Identification and characterisation of de novo germline structural variants in two commercial pig lines using trio-based whole genome sequencing.

BACKGROUND: De novo mutations arising in the germline are a source of genetic variation and their discovery broadens our understanding of genetic disorders and evolutionary patterns. Although the number of de novo single nucleotide variants (dnSNVs) has been studied in a number of species, relatively little is known about the occurrence of de novo structural variants (dnSVs). In this study, we investigated 37 deeply sequenced pig trios from two commercial lines to identify dnSVs present in the offspring. The identified dnSVs were characterised by identifying their parent of origin, their functional annotations and characterizing sequence homology at the breakpoints. RESULTS: We identified four swine germline dnSVs, all located in intronic regions of protein-coding genes. Our conservative, first estimate of the swine germline dnSV rate is 0.108 (95% CI 0.038-0.255) per generation (one dnSV per nine offspring), detected using short-read sequencing. Two detected dnSVs are clusters of mutations. Mutation cluster 1 contains a de novo duplication, a dnSNV and a de novo deletion. Mutation cluster 2 contains a de novo deletion and three de novo duplications, of which one is inverted. Mutation cluster 2 is 25 kb in size, whereas mutation cluster 1 (197 bp) and the other two individual dnSVs (64 and 573 bp) are smaller. Only mutation cluster 2 could be phased and is located on the paternal haplotype. Mutation cluster 2 originates from both micro-homology as well as non-homology mutation mechanisms, where mutation cluster 1 and the other two dnSVs are caused by mutation mechanisms lacking sequence homology. The 64 bp deletion and mutation cluster 1 were validated through PCR. Lastly, the 64 bp deletion and the 573 bp duplication were validated in sequenced offspring of probands with three generations of sequence data. CONCLUSIONS: Our estimate of 0.108 dnSVs per generation in the swine germline is conservative, due to our small sample size and restricted possibilities of dnSV detection from short-read sequencing. The current study highlights the complexity of dnSVs and shows the potential of breeding programs for pigs and livestock species in general, to provide a suitable population structure for identification and characterisation of dnSVs.

The impact of geriatric characteristics and comorbidities on distant metastases and other cause mortality in older women with non-metastatic breast cancer treated with primary endocrine therapy.

INTRODUCTION: In recent years, primary surgical treatment of older women with non-metastatic breast cancer has decreased in favor of primary endocrine therapy (PET). PET can be considered in women with a remaining life expectancy of less than five years. The aim of this study was to (1) assess the risk of distant metastases and other cause mortality over ten years in women aged 65 and older with stage I-III breast cancer treated with PET, (2) whether this was associated with geriatric characteristics and comorbidities and to (3) describe the reasons on which the choice for PET was made. METHODS: Women were included from the retrospective FOCUS cohort, which comprises all incident women diagnosed with breast cancer aged 65 or older between January 1997 and December 2004 in the Comprehensive Cancer Center Region West in the Netherlands. We selected women (N = 257) with stage I-III breast cancer and treated with PET from this cohort. Patient characteristics (including comorbidity, polypharmacy, walking, cognitive and sensory impairment), treatment and tumor characteristics were retrospectively extracted from charts. Outcomes were distant metastasis and other cause mortality. Cumulative incidences were calculated using the Cumulative Incidence for Competing Risks method (CICR); and subdistribution hazard ratios (SHR) were tested between groups based on age, geriatric characteristics and comorbidity with the Fine and Gray model. RESULTS: Women treated with PET were on average 84 years old and 41% had one or more geriatric characteristics. Other cause mortality exceeded the cumulative incidence of distant metastasis over ten years (83 versus 5.6%). The risk of dying from another cause further increased in women with geriatric characteristics (SHR 2.06, p < 0.001) or two or more comorbidities (SHR 1.72, p < 0.001). Often the reason for omitting surgery was not recorded (52.9%), but if recorded surgery was omitted mainly at the patient's request (18.7%). DISCUSSION: This study shows that the cumulative incidence of distant metastasis is much lower than other cause mortality in older women with breast cancer treated with PET, especially in the presence of geriatric characteristics or comorbidities. This confirms the importance of assessment of geriatric characteristics to aid counseling of older women.

A natural knockout of the MYO7A gene leads to pre-weaning mortality in pigs.

The pig breeding system provides a unique framework to study recessive defects and the consequence on the phenotype. We examined a commercial synthetic Duroc population for recessive defects and identified a haplotype on chromosome 9 significantly affecting pre-weaning mortality. To identify the causal variant underlying the mortality, we examined sequence data of four carrier animals and 21 non-carrier animals from the same population. The results yield a strong candidate causal stop-gained variant (NM_001099928.1:c.541C>T) affecting the MYO7A gene in complete linkage disequilibrium with the lethal haplotype. The variant leads to an impaired (p.Gln181*) MYO7A protein that truncates 2032 amino acids from the protein. We examined a litter from a carrier sow inseminated by a carrier boar. From the resulting piglets, two confirmed homozygous piglets suffered from severe balance difficulties and the inability to walk properly. The variant segregates at a carrier frequency of 8.2% in the evaluated population and will be gradually purged from the population, improving animal welfare. Finally, this 'natural knockout' will increase our understanding of the functioning of the MYO7A gene and provides a potential model for Usher syndrome in humans.

A longitudinal mixed methods study on changes in body weight, body composition, and lifestyle in breast cancer patients during chemotherapy and in a comparison group of women without cancer: study protocol.

BACKGROUND: More than 60% of women diagnosed with early stage breast cancer receive (neo)adjuvant chemotherapy. Breast cancer patients receiving chemotherapy often experience symptoms such as nausea, vomiting and loss of appetite that potentially affect body weight and body composition. Changes in body weight and body composition may detrimentally affect their quality of life, and could potentially increase the risk of disease recurrence, cardiovascular disease and diabetes. To date, from existing single method (quantitative or qualitative) studies is not clear whether changes in body weight and body composition in breast cancer patients are treatment related because previous studies have not included a control group of women without breast cancer. METHODS: We therefore developed the COBRA-study (Change Of Body composition in BReast cancer: All-in Assessment-study) to assess changes in body weight, body composition and related lifestyle factors such as changes in physical activity, dietary intake and other behaviours. Important and unique features of the COBRA-study is that it used I) a "Mixed Methods Design", in order to quantitatively assess changes in body weight, body composition and lifestyle factors and, to qualitatively assess how perceptions of women may have influenced these measured changes pre-, during and post-chemotherapy, and II) a control group of non-cancer women for comparison. Descriptive statistics on individual quantitative data were combined with results from a thematic analysis on the interviews- and focus group data to understand patients' experiences before, during and after chemotherapy. DISCUSSION: The findings of our mixed methods study, on chemotherapy treated cancer patients and a comparison group, can enable healthcare researchers and professionals to develop tailored intervention schemes to help breast cancer patients prevent or handle the physical and mental changes they experience as a result of their chemotherapy. This will ultimately improve their quality of life and could potentially reduce their risk for other co-morbidity health issues such as cardiovascular disease and diabetes.

Estimating probability of insemination success using milk progesterone measurements.

The aim of this study was to quantify the effects of progesterone profile features and other cow-level factors on insemination success to provide a real-time predictor equation of probability of insemination success. Progesterone profiles from 26 dairy herds were analyzed and the effects of profile features (progesterone slope, cycle length, and cycle height) and cow traits (milk yield, parity, insemination during the previous estrus) on likelihood of artificial insemination success were estimated. The equation was fitted on a training data set containing data from 16 herds (6,246 estrous cycles from 3,404 lactations). The equation was tested on a testing data set containing data from 10 herds (8,105 estrous cycles from 3,038 lactations). Predictors were selected to be implemented in the final equation if adding them to a base model correcting for timing of insemination and parity decreased the overall likelihood distance of the model. Selected variables (cycle length, milk yield, cycle height, and insemination during the previous estrus) were used to build the final model using a stepwise approach. Predictors were added 1 by 1 in different order, and the model that had the smallest likelihood distance was selected. The final equation included the variables timing of insemination, parity, milk yield, cycle length, cycle height, and insemination during the previous estrus, respectively. The final model was applied to the testing data set and area under the curve (AUC) was calculated. On the testing data set, the final model had an AUC of 58%. When the farm effect was taken into account, the AUC increased to 63%. This equation can be implemented on farms that monitor progesterone and can support the farmer in deciding when to inseminate a cow. This can be the first step in moving the focus away from the current paradigm associated with poorer estrus detection, where each detected estrus is automatically inseminated, to near perfect estrus detection, where the question is which estrous cycle is worth inseminating?

Sexual distress and associated factors among cervical cancer survivors: A cross-sectional multicenter observational study.

BACKGROUND: To assess whether sexual distress among cervical cancer (CC) survivors is associated with frequently reported vaginal sexual symptoms, other proposed biopsychosocial factors and whether worries about painful intercourse mediate the relation between vaginal sexual symptoms and sexual distress. METHODS: A cross-sectional study was conducted among 194 sexually active partnered CC survivors aged 25 to 69 years. Sexual distress, vaginal sexual symptoms, sexual pain worry, anxiety, depression, body image concerns, and relationship dissatisfaction and the sociodemographic variables age, time since treatment, and relationship duration were assessed by using validated self-administrated questionnaires. RESULTS: In total, 33% (n = 64) of the survivors scored above the cut-off score for sexual distress. Higher levels of sexual distress were shown to be associated with higher levels of vaginal sexual symptoms, sexual pain worry, relationship dissatisfaction, and body image concerns. Furthermore, the results showed that sexual pain worry partly mediated the association between vaginal sexual symptoms and sexual distress, when controlling for relationship dissatisfaction and body image concerns. CONCLUSIONS: Appropriate rehabilitation programs should be developed for CC survivors to prevent and reduce not only vaginal sexual symptoms but also sexual pain worry, relationship dissatisfaction, and body image concerns to reduce sexual distress.

Lymphatic drainage pathways from the cervix uteri: implications for radical hysterectomy?

OBJECTIVE: Radical hysterectomy with pelvic lymphadenectomy is the treatment of choice for early-stage cervical cancer. Wertheim's original technique has been often modified, mainly in the extent of parametrectomy. Okabayashi's technique is considered as the most radical variant regarding removal of the ventral parametrium and paracolpal tissues. Surgical outcome concerning recurrence and survival is good, but morbidity is high due to autonomic nerve damage. While the autonomic network has been studied extensively, the lymphatic system is less understood. This study describes the lymphatic drainage pathways of the cervix uteri and specifically the presence of lymphatics in the vesico-uterine ligament (VUL). METHODS: A developmental series of 10 human female fetal pelves was studied. Paraffin embedded blocks were sliced in transverse sections of 8 or 10 µm. Analysis was performed by staining with antibodies against LYVE-1 (lymphatic endothelium), S100 (Schwann cells), alpha-Smooth Muscle Actin (smooth muscle cells) and CD68 (macrophages). The results were three-dimensionally represented. RESULTS: Two major pathways drained the cervix uteri: a supra-ureteral pathway, running in the cardinal ligament superior to the ureter, and a dorsal pathway, running in the utero-sacral ligament towards the rectal pillars. No lymph vessels draining the cervix uteri were detected in the VUL. In the paracolpal parametrium lymph vessels draining the upper vagina fused with those from the bladder. CONCLUSIONS: The VUL does not contain lymphatics from the cervix uteri. Hence, the favorable survival outcomes of the Okabayashi technique cannot be explained by radical removal of lymphatic pathways in the ventrocaudal parametrium.

Associations between farmer participation in veterinary herd health management programs and farm performance.

In the past few decades, farms have increased in size and the focus of management has changed from curative to preventive. To help farmers cope with these changes, veterinarians offer veterinary herd health management (VHHM) programs, whose major objective is to support the farmer in reaching his farm performance goals. The association between farm performance and participation in VHHM, however, remains unknown. The aim of this paper was to compare farm performance parameters between participants and nonparticipants in VHHM and to differentiate within participation to evaluate the possible added value of VHHM on the farm. Five thousand farmers received a questionnaire about the level of VHHM on their farm. Farm performance parameters of these 5,000 farms were provided. For all respondents (n=1,013), farm performance was compared between participants and nonparticipants and within level of participation, using linear mixed and linear regression models. Farmers who participated in VHHM produced 336 kg of milk/cow per year more and their average milk somatic cell count (SCC) was 8,340 cells/mL lower than farmers who did not participate in VHHM. Participating herds, however, had an older age at first calving (+12d), a lower 56-d nonreturn rate percentage (-3.34%), and a higher number of inseminations per cow (+0.09 inseminations). They also had more cows culled per year (+1.05%), and a lower age at culling (-70 d). Participants in the most-extended form of VHHM (level 3) had a lower SCC (-19,800 cells/mL), fewer cows with high SCC (-1.70%), fewer cows with new high SCC (-0.47%), a shorter calving interval (-6.01 d), and fewer inseminations per heifer (-0.07 inseminations) than participants in the least-extended form of VHHM (level 1). Level 3 participants, however, also had more cows culled per year (+1.74%) and a lower age at culling (-103 d). Discussing specific topics with the veterinarian (milk production, fertility, and udder health) had only marginal effects on improving the farm performance parameters related to those topics. Given the relevance of fertility on the farm and the focus on longevity by society, it is important to determine underlying reasons for the negative associations of these topics with participation in VHHM. A longitudinal study could provide answers to this. For now, veterinarians should be aware of the associations. The increased milk production and milk quality could help the marketing of VHHM to farmers.

Veterinary herd health management programs on dairy farms in the Netherlands: use, execution, and relations to farmer characteristics.

Veterinary herd health management (VHHM) programs are of growing importance to the dairy industry; they support farmers in the shift from curative to preventive health management, caused by increased herd sizes and quality standards in dairy farming. Farmers participating in VHHM are visited every 4 to 6 wk by their veterinarian, who checks the animals and herd management to intervene in a proactive way with problems regarding animal health and animal welfare. At present, no good overview exists of how VHHM is executed on Dutch dairy farms, and whether different farmers require different types of VHHM. Aims of this study were to (1) map out how many farmers participate in VHHM, (2) describe how VHHM is executed on the farms, and (3) see whether certain farmer characteristics are related to farmers' participation in VHHM. In 2011, a questionnaire was sent to 5,000 Dutch dairy farmers per e-mail. Part 1 of the questionnaire focused on participation in and execution of VHHM and part 2 focused on farmer characteristics regarding external information. Returned questionnaires (n=1,013) were summarized and statistically analyzed. In this study 68.6% of the responding farmers participated in any form of VHHM. The most important activities were fertility checks and advice about fertility; the least important were housing and claw health. Relationships between farmer characteristics (use of and trust in information) and participation in VHHM were found.

The impact of Box-Cox transformation on phenotypic and genomic characteristics of litter size variability in Landrace pigs.

The genetic background of variability remains of interest especially in traits of high economic importance, e.g. litter size in pigs. It has been indicated that the data transformation can affect the variability phenotype. This study aims to evaluate the phenotypic and genomic background of variability of litter size obtained from data before and after the Box-Cox transformation. In total, 67 500 records on the total number born (TNB) in Landrace pig population were used. Since the data presented skewness, the decision was made to perform Box-Cox transformation on TNB and obtain bcTNB. Next, the phenotypic variability was estimated as log-transformed variance of residuals (LnVar) for both TNB (LnVar_TNB) and bcTNB (LnVar_bcTNB). The variability traits were further used in the genome-wide association study (GWAS) performed on 10 688 sows genotyped with Axiom porcine 660 K or imputed to 660 K SNP-chip. The substantial difference in skewness was observed after data transformation, represented as a change from -0.46 to -0.02. Heritability for TNB was 0.118 vs 0.125 for bcTNB. The heritability for LnVar_TNB was 0.0025 vs 0.0037 for LnVar_bcTNB. The change in the genetic variance was confirmed when genetic coefficients on SD level were compared: 2% for LnVar_TNB vs 4% for LnVar_bcTNB. In bivariate analysis, the genetic correlation between the additive genetic effects of the mean TNB and its variability changed from 0.38 to 0.63. The observed positive genetic correlations indicated that selection focused on increasing the litter size will simultaneously cause an increase in litter size variability. Based on GWAS, 14 SNPs were detected for LnVar_TNB and eight for LnVar_bcTNB, with two of them indicating the most promising candidate genes. First candidate gene located on Sus scrofa chromosome (SSC) 3 is STAG3, which plays an essential role in gametogenesis. Second gene located on SSC 10 is ESRRG, which affects placenta development. The additional post-GWAS analysis indicated even more candidate genes for LnVar_TNB and LnVar_bcTNB. The most promising candidate gene was located on SSC 13 - MFN1, which is involved in embryonic development. The results of this study indicated a substantial change in variance components for variability when the Box-Cox transformation was applied to data presenting skewness. Moreover, the data transformation changed the phenotype substantially enough that only part of SNP overlapped between two variability traits. Our investigation shows that it is essential to perform Box-Cox transformation for skewed data in order to properly describe phenotypic and genomic properties of litter size variability in Landrace pigs.

Gene expression signatures in older patients with breast cancer: A systematic review.

BACKGROUND: Gene expression signatures have emerged to predict prognosis and guide the use of adjuvant therapy in patients with hormone receptor-positive breast cancer. The objective of this systematic review was to evaluate the prognostic and predictive value of commercially available gene expression signatures as a tool in adjuvant treatment decision-making in older patients with breast cancer. METHODS: PubMed, MEDLINE, Embase, Web of Science, Cochrane Library, and Emcare were reviewed for relevant articles published before December 2021. Eligible studies were randomised trials and cohort studies that externally validated commercially available gene expression signatures in patients aged 65 years and older, including studies that presented subanalyses of this age group. Data extraction and risk of bias assessment was performed independently by two investigators. RESULTS: Fifteen studies were included. Most studies investigated Oncotype DX, while results from other gene expression signatures were limited. Several studies underlined the prognostic performance of Oncotype DX and Prosigna Risk of Recurrence in older patients. Moreover, Oncotype DX was predictive for older patients with an intermediate-risk recurrence score; chemotherapy could be spared in both lymph node-positive and lymph node-negative disease. CONCLUSIONS: Prognostic performance has been demonstrated in older patients for several gene expression signatures. However, additional validation in patients with high-risk tumours is needed before gene expression signatures can be implemented in clinical practice as a prediction tool for adjuvant chemotherapy decision-making in the older age group.

Urinary calcium excretion in non-lactating dairy cows in relation to intake of fat-coated rice bran.

At calving, many older cows fail to compensate the sudden demand of calcium by an adequate activation of intestinal absorption. This results in a variable degree of hypocalcaemia. Reducing intestinal availability of calcium during the close-up period can prevent milk fever. Fat-coated rice bran (FCRB) was investigated for its potential to reduce Ca availability in pre-calving cows. Fat-coated rice bran was incubated in situ to estimate ruminal degradation of dry matter and phytic acid. Also, seven dry multiparous dairy cows were used for a feeding trial in three periods of approximately 1 week each: P1: adaptation; P2: feeding of 2 kg of FCRB and P3: withdrawal of FCRB. Feed intake was recorded and daily urine samples were analysed for pH, Ca and creatinine. The bypass fraction of phytic acid (passage rate: 5%/h) was 30%. Fat-coated rice bran depressed dry matter intake in P2, resulting in a lower Ca intake. In P2 urine pH and calcium excretion were lower. Daily calcium excretion decreased after introduction of FCRB, peaked after withdrawal and dropped 2 days later. Changes in urinary Ca excretion by feeding FCRB indicate that FCRB affected Ca homeostasis in dry multiparous dairy cows.

Coupling a reproductive function model to a productive function model to simulate lifetime performance in dairy cows.

Reproductive success is a key component of lifetime performance in dairy cows but is difficult to predict due to interactions with productive function. Accordingly, this study introduces a dynamic model to simulate the productive and reproductive performance of a cow during her lifetime. The cow model consists of an existing productive function model (GARUNS) which is coupled to a new reproductive function model (RFM). The GARUNS model simulates the individual productive performance of a dairy cow throughout her lifespan. It provides, with a daily time step, changes in BW and composition, fetal growth, milk yield and composition and food intake. Genetic-scaling parameters are incorporated to scale individual performance and simulate differences within and between breeds. GARUNS responds to the discrete event signals 'conception' and 'death' (of embryo or fetus) generated by RFM. In turn, RFM responds to the GARUNS outputs concerning the cow's energetic status: the daily total processed metabolizable energy per kg BW (TPEW) and the net energy balance (EB). Reproductive function model models the reproductive system as a compartmental system transitioning between nine competence stages: prepubertal (PRPB), anestrous (ANST), anovulatory (ANOV), pre-ovulating (PREO), ovulating (OVUL), post-ovulating (PSTO), luteinizing (LUTZ), luteal (LUTL) and gestating (GEST). The transition from PRPB to ANST represents the start of reproductive activity at puberty. The cyclic path through ANST, PREO, OVUL, PSTO, LUTZ and LUTL forms the regime of ovulatory cycles, whereas ANOV and GEST are transient stages that interrupt this regime. Anovulatory refers explicitly to a stage in which ovulation cannot occur (i.e. interrupted cyclicity), whereas ANST is a pivotal stage within ovulatory cycles. Reproductive function model generates estradiol and progesterone hormonal profiles consistent with reference profiles derived from literature. Cyclicity is impacted by the GARUNS output EB and clearance of estradiol is impacted by TPEW. A farming system model was designed to describe different farm protocols of heat detection, insemination, feeding (amount and energy density), drying-off and culling. Results of model simulation (10 000 simulations of individual cows over 5000 days lifetime period, with randomly drawn genetic-scaling parameters and standard diet) are consistent with literature for reproductive performance. This model allows simulation of deviations in reproductive trajectories along physiological stages of the cow reproductive cycle. It thus provides the basis for evaluation of the relative importance of different factors affecting fertility at individual cow and herd levels across different breeds and management environments.

Impact of age on breast cancer mortality and competing causes of death at 10 years follow-up in the adjuvant TEAM trial.

AIM: Due to increasing life expectancy, patients with breast cancer remain at risk of dying due to breast cancer over a long time. This study aims to assess the impact of age on breast cancer mortality and other cause mortality 10 years after diagnosis. METHODS: Postmenopausal patients with hormone-receptor positive breast cancer were included in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial between 2001 and 2006. Age at diagnosis was categorised as <65 years (n = 3369), 65-74 years (n = 1896) and ≥75 years (n = 854). Breast cancer mortality was assessed considering other cause mortality as competing event using competing risk analysis. RESULTS: After a median follow-up of 9.8 years (interquartile range 8.0-10.3), cumulative incidence of breast cancer mortality increased with increasing age (age <65 years, 11.7% [95% confidence interval {CI}: 10.2-13.2]; 65-74 years, 12.7% (11.2-14.2) and ≥75 years, 15.6% (13.1-18.0)). Univariate subdistribution hazard ratio (sHR) increased with increasing age (age: 65-74 years, sHR: 1.08, 95% CI: 0.92-1.27 and ≥75 years sHR: 1.30, 95% CI: 1.06-1.58, P = 0.013). Multivariable sHR adjusted for tumour and treatment characteristics increased with age but did not reach significance (age 65-74 years, sHR: 1.11, 95% CI: 0.94-1.31; ≥75 years, sHR: 1.18, 95% CI: 0.94-1.48, P = 0.055). CONCLUSION: Ten years after diagnosis, older age at diagnosis is associated with increasing breast cancer mortality in univariate analysis, but it did not reach significance in multivariable analysis. This is not outweighed by a substantially higher other cause mortality with older age. This underlines the need to improve the balance between undertreatment and overtreatment in older patients with breast cancer. The trial was registered in International Trial Databases (ClinicalTrials.govNCT00279448, NCT00032136, and NCT00036270; the Netherlands Trial Registry NTR267).

[Influence of the donor age on graft survival : Is the demographic change also important for corneal tissue donation?] / Einfluss des Donoralters auf das Transplantatüberleben : Ist der demografische Wandel auch von Bedeutung für die Augenhornhautgewebespende?

The success of corneal transplantation highly depends on the quality of the used graft. Various factors play a crucial role such as a perfect stroma without optically relevant, centrally located cloudiness or changes (e. g. scars) or an adherent Descemet membrane. One of the most important parameters is the quality of the endothelial cell layer with a sufficiently large endothelial cell count. An open question is so far whether the donor age affects corneal quality and therefore has an impact on the success of transplantation. A comprehensive review of the available literature revealed that a large amount of scientific data on the influence of donor age exist to answer this question. In a variety of studies, no significant dependence of graft quality of donor age could be detected. Rather the studies prove that graft survival depends primarily on the state of the endothelial cell layer, and postoperative endothelial cell loss must be considered as a major cause of graft failure. Extensive quality assurance procedures in tissue preparation and cornea processing in the eye banks in Germany (Europe) ensures that only corneas with tested high quality are allocated for transplantation regardless of the donor age. Against the background of an aging population, the use of grafts from older donors should not be waived.

Overview of progesterone profiles in dairy cows.

The aim of this study was to gain a better understanding of the variability in shape and features of all progesterone profiles during estrus cycles in cows and to create templates for cycle shapes and features as a base for further research. Milk progesterone data from 1418 estrus cycles, coming from 1009 lactations, was obtained from the Danish Cattle Research Centre in Foulum, Denmark. Milk samples were analyzed daily using a Ridgeway ELISA-kit. Estrus cycles with less than 10 data points or shorter than 4 days were discarded, after which 1006 cycles remained in the analysis. A median kernel of three data points was used to smooth the progesterone time series. The time between start of progesterone rise and end of progesterone decline was identified by fitting a simple model consisting of base length and a quadratic curve to progesterone data, and this luteal-like phase (LLP) was used for further analysis. The data set of 1006 LLP's was divided into five quantiles based on length. Within quantiles, a cluster analysis was performed on the basis of shape distance. Height, upward and downward slope, and progesterone level on Day 5 were compared between quantiles. Also, the ratio of typical versus atypical shapes was described, using a reference curve on the basis of data in Q1-Q4. The main results of this article were that (1) most of the progesterone profiles showed a typical profile, including the ones that exceeded the optimum cycle length of 24 days; (2) cycles in Q2 and Q3 had steeper slopes and higher peak progesterone levels than cycles in Q1 and Q4 but, when normalized, had a similar shape. Results were used to define differences between quantiles that can be used as templates. Compared to Q1, LLP's in Q2 had a shape that is 1.068 times steeper and 1.048 times higher. Luteal-like phases in Q3 were 1.053 times steeper and 1.018 times higher. Luteal-like phases in Q4 were 0.977 times steeper and 0.973 times higher than LLP's in Q1. This article adds to our knowledge about the variability of progesterone profiles and their shape differences. The profile clustering procedure described in this article can be used as a means to classify progesterone profiles without recourse to an a priori set of rules, which arbitrarily segment the natural variability in these profiles. Using data-derived profile shapes may allow a more accurate assessment of the effects of, e.g., nutritional management or breeding system on progesterone profiles.

Extended adjuvant endocrine therapy in hormone-receptor positive early breast cancer: current and future evidence.

The optimal duration and regimen of adjuvant hormonal therapy for premenopausal and postmenopausal patients with hormone receptor positive early breast cancer has not yet been established. This review will give an overview of published and ongoing studies concerning extended endocrine treatment. Most of the currently published studies are based on the adjuvant treatment regime of 5 years tamoxifen, which has been proven to be inferior compared to aromatase inhibitor (AI)-containing regimes. Therefore, until today, there is no clear evidence for the extension of endocrine therapy after upfront AI-based adjuvant treatment regimes. Multiple clinical trials, which will be discussed in this review, are ongoing to elucidate on this matter. We emphasize the need for tailoring of extended adjuvant endocrine treatment. The quest for predictive biomarkers, which are currently being investigated in the context of decision-making whether or not to start adjuvant chemotherapy, should be expanded to include the feasibility of extended endocrine treatment based on these markers. By tailoring the extension of endocrine treatment, overtreatment, side effects and unnecessary costs will be prevented.

Intrathecal production of HIV antibodies in suspected AIDS encephalopathy.

Thirty-one serum and CSF samples from 21 HIV-antibody-positive patients with neurological deficits were examined to prove or exclude intrathecal production of HIV antibodies. By dilution, sera were adjusted to the IgG concentration of the corresponding CSF samples. Both samples were then serially diluted in log2 steps down to the detection limit and were tested in an anti-HIV ELISA. From the dilution obtained at the cut-off level, a quotient QHIV was derived as an indicator of intrathecal production of HIV antibodies. Six of a total of eight samples with a QHIV value of greater than or equal to 2 were correlated which the clinical diagnosis of AIDS-related dementia complex (ARDC). However, a QHIV less than 1 did not exclude the development of ARDC, as was shown during follow-up in one case. Different methods are compared for the determination of intrathecal production of IgG and anti-HIV. A quotient QHIV greater than or equal to 2 is suggested to be highly indicative of intrathecal production of anti-HIV as well as of the development of ARDC.