% confidence interval [CI] 0.86-1.17), as the proportion of N0 patients who received chemotherapy in the absence of 70-GS use decreased during the study period. In patients with N1a disease, 70-GS testing was associated with a decreased likelihood to receive chemotherapy (OR 0.21; 95% CI 0.15-0.29). In patients < 50 years and 50-59 years of age, 70-GS use was associated with a consistent lower proportion of patients receiving chemotherapy throughout the study period (OR 0.17; 95% CI 0.13-0.23 and OR 0.53; 95% CI 0.43-0.65, respectively). CONCLUSIONS: In this population-based study, the administration of adjuvant chemotherapy in ER+ breast cancer strongly declined. For node-positive and younger patients, 70-GS use was associated with a decreased probability for patients to receive adjuvant chemotherapy.

Energy profiling of dairy cows from routine milk mid-infrared analysis.

The balance of body energy within and across lactations can have health and fertility consequences for the dairy cow. This study aimed to create a large calibration data set of dairy cow body energy traits across the cow's productive life, with concurrent milk mid-infrared (MIR) spectral data, to generate a prediction tool for use in commercial dairy herds. Detailed phenotypic data from 1,101 Holstein Friesian cows from the Langhill research herd (SRUC, Scotland) were used to generate energy balance (EB) and effective energy intake (EI), both in megajoules per day. Pretreatment of spectral data involved standardization to account for drift over time and machine. Body energy estimates were aligned with their spectral data to generate a prediction of these traits based on milk MIR spectroscopy. After data edits, partial least squares analysis generated prediction equations with a coefficient of determination from split sample 10-fold cross validation of 0.77 and 0.75 for EB and EI, respectively. These prediction equations were applied to national milk MIR spectra on over 11 million animal test dates (January 2013 to December 2016) from 4,453 farms. The predictions generated from these were subject to phenotypic analyses with a fixed regression model highlighting differences between the main dairy breeds in terms of energy traits. Genetic analyses generated heritability estimates for EB and EI ranging from 0.12 to 0.17 and 0.13 to 0.15, respectively. This study shows that MIR-based predictions from routinely collected national data can be used to generate predictions of dairy cow energy turnover profiles for both animal management and genetic improvement of such difficult and expensive-to-record traits.

Short communication: Heritability of methane production and genetic correlations with milk yield and body weight in Holstein-Friesian dairy cows.

Greenhouse gases originating from the dairy sector, including methane (CH4), contribute to global warming. A possible strategy to reduce CH4 production is to use genetic selection. This requires genetic parameters for CH4 production and correlations with production traits. Data were available on 184 Holstein-Friesian cows. Methane production was measured in the milking robot during milking from December 2009 to April 2010. In total 2,456 observations for CH4 production were available. Milk yield (MY) and body weight (BW) were obtained at every milking from November 2008 to October 2010. In total 4,567 observations for milk yield and 4,570 observations for BW were available. Restricted maximum likelihood, using random regression models, was used to analyze the data. Heritability (standard error given in parentheses) for CH4 production ranged from 0.12 (0.16) to 0.45 (0.11), and genetic correlations with MY ranged from 0.49 (0.12) to 0.54 (0.26). The positive genetic correlation between CH4 production and milk yield indicates that care needs to be taken when genetically selecting for lower CH4 production, to avoid a decrease in MY at the animal level. However, this study shows that CH4 production is moderately heritable and therefore progress through genetic selection is possible.

Acceptance of flavored concentrate premixes by young ruminants following a short-term exposure.

Three cafeteria feeding design experiments were conducted to test whether young ruminants have flavor preferences. Experiment 1 was with 11 Dorset × Suffolk weaned lambs of both sexes, aged 5 mo and averaging 47.5 (standard deviation = 5.8) kg of body weight. The lambs were offered a choice of 5 flavored concentrate premixes (FCP) and an unflavored control for 5 min 4 times over 10 d. The FCP were prepared by mixing 200 to 300 g/t (as-is basis) of synthetic flavors (vanilla, milky, spicy/fenugreek, red summer fruits, and molasses) into a basal diet. The unflavored control and the milky flavor were consumed in greater amounts than all other flavors at 83.9 and 65.8 g/test, respectively. The consumption rate of FCP (g/min) was similar among treatments. Lambs spent more time consuming the milky flavor and the control at 123 and 144 s/test, respectively, compared with all other FCP (average of 65 s/test). In experiment 2, 12 weaned female Holstein Friesian calves (56-68 d of age) averaging 75.8 kg (standard deviation = 8.45) of body weight were offered a choice of 4 FCP (vanilla, milky, spicy/fenugreek, and red summer fruits) at an inclusion rate of 150 to 200 g/t (as-is basis) and the unflavored control for 5 min 4 times over 10 d. The average consumption rate was 27.8 g/min, and there were no differences among FCP. In experiment 3, a choice of 4 FCP with 2 different flavor combinations (vanilla-fenugreek and milky-vanilla) included at 75 g/t (as-is basis; low) or 150 g/t (high) was offered to a total of 12 weaned female Holstein Friesian calves (47-62 d of age) with an average body weight of 65.3 kg (standard deviation = 7.91). The FCP were offered daily for 14 d for 30 to 60 min/d. Vanilla-fenugreek (low) was consumed less at 57.5 g/test per calf compared with the other FCP (average of 87.5 g/test per calf). There were no other differences among FCP in experiment 3. Overall, compared with the control, flavors used in the present experiments did not affect feed intake of weaned lambs and calves. Other factors, such as taste, sight, texture of the feed, effect of the dams as previous experience (via maternal ingestion, which influences neonatal feeding), and their interactions, may also play a role in flavor preferences of young ruminants.