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Graphical Abstract Abstract Studies evaluating pregnancy outcomes after assisted reproductive treatment (ART) in women with high-normal (2.5–4.5 mIU/L) thyroid-stimulating hormone (TSH) levels are conflicting, possibly due to different patient charactistics and subfertility indications. The aim of this study was to examine the hypothesis that high-normal compared to low-normal TSH levels are associated with adverse implications for pregnancy outcomes in conventional in vitro fertilization (IVF)-treated women. Therefore, we analyzed retrospectively the characteristics and pregnancy outcomes of 949 subfertile women with TSH 0.3–4.5 mIU/L, treated with conventional IVF between January 2008 and March 2012. Demographic and baseline characteristics were compared between groups of patients based on TSH quartiles, using one-way Anova, Kruskal–Wallis ANOVA and chi-square test. Women with high-normal quartile TSH were significantly more likely to be primary subfertile (P = 0.01), with a higher prevalence of unexplained subfertility and with 15% fewer live births after IVF compared to lower TSH quartiles (P = 0.02). In secondary subfertile women with high-normal TSH, male factor subfertility prevailed (P = 0.01), with more live births (P = 0.01). When analyzing primary and secondary subfertile women as one group, these differences failed to be observed, showing no differences in cumulative pregnancy outcomes of IVF between TSH quartiles (I: 0.3–1.21 mIU/L; II: 1.22–1.68 mIU/L; III: 1.69–2.31 mIU/L; IV: 2.32–4.5 mIU/L). In conclusion, primary subfertile women predominate in the high-normal TSH quartile, associated with significantly fewer live births in a subgroup of primary unexplained subfertile women (9%; n = 87/949), while in secondary subfertile women, dominated by male factor subfertility, high-normal TSH is associated with more live births. Lay summary Thyroid hormones are required for all cell processes in the body. An underactive thyroid gland, in which insufficient thyroid hormones are produced and thyroid-stimulating hormone (TSH) rises, is associated with a lower chance of pregnancy. It is not yet clear above which TSH level, 4.5 or also 2.5 mIU/L, this lower probability occurs. Therefore, in 949 couples treated with conventional IVF, we examined whether high-normal TSH levels (TSH: 2.5–4.5 mIU/L) compared to low normal TSH levels (0.3–2.5 mIU/L) affect the live birth rate. We found that women who were trying to become pregnant for the first time, especially without any other cause, that is unexplained subfertility, were more likely to have higher TSH levels. These women had a much lower chance of having a baby compared to women with low-normal TSH levels.

Background Smith–Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations. Methods and analysis We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level. Conclusions This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care. Trial registration This study is registered in the Netherlands Trial Register (NTR9125).

Background In out-of-hospital cardiac arrest (OHCA) patients without ST-segment elevation, immediate coronary angiography did not improve clinical outcomes when compared to delayed angiography in the Coronary Angiography after Cardiac Arrest (COACT) trial (1,2). Whether one of the two strategies has benefits in terms of healthcare resource use and costs is currently unknown. We assess the healthcare resource use and costs in patients with OHCA. Methods 521 patients were eligible for a cost consequence analysis. Detailed healthcare resource use and cost-prices were collected from the initial hospital episode and compared between both groups. A generalized model (GLM) with a log link function and a gamma distribution was performed. Generic quality of life was measured with the RAND36 and collected at 12 months follow-up. Results Overall total mean costs were similar between both groups (EUR 33575±19612 vs EUR 33880±21044, P=0.86). GLM: (β 0.991 (95% CI 0.894–1.099), P=0.86. Mean procedural costs (CAG and/or PCI, coronary artery bypass graft) were higher in the immediate angiography group (EUR 4384±3447 vs EUR 3028±4220, P Conclusions The mean total costs between OHCA patients randomized to an immediate angiography or a delayed invasive strategy were similar. With respect to the higher invasive procedure costs in the immediate group, a strategy awaiting neurological recovery followed by coronary angiography and planned revascularization may be considered. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Supported by unrestricted research grants from the Netherlands Heart Institute, Biotronik, and AstraZeneca.

STUDY QUESTION Does pain or volume of used contrast medium impact the effectiveness of oil-based contrast during hysterosalpingography (HSG)? SUMMARY ANSWER In women who report moderate to severe pain during HSG, the use of oil-based contrast resulted in more ongoing pregnancies compared to the use of water-based contrast, whereas in women who reported mild or no pain, no difference in ongoing pregnancies was found. WHAT IS KNOWN ALREADY We recently showed that in infertile women undergoing HSG, the use of oil-based contrast results in more ongoing pregnancies within 6 months as compared to the use of water-based contrast. However, the underlying mechanism of this fertility-enhancing effect remains unclear. STUDY DESIGN, SIZE, DURATION We performed a post-hoc analysis of the H2Oil study, a multicentre randomised controlled trial (RCT) evaluating the therapeutic effect of oil- and water-based contrast at HSG. Here, we evaluated the impact of pain experienced at HSG and volume of used contrast media during HSG on ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS In a subset of 400 participating women, pain during HSG by means of the Visual Analogue Scale (VAS) (range: 0.0–10.0 cm) was reported, while in 512 women, we registered the volume of used contrast (in millilitres). We used logistic regression analyses to assess whether pain and volume of used contrast media modified the effect of oil-based contrast on ongoing pregnancy rates. Data were analysed according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE In 400 women in whom pain scores were reported, the overall median pain score was 5.0 (Interquartile range (IQR) 3.0–6.8) (oil group (n = 199) 4.8 (IQR 3.0–6.4); water group (n = 201) 5.0 (IQR 3.0–6.7); P-value 0.28). There was a significant interaction between pain (VAS ≤5 versus VAS ≥6) and the primary outcome ongoing pregnancy (P-value 0.047). In women experiencing pain (VAS ≥6), HSG with oil-based contrast resulted in better 6-month ongoing pregnancy rates compared to HSG with water-based contrast (49.4% versus 29.6%; RR 1.7; 95% CI, 1.1–2.5), while in women with a pain score ≤5, 6-month ongoing pregnancy rates were not significantly different between the use of oil- (28.8%) versus water-based contrast (29.2%) (RR 0.99; 95% CI, 0.66–1.5). In the 512 women in whom we recorded contrast, median volume was 9.0 ml (IQR 5.7–15.0) in the oil group versus 8.0 ml (IQR 5.9–13.0) in the water group, respectively (P-value 0.72). Volume of used contrast was not found to modify the effect of oil-based contrast on ongoing pregnancy (P-value for interaction 0.23). LIMITATIONS, REASONS FOR CAUTION This was a post-hoc analysis that should be considered as hypothesis generating. The RCT was restricted to infertile ovulatory women, younger than 39 years of age and with a low risk for tubal pathology. Therefore, our results should not be generalised to infertile women who do not share these features. WIDER IMPLICATIONS OF THE FINDINGS The underlying mechanism of the fertility-enhancing effect induced by HSG with the use of oil-based contrast remains unclear. However, these findings suggest a possible mechanistic pathway, that is increasing intrauterine pressure occurring prior to dislodging pregnancy hindering debris or mucus plugs from the proximal part of otherwise normal fallopian tubes. This information might help in the search of the underlying fertility-enhancing mechanism found by using oil-based contrast during HSG. STUDY FUNDING/COMPETING INTEREST(S) The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports consultancy for Guerbet. H.V. reports consultancy fees from Ferring. C.B.L. reports speakers’ fees from Ferring and research grants from Ferring, Merck and Guerbet. V.M. reports receiving travel and speakers fees as well as research grants from Guerbet. B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. The other authors do not report conflict of interests. TRIAL REGISTRATION NUMBER The H2Oil study was registered at the Netherlands Trial Registry (NTR 3270). TRIAL REGISTRATION DATE 1 February 2012. DATE OF FIRST PATIENT’S ENROLMENT 3 February 2012.

A recent systematic review recommends against the use of any of the current COVID-19 prediction models in clinical practice. To enable clinicians to appropriately profile and treat suspected COVID-19 patients at the emergency department (ED), externally validated models that predict poor outcome are desperately needed.Our aims were to identify predictors of poor outcome, defined as mortality or ICU admission within 30 days, in patients presenting to the ED with a clinical suspicion of COVID-19, and to develop and externally validate a prediction model for poor outcome.In this prospective, multi-center study, we enrolled suspected COVID-19 patients presenting at the EDs of two hospitals in the Netherlands. We used backward logistic regression to develop a prediction model. We used the area under the curve (AUC), Brier score and pseudo-R2 to assess model performance. The model was externally validated in an Italian cohort.We included 1193 patients between March 12 and May 27 2020, of whom 196 (16.4%) had a poor outcome. We identified 10 predictors of poor outcome: current malignancy (OR 2.774; 95%CI 1.682-4.576), systolic blood pressure (OR 0.981; 95%CI 0.964-0.998), heart rate (OR 1.001; 95%CI 0.97-1.028), respiratory rate (OR 1.078; 95%CI 1.046-1.111), oxygen saturation (OR 0.899; 95%CI 0.850-0.952), body temperature (OR 0.505; 95%CI 0.359-0.710), serum urea (OR 1.404; 95%CI 1.198-1.645), C-reactive protein (OR 1.013; 95%CI 1.001-1.024), lactate dehydrogenase (OR 1.007; 95%CI 1.002-1.013) and SARS-CoV-2 PCR result (OR 2.456; 95%CI 1.526-3.953). The AUC was 0.86 (95%CI 0.83-0.89), with a Brier score of 0.32 and, and R2 of 0.41. The AUC in the external validation in 500 patients was 0.70 (95%CI 0.65-0.75).The COVERED risk score showed excellent discriminatory ability, also in an external validation. It may aid clinical decision making, and improve triage at the ED in health care environments with high patient throughputs.

BACKGROUND Gliomas are primary brain tumors with a dismal prognosis. Reducing symptoms and maintaining quality of life (QoL) are main treatment aims in glioma patients. Mental well-being is an important subdomain of QoL. Cannabinoids have been suggested to alleviate frequently experienced symptoms of reduced mental well-being such as anxiety or depression. Glioma patients frequently report unprescribed cannabinoid use for these reasons. We performed a meta-analysis of the current evidence on cannabinoid efficacy on QoL and mental well-being to identify its added value in treatment of glioma patients. MATERIAL AND METHODS We performed a systematic PubMed, Embase and Web of Science search according to the PRISMA guidelines on September 22nd and 23rd, 2020. The effects of any dose of tetrahydrocannabinol (THC) or cannabidiol (CBD) on both general QoL and mental well-being were evaluated. The intervention had to be given for at least a week to establish a steady-state concentration. Effect size was calculated using Hedges g. Risk of bias of included studies was assessed using Cochrane’s Risk of Bias tool 2.0. RESULTS We retrieved no publications on cannabinoids use and QoL in glioma and, therefore, we expanded the search to cannabinoid use in other cancer types and chronic central nervous system (CNS) diseases. Sixteen studies were identified: four in cancer and twelve in CNS disease. Meta-analysis showed no effect of cannabinoids on general QoL (twelve studies in 1,740 patients; g = -0.02, 95% CI -0.11 to 0.07, p = 0.65) and mental well-being (twelve studies in 1,587 patients; g = -0.00, 95% CI -0.15 to 0.14, p = 0.96). Risk of bias was low in five studies, raised some concern in one study and was high in ten studies, mainly due to possible unblinding of patients after psychoactive adverse effects. CONCLUSION No studies on the effects of cannabinoids on QoL in glioma patients have been reported. A pooled analysis of studies in oncological patients and patients with CNS disease showed no effect of cannabinoids on QoL or mental well-being. However, studies were clinically heterogeneous and only one small study investigated monotherapy CBD with undecided results. As many glioma patients currently use cannabinoids, and monotherapy CBD has not been sufficiently investigated, future studies are necessary to evaluate its value in this specific population. SUPPORT/DISCLOSURE This meta-analysis has been funded by The Anita Veldman Foundation (CCA-2019-2-21).

BACKGROUND: A recent systematic review recommends against the use of any of the current COVID-19 prediction models in clinical practice. To enable clinicians to appropriately profile and treat suspected COVID-19 patients at the emergency department (ED), externally validated models that predict poor outcome are desperately needed.OBJECTIVE: Our aims were to identify predictors of poor outcome, defined as mortality or ICU admission within 30 days, in patients presenting to the ED with a clinical suspicion of COVID-19, and to develop and externally validate a prediction model for poor outcome.METHODS: In this prospective, multi-center study, we enrolled suspected COVID-19 patients presenting at the EDs of two hospitals in the Netherlands. We used backward logistic regression to develop a prediction model. We used the area under the curve (AUC), Brier score and pseudo-R2 to assess model performance. The model was externally validated in an Italian cohort.RESULTS: We included 1193 patients between March 12 and May 27 2020, of whom 196 (16.4%) had a poor outcome. We identified 10 predictors of poor outcome: current malignancy (OR 2.774; 95%CI 1.682-4.576), systolic blood pressure (OR 0.981; 95%CI 0.964-0.998), heart rate (OR 1.001; 95%CI 0.97-1.028), respiratory rate (OR 1.078; 95%CI 1.046-1.111), oxygen saturation (OR 0.899; 95%CI 0.850-0.952), body temperature (OR 0.505; 95%CI 0.359-0.710), serum urea (OR 1.404; 95%CI 1.198-1.645), C-reactive protein (OR 1.013; 95%CI 1.001-1.024), lactate dehydrogenase (OR 1.007; 95%CI 1.002-1.013) and SARS-CoV-2 PCR result (OR 2.456; 95%CI 1.526-3.953). The AUC was 0.86 (95%CI 0.83-0.89), with a Brier score of 0.32 and, and R2 of 0.41. The AUC in the external validation in 500 patients was 0.70 (95%CI 0.65-0.75).CONCLUSION: The COVERED risk score showed excellent discriminatory ability, also in an external validation. It may aid clinical decision making, and improve triage at the ED in health care environments with high patient throughputs.

Funding Acknowledgements Type of funding sources: None. Background Inflammation is a key component in the atherosclerotic process, initiating and sustaining plaques and serving as a trigger for plaque rupture leading to myocardial infarction. Coronary computed tomography angiography (CCTA) derived pericoronary adipose tissue attenuation (PCATa) has been proposed as surrogate marker for coronary inflammation and might improve risk assessment on top of CCTA derived cardiovascular risk-factors: atherosclerotic burden and plaque vulnerability. Purpose To assess the prognostic value of PCATa beyond atherosclerotic burden and high-risk plaques (HRPs). Methods A total of 543 patients who underwent CCTA because of suspected CAD were included. CCTA assessment comprised coronary artery calcium score (CACS), presence of obstructive CAD (≥50% stenosis) and HRPs, total plaque volume (TPV), non-calcified plaque volume (NCPV), and PCATa. The endpoint was a composite of death and non-fatal myocardial infarction (MI). Prognostic thresholds were determined for quantitative CCTA variables. Results During a median follow-up of 6.6 [interquartile range: 4.7-7.8] years, the endpoint was observed in 42 (20 MI/22 death) patients. CACS >83, obstructive CAD, HRPs, TPV >269mm3, and NCPV >83mm3 were associated with shorter time to the endpoint with unadujsted hazard ratio’s (HR) of 5.37 (95% confidence interval (CI): 2.56-11.29), 5.70 (95% CI: 2.40-13.55), 3.31 (95% CI: 1.80-6.07), 7.76 (95% CI: 3.59-16.81), and 6.77 (95% CI: 3.24-14.16), respectively (p -74.4 Hounsfield units was associated with worse prognosis (unadjusted HR: 1.99, 95% CI: 1.04-3.79, p = 0.037), whereas PCATa of the LAD and Cx were not associated with prognosis. PCATa of the RCA remained a significant predictor of death and non-fatal MI corrected for CCTA variables and clincal chacteristics associated with the endpoint (adjusted HR: 2.11, 95% CI: 1.11-4.04, p = 0.024). Conclusion Coronary inflammation determined by PCATa of the RCA provides incremental prognostic value beyond clinical characteristics and comprehensive CCTA assessment. Abstract Figure. Take-home figure

Background Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) leads to major reductions in ischemic burden. However, to date, studies investigating if more ischemia reduction after CTO PCI translates into an improved patient prognosis, are lacking. Purpose To evaluate if change in absolute myocardial perfusion after CTO PCI is related to patient prognosis. Methods Between 2013–2019, 219 prospectively recruited patients with a CTO underwent quantitative [15O]H2O positron emission tomography perfusion imaging before and 3 months after successful CTO PCI in a single high-volume CTO PCI center (175 procedures/year). Changes in perfusion defect size (in myocardial segments) and hyperemic myocardial blood flow (MBF, in mL min–1 g–1) within the CTO territory after PCI were related to the combined endpoint of death or myocardial infarction (MI). Kaplan-Meier curves (log-rank test) and multivariable Cox regression (including covariates age, gender, prior MI, and left ventricular function) were used to analyze unadjusted and risk-adjusted event-free survivals with HR [95% CI]. Results Out of 213 (97%) patients with a median follow-up of 3.2 [2.1–4.7] years, 22 (10%) patients experienced the composite of death (19, 9%) or MI (5, 2%). Event-free survival was significantly improved in patients with a perfusion defect size reduction of ≥3 segments (N=132, 62%) after CTO PCI compared to 1.13 mL min–1 g–1) as compared to below the median (p2.30 mL min–1 g–1 (N=105, 49%) showed a better event-free survival compared to patients with lower residual hyperemic MBF levels (p=0.02, risk-adjusted: p=0.04 with HR 0.33 [0.12–0.95]). Conclusions Patients with more ischemic burden reduction and less residual ischemia following CTO PCI showed a major improved survival free of death or MI. A limitation was the low absolute number of events that prohibited more extensive risk-adjustment of the analyses. Funding Acknowledgement Type of funding source: None

Background A myocardial ischemic burden (IB) of 10% is used to denote high-risk patients with coronary artery disease (CAD). This threshold has primarily been assessed by single-photon emission computed tomography. Differences in the pharmacokinetics of the utilized traces, higher resolution of positron emission tomography (PET), and lastly differences in assessment of IB might lead to a higher prognostic threshold for quantitative PET. Purpose To determine a [15O]H2O PET derived IB to identify low (annualized event rate (AER) Methods 623 patients who underwent [15O]H2O PET because of suspected CAD and in whom follow-up was obtained were included. The IB was defined as the percentage of myocardium with a hyperemic blood flow (hMBF) ≤2.3 ml/min/g and by a coronary flow reserve (CFR) of ≤2.5. The endpoint was a composite of death and non-fatal myocardial infarction (MI). Time-dependent ROC curves were constructed for the prediction of the endpoint within the first 5-years, based on these curves thresholds were selected for which specificity was maximized and sensitivity was at least 80%. Patients were classified as having a high IB if their respective IBs were above the prognostic thresholds and as having a low IB if not. Results During a median follow-up of 6.7 years, 34 (6%) patients died and 28 (4%) experienced a MI resulting in 62 (10%) endpoints. An IB of 24% and 28% for hMBF and CFR, respectively, was found to be the optimal threshold to define prognosis. Patients with a high hMBF or high CFR IB had worse outcome compared to patients with a low IB (log-rank p Conclusion An IB of 24% and 28% for hMBF and CFR was found to be the optimal prognostic threshold. Both measurements can be used to determine patients outcome. However combining hMBF and CFR IB results leads to a further refinement of risk-stratification allowing for the identification of low (concordant low or discordant IB result) and high (concordant high IB result) risk CAD patients. Funding Acknowledgement Type of funding source: None

Background Coronary computed tomography angiography (CCTA) derived parameters linked to severity and extent of atherosclerosis are associated with prognosis in patients with coronary artery disease (CAD). Furthermore, coronary inflammation, by determining pericoronary adipose tissue CT-attenuation (PCATa), can be assessed on CCTA as well and has been proposed as promising prognostic marker. Objective To assess the prognostic value of PCATa on top of traditional CCTA derived atherosclerotic parameters. Methods A total of 543 patients who underwent CCTA because of suspected CAD and in whom follow-up was obtained were included. CCTA assessment comprised; coronary artery calcium score (CACS), presence of obstructive CAD (≥50% stenosis) and high-risk plaques (HRP), total plaque volume (TPV), non-calcified plaque volume (NCPV), and PCATa. The endpoint was a composite of death and non-fatal myocardial infarction (MI). Optimal prognostic thresholds were determined for quantitative CCTA variables. Univariable Cox regression analyses were performed to determine clinical characteristics and CCTA variables associated with the endpoint, a subsequent multivariable Cox regression analysis that included variables associated with the endpoint was used to determine independent predictors of the endpoint. An additional Cox regression analysis was performed to test the incremental prognostic value of CCTA variables over clinical characteristics, significance of each sequentially added variable was tested using the likelihood ratio test. Results During a median follow-up time of 6.6 [interquartile range: 4.7–7.8] years, a total of 42 (20 MI/22 death) (8%) patients suffered an endpoint. CACS >83.2, obstructive CAD, HRP, TPV >269mm3, and NCPV >83mm3 were all associated with occurrence of the endpoint with unadujsted hazard ratio's (HR) of; 5.37, 5.70, 3.31, 7.76, and 6.77, respectively (p Conclusion Coronary inflammation of the RCA determined by PCATa provides incremental prognostic value on top of traditional CCTA parameters linked to extent and severity of CAD. Figure 1. Cox regression analysis demonstrating the incremental prognostic value of sequentially added CCTA variables over clinical characteristics tested for significance using the likelihood ratio test. Funding Acknowledgement Type of funding source: None

The value of serial coronary artery calcium (CAC) scores to predict changes in absolute myocardial perfusion and epicardial vasomotor function is poorly documented. This study explored the association between progression of CAC score and changes in absolute myocardial perfusion.Fifty-three patients (26% female) with de novo single-vessel coronary artery disease underwent [Baseline CAC score was 0 in 9%, 0.1-99.9 in 40%, 100-399.9 in 36% and ≥400 in 15% of patients, respectively. Mixed model-analysis allowed for averaging perfusion indices over all time points: hMBF (3.74 ± 0.83; 3.33 ± 0.79; 3.08 ± 0.78 and 2.44 ± 0.74 mL minHigher baseline CAC was associated with lower hMBF and CFR. However, both baseline CAC and its progression were not associated with evolution of absolute hMBF, CFR and CPT-MBF over time, suggesting that CAC score and progression of CAC are poor indicators of change in absolute myocardial perfusion.

STUDY QUESTION What is the performance of the patient-centredness of endometriosis care in a secondary and a tertiary care setting and how can it be improved? SUMMARY ANSWER Overall, patient-centredness was comparable in the two endometriosis care centres, but differed regarding ‘physical comfort’ and ‘continuity and transition’; both centres can learn how to improve several of their targets from the other’s strengths. WHAT IS KNOWN ALREADY The ENDOCARE questionnaire (ECQ) is a validated questionnaire for assessing the important quality dimension ‘patient-centredness’. Patient-centredness is associated with quality of life, although this should be explored further by larger-scale studies. STUDY DESIGN, SIZE, DURATION A cross-sectional survey, relying on the ECQ, was performed (during 2015 and 2016) among 407 women with surgically diagnosed endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was conducted in a secondary and a tertiary care centre in the Netherlands. A total of 209 Dutch-speaking women who had endometriosis surgery (2013–2014), completed the ECQ after a postal invitation and, if needed, postal reminders. The assessed outcomes were: overall patient-centredness, the patient-centredness for each of its 10 dimensions, and the patient-centred strengths and targets for improvement. Case-mix adjusted patient-centredness scores (PCS) were compared and strengths and targets for improvement were identified with a matrix modelling importance against experience. The need to improve the targets was quantified with quality impact indices. MAIN RESULTS AND THE ROLE OF CHANCE No difference was demonstrated between the overall PCS of the secondary and tertiary centres (respectively: 4.8 and 4.5; P = 0.15). No difference was found in PCS per dimension between the two clinics except for the secondary care centre performing better regarding ‘physical comfort’ (respectively: 4.5 and 3.0; P = 0.01) and ‘continuity and transition’ (respectively: 6.0 and 4.2; P = 0.01). The two centres had nine targets for improvement in common. The secondary and tertiary centres, respectively, had five and seven additional centre-specific targets for improvement. Cross-centre learning is encouraged as 9 out the 12 additional centre-specific targets were strengths in the other centre. The main improvement targets were being able to contact the centre in case of emergency (both centres), the involvement of a significant other (secondary centre), diagnostic delay (secondary centre), personal follow-up (tertiary centre) and disclosing the level of competence of healthcare providers (tertiary centre). LIMITATIONS, REASON FOR CAUTION Responders did not differ from non-responders in their stage of endometriosis, educational level, rating of endometriosis care and degree to which their complaints are suppressed. Endometriosis is a chronic condition and patient-centredness might be experienced differently at other points of the endometriosis care trajectory. WIDER IMPLICATION OF THE FINDINGS The ECQ is a useful tool to assess patient-centredness in both secondary and tertiary care centres. Further research should focus on how to improve endometriosis care. STUDY FUNDING/COMPETING INTEREST(S) No external funding was used. V.M. and C.B.L. report grants from Guerbet, grants from Merck and grants from Ferring outside the submitted work. All authors declare that they have no competing interests concerning this publication.

Background: Scan quality can have a significant effect on the diagnostic performance of non-invasive imaging techniques. However, the extent of its influence has scarcely been investigated in a head-to-head manner. Methods: Two-hundred and eight patients underwent CCTA, SPECT, and PET prior to invasive fractional flow reserve measurements. Scan quality was classified as either good, moderate, or poor. Results: Distribution of good, moderate, and poor quality scans was; CCTA; 66%, 22%, 13%; SPECT; 52%, 38%, 9%; PET; 86%, 13%, 1%. Good quality CCTA scans possessed a higher specificity (75% vs. 31%, p = 0.001), positive predictive value (PPV, 71% vs. 51%, p = 0.050), and accuracy (80% vs. 60%, p = 0.009) compared to moderate quality scans, while sensitivity (94%) and negative predictive value (NPV, 88%) were similar to moderate and poor quality scans. Sensitivity (76%), NPV (84%), and accuracy (85%) of good quality SPECT scans was superior to those of moderate (41% p = 0.001, 56% p = 0.010, 70% p = 0.010) and poor quality (30% p = 0.003, 65% p = 0.069, 63% p = 0.038). Specificity (92%) and PPV (87%) of good quality SPECT scans did not differ from scans of diminished quality. Good quality PET scans exhibited high sensitivity (84%), specificity (86%), NPV (88%), PPV (81%) and accuracy (85%), which was comparable to scans of lesser quality. Good quality CCTA, SPECT, and PET scans demonstrated a similar diagnostic accuracy (p = 0.247). Conclusion: Diagnostic performance of CCTA, and SPECT is hampered by scan quality, while the diagnostic value of PET is not affected. Good quality CCTA, SPECT, and PET scans possess a high diagnostic accuracy.

STUDY QUESTION What are the patient-specific determinants associated with patient-centered endometriosis care as measured by the ENDOCARE questionnaire (ECQ)? SUMMARY ANSWER ‘Overall grade for endometriosis care’, ‘educational level’, ‘membership of a patient organization’ and ‘having seen other specialists for endometriosis complaints’ are correlated with overall patient-centeredness scores (PCS). WHAT IS KNOWN ALREADY Patient-centeredness of endometriosis care can be evaluated using the validated ECQ. The ECQ leads to an overall PCS and separate PCS for 10 dimensions of endometriosis care. Previously, educational level and quality of life scores were found to be associated with ECQ results. STUDY DESIGN, SIZE, DURATION First, a systematic literature review was performed (PROSPERO registration number: CRD42020169872). MEDLINE, Cochrane CENTRAL and EMBASE databases were searched from inception to May 2020 for studies in any language reporting on the results of the ECQ in patients with endometriosis. Two studies were identified. From the two studies, all original data were merged. In total, data from 546 patients were available for analysis. Second, univariate and multivariate regression analyses were performed to identify determinants for patient-centeredness of endometriosis care. PARTICIPANTS/MATERIALS, SETTING, METHODS The two included studies evaluated patient-centeredness in four endometriosis care centers in Belgium and the Netherlands. All participants had surgically proven endometriosis. Possible patient-specific determinants were selected from the demographic and medical questions from the first part of the ECQ. These determinants were evaluated using linear regression analysis and all possible determinants with a P > 0.2 in the univariate analysis were selected for stepwise multivariate analysis. Separate analyses were performed for overall PCS and each of the 10 dimensions. MAIN RESULTS AND THE ROLE OF CHANCE The two included studies provided data from 546 patients. After adjustment for care center, multivariate analysis showed that a higher ‘grade for endometriosis care’ (B = 0.66), a ‘lower educational level’ (B = 0.50), ‘being member of a patient organization’ (B = 0.49) and ‘having seen other specialists for endometriosis complaints’ (B = 0.34) were independently associated with higher overall PCS (R2 = 0.41). ‘Grade for endometriosis care’ was a determinant for all dimensions of endometriosis care. ‘Having seen other specialists for endometriosis complaints’ was positively associated with the care dimensions ‘respect for patients’ values, preferences and expressed needs’, ‘continuity and transition’ and ‘technical skills’. Members of a patient organization showed higher scores on the care dimensions ‘emotional support and alleviation of fear and anxiety’, ‘continuity and transition’ and ‘endometriosis clinic staff’. Furthermore, we found that having a higher level of education is associated with lower scores in the care dimensions ‘physical comfort’, ‘emotional support and alleviation of fear and anxiety’ and ‘involvement of significant other’. LIMITATIONS, REASONS FOR CAUTION These results delineate the patient-specific determinants of patient-centered care as measured using the Dutch ECQ. Whether results are generalizable to other countries should be investigated in an international study. This requires the ECQ to be validated in other languages first. WIDER IMPLICATIONS OF THE FINDINGS The aforementioned determinants of patient-centered care are of value for studies benchmarking clinics for their patient-centeredness. In addition, they help clinicians to determine how to tailor their care to individual patients. At every visit, patients could be asked to grade the endometriosis care (on a scale of 0–10) to easily investigate patient-centeredness. When there is more time, women with endometriosis should be asked to complete the entire ECQ to investigate patient-centeredness in depth. STUDY FUNDING/COMPETING INTEREST(S) The department of reproductive medicine (involving C.B.L. and V.M.) of the Amsterdam UMC, Vrije Universiteit Amsterdam has received several research and educational grants from Guerbet, Merck and Ferring. The authors have no conflict of interest related to this manuscript.

Scan quality directly impacts the diagnostic performance of non-invasive imaging modalities as reported in a substudy of the PACIFC-trial: “Impact of Scan Quality on the Diagnostic Performance of CCTA, SPECT, and PET for Diagnosing Myocardial Ischemia Defined by Fractional Flow Reserve” [1]. This Data-in-Brief paper supplements the hereinabove mentioned article by presenting the diagnostic performance of CCTA, SPECT, and PET on a per vessel level for the detection of hemodynamic significant coronary artery disease (CAD) when stratified according to scan quality and vascular territory. Keywords: Coronary artery disease, Fractional flow reserve, Coronary computed tomography angiography, Single photon emission computed tomography, Positron emission tomography

Background Caesarean section (CS) rates are rising globally. Long-term adverse outcomes after CS might be reduced when the optimal uterine closure technique becomes evident. Objective To determine the effect of uterine closure techniques after CS on maternal and ultrasound outcomes. Search strategy Literature search in electronic databases. Selection criteria Randomised controlled trials (RCTs) or prospective cohort studies that evaluated uterine closure techniques and reported on ultrasound findings, perioperative or long-term outcomes. Data collection and analysis Twenty studies (15 053 women) were included in our meta-analyses for various outcomes. We calculated pooled risk ratios (RR) and weighted mean differences (WMD) with 95% CI through random-effect analysis. Main results Residual myometrium thickness (RMT), reported in eight studies (508 women), decreased by 1.26 mm after single- compared with double-layer closure (95% CI -1.93 to -0.58), particularly when locked sutures were used. Healing ratio [RMT/adjacent myometrium thickness (AMT)] decreased after single-layer closure (WMD -7.74%, 95% CI -13.31 to -2.17), particularly in the case of locked sutures. Niche prevalence increased (RR 1.71, 95% CI 1.11-2.62) when the decidua was excluded. Dysmenorrhea occurred more often in the single-layer group (RR 1.23, 95% CI 1.01-1.48), whereas incidence of uterine rupture was similar (RR 1.91, 95% CI 0.63-5.74). Conclusion Double-layer unlocked sutures are preferable to single-layer locked sutures regarding RMT, healing ratio and dysmenorrhoea. Excluding the decidua seems to result in higher niche prevalence. As thin residual myometrium or niches may serve as intermediates for gynaecological and reproductive outcomes, future studies should focus on these outcomes. TWEETABLE ABSTRACT: #Uterineclosuretechniques after #caesarean affect #longtermoutcomes.

STUDY QUESTION: Does 15 min of immobilization after IUI improve pregnancy rates?SUMMARY ANSWER: Immobilization for 15 min after IUI does not improve pregnancy rates.WHAT IS KNOWN ALREADY: Prior RCTs report a beneficial effect of supine immobilization for 15 min following IUI compared to immediate mobilization, however, these studies can be criticized. Given the importance for the logistics in daily practice and the lack of biological plausibility we planned a replication study prior to potential implementation of this procedure.STUDY DESIGN, SIZE, DURATION: A single centre RCT, based in an academic setting in the Netherlands, was performed. Participants were randomly assigned for 15 min of supine immobilization following IUI for a maximum of six cycles compared to the standard procedure of immediate mobilization following IUI. Participants and caregivers were not blinded to group assignment. An independent researcher used computer-generated tables to allocate treatments. Stratification occurred to the indication of IUI (unexplained or mild male subfertility). Revelation of allocation took place just before the insemination by the caregiver. The primary outcome was ongoing pregnancy rate per couple.PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 498 couples diagnosed with unexplained or mild male subfertility and an indication for treatment with IUI were approached and randomized in the study, of which 244 participants were assigned to 15 min of supine immobilization and 254 participants to immediate mobilization.MAIN RESULTS AND THE ROLE OF CHANCE: Participant characteristics were comparable between the groups, and 236 participants were analysed in the immobilization group, versus 245 in the mobilization group. The ongoing pregnancy rate per couple was not found to be superior in the immobilization group (one-sided P-value = 0.97) with 76/236 ongoing pregnancies (32.2%) being accomplished in the immobilization and 98/245 ongoing pregnancies (40.0%) in the immediate mobilization group (relative risk 0.81; 95% CI [0.63, 1.02], risk difference: -7.8%, 95% CI [-16.4%, 0.8%]). No difference was found in miscarriage rate, multiple gestation rate, live birth rate and time to pregnancy between the groups.LIMITATIONS, REASONS FOR CAUTION: Owing to discontinuation of the planned treatment not all participants reached six IUI cycles or an ongoing pregnancy. However, this is as expected in IUI treatment and mirrors clinical practice. These participants were equally distributed across the two groups. Women with tubal pathology and endocrine disorders were excluded for this trial, and this might narrow generalizability.WIDER IMPLICATIONS OF THE FINDINGS: This study shows no positive effect of 15 min of immobilization following IUI on pregnancy rates. Based on available evidence today, including our study, a possible beneficial effect of supine immobilization after IUI is at least doubtful and straightforward implementation does not seem to be justified.STUDY FUNDING/COMPETING INTEREST(S): No funding was received. All authors have nothing to disclose.TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR 2418.TRIAL REGISTRATION DATE: 20 July 2010.DATE OF FIRST PATIENT's ENROLMENT: 11 August 2010.

Background Microvascular injury (MVI) occurs in about 50% of successfully revascularized ST-elevation myocardial infarction (STEMI) patients and is associated with a decreased clinical outcome. MVI results from myocardial reperfusion injury, subsequent inflammation and coronary endothelial dysfunction. A correlation between peripheral and coronary endothelial function has been suggested and peripheral endothelial dysfunction is associated with the occurrence of cardiovascular events. Therefore we hypothesize a relation between peripheral and coronary endothelial function. Purpose The primary aim of our study was to assess the relationship between peripheral endothelial function and microvascular injury in successfully resvascularized STEMI patients. Methods Peripheral endothelial function and laboratory values were measured in the acute and stable setting (at 1 year follow-up). Reactive hyperemia-pulse amplitude tomography on the index finger was used to assess peripheral endothelial function by means of the reactive hyperemia index (LnRHI). After revascularization of the culprit vessel, we measured intracoronary coronary flow reserve (CFR). Cardiac magnetic resonance imaging (CMR) at day 5 evaluated the occurrence of MVI defined as microvascular obstruction (MVO) or intramyocardial hemorrhage. Myocardial salvage index (MSI) was calculated as (area at risk − final infarct size) / area at risk. Results We included 110 STEMI patients with the age of 60.1±9.5 years. Acute LnRHI was 0.56±0.33 and stable LnRHI was 0.64±0.27 (p=0.070). In the acute setting, LnRHI was impaired in patients with MVI compared to patients without MVI (0.44±0.37 vs. 0.61±0.34, p=0.045). The quantity of MVO (in grams) correlated with acute LnRHI (rho=-0.24, p=0.028). Acute LnRHI correlated to CFR in the revascularized culprit vessel (rho=0.25, p=0.015). In patients with decreased coronary blood flow after successful revascularization (TIMI-flow≤2), stable LnRHI was decreased (0.51±0.36 vs. 0.67±0.24, p=0.019). Stable LnRHI correlated to MSI (rho=0.28, p=0.020). Acute LnRHI correlated to leukocyte count (rho=-0.21, p=0.028) and LDH (rho=-0.25, p=0.018). LnRHI was impaired in patients who were hospitalized during 1 year follow-up (0.45±0.35 vs. 0.66±0.25, p=0.024). Conclusion(s) In patients with successfully revascularized STEMI, impaired peripheral endothelial function is associated with microvascular injury, decreased coronary flow and an increased inflammatory status. Furthermore, impaired peripheral endothelial function was associated with the occurrence of clinical events.

Background A low coronary lumen volume to left ventricle mass ratio (V/M) derived from coronary computed tomography angiography (CCTA) has been proposed as a factor contributing to impaired myocardial blood flow (MBF) even in the absence of obstructive coronary artery disease (CAD). Objective To elucidate the association of V/M with non-invasively obtained MBF parameters by means of [15O]H2O positron emission tomography (PET), as well as its correlations with invasively measured fractional flow reserve (FFR), overall and specifically in vessel with non-obstructive CAD. Methods This is a substudy of the PACIFIC trial, in which 208 patients underwent CCTA, and [15O]H2O PET prior to invasive coronary angiography (ICA) in conjunction with 3 vessel FFR measurements. Patient specific V/M was calculated for 152 patients. Matched vessel specific hyperemic MBF (hMBF), coronary flow reserve (CFR), FFR, and patient specific V/M were available for 431 vessels. The median V/M (20.71 mm3/g) was used to divide the study population into a group with a low V/M ( Results Overall, a higher percentage of vessels with an abnormal hMBF (34% vs. 19%, p=0.009), lower FFR values (0.93 [interquartile range: 0.85–0.97] vs. 0.95 [0.89–0.98], p=0.016), and a higher number of positive FFR values (20% vs. 9%, p=0.004) were observed among vessels in the low V/M group. Furthermore, a weak correlation between V/M, global hMBF (R=0.179, p=0.027), and global CFR (R=0.163, p=0.045) as well as a weak significant association with vessel specific hMBF (p=0.027), and FFR (p Conclusion Overall, vessels with an abnormal hMBF, and positive FFR measurements were more frequently observed in patients with a low V/M compared to those with a high V/M. Furthermore, V/M weakly correlated with global hMBF as well as with CFR and was associated with vessel specific hMBF and FFR. However, there was no correlation between V/M and global nor vessel specific blood flow parameters in the absence of obstructive CAD, notwithstanding a weak association of V/M with FFR within this group was noted.

Background Multiple techniques in chronic coronary total occlusion (CTO) percutaneous coronary intervention (PCI) have been developed to cross CTOs. Purpose To compare recovery of quantitative myocardial blood flow (MBF) after different CTO PCI techniques. Methods Consecutive patients with [15O]H2O positron emission tomography perfusion imaging before and three months after successful CTO PCI were included. Change in quantitative hyperemic MBF, coronary flow reserve (CFR) and perfusion defect size were compared between antegrade wire escalation (AWE), retrograde wire escalation (RWE), antegrade dissection and reentry (ADR) and retrograde dissection and reentry (RDR), and further between specific subintimal crossing and reentry techniques. Results 193 patients were treated with AWE (N=90), RWE (N=24), ADR (N=35) and RDR (N=44). Significant improvements (all p Conclusions Recovery of hyperemic MBF, CFR, and perfusion defect size was significant after CTO PCI and comparable between different crossing techniques. Improvement of hyperemic MBF was inferior after using the knuckle-wire subintimal crossing technique and STAR compared to other subintimal crossing and reentry techniques. Acknowledgement/Funding None

Background Up to 24% of acute coronary syndrome patients present with ST-elevation but show complete resolution of ST-elevation and symptoms before revascularization. The current guidelines do not clearly state whether these transient ST-elevation myocardial infarction (TSTEMI) patients should be treated with a ST-elevation myocardial infarction (STEMI)-like or a non-STEMI-like invasive approach. Purpose The aim of the present study is to determine the effect of an immediate versus a delayed invasive strategy on infarct size measured by 4-month cardiac magnetic resonance imaging (CMR) and clinical outcome up to one year. Methods In this multicenter trial, 142 TSTEMI patients were randomized 1:1 to either an immediate or a delayed intervention. CMR was performed at four days and at 4-month follow-up to assess infarct size and myocardial function. Clinical follow-up was performed at four months and one year. Results Both in the immediate (0.4 h) and the delayed invasive group (22.7 h) CMR-derived infarct size at four months was very small and left ventricular function was good. In addition, major adverse cardiac events and all-cause mortality at one year were low and not different between both groups (table 1). CMR and clinical outcomes up to one year Outcome Immediate invasive group (n=70) Delayed invasive group (n=72) p-value Myocardial infarct size (% of LV), median (IQR) 0.4 (0.0–3.5) 0.4 (0.0–2.5) 0.79 LVEF (%), mean ± SD 59.9±5.4 59.3±6.5 0.63 LVEF recovery (%), mean ± SD 2.2±5.4 1.7±5.3 0.66 MVO present, No. (%) 0 (0.0) 1 (1.9) 0.50 MACE (death, reinfarction, target lesion revascularization), No. (%) 3 (4.4) 4 (5.7) 1.00 Death from any cause, No. (%) 0 (0.0) 3 (4.3) 0.24 Reinfarction, No. (%) 2 (3.0) 1 (1.4) 0.62 Target lesion revascularization, No. (%) 2 (3.0) 1 (1.4) 0.62 Definite stent thrombosis, No. (%) 1 (1.5) 1 (1.4) 1.00 Abbreviations: IQR, interquartile range; LV, left ventricle; LVEF, left ventricle ejection fraction; MACE, major adverse cardiac events; MVO, microvascular obstruction; NA, not applicable; SD, standard deviation. Conclusions We demonstrated that patients with TSTEMI have limited infarct size and preserved left ventricular function and that an immediate or delayed approach has no effect on clinical outcome up to one year. Therefore, patients with TSTEMI can be treated with both an immediate or a delayed invasive strategy with similar outcome. These findings extend our current knowledge about the optimal timing of coronary intervention in patients with TSTEMI and complement the guidelines. Acknowledgement/Funding AstraZeneca, Biotronik

Background Quantification of absolute myocardial perfusion using positron emission tomography (PET) augments diagnostic performance and aids risk stratification in patients with coronary artery disease (CAD). Similar to PET, cardiac magnetic resonance imaging (CMR) allows for quantification of absolute myocardial blood flow (MBF). To date, quantitative CMR perfusion has not been compared with [15O]H2O PET, which is considered to be the gold standard for quantification of MBF. Purpose The purpose of this study was to compare CMR measurements of absolute myocardial perfusion to those obtained using [15O]H2O PET. Methods Fifty-one patients with stable CAD underwent [15O]H2O PET followed by CMR within 7 days. Late gadolinium enhancement was used to rule out presence of scar tissue. CMR perfusion imaging was performed using a single bolus dual sequence technique. Myocardial perfusion was quantified for the three main vascular territories at rest and during vasodilator stress. Results Pooled CMR estimates of absolute MBF correlated well with PET (r=0.79; p Per vessel – CMR vs PET perfusion Conclusions Resting MBF, stress MBF and CFR measurements correlated poorly with [15O]H2O PET. Nevertheless, stress MBF and CFR were concordant between CMR and [15O]H2O PET in 79% and 75% of vascular territories, respectively. Acknowledgement/Funding None

Quality of life of people with advanced dementia living in nursing homes is often suboptimal. Family caregivers can feel frustrated with limited contact with their relatives, which results in visits that are perceived as stressful and not very meaningful. Few psychosocial interventions are specifically developed for people with advanced dementia, and actively involve family caregivers or volunteers. Also, interventions usually stop when it becomes difficult for people to participate. The Namaste Care Family programme aims to increase the quality of life of people with advanced dementia, and improve family caregiving experiences through connecting to people and making them comfortable.Our study will evaluate the effects of the Namaste Care Family programme on quality of life of people with advanced dementia living in nursing homes and family caregiving experiences using a cluster-randomised controlled trial. Longitudinal analyses will be performed taking into account clustering at the nursing home level. Both a cost-effectiveness and a cost-utility analysis from a societal perspective will be performed. We will modify the Namaste Care Family programme to increase family and volunteer involvement in ongoing and end-of-life care. Data collection involves assessments by family caregivers, nursing staff and elderly care physicians using questionnaires, and observations by the researchers at baseline and multiple times over 12 months. The last questionnaire will be sent up to month 24 after the death of the person with dementia. During semistructured interviews, the feasibility, accessibility and sustainability of the Namaste Care Family programme will be assessed.The study protocol is approved by the Medical Ethics Review Committee of the VU University Medical Center in Amsterdam (protocol no. 2016.399) and registered with the Nederlands Trial Register (NTR5692). The findings will be disseminated via publications in peer-reviewed journals, conference presentations and presentations for healthcare professionals where appropriate.NTR5692.

Background: A diminished coronary lumen volume to left ventricle mass ratio (V/M) derived from coronary computed tomography angiography (CCTA) has been proposed as factor contributing to impaired myocardial blood flow (MBF) even in the absence of obstructive disease on invasive coronary angiography (ICA). Methods: Patients underwent CCTA, and positron emission tomography (PET) prior to ICA. Matched global V/M, global, and vessel specific hyperaemic MBF (hMBF), coronary flow reserve (CFR), and, FFR were available for 431 vessels in 152 patients. The median V/M (20.71 mm3/g) was used to divide the population into patients with either a low V/M or a high V/M. Results: Overall, a higher percentage of vessels with an abnormal hMBF and FFR (34% vs. 19%, p = 0.009 and 20% vs. 9%, p = 0.004), as well as a lower FFR (0.93 [interquartile range: 0.85–0.97] vs. 0.95 [0.89–0.98], p = 0.016) values were observed in the low V/M group. V/M was weakly associated with vessel specific hMBF (R = 0.148, p = 0.027), and FFR (R = 0.156, p < 0.001). Among vessels with non-obstructive CAD on ICA (361 vessels), no association between V/M and vessel specific hMBF nor CFR was noted. However, in the absence of obstructive CAD, V/M was associated with (R = 0.081, p = 0.027), and independently predictive for FFR (p = 0.047). Conclusion: Overall, an abnormal vessel specific hMBF and FFR were more prevalent in patients with a low V/M compared to those with a high V/M. Furthermore, V/M was weakly associated with vessel specific hMBF and FFR. In the absence of obstructive CAD on ICA, V/M was weakly associated with notwithstanding independently predictive for FFR.

Background Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. Methods Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. Discussion This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. Trial registration Dutch Trial Register (NTR5480). Registered 29 October 2015. Electronic supplementary material The online version of this article (10.1186/s12884-019-2221-y) contains supplementary material, which is available to authorized users.

STUDY QUESTION: Does lower quartile normal range thyroid stimulating hormone (TSH) compared to higher quartile normal range in women without thyroid hormone substitution affect live birth rate after a complete IUI treatment series?SUMMARY ANSWER: Lower quartile normal range TSH, in women without thyroid hormone substitution, does not affect live birth rate after a complete intrauterine insemination treatment series compared to higher quartile normal range TSH.WHAT IS KNOWN ALREADY: TSH is historically seen as the most sensitive test for thyroid function. Its distribution is right-skewed. Whether the preconceptional upper reference TSH values in subfertile women should be 2.5 or 4.5 mIU/L is under debate. Studies have shown that IUI patients treated with levothyroxine for TSH levels above 2.5 mIU/L show higher pregnancy rates. However, no adverse outcome is associated with untreated high normal TSH levels studied in first IUI cycles. Thyroid peroxidase antibodies have also impaired outcomes in some studies whereas others have shown an effect only in combination with high normal TSH levels. As a subgroup, patients with unexplained infertility showed increased levels of TSH. This article adds to the value of TSH evaluation and fertility outcome in four quartiles and in the context of a completed IUI treatment modus of a maximum of six inseminations.STUDY DESIGN SIZE DURATION: This is a retrospective cohort study in 909 women undergoing 3588 IUI cycles starting treatment between the first of January 2008 and the first of March 2012.PARTICIPANTS/MATERIALS SETTING METHODS: Women aged 22-45 years with TSH 0.3-4.5 mIU/L without thyroid hormone substitution were included at Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands, an Iodine-sufficient area. The primary endpoint was live birth. Clinical pregnancy, pregnancy loss and ongoing pregnancy were secondary endpoints. Logistic regression was used with the natural logarithm of TSH as a continuous predictor. Chi-square tests and logistic regression were used to compare groups of patients based on TSH values in four quartile TSH groups (0.3-1.21 mIU/L; 1.22-1.75 mIU/L; 1.76-2.34 mIU/L; 2.35-4.5 mIU/L) on basic characteristics and on the endpoints while adjusting for confounders.MAIN RESULTS AND THE ROLE OF CHANCE: Analysis with the natural logarithm of TSH as a continuous variable showed no association with live birth, pregnancy chance or pregnancy loss. There were no differences in any of the outcomes across the quartile TSH level ranges after regression analysis before and after adjusting for age, BMI, use of alcohol, tobacco, use or gonadotrophins, sperm count, diminished ovarian reserve, unexplained infertility and primary or secondary subfertility.The distribution of primary and secondary subfertility and smoking characteristics were remarkably different across the four groups, with proportionally the lowest prevalence of primary subfertility and the highest rate of smoking in the lowest TSH group (0.3-1.20 mIU/L).LIMITATIONS REASONS FOR CAUTION: Unknown values of free thyroxine and thyroid peroxidase antibodies, as well as the retrospective character of the study, limit the clinical interpretability.WIDER IMPLICATIONS OF THE FINDINGS: TSH in the highest quartile range (2.35-4.5 mIU/L) in subfertile women preceding IUI is not associated with a lower live birth rate or rate of clinical and ongoing pregnancy, or with loss of pregnancies, compared to subfertile women with TSH in the lower three quartile groups after complete intrauterine insemination treatment.STUDY FUNDING/COMPETING INTERESTs: The department of Obstetrics and Gynaecology, division of Reproductive Medicine, and of Internal Medicine, division of Endocrinology provided support. There are no competing interests.TRIAL REGISTRATION NUMBER: N/A.

BACKGROUND: Blood cultures remain the gold standard for detecting bacteremia despite their limitations. The current practice of blood culture collection is still inefficient with low yields. Limited focus has been given to the association between timing of specimen collection at different time points during admission and their yield.METHODS: We carried out a retrospective observational study by analyzing all 3,890 sets of cultures collected from the 1,962 admitted patients over the seven-month period of this study. We compared the blood culture yield between the early group (≤24 hours after admission) and the late group (> 24 hours of admission). We also investigated the effect of prehospital oral antibiotics and pre-analytical time on the first cultures in the emergency department. Epidemiology and efficiency of blood cultures were studied for each medical specialty.RESULTS: In total, 3,349(86.1%) blood cultures were negative and 541(13.9%) were positive for one or more microorganisms. After correcting for contamination, the overall yield was 290 (7.5%). The early group (n = 1,490) yielded significantly more true-positive cultures (10.1% versus 5.8%, PCONCLUSION: This study showed that blood cultures are inefficient in detecting bacteremia. Cultures collected during 24 hours after admission yielded more positive results than those collected later. Significant variations in blood culture epidemiology and efficiency per specialty suggest that guidelines should be reevaluated. Future studies should aim at improving blood culture yield, implementing educational programs to reduce contamination and cost-effective application of modern molecular diagnostic technologies.

INTRODUCTION: Neutrophilic granulocytes express cluster of differentiation 64 (CD64) antigen upon activation. CD64 can be used as a marker of bacterial infection and sepsis. The goal of this study was to determine whether CD64 is a useful biomarker for critically ill patients and analyze longitudinal measurements with regard to outcome and sepsis severity. METHODS: In this prospective observational study, CD64 analysis was performed daily until discharge from ICU or death. Demographics, clinical, laboratory data, and outcome defined as 28-day survival were recorded. Patients were included when admitted to the ICU with sepsis, severe sepsis, or septic shock and within 24 h from start of antibiotic treatment. RESULTS: Hundred and fifty-five consecutive patients were enrolled. At baseline, a difference in CD64 of 2.26 (1.33-4.47) vs. 1.49 (0.89-2.24) (P = 0.004) was seen between patients with a positive culture and negative culture. CD64 at day 1 was higher with patients with septic shock when compared with sepsis (P = 0.012). No difference of CD64 between survivors and nonsurvivors was seen. CONCLUSION: This study demonstrated that CD64 discriminates between critically ill patients with culture positive and negative sepsis and correlates with severity of disease. However, CD64 index is not a good predictor for 28-day mortality in the critically ill patient.