STUDY QUESTION
Is post-natal growth during the first 2 years of life in IVF singletons affected by type of medium used for culturing human embryos during an IVF treatment?
SUMMARY ANSWER
The in vitro ...culture of human embryos in medium from Cook resulted in singletons with a lower weight during the first 2 years of life compared with singletons born after embryo culture in medium from Vitrolife.
WHAT IS KNOWN ALREADY
In a previous study, we reported that type of medium used for culturing human IVF embryos during the first few days after fertilization until fresh embryo transfer significantly affects fetal growth and consequently birthweight of the resulting singletons.
STUDY DESIGN, SIZE, DURATION
From July 2003 to December 2006, a total of 1432 IVF treatment cycles with fresh embryo transfer were randomly allocated to have all embryos cultured in medium from Vitrolife AB (n = 715) or from Cook (n = 717). Two years after delivery, questionnaires were sent to the parents of all children requesting data about weight, height and head circumference around 1, 2, 3, 4, 6, 7.5, 9, 11, 14, 18 and 24 months of age. These measurements were collected as part of the children's health programme at municipal infant welfare centres in the Netherlands by health professionals unaware of this study.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Patients requiring donor oocytes or applying for PGD were excluded from the study. From the 294 live born singletons that fulfilled our inclusion criteria, 29 were lost to follow-up. The remaining 265 singletons (Cook group: 117, Vitrolife group: 148) were included in the analysis. Data analysis included linear regression, to compare cross-sectionally weight standard deviation score (SDS), height SDS and head circumference, and the first order Berkey-Reed model for a longitudinal analysis of the growth data.
MAIN RESULTS AND THE ROLE OF CHANCE
Singletons in the Vitrolife group were heavier during the first 2 years of life compared with singletons in the Cook group. Cross-sectional analyses showed that adjusted weight SDS differed between groups at 1 (0.35 ± 0.14, P = 0.010), 2 (0.39 ± 0.14, P = 0.006), 3 (0.35 ± 0.14, P = 0.011), 4 (0.30 ± 0.13, P = 0.020), 11 (0.28 ± 0.13, P = 0.036), 14 (0.32 ± 0.13, P = 0.014) and 24 (0.39 ± 0.15, P = 0.011) months of age, while adjusted height SDS was only significantly different at 1 (0.21 ± 0.11, P = 0.048) month of age. Head circumference was similar between the two groups at all ages. Longitudinal analyses showed that both post-natal weight (P = 0.005) and height (P = 0.031) differed between the groups throughout the first 2 years of life, while the growth velocity was not significantly different between the two groups.
LIMITATIONS, REASONS FOR CAUTION
Factors that might influence post-natal growth were included in the analysis; however, it was not possible to include all such factors, for example childhood diseases or nutrition, as this information was not available.
WIDER IMPLICATIONS OF THE FINDINGS
The effect of culture medium during the first few days after fertilization on prenatal growth and birthweight persists during the first 2 years of life. This suggests that the human embryo is sensitive to its very early environment, and that the culture medium used in IVF may have lasting consequences. Further monitoring of the long-term growth, development and health of IVF children is therefore warranted.
STUDY FUNDING/COMPETING INTEREST(S)
W.V. was funded with an unrestricted research grant from the Stichting Fertility Foundation. The authors declare no conflict of interest.
TRIAL REGISTRATION NUMBER
Not applicable.
We report on the high-precision timing of 42 radio millisecond pulsars (MSPs) observed by the European Pulsar Timing Array (EPTA). This EPTA Data Release 1.0 extends up to mid-2014 and baselines ...range from 7–18 yr. It forms the basis for the stochastic gravitational-wave background, anisotropic background, and continuous-wave limits recently presented by the EPTA elsewhere. The Bayesian timing analysis performed with temponest
yields the detection of several new parameters: seven parallaxes, nine proper motions and, in the case of six binary pulsars, an apparent change of the semimajor axis. We find the NE2001 Galactic electron density model to be a better match to our parallax distances (after correction from the Lutz–Kelker bias) than the M2 and M3 models by Schnitzeler. However, we measure an average uncertainty of 80 per cent (fractional) for NE2001, three times larger than what is typically assumed in the literature. We revisit the transverse velocity distribution for a set of 19 isolated and 57 binary MSPs and find no statistical difference between these two populations. We detect Shapiro delay in the timing residuals of PSRs J1600−3053 and J1918−0642, implying pulsar and companion masses
$m_{\rm p}=1.22_{-0.35}^{+0.5}\ {\rm M}_{{\odot }}$
,
$m_{\rm c} = 0.21_{-0.04}^{+0.06}\ {\rm M}_{{\odot } }$
and
$m_{\rm p}=1.25_{-0.4}^{+0.6}\ {\rm M}_{{\odot }}$
,
$m_{\rm c} = 0.23_{-0.05}^{+0.07}\ {\rm M}_{{\odot } }$
, respectively. Finally, we use the measurement of the orbital period derivative to set a stringent constraint on the distance to PSRs J1012+5307 and J1909−3744, and set limits on the longitude of ascending node through the search of the annual-orbital parallax for PSRs J1600−3053 and J1909−3744.
Abstract
Background and Aims
There is paucity of data on safety and efficacy of anti-tumour necrosis factor TNF in elderly inflammatory bowel disease IBD patients. We aimed to compare the long-term ...treatment failure rates and safety of a first anti-TNF agent in IBD patients between different age groups <40 years/40–59 years/≥60 years.
Methods
IBD patients who started a first anti-TNF agent were identified through IBDREAM, a multicentre prospective IBD registry. Competing risk regression was used to study treatment failure, defined as time to drug discontinuation due to adverse events AEs or lack of effectiveness, with discontinuation due to remission as a competing risk.
Results
A total of 895 IBD patients were included; 546 started anti-TNF at age <40 61.0%, 268 at age 40–59 29.9%, and 81 at age ≥60 9.1%. Treatment failure rate was higher in the two older groups (subhazard rate SHR age ≥60 1.46, SHR age 40–59 1.21; p = 0.03). The SHR in the elderly >60 was 1.52 for discontinuation due to AEs and 1.11 for lack of effectiveness. Concomitant thiopurine use was associated with a lower treatment failure rate (SHR 0.78, 95% confidence interval CI 0.62–0.98, p = 0.031). Serious adverse event SAE rate, as well as serious infection rate, were significantly higher in elderly IBD patients 61.2 versus 16.0 and 12.4 per 1000 patient-years, respectively whereas the malignancy rate was low in all age groups.
Conclusions
Elderly IBD patients starting a first anti-TNF agent showed higher treatment failure rates, but concomitant thiopurine use at baseline was associated with lower failure rates. Elderly IBD patients demonstrated higher rates of SAEs and serious infections.
Abstract
STUDY QUESTION
Is embryo culture media used during an IVF/ICSI treatment associated with differences in growth, body composition and cardiovascular development as determined in 9-year-old ...singleton IVF children?
SUMMARY ANSWER
The choice of in vitro culture medium for human embryos is associated with differences in body weight, BMI, truncal adiposity, waist circumference and waist/hip ratio at the age of 9, while no significant differences were observed in cardiovascular development.
WHAT IS KNOWN ALREADY
Children born after IVF/ICSI have an increased risk of low birthweight, which is correlated with a higher risk of cardiovascular diseases. Some studies show that IVF children exhibit a significantly higher systolic and diastolic blood pressure and higher fasting glucose levels compared to naturally conceived children. After alternating assignment to G1™ Version 3 (Vitrolife) or K-SICM (Cook) embryo culture media, birthweight of the resulting children was significantly higher in the Vitrolife group and they remained heavier during the first 2 years of life.
STUDY DESIGN, SIZE, DURATION
In this observational cohort study (MEDIUM-KIDS), parents of singletons from a previous study were approached for further follow-up after the ninth birthday of their child. The singletons were born after fresh embryo transfer of cleavage stage embryos resulting from an IVF/ICSI treatment performed between July 2003 and December 2006 in our clinic, when two different culture media were used alternately: either G1™ Version 3 (Vitrolife) or K-SICM (Cook). Follow-up measurements were performed between March 2014 and December 2016.
PARTICIPANT/MATERIALS, SETTINGS, METHODS
Parents were invited to attend our clinic with their child for a single visit lasting ~2.5 h. Two experienced clinicians performed all measurements as part of the MEDIUM-KIDS study in a standardized way. Height and weight of the child was measured using calibrated scales, 4-point skinfold thickness measurements were measured in triplicate and waist and hip circumference were measured using a tape measure. The following cardiovascular parameters were measured in a standardized way: blood pressure, heart rate and endothelial function by skin laser-Doppler with iontophoresis using vasodilatory drugs. Cortisol and cortisone concentrations in hair were measured. A blood sample was taken after an overnight fast for insulin, glucose, TSH and lipid analysis. Blood samples of the IVF children were compared with a non-IVF control group. Differences between culture medium groups were analysed by Student's t-test and effects of confounders were analysed using multivariable regression analysis.
MAIN RESULTS AND THE ROLE OF CHANCE
Of the 294 eligible children (168 Vitrolife and 126 Cook), 136 children (75 Vitrolife and 61 Cook) participated in the study. Baseline characteristics of the participating children from the Vitrolife and Cook group were similar. Birthweight was higher in the Vitrolife group, in keeping with the full cohort. After correction for confounders, the difference in weight and BMI attributable to culture medium was 1.58 kg (95% CI: 0.01-3.14) and 0.84 kg/m2 (95% CI: 0.02-1.67), respectively, with the Vitrolife children being heavier. Height and height corrected for age and gender (SDS scores) were similar in both groups. Furthermore, waist circumference was significantly higher in the Vitrolife group with a corrected difference of 3.21 cm (95%CI: 0.60-5.81) leading to a 0.03 increase (95% CI: 0.01-0.05) in waist/hip ratio. Subscapular skinfolds combined with suprailiacal skinfolds (defined as truncal adiposity), was also significantly higher in Vitrolife children (adjusted difference 3.44 cm 95% CI: 0.27-6.62). Both systolic (adj. beta 0.364 95% CI: −2.129 to 2.856,) and diastolic (adj. beta 0.275 95% CI: −2.105 to 2.654) blood pressures (mmHg) were comparable for the two groups. After an overnight fast, cholesterol, glucose, insulin, low and high-density lipoprotein, triglycerides and TSH were normal and similar in the two groups. Endothelial function in the microcirculation was compared by using maximum perfusion units corrected for the baseline value as a measure for vasodilatory capacity. There were no significant differences between the two groups. Cortisol and cortisone concentration in hair samples were comparable.
LIMITATIONS, REASONS FOR CAUTION
A limitation of the original study was its pseudo-randomized design. This and the dwindling enthusiasm of families for participation (47.7% after 9 years) prevent us from drawing robust causal conclusions from the observed association. Nevertheless, to date this is oldest cohort of IVF/ICSI children where culture medium was allocated alternatingly and used in a blinded setting, to be studied. We believe that our participants are representative for the full cohort. The current number of participants was sufficient to rule out differences as little as 3 mmHg in systolic and diastolic blood pressures.
WIDER IMPLICATIONS OF THE FINDINGS
This study underlines the importance of structured follow-up of IVF/ICSI children to further elucidate possible long-term health effects. Health professionals and culture medium manufacturers should be aware that small changes in culture conditions and culture medium composition for the early embryo can have long-term health effects. The similar cardiovascular results for the two groups are reassuring but the children may still be too young to detect differences in cardiovascular development. Prolonged follow-up and structured investigations up until adulthood are necessary to gain more insight and reassurance in the cardiovascular development of IVF offspring, although long-term follow-up will become more complicated by confounding life-style and environmental factors possibly influencing development.
STUDY FUNDING/COMPETING INTEREST(S)
The study was financially supported by the March of Dimes (Grant number #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
NTR4220.
We have searched for continuous gravitational wave (CGW) signals produced by individually resolvable, circular supermassive black hole binaries (SMBHBs) in the latest European Pulsar Timing Array ...(EPTA) data set, which consists of ultraprecise timing data on 41-ms pulsars. We develop frequentist and Bayesian detection algorithms to search both for monochromatic and frequency-evolving systems. None of the adopted algorithms show evidence for the presence of such a CGW signal, indicating that the data are best described by pulsar and radiometer noise only. Depending on the adopted detection algorithm, the 95 per cent upper limit on the sky-averaged strain amplitude lies in the range ... This limit varies by a factor of five, depending on the assumed source position and the most constraining limit is achieved towards the positions of the most sensitive pulsars in the timing array. The most robust upper limit - obtained via a full Bayesian analysis searching simultaneously over the signal and pulsar noise on the subset of ours six best pulsars -- is ... These limits, the most stringent to date at f < 10...nHz, exclude the presence of sub-centiparsec binaries with chirp mass ... out to a distance of about 25 Mpc, and with ... out to a distance of about 1Gpc (...). We show that state-of-the-art SMBHB population models predict <1 per cent probability of detecting a CGW with the current EPTA data set, consistent with the reported non-detection. We stress, however, that PTA limits on individual CGW have improved by almost an order of magnitude in the last five years. The continuing advances in pulsar timing data acquisition and analysis techniques will allow for strong astrophysical constraints on the population of nearby SMBHBs in the coming years. (ProQuest: ... denotes formulae/symbols omitted.)
Purpose
Aim of this study was to investigate a dose-response relationship, dose-toxicity relationship, progression free survival (PFS) and overall survival (OS) in neuroendocrine tumour liver ...metastases (NELM) treated with holmium-166-microspheres radioembolization (
166
Ho-radioembolization).
Materials and methods
Single center, retrospective study included patients with NELM that received
166
Ho-radioembolization with post-treatment SPECT/CT and CECT or MRI imaging for 3 months follow-up. Post-treatment SPECT/CT was used to calculate tumour (D
t
) and whole liver healthy tissue (D
h
) absorbed dose. Clinical and laboratory toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 5 at baseline and three-months follow-up. Response was determined according to RECIST 1.1. The tumour and healthy doses was correlated to lesion-based objective response and patient-based toxicity. Kaplan Meier analyses were performed for progression free survival (PFS) and overall survival (OS).
Results
Twenty-seven treatments in 25 patients were included, with a total of 114 tumours. Median follow-up was 14 months (3 – 82 months). Mean D
t
in non-responders was 68 Gy versus 118 Gy in responders,
p
= 0.01. ROC analysis determined 86 Gy to have the highest sensitivity and specificity, resp. 83% and 81%. Achieving a D
t
of ≥ 120 Gy provided the highest likelihood of response (90%) for obtaining response. Sixteen patients had grade 1–2 clinical toxicity and only one patient grade 3. No clear healthy liver dose-toxicity relationship was found. The median PFS was 15 months (95% CI 10.2;19.8) and median OS was not reached.
Conclusion
This study confirms the safety and efficacy of
166
Ho-radioembolization in NELM in a real-world setting. A clear dose–response relationship was demonstrated and future studies should aim at a D
t
of ≥ 120 Gy, being predictive of response. No dose-toxicity relationship could be established.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
Peptide receptor radionuclide therapy (PRRT) using
177
LuLu-DOTATATE has been shown to effectively prolong progression free survival in grade 1–2 gastroenteropancreatic neuroendocrine ...tumours (GEP-NET), but is less efficacious in patients with extensive liver metastases. The aim was to investigate whether tumour uptake in liver metastases can be enhanced by intra-arterial administration of
177
LuLu-DOTATATE into the hepatic artery, in order to improve tumour response without increasing toxicity.
Methods
Twenty-seven patients with grade 1–2 GEP-NET, and bi-lobar liver metastases were randomized to receive intra-arterial PRRT in the left or right liver lobe for four consecutive cycles. The contralateral liver lobe and extrahepatic disease were treated via a “second-pass” effect and the contralateral lobe was used as the control lobe. Up to three metastases (> 3 cm) per liver lobe were identified as target lesions at baseline on contrast-enhanced CT. The primary endpoint was the tumour-to-non-tumour (T/N) uptake ratio on the 24 h post-treatment
177
LuLu-SPECT/CT after the first cycle. This was calculated for each target lesion in both lobes using the mean uptake. T/N ratios in both lobes were compared using paired-samples
t
-test.
Findings
After the first cycle, a non-significant difference in T/N uptake ratio was observed: T/N
IA
= 17·4 vs. T/N
control
= 16·2 (
p
= 0·299). The mean increase in T/N was 17% (1·17; 95% CI 1·00; 1·37). Of all patients, 67% (18/27) showed any increase in T/N ratio after the first cycle.
Conclusion
Intra-arterial
177
LuLu-DOTATATE is safe, but does not lead to a clinically significant increase in tumour uptake.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
The objective of this study was to investigate whether the use of an anti-reflux catheter improves tumor targeting for colorectal cancer patients with unresectable, chemorefractory liver ...metastases (mCRC) treated with holmium-166 (
166
Ho)-radioembolization.
Materials and methods
In this perspective, within-patient randomized study, left and right hepatic perfusion territories were randomized between infusion with a Surefire® anti-reflux catheter or a standard microcatheter. The primary outcome was the difference in tumor to non-tumor (T/N) activity distribution. Secondary outcomes included the difference in infusion efficiency, absorbed doses, predictive value of
166
Ho-scout, dose-response relation, and survival.
Results
Twenty-one patients were treated in this study (the intended number of patients was 25). The median T/N activity concentration ratio with the use of the anti-reflux catheter was 3.2 (range 0.9–8.7) versus 3.6 (range 0.8–13.3) with a standard microcatheter. There was no difference in infusion efficiency (0.04% vs. 0.03% residual activity for the standard microcatheter and anti-reflux catheter, respectively) (95%CI − 0.05–0.03). No influence of the anti-reflux catheter on the dose-response rate was found. Median overall survival was 7.8 months (95%CI 6–13).
Conclusion
Using a Surefire® anti-reflux catheter did not result in a higher T/N activity concentration ratio in mCRC patients treated with
166
Ho-radioembolization, nor did it result in improved secondary outcomes measures.
Trial registration
clinicaltrials.gov
identifier: NCT02208804
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
IMPORTANCE: Postoperative pancreatic fistula is a potentially life-threatening complication after pancreatoduodenectomy. Evidence for best management is lacking. OBJECTIVE: To evaluate the clinical ...outcome of patients undergoing catheter drainage compared with relaparotomy as primary treatment for pancreatic fistula after pancreatoduodenectomy. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, retrospective, propensity-matched cohort study was conducted in 9 centers of the Dutch Pancreatic Cancer Group from January 1, 2005, to September 30, 2013. From a cohort of 2196 consecutive patients who underwent pancreatoduodenectomy, 309 patients with severe pancreatic fistula were included. Propensity score matching (based on sex, age, comorbidity, disease severity, and previous reinterventions) was used to minimize selection bias. Data analysis was performed from January to July 2016. EXPOSURES: First intervention for pancreatic fistula: catheter drainage or relaparotomy. MAIN OUTCOMES AND MEASURES: Primary end point was in-hospital mortality; secondary end points included new-onset organ failure. RESULTS: Of the 309 patients included in the analysis, 209 (67.6%) were men, and mean (SD) age was 64.6 (10.1) years. Overall in-hospital mortality was 17.8% (55 patients): 227 patients (73.5%) underwent primary catheter drainage and 82 patients (26.5%) underwent primary relaparotomy. Primary catheter drainage was successful (ie, survival without relaparotomy) in 175 patients (77.1%). With propensity score matching, 64 patients undergoing primary relaparotomy were matched to 64 patients undergoing primary catheter drainage. Mortality was lower after catheter drainage (14.1% vs 35.9%; P = .007; risk ratio, 0.39; 95% CI, 0.20-0.76). The rate of new-onset single-organ failure (4.7% vs 20.3%; P = .007; risk ratio, 0.15; 95% CI, 0.03-0.60) and new-onset multiple-organ failure (15.6% vs 39.1%; P = .008; risk ratio, 0.40; 95% CI, 0.20-0.77) were also lower after primary catheter drainage. CONCLUSIONS AND RELEVANCE: In this propensity-matched cohort, catheter drainage as first intervention for severe pancreatic fistula after pancreatoduodenectomy was associated with a better clinical outcome, including lower mortality, compared with primary relaparotomy.
To evaluate the performance of published fistula risk models by external validation, and to identify independent risk factors for postoperative pancreatic fistula (POPF).
Multiple risk models have ...been developed to predict POPF after pancreatoduodenectomy. External validation in high-quality prospective cohorts is, however, lacking or only performed for individual models.
A post-hoc analysis of data from the stepped-wedge cluster randomized PORSCH trial was performed. Included were all patients undergoing pancreatoduodenectomy in the Netherlands (January 2018-November 2019). Risk models on POPF were identified by a systematic literature search. Model performance was evaluated by calculating the area under the receiver operating curves (AUC) and calibration plots. Multivariable logistic regression was performed to identify independent risk factors associated with clinically relevant POPF.
Overall, 1358 patients undergoing pancreatoduodenectomy were included, of whom 341 patients (25%) developed clinically relevant POPF. Fourteen risk models for POPF were evaluated, with AUCs ranging from 0.62-0.70. The updated alternative fistula risk score had an AUC of 0.70 (95% CI 0.69-0.72). The alternative fistula risk score demonstrated an AUC of 0.70 (95% CI 0.68-0.71), whilst an AUC of 0.70 (95% CI 0.69-0.71) was also found for the model by Petrova et al Soft pancreatic texture, pathology other than pancreatic ductal adenocarcinoma or chronic pancreatitis, small pancreatic duct diameter, higher body-mass index, minimally invasive resection and male sex were identified as independent predictors of POPF.
Published risk models predicting clinically relevant POPF after pancreatoduodenectomy have a moderate predictive accuracy. Their clinical applicability to identify high-risk patients and guide treatment strategies is therefore questionable.
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