Early pregnancy bleeding after assisted reproductive technology: a systematic review and secondary data analysis from 320 patients undergoing hormone replacement therapy frozen embryo transfer.

STUDY QUESTION: How common is bleeding in early pregnancy after Hormone Replacement Therapy (HRT) Frozen Embryo Transfer (FET) and does bleeding affect the reproductive outcome? SUMMARY ANSWER: A total of 47% of HRT-FET patients experience bleeding before the eighth week of gestation, however, bleeding does not affect the reproductive outcome. WHAT IS KNOWN ALREADY: Bleeding occurs in 20% of spontaneously conceived pregnancies, although most will proceed to term. However, our knowledge regarding bleeding in early pregnancy after HRT-FET and the reproductive outcome is sparse. STUDY DESIGN, SIZE, DURATION: We performed a systematic review of the existing literature on early pregnancy bleeding after assisted reproductive technology (ART) to evaluate the bleeding prevalence and resulting reproductive outcome in this population. A random-effects proportional meta-analysis was conducted. Subsequently, we performed a prospective cohort study including 320 pregnant patients undergoing HRT-FET and a secondary analysis of the cohort study was performed to evaluate bleeding prevalence and reproductive outcome. The trial was conducted from January 2020 to November 2022 in a public fertility clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: A systematic literature search was performed, using MESH terms and included studies with data from ART patients and with early pregnancy bleeding as a separate outcome. The cohort study included patients with autologous vitrified blastocyst transfer treated in an HRT-FET protocol. In the event of a positive HCG-test, an early pregnancy scan was performed around 8 weeks of gestation. During this visit, patients answered a questionnaire regarding bleeding or spotting and its duration after the positive pregnancy test. The information was verified through medical files, and these were used to obtain information on reproductive outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: The review revealed a total of 12 studies of interest. The studies reported a prevalence of early pregnancy bleeding ranging from 2.1% to 36.2%. The random effects proportional meta-analysis resulted in a pooled effect estimate of the prevalence of early pregnancy bleeding in the ART population of 18.1% (95% CI (10.5; 27.1)). Four of the included studies included data on miscarriage rate following an episode of bleeding. All four studies showed a significantly increased risk of miscarriage in patients with early pregnancy bleeding as compared to patients with no history of bleeding. No studies investigated bleeding after HRT-FET specifically. In our HRT-FET cohort study, we found that a total of 47% (149/320) of patients with a positive pregnancy test experienced bleeding before 8 weeks of gestation. Generally, the bleeding was described as spotting with a median of 2 days (range 0.5-16 days). Out of 149 patients with one or several bleeding episodes, a total of 106 patients (71%) had an ongoing pregnancy at 12 weeks of gestation. In comparison, 171 patients reported no bleeding episodes and a total of 115 (67%) of these patients had an ongoing pregnancy at 12 weeks of gestation. This difference was not significant (P = 0.45). Furthermore there was no difference in the live birth rate between the two groups (P = 0.29). LIMITATIONS, REASONS FOR CAUTION: Most studies included in the review were older and not all studies specified the type of ART. Moreover, the studies were of moderate methodological quality. The patients in the cohort study were treated in a personalized HRT-FET protocol using a rectal supplementary rescue regimen if serum progesterone levels were <35 nmol/l at embryo transfer. The results may not be applicable to other FET protocols, and the present data were based on self-reported symptoms. The systematic review revealed an increased risk of miscarriage following an episode of early pregnancy bleeding. However our cohort study found no such association. This discrepancy can partly be due to the fact, that the four studies in the review only included episodes of heavy bleeding. Also, none of the four studies included data on HRT-FET cycles making them unfit for direct comparison. WIDER IMPLICATIONS OF THE FINDINGS: Episodes of early bleeding during pregnancy are associated with distress for the pregnant woman, especially in a cohort of infertile patients. Our cohort study showed that at least minor bleeding seems to be a common adverse event of early pregnancy after HRT-FET. From the systematic review, it seems that this prevalence is higher than what has previously been described in relation to other types of ART. However, minor bleeding during early pregnancy after HRT-FET does not seem to affect the reproductive outcome. Knowledge regarding the frequent occurrence of bleeding during early pregnancy after HRT-FET and the fact that this should not be used as a prognostic parameter will help the clinician in counselling patients. STUDY FUNDING/COMPETING INTEREST(S): Gedeon Richter Nordic supported this investigator-initiated study with an unrestricted grant as well as study medication (Cyclogest). B.A. has received an unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA, and Marckyrl Pharma. P.H. received honoraria for lectures from Merck, Gedeon Richter, Institut Biochimique SA (IBSA), and Besins as well as unrestricted research grants from Merck, Gedeon Richter, and Institut Biochimique SA (IBSA). The other authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: EudraCT no.: 2019-001539-29.

Rectal progesterone administration secures a high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol: a prospective interventional study.

STUDY QUESTION: Can supplementation with rectal administration of progesterone secure high ongoing pregnancy rates (OPRs) in patients with low serum progesterone (P4) on the day of blastocyst transfer (ET)? SUMMARY ANSWER: Rectally administered progesterone commencing on the ET day secures high OPRs in patients with serum P4 levels below 35 nmol/l (11 ng/ml). WHAT IS KNOWN ALREADY: Low serum P4 levels at peri-implantation in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles impact reproductive outcomes negatively. However, studies have shown that patients with low P4 after a standard vaginal progesterone treatment can obtain live birth rates (LBRs) comparable to patients with optimal P4 levels if they receive additionalsubcutaneous progesterone, starting around the day of blastocyst transfer. In contrast, increasing vaginal progesterone supplementation in low serum P4 patients does not increase LBR. Another route of administration rarely used in ART is the rectal route, despite the fact that progesterone is well absorbed and serum P4 levels reach a maximum level after ∼2 h. STUDY DESIGN, SIZE, DURATION: This prospective interventional study included a cohort of 488 HRT-FET cycles, in which a total of 374 patients had serum P4 levels ≥35 nmol/l (11 ng/ml) at ET, and 114 patients had serum P4 levels <35 nmol/l (11 ng/ml). The study was conducted from January 2020 to November 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients underwent HRT-FET in a public Fertility Clinic, and endometrial preparation included oral oestradiol (6 mg/24 h), followed by vaginal micronized progesterone, 400 mg/12 h. Blastocyst transfer and P4 measurements were performed on the sixth day of progesterone administration. In patients with serum P4 <35 nmol/l (11 ng/ml), 'rescue' was performed by rectal administration of progesterone (400 mg/12 h) starting that same day. In pregnant patients, rectal administration continued until Week 8 of gestation, and oestradiol and vaginal progesterone treatment continued until Week 10 of gestation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 488 HRT-FET single blastocyst transfers, the mean age of the patients at oocyte retrieval (OR) was 30.9 ± 4.6 years and the mean BMI at ET 25.1 ± 3.5 kg/m2. The mean serum P4 level after vaginal progesterone administration on the day of ET was 48.9 ± 21.0 nmol/l (15.4 ± 6.6 ng/ml), and a total of 23% (114/488) of the patients had a serum P4 level lower than 35 nmol/l (11 ng/ml). The overall, positive hCG rate, clinical pregnancy rate, OPR week 12, and total pregnancy loss rate were 66% (320/488), 54% (265/488), 45% (221/488), and 31% (99/320), respectively. There was no significant difference in either OPR week 12 or total pregnancy loss rate between patients with P4 ≥35 nmol/l (11 ng/ml) and patients with P4 <35 nmol/l, who received rescue in terms of rectally administered progesterone, 45% versus 46%, P = 0.77 and 30% versus 34%, P = 0.53, respectively. OPR did not differ whether patients had initially low P4 and rectal rescue or were above the P4 cut-off. Logistic regression analysis showed that only age at OR and blastocyst scoring correlated with OPR week 12, independently of other factors like BMI and vitrification day of blastocysts (Day 5 or 6). LIMITATIONS, REASONS FOR CAUTION: In this study, vaginal micronized progesterone pessaries, a solid pessary with progesterone suspended in vegetable hard fat, were used vaginally as well as rectally. It is unknown whether other vaginal progesterone products, such as capsules, gel, or tablet, could be used rectally with the same rescue effect. WIDER IMPLICATIONS OF THE FINDINGS: A substantial part of HRT-FET patients receiving vaginal progesterone treatment has lowserum P4. Adding rectally administered progesterone in these patients increases the reproductive outcome. Importantly, rectal progesterone administration is considered convenient, and progesterone pessaries are easy to administer rectally and of low cost. STUDY FUNDING/COMPETING INTEREST(S): Gedeon Richter Nordic supported the study with an unrestricted grant as well as study medication. B.A. has received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA and Marckyrl Pharma. P.H. has received honoraria for lectures from Gedeon Richter, Merck, IBSA and U.S.K. has received grant from Gedeon Richter Nordic, IBSA and Merck for studies outside this work and honoraria for teaching from Merck and Thillotts Pharma AB and conference expenses covered by Merck. The other co-authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER (25): EudraCT no.: 2019-001539-29.

Social and locomotor play behavior of dairy calves kept with the dam either full time or half time in straw-bedded pens.

This study investigated play behavior of dairy calves kept with the cow either full time or half time in groups of 4 dam-calf pairs in 68-m2 straw-bedded pens. Twenty-four of 48 calves entering the experiment (2 calves in each of 12 pens) were observed during 24 h at 3 and 7 wk of age. The total duration of locomotor play did not differ between the 2 treatments, but full-time calves performed less frontal pushing (social play). Irrespective of treatment, calves performed less parallel locomotor play and more frontal pushing at 7 wk than 3 wk of age. Analyzing the intensity of play behavior during milking times (morning and afternoon, respectively), during the night and between morning and afternoon milking, showed that calves performed locomotor play more intensively after the cows had left the pen for milking than during other periods. The results illustrate the importance of space and external stimulation for the performance of play behavior.

Invited review: The effect of milk feeding practices on dairy calf behavior, health, and performance-A systematic review.

The aim of this systematic review was to summarize the literature assessing the effects of milk feeding practices on behavior, health, and performance on dairy calves. Peer-reviewed, published articles, written in English, directly comparing the effects of milk allowance, milk feeding methods, or milk feeding frequency on dairy calves were eligible for inclusion. Outcome measures could include sucking behavior, sucking on a teat (nutritive sucking, non-nutritive sucking on a teat), abnormal sucking behavior (non-nutritive sucking on pen fixtures, other oral behaviors, or cross-sucking), signs of hunger (vocalizations or unrewarded visits at the milk feeder), activity (lying time or locomotor play), feeding behavior (milk intake, starter intake, milk meal duration, or starter meal duration), growth (body weight or average daily gain), and health (occurrence of diarrhea, respiratory disease, or mortality). We conducted 2 targeted searches using Web of Science and PubMed to identify key literature. The resulting articles underwent a 2-step screening process. This process resulted in a final sample of 94 studies. The majority of studies investigated milk allowance (n = 69). Feeding higher milk allowances had a positive or desirable effect on growth, reduced signs of hunger, and increased locomotor play behavior during the preweaning period, whereas starter intake was reduced. Studies addressing health pointed to no effect of milk allowance, with no consistent evidence indicating that higher milk allowances result in diarrhea. Studies addressing milk feeding methods (n = 14) found that feeding milk by teat reduced cross-sucking and other abnormal oral behaviors. However, results on the effect of access to a dry teat were few and mixed. Milk feeding frequency (n = 14 studies) appeared to have little effect on feed intakes and growth; however, there is some evidence that calves with lower feeding frequency experience hunger. Overall, findings strongly suggest feeding higher volumes of milk using a teat; however, further work is needed to determine the optimal feeding frequency for dairy calves.

Multigene profiles to guide the use of neoadjuvant chemotherapy for breast cancer: a Copenhagen Breast Cancer Genomics Study.

Estrogen receptor (ER) and human epidermal growth factor 2 (HER2) expression guide the use of neoadjuvant chemotherapy (NACT) in patients with early breast cancer. We evaluate the independent predictive value of adding a multigene profile (CIT256 and PAM50) to immunohistochemical (IHC) profile regarding pathological complete response (pCR) and conversion of positive to negative axillary lymph node status. The cohort includes 458 patients who had genomic profiling performed as standard of care. Using logistic regression, higher pCR and node conversion rates among patients with Non-luminal subtypes are shown, and importantly the predictive value is independent of IHC profile. In patients with ER-positive and HER2-negative breast cancer an odds ratio of 9.78 (95% CI 2.60;36.8), P < 0.001 is found for pCR among CIT256 Non-luminal vs. Luminal subtypes. The results suggest a role for integrated use of up-front multigene subtyping for selection of a neoadjuvant approach in ER-positive HER2-negative breast cancer.

Impact of early dam contact on veal calf welfare.

Dairy calves, including surplus calves, are typically separated from their dam within hours of birth. The aim of this study was to assess the welfare impacts of raising surplus calves destined for veal with their dam for 2 or 4 weeks until transport. Surplus calves from one dairy farm were separated from their dam at birth (n = 39) or kept with the dam (n = 37) until transport to the veal farm at either 2 (n = 50) or 4 (n = 26) weeks of age, with abrupt separation for dam-reared calves. Calf measures of body weight, health, immunity, haematology and behaviour were recorded at the dairy and veal farms. Dam-reared calves had higher body weights in weeks 3, 4 and 5 at the DF, as well as at arrival at the veal farm, but by slaughter this advantage was lost. More dam-reared calves had fever in week 3 and showed signs of disease in week 5 at the dairy farm. Dam-reared calves did not differ in IgG, IgA or IgM levels but had higher counts of white blood cells, which could reflect a higher pathogen exposure rather than improved immunity. Dam-reared calves displayed more fear towards humans in a human approach test at 5 and 7 weeks after arrival at the veal farm, and more frequent social behaviours at the veal farm at 9 and 16 weeks of age. In conclusion, it seems that there may be both advantages and disadvantages to keeping veal calves with the dam in terms of welfare in the current system.

Effects of changes in diet energy density and milking frequency and a single injection of cabergoline at dry-off on feeding behavior and rumination time in dairy cows.

Dry-off is a typical management practice, but research on the effects of dry-off on feeding behavior in high-yielding cows is limited. The present study investigated the effects of 2 diet energy densities: lactation diet (normal energy density, NORM) versus a lactation diet diluted with 30% straw (reduced energy density, REDU), both offered ad libitum, and 2 daily milking frequencies (2× vs. 1×) during the 7 d before dry-off day (d 0), and the effects of an injection of either a dopamine agonist [cabergoline (CAB); Velactis, Ceva Santé Animale; labeled for use only with abrupt dry-off; i.e., no reduction in feeding level or milking frequency before the last milking] or saline (SAL) following the last milking on d 0 (2 × 2 × 2 factorial arrangement), on automatically monitored feeding behavior and rumination time in 119 clinically healthy, loose-housed, pregnant, lactating Holstein cows during the week before and after d 0. From d 0, all cows were fed the same dry-cow diet ad libitum. Data were analyzed in R using mixed-effects models. Over the days before d 0, REDU cows spent 30% more time feeding at a 50% lower feeding rate, visited both assigned and unassigned feed bins more frequently, and spent more time ruminating than NORM cows. No clear behavioral effects of reduced milking frequency were found. Within 24 h following injection, CAB cows spent approximately 40% less time feeding at a lower feeding rate, visited their feed bin 28% less often, and spent 40% less time ruminating than SAL cows, irrespective of treatment before dry-off. The current study demonstrates that reducing diet energy density for 1 wk before dry-off led to clear behavioral changes in high-yielding cows. Administering CAB after the last milking induced decreased feeding behavior lasting approximately 24 h, indicating collateral effects other than reduced prolactin secretion.

Comparison of off-the-shelf ß-tricalcium phosphate implants with novel resorbable 3D printed implants in mandible ramus of pigs.

Facial reconstructive surgery has already implemented the use of 3D printed Patient Specific Implants derived from CAD/CAM-based technologies as an alternative to preformed bone graft substitutes. 3D-printed patient-specific implants derived from CAD/CAM-based technologies are used in facial reconstructive surgery as an alternative to preformed bone graft substitutes. However, to minimize the invasiveness and long-term adverse effects of surgical interventions, the implant needs to exhibit exact fitting, porosity, density, and volume and be made from resorbable materials that allow ingrowth and formation of new bone tissue. Therefore, we present this pilot study using 3D-printed implants consisting of pure ß-TCP, produced using a novel technique that assures these properties. Eight pigs received 3D-printed truncated porous cone bone implants paired with either an off-the-shelve a chronOS (DePuy Synthes chronOS Vivify Preforms) preformed block (n = 4) or a no-implant void (n = 4) in a surgically created defect on each side of the angle of the mandible. After 6 months, CT data showed that all 3D-printed implants performed as well as did the off-the-shelve implants, with predicted osteointegration medially and laterally and with minimal gapping between the implants and native bone. The CT findings were confirmed by histological analysis that revealed that the 3D-printed implants together with the off-the-shelve implants were almost complete resorbed. Much of the resorbed volume had been replaced by vascularized compact bone, and fusion between newly formed bone and native bone was observed in all implants, further indicating that the 3D-printed implants and off-the-shelve implants performed equally well. Only soft tissue developed in the void control sites. Further studies are needed to confirm these initial findings.

Effects of dietary and milking frequency changes and administration of cabergoline on clinical udder characteristics in dairy cows during dry-off.

We investigated the effects of 2 diet energy densities [normal lactation diet (NORM) vs. energy-reduced diet (REDU), both fed for ad libitum intake] and 2 daily milking frequencies [twice (2×) vs. once (1×)] during 1 week before the dry-off day, as well as effects of an injection of either a dopamine agonist [cabergoline (CAB); Velactis, Ceva Santé Animale, Libourne, France; labelled for use only with abrupt dry-off, e.g. no reduction in diet energy density or milking frequency before the last milking] or saline (SAL) following the last milking, on clinical udder characteristics of Holstein cows. During a week before and after the last milking, the following measures were recorded: palpation-based udder firmness and soreness; image-based hock-hock distance; responsiveness to mechanical udder stimulation and degree of udder fill measured with a dynamometer. Before the last milking, REDU cows displayed lower odds of having a firm udder and lower degree of udder fill, as well as lower responsiveness to mechanical udder stimulation, than NORM cows. After the last milking, REDU cows displayed shorter hock-hock distance compared with NORM cows. The effects of milking frequency on the clinical udder characteristics were unclear. Within 24 h following injection, CAB cows showed lower odds of having a firm udder, shorter hock-hock distance, and lower degree of udder fill than SAL cows, irrespective of treatment group before dry-off. In this study, reducing diet energy density prior to dry-off, and to some extent administering the dopamine agonist cabergoline after the last milking, resulted in fewest clinical udder changes.

Assessing effects of dietary and milking frequency changes and injection of cabergoline during dry-off on hunger in dairy cows using 2 feed-thwarting tests.

We investigated the single and combined effects of 2 feeding levels (normal lactation diet vs. energy-reduced diet, both fed for ad libitum intake) and 2 daily milking frequencies (twice vs. once) during 1 wk before the dry-off day (d 0), as well as an intramuscular injection of either a dopamine agonist (cabergoline; Velactis, Ceva Santé Animale; labeled for use only with abrupt dry-off, e.g., no reduction in feeding level or milking frequency before the last milking) or saline after the last milking on d 0 on the feeding motivation of clinically healthy, loose-housed, pregnant, lactating Holstein cows. From d 0, all cows were fed the same dry-cow diet for ad libitum intake. Cows were subjected to 2 feed-thwarting tests, a test in the home pen using their diets (test A: d -6, -1, and 1; during 35 min when the feed bins were filled, but locked) and another test carried out in an adjacent pen in which access to concentrate provided in a familiar plastic box was blocked by a wire-mesh lid (test B: d -5 and 2). In test A, we recorded how often cows attempted to feed per 35 min, whether cows vocalized during the 35-min period, and latency to feed within 300 s after feed bins were unlocked. In test B, we recorded latency to approach either of 2 familiar boxes (the wire-mesh box and an identical open box with a small portion of concentrate) within 600 s and how often cows directed behaviors toward the wire-mesh box (number of occurences/5 min). On d -6 (test A), no clear differences in feeding motivation among treatments were found. On d -5 and -1, cows fed the energy-reduced diet displayed a higher probability of vocalizing (test A), were more than 50% quicker to feed (test A), were approximately 5× quicker to approach a box (test B), and directed 60% more behavior toward the wire-mesh box (test B) than cows fed the normal diet. Moreover, cows fed the energy-reduced diet attempted to feed approximately 75% more on d -1 compared with d -6 (test A). On d 2 (test B), cows previously fed the normal diet directed 40% more behavior toward the wire-mesh box than cows previously fed the energy-reduced diet. Reducing feeding level, either before or on the dry-off day, resulted in consistently increased feeding motivation, interpreted as a sign of hunger. No clear effects of change in milking frequency, singly or combined with reduced diet energy density, on feeding motivation were found before d 0. Whereas, on d 2, cows previously milked twice daily were quicker to approach a box than cows previously milked once daily. Cows injected with cabergoline attempted to feed more, but showed lower probability of vocalizing compared with saline-injected cows (d 1; test A), irrespective of treatment before d 0. The effects of cabergoline on feeding motivation are not easily interpreted and warrant further investigation. From a hunger perspective, reducing milking frequency rather than diet energy density seems to be a less negative management to reduce milk production before dry-off.

Dose constraints for whole breast radiation therapy based on the quality assessment of treatment plans in the randomised Danish breast cancer group (DBCG) HYPO trial.

PURPOSE: Quality assessment of the treatment plans in the Danish Breast Cancer Group (DBCG) HYPO trial was carried out based on prospectively reported dosimetric parameters and evidence-based dose constraints for whole breast radiation therapy were derived. MATERIALS AND METHODS: From 2009 to 2014, 1882 patients (pts) were randomised between 50 Gy/25fractions (fr) versus 40 Gy/15fr. Doses to CTVp_breast (V95%, V107%-V110%, Dmax, and in addition for 40 Gy plans V105%-V107%), ipsilateral lung (V20Gy/V17Gy), heart (V20Gy/V17Gy, V40Gy/V35Gy), and left anterior descending coronary artery (LADCA) (Dmax) and use of respiratory gated technique were prospectively reported to the DBCG database. After end of accrual, these dosimetric parameters from all plans in the trial were compared to the pre-specified treatment constraints. RESULTS: In total, 1854 pts from eight radiation therapy (RT) centres in three countries were treated. No statistically significant differences were found between the results for 40 Gy and 50 Gy plans, except for CTVp_breast hot-spot volume (V107%-V110%). Of the 40 Gy pts, 90% with CTVp_breast > 600 mL and 95% with CTVp_breast ≤ 600 mL had a CTVp_breast hot-spot volume (V105%-V107%) <2%. In 95% of the 50 Gy plans, the CTVp_breast absolute hot-spot volume (V107%-V110%) was <0.5 mL and 1.7 mL for CTVp_breast ≤ 600 mL and > 600 mL, respectively. Compliance was >99% for both heart and lung constraints. Largest deviation from protocol constraints was found for the volume of CTVp_breast covered with 95% of the prescription dose or more (V95%). The CTV dose coverage (V95%) was >94.3% in 95% of the right-sided pts, whereas the figures for 95% of the left-sided pts treated with and without respiratory gating were 93.2% and 88.8%, respectively. CONCLUSION: A high degree of compliance with protocol dose constraints was found for treatment plans in the DBCG HYPO trial. New constraints for dose to organs at risk and high-dose volumes in the breast are suggested for breast-only RT planning.

Cognitive processing of infant stimuli in pregnant women with and without affective disorders and the association to postpartum depression.

Pregnancy and childbirth are among the strongest risk factors for depression but the neurocognitive mechanisms underlying this enhanced risk are unknown. This study investigated emotional and non-emotional cognition in 57 pregnant women with or without an affective disorder during their third trimester, and the association between cognitive biases and subsequent postpartum depression (PPD). Of the pregnant women, 22 had a diagnosis of unipolar disorder (UD) and seven of bipolar disorder (BD) in full or partial remission, while 28 had no history of affective disorder. We included a control group of 29 healthy non-pregnant women. First, participants were interviewed, completed non-emotional and emotional cognitive tests and lastly filled out questionnaires. The participants were assessed two times after birth: at a home visit shortly after birth, and with a telephone interview to assess PPD in the first six months after birth. Healthy pregnant women rated infant cries less negatively than non-pregnant women, possibly reflecting preparation for motherhood. Pregnant women with UD exhibited a negative bias in ratings of infant cries, whereas pregnant women with BD showed a positive bias in ratings of infant happy faces and recognition of adult facial expressions. Across all pregnant women, more negative ratings of infant cries were associated with enhanced risk of PPD. Negatively biased perception of infant cries during pregnancy may thus signal vulnerability toward PPD.

Rates of re-excision and conversion to mastectomy after breast-conserving surgery with or without oncoplastic surgery: a nationwide population-based study.

BACKGROUND: There is no consensus regarding the impact of oncoplastic surgery (OPS) on rates of re-excision and conversion to mastectomy following breast-conserving surgery (BCS). Here these two outcomes after BCS and OPS were compared in a nationwide population-based setting. METHODS: In Denmark, all OPS is registered and categorized into volume displacement, volume reduction or volume replacement. Patients who underwent BCS or OPS between 2012 and 2018 were selected from the Danish Breast Cancer Group database. Multivariable analyses were performed to adjust for confounders, and propensity score matching to limit potential confounding by indication bias. RESULTS: A total of 13 185 patients (72·5 per cent) underwent BCS and 5003 (27·5 per cent) OPS. Volume displacement was used in 4171 patients (83·4 per cent), volume reduction in 679 (13·6 per cent) and volume replacement in 153 (3·1 per cent). Re-excision rates were 15·6 and 14·1 per cent after BCS and OPS respectively. After adjusting for confounders, patients were less likely to have a re-excision following OPS than BCS (odds ratio (OR) 0·80, 95 per cent c.i. 0·72 to 0·88), specifically after volume displacement and reduction. The rate of conversion to mastectomy was similar after OPS and BCS (3·2 versus 3·7 per cent; P = 0·105), but with a lower risk in adjusted analysis (OR 0·69, 0·58 to 0·84), specifically after volume displacement and reduction procedures. Findings were similar after propensity score matching. CONCLUSION: A modest decrease in re-excision rate and less frequent conversion to mastectomy were observed after OPS compared with BCS.

ANTECEDENTES: No existe consenso con respecto al impacto de la cirugía oncoplástica (oncoplastic surgery, OPS) en las tasas de re-exéresis y conversión a mastectomía tras la cirugía conservadora de la mama (breast conserving surgery, BCS). En este estudio se compararon los dos resultados después de BCS y OPS en una base de datos poblacional de ámbito nacional. MÉTODOS: En Dinamarca, todas las OPS se registran y clasifican en procedimientos que incluyen 1) desplazamiento (o remodelación) de volumen, 2) reducción de volumen o 3) restitución de volumen. Todas las pacientes sometidas a BCS o OPS entre 2012 y 2018 fueron seleccionadas de la base de datos del Grupo de Cáncer de Mama Danés. Se realizaron análisis multivariables para ajustar por factores de confusión y un emparejamiento por puntaje de propensión para limitar las variables de confusión potenciales por el sesgo en la indicación. RESULTADOS: Un total de 13.185 (72,5%) pacientes fueron sometidos a BCS y 5.003 (27,5%) a OPS. Se utilizó el desplazamiento de volumen en 4.171 (83,4%) pacientes, reducción de volumen en 679 (13,6%) pacientes y restitución de volumen en 153 (3,1%) pacientes. Las tasas de re-exéresis fueron del 15,6% y 14,1% tras BCS y OPS, respectivamente. Tras ajustar por factores de confusión, las pacientes tuvieron menos probabilidad (razón de oportunidades, odds ratio, OR 0,80, i.c. del 95%. 0,72-0,88) de requerir re-exéresis tras OPS, específicamente después de desplazamiento y reducción de volumen, en comparación con BCS. La tasa de conversión a mastectomía fue inferior (3,2% versus 3,7%, P = 0,04) y menos probable (OR 0,71, i.c. del 95% 0,58-0,87) tras OPS, específicamente en el desplazamiento y reducción de volumen, en comparación con BCS. Los resultados fueron similares después del emparejamiento por puntuación de propensión. CONCLUSIÓN: Se observó un descenso modesto en las tasas de re-exéresis y una menor frecuencia de conversiones a mastectomía después de la cirugía oncoplástica cuando se comparó con la cirugía conservadora de la mama.

Breast-contour preserving procedures for early-stage breast cancer: a population-based study of the trends, variation in practice and predictive characteristics in Denmark and the Netherlands.

PURPOSE: Breast-contour preservation (BCP) is possible for most women treated for early-stage breast cancer. BCP can be defined as primary breast-conserving treatment (BCT), neoadjuvant chemotherapy (NAC) followed by BCT and immediate postmastectomy breast reconstruction (IBR). This study provides insight in current BCP strategies in Denmark and the Netherlands and aims to identify opportunities for improvement within both countries. METHODS: A total of 92,881 patients with early-stage breast cancer who were operated in Denmark and the Netherlands between 2012 and 2017 were selected from the Danish Breast Cancer Group and the Dutch National Breast Cancer Audit databases. BCP procedures and predictive factors were analyzed within and between both countries. RESULTS: BCP was achieved in 76.7% (n = 16,355) of the Danish and in 74.5% (n = 53,328) of the Dutch patients. While BCP rate did not change significantly over time in Denmark (p = 0.250), a significant increase in BCP rate from 69.5% in 2012 to 78.5% in 2017 (p < 0.001) was observed in the Netherlands. In both countries, variation in BCP rates between hospitals decreased over time. NAC followed by BCT and postmastectomy IBR was substantially more often used in the Netherlands compared to Denmark, specifically in patients younger than 50 years. CONCLUSIONS: In more than 75% of all Danish and Dutch patients, surgically treated for early-stage breast cancer, the breast-contour was preserved. The different use of BCP strategies within Denmark and the Netherlands and the differences observed between hospitals in both countries emphasize the need for more (inter)national consensus on treatment modalities.

Effect of straw amount on feed intake and weight gain in growing pigs housed in pens with partly slatted floor.

The provision of straw to pigs kept in conventional pens with concrete floor improves animal welfare, but the effects of straw on pigs' performance are unclear. In two steps, we investigated the relationship between amount of straw provided to pigs and measures of performance in a set-up maintaining constant space allowance and controlled room temperature. From approximately 30- to 85-kg BW, pigs were housed in groups of 18 in pens (5.48 m × 2.48 m) with concrete floor (1/3 solid, 1/3 drained and 1/3 slatted). The pens were cleaned manually twice a week, and the designated amount of fresh uncut wheat straw was provided daily onto the solid part of the floor. In the first step, 48 pens were assigned to 10-, 500- or 1000-g straw per pig per day, while in the second step, 90 pens were assigned to 10-, 80-, 150-, 220-, 290-, 360-, 430- or 500-g straw per pig per day. Pigs were weighed at the start of the experimental period at approximately 30 kg and again at approximately 85-kg BW. The average daily gain increased 8.1 g (SEM 17) for every extra 100-g straw added daily (P < 0.001) resulting in 40 g higher average daily gain with 500 compared to 10-g straw per pig per day. The feed conversion ratio was not affected by the amount of straw provided, as the feed intake tended to be higher with increasing amounts of straw. Thus, between 10 and 500 g, the more straw provided, the higher the daily weight gain. As the nutritional value of straw is considered minimal, this result is likely due to improved gut health from the increasing amounts of straw ingested and increased feed intake due to increased stimulation of exploratory behaviour with increasing amounts of straw available, or a combination of these. The observed tendency for a higher feed intake supports this suggestion, but studies are needed to establish the impact of these two contributing factors.

Grey water treatment in stacked multi-layer reactors with passive aeration and particle trapping.

When adequately treated, grey water represents a potent alternative water resource, as it constitutes a large proportion of household wastewater. The objective of this paper was to test a full scale version of a novel compact grey water treatment technology, based on passive aeration and particle trapping in multiple layers. Using a modified dual porosity filtration technology, grey water from a public bath was passed through a stack of eight reactors, each 0.75 m × 0.55 × 0.22 m, serially connected for gravity driven flow from top to bottom in a zig-zag pattern. The topmost reactor served as pre-filter for removal of hair and other larger debris. The lower seven reactors facilitated degradation of bulk organic contaminants in biofilm established on a stack of five fibrous polyamide nets, and trapping of particles by sedimentation on five interlaid corrugated plastic plates. By operating the reactors in a time-controlled batch-mode, the corrugated plates further served to trap air and thus ensure passive aeration of the subsequent batch. The production rate was 1.2 m3/d and the hydraulic retention time 2 h, at an aerial footprint of 0.4 m2, excluding storage tanks. After two weeks of initialization, a biofilm had established and the system was monitored for additionally three weeks. Significantly improved effluent quality was obtained as measured from reductions in turbidity (95%), total suspended solids (94%), chemical oxygen demand (87%), and microbiological parameters (55-98%), and from stable level of dissolved oxygen in effluent of 3.5 mg/L. Future optimization includes custom-made reactors for maximizing production capacity, improved removal of total N and total P, and addition of final disinfection.

The effect of transition cow housing on lying and feeding behavior in Holstein dairy cows.

The present study investigated the effect of straw yard housing during the dry period and 2 d of additional maternity pen housing postcalving on lying and feeding behavior and calving difficulty in Holstein dairy cows. In this study, 122 multiparous cows were moved to either a straw yard or into freestall housing 4 wk before their expected calving date. Cows that had been housed in straw yards stayed in the maternity pen for an additional 2 d after their calving day, but cows that had been housed in freestalls were moved to the general lactation group the morning after calving. Lying time, lying bouts, feeding time, number of feeder visits, feed intake, feeding rate, and assisted calvings were recorded. Observations were divided into 2 periods: precalving (the 4-wk dry period before calving) and postcalving (the day of calving and the 2 d after). During the precalving period, cows housed in straw yards showed a higher number of lying bouts but no difference in lying time compared with cows housed in freestalls. Cows that were housed longer in the straw-bedded maternity pen postcalving spent more time lying during the 2 d postcalving and had a higher number of lying bouts on the day of calving than cows moved to the freestall area on the day postcalving. Additionally, cows that were housed longer in the maternity pen had a slower feeding rate and longer total feeding time during the 2 d after calving than cows with a shorter stay in the maternity pen. We found no difference in the number of assisted calvings. This study suggests that straw yard housing during the dry period may facilitate the transition between standing and lying. Furthermore, the extended stay in the maternity pen postcalving increased lying time, the number of lying bouts, and feeding time, but decreased feeding rate compared with cows that were moved to the general lactation group on the day postcalving. These results suggest potential recovery benefits with an extended stay in a maternity pen postcalving. However, further studies are needed to separate the effects of housing in the dry period and the effects of an extended housing in individual maternity pens.

Evaluation of tumor-infiltrating lymphocytes and association with prognosis in BRCA-mutated breast cancer.

BACKGROUND: Patients with a BRCA1 or BRCA2 mutation (BRCA-mutated breast cancer) are frequently diagnosed with low differentiated and highly proliferating breast cancer characterized by high amounts of tumor-infiltrating lymphocytes (Tils). Stromal Tils (sTils) are highly prognostic in sporadic triple-negative and HER2 positive breast cancer however, their prognostic importance in BRCA-mutated breast cancers is unknown. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded primary tumor tissue from 411 patients with a germline BRCA1 or BRCA2 mutation and diagnosed with early breast cancer was included. The percentage of sTils was quantified on full HE sections according to guidelines proposed by the Immuno-Oncology Biomarker in Breast Cancer Working Group. Distribution of sTils and associates with patient and tumor characteristics were assessed according to categorical sTils groups defined as low (<10%), intermediate (10-59%) and high (≥60%). Prognostic associations of sTils were evaluated as a continuous variable in univariate and multivariate models. Only follow-up time beyond date of BRCA mutation test was included. RESULTS: A large proportion had high sTils (27% in the full cohort, 36% in BRCA1-mutated, and 44% in ER negative breast cancers). Higher sTils were associated with BRCA1, ER negative breast cancer, high histological grade and medullary histology. In combined analysis for BRCA1 and BRCA2-mutated breast cancers, increasing sTils in 10% intervals were significantly associated with OS (HR 0.92, 95% CI 0.84-1.00, p = .05). For each 10% increment of sTils in BRCA1 breast cancers, a 10% reduction of mortality (adjusted HR 0.90 95% CI 0.81-0.99, p = .03) and a 13% reduction in risk of DFS-event (HR 0.87 95% CI 0.76-1.00, p = .05) was observed even after adjustment for ER status. No significant association with survival was of observed in the BRCA2 subgroup. Test for interaction of sTils and BRCA status was not statistically significant (p = .3). CONCLUSIONS: Breast cancer patients with a germline BRCA mutation had higher sTils than previously reported in sporadic breast cancers, and sTils were associated with favorable survival among BRCA carriers.

Adherence to subcutaneous interferon beta-1a treatment using an electronic injection device: a prospective open-label Scandinavian noninterventional study (the ScanSmart study).

BACKGROUND: Disease modifying drugs help control the course of relapsing remitting multiple sclerosis (RRMS); however, good adherence is needed for long-term outcomes. OBJECTIVE: To evaluate patient adherence to treatment with subcutaneous interferon beta-1a using RebiSmart® and assess injection-site reactions and treatment satisfaction. METHODS: This prospective, single-arm, open-label, noninterventional multicenter Phase IV trial included disease modifying drug-experienced mobile patients with RRMS. Adherence was measured over 12 weeks. Items 13-23, 35, 37, and 38 of the Multiple Sclerosis Treatment Concerns Questionnaire (injection-site reactions and treatment satisfaction) were recorded at 12 weeks. RESULTS: Sixty patients were recruited (mean age 43.7 [±SD 7.9] years; 83% female; mean years since multiple sclerosis diagnosis 6.7 [SD 4.5]). Adherence data were obtained in 54 patients only due to technical problems with six devices. Over 12 weeks, 89% (n=48) of patients had ≥90% adherence to treatment. Most patients experienced mild influenza-like symptoms and injection-site reactions, and global side effects were minimal. Most patients (78%) rated the convenience as the most important aspect of the device, and most experienced no or mild pain. CONCLUSION: RRMS patients treated with subcutaneous interferon beta-1a, administered with RebiSmart, demonstrated generally good adherence, and the treatment was generally well tolerated.

Clinical and molecular characterization of BRCA-associated breast cancer: results from the DBCG.

BACKGROUND: In breast cancer (BC) patients a cancer predisposing BRCA1/2 mutation is associated with adverse tumor characteristics, risk assessment and treatment allocation. We aimed to estimate overall- (OS) and disease-free survival (DFS) according to tumor characteristics and treatment among women who within two years of definitive surgery for primary BC were shown to carry a mutation in BRCA1/2 . MATERIAL AND METHODS: From the clinical database of the Danish Breast Cancer Group we included 141 BRCA1 and 96 BRCA2 BC patients. Estrogen receptor and HER2 status were centrally reviewed on paraffin-embedded tumor tissue. Information on risk reducing surgery was obtained from the Danish Pathology and Patient Registries and included as time-dependent variables in Cox proportional hazard models. RESULTS: Ten-year OS and DFS for BRCA1 BC patients were 78% (95% CI 69-85) and 74% (95% CI 64-81). Ten-year OS and DFS for BRCA2 BC were 88% (95% CI 78-94) and 84% (95% CI 74-91). BRCA1 BC patients as compared to BRCA2 BC patients had a higher risk of BC relapse or non-breast cancer within ten years of follow-up, independent of ER status (adjusted HR 2.78 95% CI 1.28-6.05, p = .01), but BRCA mutation was not associated with OS (adjusted HR 1.98, 95% CI 0.87-4.52, p = .10). In multivariate analysis, including both BRCA1 and BRCA2 carriers, no chemotherapy was associated with a higher risk of death (adjusted OS HR 3.58, 95% CI 1.29-9.97, p = .01) and risk reducing contralateral mastectomy (RRCM) was associated with a significantly reduced risk of death (adjusted OS HR 0.42, 95% CI =0.21-0.84, p = .01). CONCLUSION: Difference in OS between BRCA1 and BRCA2 BC patients could be ascribed to tumor-biology. BRCA1 BC patients may have a shorter ten-year DFS than BRCA2 BC patients. Chemotherapy and risk reducing contralateral mastectomy reduce mortality for both BRCA1 and BRCA2 BC patients.