The web-based Pleasure&Pregnancy programme in the treatment of unexplained infertility: a randomized controlled trial.

STUDY QUESTION: Does offering the Pleasure&Pregnancy (P&P) programme rather than expectant management improve naturally conceived ongoing pregnancy rates in couples diagnosed with unexplained infertility? SUMMARY ANSWER: The P&P programme had no effect on the ongoing pregnancy rates of couples with unexplained infertility. WHAT IS KNOWN ALREADY: Underpowered studies suggested that face-to-face interventions targeting sexual health may increase pregnancy rates. The impact of an eHealth sexual health programme had yet to be evaluated by a large randomized controlled trial. STUDY DESIGN, SIZE, DURATION: This is a nationwide multi-centre, unblinded, randomized controlled superiority trial (web-based randomization programme, 1:1 allocation ratio). This RCT intended to recruit 1164 couples within 3 years but was put on hold after having included 700 couples over 5 years (2016-2021). The web-based P&P programme contains psychosexual information and couple communication, mindfulness and sensate focus exercises aiming to help maintain or improve sexual health, mainly pleasure, and hence increase pregnancy rates. The P&P programme additionally offers information on the biology of conception and enables couples to interact online with peers and via email with coaches. PARTICIPANTS/MATERIALS, SETTING, METHODS: Heterosexual couples with unexplained infertility and a Hunault-prognosis of at least 30% chance of naturally conceiving a live-born child within 12 months were included, after their diagnostic work-up in 41 Dutch secondary and tertiary fertility centres. The primary outcome was an ongoing pregnancy, defined as a viable intrauterine pregnancy of at least 12 weeks duration confirmed by an ultrasound scan, conceived naturally within 6 months after randomization. Secondary outcomes were time to pregnancy, live birth, sexual health, and personal and relational well-being at baseline and after 3 and 6 months. The primary analyses were according to intention-to-treat principles. We calculated relative risks (RRs, pregnancy rates) and a risk difference (RD, pregnancy rates), Kaplan-Meier survival curves (live birth over time), and time, group, and interactive effects with mixed models analyses (sexual health and well-being). MAIN RESULTS AND THE ROLE OF CHANCE: Totals of 352 (one withdrawal) and 348 (three withdrawals) couples were allocated to, respectively the P&P group and the expectant management group. Web-based tracking of the intervention group showed a high attrition rate (57% of couples) and limited engagement (i.e. median of 16 visits and 33 min total visitation time per couple). Intention-to-treat analyses showed that 19.4% (n = 68/351) of the P&P group and 22.6% (n = 78/345) of the expectant management group achieved a naturally conceived ongoing pregnancy (RR = 0.86; 95% CI = 0.64-1.15, RD = -3.24%; 95% CI -9.28 to 2.81). The time to pregnancy did not differ between the groups (Log rank = 0.23). Live birth occurred in 18.8% (n = 66/351) of the couples of the P&P group and 22.3% (n = 77/345) of the couples of the expectant management group (RR = 0.84; 95% CI = 0.63-1.1). Intercourse frequency decreased equally over time in both groups. Sexual pleasure, orgasm, and satisfaction of women of the P&P group improved while these outcomes remained stable in the expectant management group. Male orgasm, intercourse satisfaction, and overall satisfaction decreased over time with no differences between groups. The intervention did not affect personal and relational well-being. Non-compliance by prematurely starting medically assisted reproduction, and clinical loss to follow-up were, respectively, 15.1% and 1.4% for the complete study population. Per protocol analysis for the primary outcome did not indicate a difference between the groups. Comparing the most engaged users with the expectant management group added that coital frequency decreased less, and that male sexual desire improved in the intervention group. LIMITATIONS, REASONS FOR CAUTION: The intended sample size of 1164 was not reached because of a slow recruitment rate. The achieved sample size was, however, large enough to exclude an improvement of more than 8% of the P&P programme on our primary outcome. WIDER IMPLICATIONS OF THE FINDINGS: The P&P programme should not be offered to increase natural pregnancy rates but may be considered to improve sexual health. The attrition from and limited engagement with the P&P programme is in line with research on other eHealth programmes and underlines the importance of a user experience study. STUDY FUNDING/COMPETING INTEREST(S): Funded by The Netherlands Organisation for Health Research and Development (ZonMw, reference: 843001605) and Flanders Research Foundation. C.B.L. is editor-in-chief of Human Reproduction. H.W.L. received royalties or licences from Prometheus Publishers Springer Media Thieme Verlag. J.B. received support from MercK for attending the ESHRE course 'The ESHRE guideline on ovarian stimulation, do we have agreement?' J.v.D. reports consulting fees and lecture payments from Ferring, not related to the presented work, and support for attending ESHRE from Goodlife and for attending NFI Riga from Merck. A.H. reports consulting fees by Ferring Pharmaceutical company, The Netherlands, paid to institution UMCG, not related to the presented work. H.V. reports consulting fees from Ferring Pharmaceutical company, The Netherlands, and he is a member of the ESHRE guideline development group unexplained infertility and Chair of the Dutch guideline on unexplained infertility (unpaid). M.G. declares unrestricted research and educational grants from Ferring not related to the presented work, paid to their institution VU Medical Centre. The other authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: NTR5709. TRIAL REGISTRATION DATE: 4 February 2016. DATE OF FIRST PATIENT'S ENROLMENT: 27 June 2016.

The effect of surgery or medication on pain and quality of life in women with endometrioma. A systematic review and meta-analysis.

For patients with endometrioma it is unclear what treatment: surgery and/or medication, is more effective in reducing pain and improving quality of life (QoL). This systematic review and meta- analysis aimed to provide an overview of the existing evidence on the effects of surgery and/or medication (i.e. analgesics and/or hormonal medication) on pain and QoL. A search through CENTRAL, MEDLINE and Embase was conducted. The study population had to be women treated for endometrioma. Retrospective or prospective studies reporting about QoL and/or the following types of pain were reviewed: dysmenorrhea, dyspareunia, chronic pelvic pain, and pain that was not well defined in the included article (referred to as pain). We performed a meta-analysis on mean visual analogue scale (VAS) scores and proportions of patients experiencing different types of pain over time. QoL was described narratively. Out of 11.515 articles, 76 studies including 7148 patients were included for the systematic review. The meta-analysis consisted of 52 studies including 4556 patients. No studies compared medication with surgery. And there were no studies on analgesics. Meta-analysis showed that surgery and/or medication often reduced VAS scores and proportions of all types of pain over time. Surgery and medication combined seems more effective in reducing VAS scores of pain compared to surgery alone, but not to medication alone (estimated mean difference = 0.17, p < 0.0001 and -0.98, p = 0.0339). QoL improved after medication (follow up ≤ 12 months) and QoL was unchanged or worsened after surgery and medication combined (follow up ≤ 24 months). However, these were results from a total of 5 studies. Both surgery and medication reduce endometriosis-related pain in patients with endometrioma. However, there is lack of uniform, good quality data comparing surgery with medication to draw firm conclusions. For better-informed treatment decisions, further studies including a standardized core-outcome set at fixed follow-up times, are necessary.

Computational Investigation of Precursor Blocking during Area-Selective Atomic Layer Deposition Using Aniline as a Small-Molecule Inhibitor.

Area-selective atomic layer deposition using small-molecule inhibitors (SMIs) involves vapor-phase dosing of inhibitor molecules, resulting in an industry-compatible approach. However, the identification of suitable SMIs that yield a high selectivity remains a challenging task. Recently, aniline (C6H5NH2) was shown to be an effective SMI during the area-selective deposition (ASD) of TiN, giving 6 nm of selective growth on SiO2 in the presence of Ru and Co non-growth areas. In this work, using density functional theory (DFT) and random sequential adsorption (RSA) simulations, we investigated how aniline can effectively block precursor adsorption on specific areas. Our DFT calculations confirmed that aniline selectively adsorbs on Ru and Co non-growth areas, whereas its adsorption on the SiO2 growth area is limited to physisorption. DFT reveals two stable adsorption configurations of aniline on the metal surfaces. Further calculations on the aniline-functionalized surfaces show that the aniline inhibitor significantly reduces the interaction of Ti precursor, tetrakis(dimethylamino)titanium, with the non-growth area. In addition, RSA simulations showed that the co-presence of two stable adsorption configurations allows for a high surface inhibitor coverage on both Co and Ru surfaces. As the surface saturates, there is a transition from the thermodynamically most favorable adsorption configuration to the sterically most favorable adsorption configuration, which results in a sufficiently dense inhibition layer, such that an incoming precursor molecule cannot fit in between the adsorbed precursor molecules. We also found that, as a result of the catalytic activity of the metallic non-growth area, further reactions of inhibitor molecules, such as hydrogenolysis, can play a role in precursor blocking.

Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial.

STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain. STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S): The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER: Dutch Trial register NL5455 (NTR5599). TRIAL REGISTRATION DATE: 18 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2017.

Design of the PERSPECTIVE study: PERsonalized SPEeCh Therapy for actIVE conversation in Parkinson's disease (randomized controlled trial).

OBJECTIVE: To evaluate the effectiveness of personalized and home-based speech therapy on quality of life, intelligibility, and social participation for people with Parkinson's disease (PD) who have a reduced intelligibility of speech. BACKGROUND: Speech problems in PD have a profound negative impact on social interaction and quality of life. Evidence for speech therapy in PD is growing, but more work remains needed to explore its full potential. Efficacy exists for highly intensive standardized speech treatment programs, but not all patients can comply with this rather intense intervention, especially the more severely affected ones. Here, we aim to study the effectiveness of personalized and home-based (remote) speech therapy in PD on quality of life and speech. The intervention will be supported by a dedicated speech training app. We expect that this approach will improve speech intelligibility and quality of life in patients irrespective of disease stage. METHODS: We will perform a single blind, randomized controlled trial, comparing 8 weeks of speech therapy to no intervention using a waiting list design. A total of 215 PD patients with problems in intelligibility will be recruited by 12 highly experienced speech therapists. All patients will be measured at baseline and after 8 weeks (primary endpoint). Additionally, the experimental group will be re-assessed one more time, after a wash-out period of 24 weeks. The control group will receive deferred treatment after 8 weeks, but without additional follow-up assessments. Our primary outcome is quality of life (as measured with PDQ-39). Secondary outcomes include speech and voice quality, intelligibility, severity of voice and speech complaints, and caregiver burden. RESULTS: The inclusion of participants has started on March 1, 2019, and is expected to be finalized on April 1, 2021. We expect to have the first results in January 2022. CONCLUSIONS: We will investigate the effectiveness of speech therapy in PD. Particular strengths of our study include a randomized and single-blinded design, the personalized treatment approach, the inclusion of PD patients irrespective of disease stage or severity of the speech complaint, the long-term follow-up, the adequate power, and the use of a patient-relevant primary endpoint. This will allow us to draw firm conclusions about the effectiveness of personalized and remote speech therapy for PD patients in all disease stages. TRIAL REGISTRATION: ClinicalTrials.gov NCT03963388 . Registered on May 24, 2019.

Risk of SARS-CoV-2 transmission upon return to work in RNA-positive healthcare workers.

BACKGROUND: Healthcare workers (HCWs) are at risk for coronavirus disease 2019 (COVID-19), and for spreading severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) amongst colleagues and patients. AIM: To study the presence of SARS-CoV-2 RNA and possible onward transmission by HCWs upon return to work after COVID-19, and association with disease severity and development of antibodies over time. METHODS: Unvaccinated HCWs with positive SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) were recruited prospectively. Data on symptoms were collected via telephone questionnaires on days 2, 7, 14 and 21 after a positive test. Upon return to work, repeat SARS-CoV-2 RT-PCR was performed and serum was collected. Repeat serum samples were collected at weeks 4, 8, 12 and 16 to determine antibody dynamics over time. Phylogenetic analysis was conducted to investigate possible transmission events originating from HCWs with a positive repeat RT-PCR. FINDINGS: Sixty-one (84.7%) participants with mild/moderate COVID-19 had a repeat SARS-CoV-2 RT-PCR performed upon return to work (median 13 days after symptom onset), of which 30 (49.1%) were positive with a median cycle threshold (Ct) value of 29.2 (IQR 26.9-29.9). All HCWs developed antibodies against SARS-CoV-2. No significant differences in symptomatology and presence of antibodies were found between repeat RT-PCR-positive and -negative HCWs. Eleven direct colleagues of six participants with a repeat RT-PCR Ct value <30 tested positive after the HCW returned to work. Phylogenetic and epidemiologic analysis did not indicate onward transmission through HCWs who were SARS-CoV-2 RNA positive upon return to work. CONCLUSIONS: HCWs regularly return to work with substantial SARS-CoV-2 RNA loads. However, this study found no evidence for subsequent in-hospital transmission.

Short-term recovery after NovaSure® endometrial ablation: a prospective cohort study.

Background: Endometrial ablation is a frequently performed treatment for heavy menstrual bleeding, but detailed information about recovery to help inform patients is lacking. Objective: To gain more insight into the short-term recovery after NovaSure® endometrial ablation, with the goal of improving preprocedural counselling. Materials and Methods: A total of 61 women who underwent endometrial ablation between March 2019 and November 2021 in a teaching hospital in the Netherlands were included in this prospective cohort study. Main outcome measures: Short-term recovery was investigated through questionnaires in the first week after the procedure. The primary outcome was the Recovery Index (RI-10). Secondary outcomes included health-related quality of life (EQ-5D-5L), pain intensity, use of analgesics, nausea, vaginal discharge, capability of performing activities (domestic chores, sports, work), self-rated health (EQ-VAS) and the feeling of full recovery. Results: A total of 33 women underwent the procedure under local anaesthesia and 28 women under procedural sedation. The RI-10 increased in the first week; median scores on day one, two and seven were 34 (IQR 28.5-41.5), 38.5 (IQR 31-47), and 42 (IQR 37.5-48), respectively. The median time for full recovery was five days. However, 23% of all women were not fully recovered within seven days. Women needed a median time of two days for returning to their work and 5.5 days for sporting activities. There were no differences in recovery between both anaesthesia techniques. Conclusions: Women undergoing endometrial ablation can be informed that most will fully recover within the first week of the procedure and that there is no difference in expected recovery time according to whether the procedure is undertaken with local anaesthesia or conscious sedation. What is New?: The short-term recovery after endometrial ablation has been mapped in this trial. This information can be used in counselling women with heavy menstrual bleeding.

Economic evaluation of endometrial scratching before the second IVF/ICSI treatment: a cost-effectiveness analysis of a randomized controlled trial (SCRaTCH trial).

STUDY QUESTION: Is a single endometrial scratch prior to the second fresh IVF/ICSI treatment cost-effective compared to no scratch, when evaluated over a 12-month follow-up period? SUMMARY ANSWER: The incremental cost-effectiveness ratio (ICER) for an endometrial scratch was €6524 per additional live birth, but due to uncertainty regarding the increase in live birth rate this has to be interpreted with caution. WHAT IS KNOWN ALREADY: Endometrial scratching is thought to improve the chances of success in couples with previously failed embryo implantation in IVF/ICSI treatment. It has been widely implemented in daily practice, despite the lack of conclusive evidence of its effectiveness and without investigating whether scratching allows for a cost-effective method to reduce the number of IVF/ICSI cycles needed to achieve a live birth. STUDY DESIGN, SIZE, DURATION: This economic evaluation is based on a multicentre randomized controlled trial carried out in the Netherlands (SCRaTCH trial) that compared a single scratch prior to the second IVF/ICSI treatment with no scratch in couples with a failed full first IVF/ICSI cycle. Follow-up was 12 months after randomization.Economic evaluation was performed from a healthcare and societal perspective by taking both direct medical costs and lost productivity costs into account. It was performed for the primary outcome of biochemical pregnancy leading to live birth after 12 months of follow-up as well as the secondary outcome of live birth after the second fresh IVF/ICSI treatment (i.e. the first after randomization). To allow for worldwide interpretation of the data, cost level scenario analysis and sensitivity analysis was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: From January 2016 until July 2018, 933 women with a failed first IVF/ICSI cycle were included in the trial. Data on treatment and pregnancy were recorded up until 12 months after randomization, and the resulting live birth outcomes (even if after 12 months) were also recorded.Total costs were calculated for the second fresh IVF/ICSI treatment and for the full 12 month period for each participant. We included costs of all treatments, medication, complications and lost productivity costs. Cost-effectiveness analysis was carried out by calculating ICERs for scratch compared to control. Bootstrap resampling was used to estimate the uncertainty around cost and effect differences and ICERs. In the sensitivity and scenario analyses, various unit costs for a single scratch were introduced, amongst them, unit costs as they apply for the United Kingdom (UK). MAIN RESULTS AND THE ROLE OF CHANCE: More live births occurred in the scratch group, but this also came with increased costs over a 12-month period. The estimated chance of a live birth after 12 months of follow-up was 44.1% in the scratch group compared to 39.3% in the control group (risk difference 4.8%, 95% CI -1.6% to +11.2%). The mean costs were on average €283 (95% CI: -€299 to €810) higher in the scratch group so that the point average ICER was €5846 per additional live birth. The ICER estimate was surrounded with a high level of uncertainty, as indicated by the fact that the cost-effectiveness acceptability curve (CEAC) showed that there is an 80% chance that endometrial scratching is cost-effective if society is willing to pay ∼€17 500 for each additional live birth. LIMITATIONS, REASONS FOR CAUTION: There was a high uncertainty surrounding the effects, mainly in the clinical effect, i.e. the difference in the chance of live birth, which meant that a single straightforward conclusion could not be ascertained as for now. WIDER IMPLICATIONS OF THE FINDINGS: This is the first formal cost-effectiveness analysis of endometrial scratching in women undergoing IVF/ICSI treatment. The results presented in this manuscript cannot provide a clear-cut expenditure for one additional birth, but they do allow for estimating costs per additional live birth in different scenarios once the clinical effectiveness of scratching is known. As the SCRaTCH trial was the only trial with a follow-up of 12 months, it allows for the most complete estimation of costs to date. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organization for funding healthcare research. A.E.P.C., F.J.M.B., E.R.G. and C.B. L. reported having received fees or grants during, but outside of, this trial. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL5193/NTR 5342).

The role of autonomy-connectedness in stress-modulating effects of social support in women: An experimental study using a virtual Trier Social Stress Test.

Social support is associated with mental well-being and favorable therapy outcomes. As autonomy-connectedness, the capacity for self-governance in interpersonal context, may affect reliance on others, we investigated whether stress-modulating effects of social support are moderated by autonomy-connectedness. Ninety-seven undergraduates completed measures on autonomy-connectedness and trait social anxiety, and attended a laboratory session with a friend (support) or alone (control). All underwent a virtual Trier Social Stress Test and completed anxiety, cortisol and heart rate (variability) measures. Preregistered analyses revealed that social support reduced anxiety reactivity and delayed heart rate variability decreases, but not heart rate. Contrary to hypotheses, autonomy-connectedness did not predict stress-reactivity or interact with condition. Exploratory analyses suggested effects of social support on cortisol reactivity and indicated that reported support quality varied by trait anxiety and self-awareness. Our findings underline the stress-modulating effects of social support and suggest that social support can benefit individuals with varying levels of autonomy-connectedness.

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH).

STUDY QUESTION: Does endometrial scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between -0.7% and +9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/111 for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by ZonMW, the Dutch organisation for funding healthcare research. J.S.E. Laven reports grants and personal fees from AnshLabs (Webster, Tx, USA), Ferring (Hoofddorp, The Netherlands) and Ministry of Health (CIBG, The Hague, The Netherlands) outside the submitted work. A.E.P. Cantineau reports 'other' from Ferring BV, personal fees from Up to date Hyperthecosis, 'other' from Theramex BV, outside the submitted work. E.R. Groenewoud reports grants from Titus Health Care during the conduct of the study. A.M. van Heusden reports personal fees from Merck Serono, personal fees from Ferring, personal fees from Goodlife, outside the submitted work. F.J.M. Broekmans reports personal fees as Member of the external advisory board for Ferring BV, The Netherlands, personal fees as Member of the external advisory board for Merck Serono, The Netherlands, personal fees as Member of the external advisory for Gedeon Richter, Belgium, personal fees from Educational activities for Ferring BV, The Netherlands, grants from Research support grant Merck Serono, grants from Research support grant Ferring, personal fees from Advisory and consultancy work Roche, outside the submitted work. C.B. Lambalk reports grants from Ferring, grants from Merck, grants from Guerbet, outside the submitted work. TRIAL REGISTRATION NUMBER: Registered in the Netherlands Trial Register (NL5193/NTR 5342). TRIAL REGISTRATION DATE: 31 July 2015. DATE OF FIRST PATIENT'S ENROLMENT: 26 January 2016.

Scatter radiation reduction with a radiation-absorbing pad in interventional radiology examinations.

PURPOSE: Radiation-absorbing pads are an additional possibility to reduce scattered radiation at its source. The goal of this study is to investigate the efficacy of a new reusable radiation-absorbing pad at its origin in an experimental setup. MATERIAL AND METHODS: All measurements were carried out using a clinical angiography system with a standardized fluoroscopy protocol, different C-arm angulations and an anthropomorphic torso phantom as a scattering body. An ionization chamber was used to measure the radiation exposure at five different heights of a simulated operator during a simulated transfemoral angiography intervention. Measurements were carried out with and without radiation-absorbing pads with lead equivalents of 0.25 and 0.5 mm placed onto the scattering body. For all measurements a mobile acrylic shield and an under-table lead curtain was used. RESULTS: At all operator heights from 100 to 165 cm a significant radiation dose reduction of up to 80.6 % (p < 0.01) using the radiation-absorbing pad was measured, when compared to no radiation-absorbing pad. At the height of 165 cm the radiation-absorbing pad with a lead equivalence of 0.5 mm showed a significant radiation dose reduction (51.4 %, p < 0.01) in comparison to a lead equivalence of 0.25 mm. CONCLUSION: The addition of a radiation-absorbing pad to the standard protection means results in a significant dose reduction for the operator, particularly for upper body parts.

SOMA-trial: surgery or medication for women with an endometrioma? Study protocol for a randomised controlled trial and cohort study.

STUDY QUESTIONS: The objective of this study is to evaluate the effectiveness and cost-effectiveness of surgical treatment of women suffering from pain due to an ovarian endometrioma when compared to treatment with medication (analgesia and/or hormones). The primary outcome is defined as successful pain reduction (-30% reduction of pain) measured by the numeric rating scale (NRS) after 6 months. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life, affective symptoms, cost-effectiveness, recurrence rate, need of adjuvant medication after surgery, ovarian reserve, adjuvant surgery and budget impact. WHAT IS KNOWN ALREADY: Evidence suggests that both medication and surgical treatment of an ovarian endometrioma are effective in reducing pain and improving quality of life. However, there are no randomised studies that compare surgery to treatment with medication. STUDY DESIGN SIZE DURATION: This study will be performed in a research network of university and teaching hospitals in the Netherlands. A multicentre randomised controlled trial and parallel prospective cohort study in patients with an ovarian endometrioma, with the exclusion of patients with deep endometriosis, will be conducted. After obtaining informed consent, eligible patients will be randomly allocated to either treatment arm (medication or surgery) by using web-based block randomisation stratified per centre. A successful pain reduction is set at a 30% decrease on the NRS at 6 months after randomisation. Based on a power of 80% and an alpha of 5% and using a continuity correction, a sample size of 69 patients in each treatment arm is needed. Accounting for a drop-out rate of 25% (i.e. loss to follow up), we need to include 92 patients in each treatment arm, i.e. 184 in total. Simultaneously, a cohort study will be performed for eligible patients who are not willing to be randomised because of a distinct preference for one of the two treatment arms. We intend to include 100 women in each treatment arm to enable standardization by inverse probability weighting, which means 200 patients in total. The expected inclusion period is 24 months with a follow-up of 18 months. PARTICIPANTS/MATERIALS SETTING METHODS: Premenopausal women (age ≥ 18 years) with pain (dysmenorrhoea, pelvic pain or dyspareunia) and an ovarian endometrioma (cyst diameter ≥ 3 cm) who visit the outpatient clinic will make up the study population. Patients with signs of deep endometriosis will be excluded. The primary outcome is successful pain reduction, which is defined as a 30% decrease of pain on the NRS at 6 months after randomisation. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life and affective symptoms, cost-effectiveness (from a healthcare and societal perspective), number of participants needing additional surgery, need of adjuvant medication after surgery, ovarian reserve and recurrence rate of endometriomas. Measurements will be performed at baseline, 6 weeks and 6, 12 and 18 months after randomisation. STUDY FUNDING/COMPETING INTERESTS: This study is funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-85200-98-91041. The Department of Reproductive Medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck KGaA and Ferring not related to the submitted work. B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck KGaA and Guerbet. V. Mijatovic reports 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. TRIAL REGISTRATION NUMBER: Dutch Trial Register (NTR 7447, http://www.trialregister.nl). TRIAL REGISTRATION DATE: 2 January 2019. DATE OF FIRST PATIENT'S ENROLMENT: First inclusion in randomised controlled trial October 4, 2019. First inclusion in cohort May 22, 2019.

The association between natural outdoor environments and common somatic symptoms.

There is growing evidence that urban natural outdoor environments (NOE) may positively impact health by reducing stress and stress-related symptoms. However, there is limited research investigating this link across a range of NOE indicators. This cross-sectional study investigated the association between neighbourhood NOE (availability, use, and satisfaction with NOE) and common somatic symptoms and the role of potential mediators. Data were analysed from 3481 adults from Barcelona (Spain), Doetinchem (Netherlands), Kaunas (Lithuania) and Stoke-on-Trent (United Kingdom). NOE data were obtained through self-reported data and environmental measurements. Common somatic symptom data were self-reported. Mixed effects regression models were used for analysis, with models adjusted for potential sociodemographic confounders. Higher satisfaction with neighbourhood NOE was associated with lower prevalence of common somatic symptoms (exp(ß) 0.97; 95% CI 0.96, 0.98); an association partially mediated by mental health, social cohesion and air quality concern. A longer time spent in NOE was associated with lower prevalence of common somatic symptoms in low socioeconomic status neighbourhoods (exp(ß) 0.98; 95% CI 0.96, 1.00). A higher number of neighbourhood green spaces (300m buffer) was associated with higher prevalence of common somatic symptoms (exp(ß) 1.03; 95% CI 1.00, 1.05). No statistically significant associations were found for other NOE indicators. Study findings suggest that higher satisfaction with NOE may be associated with lower prevalence of common somatic symptoms, with mental health, social cohesion and concern about air quality playing partial mediating roles. Little evidence was found of an association between objective NOE measurements and common somatic symptoms, underlining the importance of perceptions of NOE for conferring health benefits.

Marital Status and Survival in Patients Diagnosed with Melanoma.

INTRODUCTION: Previous research suggests the presence of a spouse may considerably affect melanoma detection rates through more frequent examinations, better access to healthcare, and improved social support. Yet, the role of marital status on melanoma survival is currently unknown. The aim of this study is to assess whether marital status is associated with survival following melanoma diagnosis. METHODS: We performed secondary analysis of data from all participants of the Florida Cancer Data System (FCDS) and included adult melanoma patients diagnosed between 2001 and 2009 with follow-up information available until 2015. Marital status was categorized as single, married, divorced, or widowed. The primary outcome was survival interval after melanoma diagnosis, which was assessed according to the time from the date of diagnosis to the time of death or last contact. Cox proportional hazard models were used to assess the independent association between marital status and survival. RESULTS: We assessed data from 36,578 melanoma patients. Married patients were significantly more likely to survive than single patients (Hazard ratio (HR) = 0.65; 99% Confidence Interval (CI): 0.57-0.74; P < 0.001) after adjusting for age, sex, race, ethnicity, geographic location, insurance status, tobacco use, primary site, stage, and histology. There was no evidence of effect modification by gender (P=0.189). CONCLUSIONS: Married patients, including both men and women, had a 35% reduction in the risk of death after melanoma diagnosis compared with single patients, and mechanisms independent of earlier detection, such as social support, may play a role in survival in patients with melanoma.

Consensus recommendations on calf- and herd-level passive immunity in dairy calves in the United States.

Passive immunity in calves is evaluated or quantified by measuring serum or plasma IgG or serum total protein within the first 7 d of age. While these measurements inform about circulating concentrations of this important protein, they are also a proxy for evaluating all of the additional benefits of colostral ingestion. The current individual calf standard for categorizing dairy calves with successful passive transfer or failure of passive transfer of immunity are based on serum IgG concentrations of ≥10 and <10 g/L, respectively. This cutoff was based on higher mortality rates in calves with serum IgG <10 g/L. Mortality rates have decreased since 1991, but the percentage of calves with morbidity events has not changed over the same time period. Almost 90% of calves sampled in the USDA National Animal Health Monitoring System's Dairy 2014 study had successful passive immunity based on the dichotomous standard. Based on these observations, a group of calf experts were assembled to evaluate current data and determine if changes to the passive immunity standards were necessary to reduce morbidity and possibly mortality. In addition to the USDA National Animal Health Monitoring System's Dairy 2014 study, other peer-reviewed publications and personal experience were used to identify and evaluate potential standards. Four options were evaluated based on the observed statistical differences between categories. The proposed standard includes 4 serum IgG categories: excellent, good, fair, and poor with serum IgG levels of ≥25.0, 18.0-24.9, 10.0-17.9, and <10 g/L, respectively. At the herd level, we propose an achievable standard of >40, 30, 20, and <10% of calves in the excellent, good, fair, and poor categories, respectively. Because serum IgG concentrations are not practical for on-farm implementation, we provide corresponding serum total protein and %Brix values for use on farm. With one-third of heifer calves in 2014 already meeting the goal of ≥25 g/L serum IgG at 24 h of life, this achievable standard will require more refinement of colostrum management programs on many dairy farms. Implementation of the proposed standard should further reduce the risk of both mortality and morbidity in preweaned dairy calves, improving overall calf health and welfare.

[Revision of guideline on Q fever fatigue syndrome (QFS)]. / Herziene richtlijn Q-koortsvermoeidheidssyndroom (QVS).

In 2012 the multidisciplinary guideline Q fever fatigue syndrome was developed for the Netherlands. The availability of new research data and developments and experiences from daily clinical practice made it necessary to revise this guideline. The multidisciplinary working group that has revised the guideline is composed of representatives from all medical professions involved in the care of patients with QFS and representatives of the patients' association. The revised guideline incorporates a number of changes, including refinement of the QFS diagnostic criteria and updates regarding advice on support and reintegration.

Proposed dairy calf birth certificate data and death loss categorization scheme.

The majority of dairy heifer calves in the United States are destined to be dairy replacements. However, many dairy heifer and bull calves die before 6 mo of age. Of these calves, about 6% (more than 500,000 calves) die at birth or shortly after (i.e., currently termed "stillbirth"). An additional 6% of dairy heifers die during the preweaning period. Death loss in dairy calves is primarily due to stillbirths, failure to adapt to extrauterine life, and infectious disease processes. The reasons for preweaning heifer calf deaths caused by infectious diseases are generally categorized based on easily recognizable clinical signs such as digestive disease/scours or respiratory disease. Most causes of calf death can be mitigated by appropriate preventive care or well-tailored treatments, meaning that the typical death loss percentage could be decreased with better management. Producers could gather information on the circumstances near birth and at death if they had appropriate guidance on what details to record and monitor. This paper provides recommendations on data to collect at the time of birth (i.e., calf birth certificate data). The recording of these critical pieces of information is valuable in evaluating trends over time in morbidity and mortality events in dairy calves. Ideally, necropsy examination would substantially improve the identification of cause of death, but even without necropsy, attribution of cause of death can be improved by more carefully defining death loss categories in on-farm record systems. We propose a death loss categorization scheme that more clearly delineates causes of death. Recommendations are provided for additional data to be collected at the time of death. Recording and analyzing birth certificate and death loss data will allow producers and veterinarians to better evaluate associations between calf risk factors and death, with the goal of reducing dairy calf mortality.

Autonomy deficits as vulnerability for anxiety: evidence from two laboratory-based studies.

BACKGROUND: Autonomous individuals are characterized by self-governance; awareness of and capacity to realize one's wishes and needs, while being connected with and sensitive towards others. In line with earlier research showing consistent associations between autonomy-connectedness deficits and anxiety, we tested in two studies whether autonomy deficits predict anxious responses to acute stressors. METHODS: In Study 1, participants (N = 177) viewed an anxiety-inducing film fragment and reported anxiety before and after viewing the clip. In experimental Study 2, participants (N = 100) were randomly allocated to one of two conditions: giving a short presentation to an audience (impromptu speech task) or watching another person's presentation (control condition). Anxiety was measured at baseline, after a preparation period and directly after the presentation. RESULTS: In Study 1, individuals' anxiety in reaction to watching the movie was positively associated with the autonomy-connectedness component sensitivity to others. In Study 2, individuals' anxiety in reaction to preparing the presentation was negatively associated with the autonomy-connectedness component self-awareness. CONCLUSIONS: Specific autonomy components may be related to experiencing anxiety in differing situations (i.e., related to others' distress or presenting one's personal views). Collectively these results indicate that autonomy-connectedness deficits may form a vulnerability factor for experiencing anxiety.