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Objective: To assess health outcomes, including growth up to 2 years of age, in children born after embryo vitrification in comparison with children born after fresh embryo transfer. Design: A prospective cohort study. Setting: A single-center university hospital. Patient(s): Singletons born after the transfer of vitrified or fresh embryos, either at the cleavage or blastocyst stage between 2014 and 2018, were included. Intervention(s): Multiple linear and logistic regression analyses were used to study the association between outcomes after vitrified versus fresh embryo transfer, controlling for neonatal, treatment, and maternal characteristics. Subgroup analysis according to cycle protocol (hormone replacement vs. natural cycle) and strategy (freeze-all vs. previous fresh cycle) was also performed. Main Outcome Measure(s): Measurements at birth and growth in infancy and childhood, as well as health outcomes, including congenital malformations, interventions, medication use, and hospitalizations are reported. Result(s): Birth characteristics were available for 1237 and 2063 children born after embryo vitrification and fresh embryo transfer, respectively. Follow-up data were available for 582 and 757 children at infancy and for 233 and 296 children at 2 years, respectively. Birthweight, height, and head circumference SD scores of children born after embryo vitrification were higher than children born after fresh embryo transfer, even after adjustment for neonatal, treatment, and maternal characteristics. In infancy, weight and height SD scores were larger for children born after embryo vitrification, but not after adjustment for covariates. In childhood, no differences in anthropometry were observed between the groups. Weight and height gain from birth to infancy and from infancy to early childhood were comparable between the groups. Comparable rates of severe developmental problems, hospital admissions, surgical interventions, and of chronic medication use were observed up to the age of 2 years. Subgroup analysis showed that growth parameters were not affected by the cycle protocol or strategy at any age. Conclusion(s): Our study indicated that embryo vitrification is associated with higher birthweight, even after controlling for confounders. However, in early childhood, anthropometry and weight and height gain was not different in children born after vitrified or fresh embryo transfer.

OBJECTIVE: Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing IVF in a modified natural cycle (MNC-IVF)? STUDY DESIGN: This is a retrospective cohort study including patients attending a tertiary referral University Hospital from 1st January 2017 until 1st March 2020. All predicted poor responders (Poseidon groups 3 and 4) who underwent MNC-IVF in our center were included. Mild ovarian stimulation (rFSH/uFSH/hp-hMG) was started when a follicle with a mean diameter of 12-14 mm was observed on ultrasound scan; GnRH antagonist was added from the next day onwards. Mature oocytes were inseminated using ICSI. RESULTS: In total 484 patients undergoing 1398 cycles were included. Mean (SD) age and serum AMH were 38.2 (3.7) years and 0.28 (0.26) ng/ml, respectively. The daily dose of gonadotropins was either

ObjectiveTo report the parent-reported behavioural outcomes of infants included in the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants study at 2 years’ corrected age (CA).DesignRandomised placebo-controlled trial.SettingDutch and Belgian neonatal intensive care units.PatientsInfants born InterventionInfants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190).Main outcome measuresParent-reported behavioural outcomes at 2 years’ CA assessed with the Child Behavior Checklist (CBCL 1½−5).ResultsParents completed the CBCL of 183 (70% (183/262)) infants (hydrocortisone group, n=96; placebo group, n=87). Multiple imputation was used to account for missing data. Infants with critically elevated T-scores (>55) were found in 22.9%, 19.1% and 29.4% of infants for total, internalising and externalising problems, respectively; these scores were not significantly different between groups (mean difference −1.52 (95% CI −4.00 to 0.96), −2.40 (95% CI −4.99 to 0.20) and −0.81 (95% CI −3.40 to 1.77), respectively). In the subscales, we found a significantly lower T-score for anxiety problems in the hydrocortisone group (mean difference −1.26, 95% CI −2.41 to –0.12).ConclusionThis study found high rates of behaviour problems at 2 years’ CA following very preterm birth, but these problems were not associated with hydrocortisone treatment initiated between 7 and 14 days after birth in ventilated preterm infants.Trial registration numberNTR2768; EudraCT 2010-023777-19.

BackgroundPreterm infants commonly receive red blood cell (RBC), platelet and fresh frozen plasma (FFP) transfusions. The aim of this Neonatal Transfusion Network survey was to describe current transfusion practices in Europe and to compare our findings to three recent randomised controlled trials to understand how clinical practice relates to the trial data.MethodsFrom October to December 2020, we performed an online survey among 597 neonatal intensive care units (NICUs) caring for infants with a gestational age (GA) of ResultsResponses from 343 NICUs (response rate: 57%) are presented and showed substantial variation in clinical practice. For RBC transfusions, 70% of NICUs transfused at thresholds above the restrictive thresholds tested in the recent trials and 22% below the restrictive thresholds. For platelet transfusions, 57% of NICUs transfused at platelet count thresholds above 25×109/L in non-bleeding infants of GA of 9/L threshold was associated with a lower risk of harm in a recent trial. FFP transfusions were administered for coagulopathy without active bleeding in 39% and for hypotension in 25% of NICUs. Transfusion volume, duration and rate varied by factors up to several folds between NICUs.ConclusionsTransfusion thresholds and aspects of administration vary widely across European NICUs. In general, transfusion thresholds used tend to be more liberal compared with data from recent trials supporting the use of more restrictive thresholds. Further research is needed to identify the barriers and enablers to incorporation of recent trial findings into neonatal transfusion practice.

RESEARCH QUESTION: Does additional supplementation with oral dydrogesterone improve reproductive outcomes in patients with low serum progesterone concentrations on the day of frozen embryo transfer (FET) after artificial (HRT) endometrial preparation? DESIGN: Retrospective, single-centre cohort study including 694 unique patients performing single blastocyst transfer in an HRT cycle. For luteal phase support, intravaginal micronized vaginal progesterone (MVP, 400 mg twice daily) was administered. Serum progesterone concentrations were assessed prior to FET and outco-mes were compared among patients with normal serum progesterone (≥8.8 ng/ml) continuing the routine protocol and patients with low serum progesterone (

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Aims Many clinical decision support systems trigger warning alerts for drug-drug interactions potentially leading to QT prolongation and torsades de pointes (QT-DDIs). Unfortunately, there is overalerting and underalerting because stratification is only based on a fixed QT-DDI severity level. We aimed to improve QT-DDI alerting by developing and validating a risk prediction model considering patient- and drug-related factors. Methods We fitted 31 predictor candidates to a stepwise linear regression for 1000 bootstrap samples and selected the predictors present in 95% of the 1000 models. A final linear regression model with those variables was fitted on the original development sample (350 QT-DDIs). This model was validated on an external dataset (143 QT-DDIs). Both true QTc and predicted QTc were stratified into three risk levels (low, moderate and high). Stratification of QT-DDIs could be appropriate (predicted risk = true risk), acceptable (one risk level difference) or inappropriate (two risk levels difference). Results The final model included 11 predictors with the three most important being use of antiarrhythmics, age and baseline QTc. Comparing current practice to the prediction model, appropriate stratification increased significantly from 37% to 54% appropriate QT-DDIs (increase of 17.5% on average [95% CI +5.4% to +29.6%], padj = 0.006) and inappropriate stratification decreased significantly from 13% to 1% inappropriate QT-DDIs (decrease of 11.2% on average [95% CI −17.7% to −4.7%], padj ≤ 0.001). Conclusion The prediction model including patient- and drug-related factors outperformed QT alerting based on QT-DDI severity alone and therefore is a promising strategy to improve DDI alerting.

Acute kidney injury (AKI) is common after pediatric cardiac surgery (CS). Several urine biomarkers have been validated to detect AKI earlier. The objective of this study was to evaluate urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® as predictors for AKI ≥ 1 in pediatric CS after 48 h and AKI ≥ 2 after 12 h. Pediatric patients (age < 18 year; body weight ≥ 2 kg) requiring CS were prospectively included. Urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® were measured during surgery and intensive care unit (ICU) stay and corrected for urine dilution. One hundred and one pediatric patients were included. AKI ≥ 1 within 48 h after ICU admission occurred in 62.4% and AKI ≥ 2 within 12 h in 30.7%. All damage biomarkers predicted AKI ≥ 1 within 48 h after ICU admission, when corrected for urine dilution: CHI3L1 (AUC-ROC: 0.642 (95% CI, 0.535–0.741)), NGAL (0.765 (0.664–0.848)), TIMP-2 (0.778 (0.662–0.868)), IGFBP7 (0.796 (0.682–0.883)), NephroCheck® (0.734 (0.614–0.832)). Similarly, AKI ≥ 2 within 12 h was predicted by all damage biomarkers when corrected for urine dilution: uCHI3L1 (AUC-ROC: 0.686 (95% CI, 0.580–0.780)), NGAL (0.714 (0.609–0.804)), TIMP-2 (0.830 (0.722–0.909)), IGFBP7 (0.834 (0.725–0.912)), NephroCheck® (0.774 (0.658–0.865)). After pediatric cardiac surgery, the damage biomarkers urine CHI3L1, NGAL, TIMP-2, IGFBP7, and NephroCheck® reliably predict AKI after correction for urine dilution.

Introduction: Although the use of 68Ga has increased substantially in nuclear medicine over the last decade, there is limited information available on occupational exposure due to 68Ga. The purpose of this study is to determine the occupational extremity exposure during the preparation, dispensing and administration of 68Ga-labelled radiopharmaceuticals. Method: Workers in eight centres wore a ring dosimeter for all tasks involving 68Ga-labelled radiopharmaceuticals for a minimum of one month. Additionally, the fingertip dose was monitored in two centres and the hand with the highest ring dose during 68Ga procedures was also identified in one centre. Results: The median normalised ring dose for 68Ga procedures was found to be 0.25 mSv GBq−1 (range 0.01–3.34). The normalised 68Ga ring doses recorded in this study are similar to that found in the literature for 18F. This study is consistent with previous findings that the highest extremity dose is found on the non-dominant hand. A limited sub study in two of the centres showed a median fingertip to base of the finger dose ratio of 4.3. Based on this median ratio, the extrapolated annual 68Ga fingertip dose for 94% of the workers monitored in this study would be below Category B dose limit (150 mSv) and no worker would exceed Category A dose limit (500 mSv). Conclusion: When appropriate shielding and radiation protection practices are employed, the extremity dose due to 68Ga is comparable to that of 18F and is expected to be well below the regulatory limits for the majority of workers.

Background Long-term sequelae of COVID-19 can result in reduced functionality of the central nervous system and substandard quality of life. Gaining insight into the recovery trajectory of admitted COVID-19 patients on their cognitive performance and global structural brain connectivity may allow a better understanding of the diseases' relevance. Objectives To assess whole-brain structural connectivity in former non-intensive-care unit (ICU)- and ICU-admitted COVID-19 survivors over 2 months following hospital discharge and correlate structural connectivity measures to cognitive performance. Methods Participants underwent Magnetic Resonance Imaging brain scans and a cognitive test battery after hospital discharge to evaluate structural connectivity and cognitive performance. Multilevel models were constructed for each graph measure and cognitive test, assessing the groups' influence, time since discharge, and interactions. Linear regression models estimated whether the graph measurements affected cognitive measures and whether they differed between ICU and non-ICU patients. Results Six former ICU and six non-ICU patients completed the study. Across the various graph measures, the characteristic path length decreased over time (β = 0.97, p = 0.006). We detected no group-level effects (β = 1.07, p = 0.442) nor interaction effects (β = 1.02, p = 0.220). Cognitive performance improved for both non-ICU and ICU COVID-19 survivors on four out of seven cognitive tests 2 months later (p Conclusion Adverse effects of COVID-19 on brain functioning and structure abate over time. These results should be supported by future research including larger sample sizes, matched control groups of healthy non-infected individuals, and more extended follow-up periods.

When a severe diagnosis is made before or after birth, perinatal palliative care (PPC) can be provided to support the infant, parents and involved healthcare providers. An integrative and systematic overview of effectiveness and working components of existing PPC programs was needed. An integrative search was conducted in MEDLINE, Embase, CENTRAL, CINAHL, PsycInfo and Web of Science. Study designs examining the effect of PPC compared to regular care, and (empirical) articles describing the components of care included in existing PPC initiatives were included. Three independent authors reviewed titles, abstracts and full texts against eligibility criteria. PRISMA guidelines were followed; 21.893 records were identified; 69 publications met inclusion criteria. Twelve publications (17.4%) discussed the effect of a PPC program. Other publications concerned the description of PPC programs, most often by means of a program description (22/69; 31.9%), guidelines (14/769; 20.3%) or case study (10/69; 14.5%). Outcome measures envisioned four main target categories: care coordination, parents and family members, care for the fetus/neonate and healthcare providers. No trials exist to date. Analysis of working components revealed components related to changes directed to the policy of the hospital wards and components involving actual care being provided within the PPC program, directed to the fetus or infant, the family, involved healthcare providers or external actors. PPC is a growing research field where evidence consists mainly of descriptive studies and guidelines. The extensive list of possible PPC components can serve as a checklist for developing future initiatives worldwide. PPC includes several important actors: the fetus/infant and their family and included healthcare providers on both maternity and neonatal wards. This leads to a large variety of possible care components. However, while some studies show proof of concept, an evidence base to determine which components are actually effective is lacking.

BACKGROUND: Extremity exposure during the handling of unsealed radioactive sources is a matter of concern for nuclear medicine workers. Next to 99mTc and 18F, other radiopharmaceuticals have seen an increase in their use over the last decade. However, limited information on their impact on extremity dose is available. This study aimed to gain insight into the status of extremity exposure and dose monitoring in Europe. METHODS: A survey was conducted at the end of 2020 among the European Association of Nuclear Medicine community. It contained 24 questions considering department characteristics, worker tasks, dosimeter use, typical worker extremity dose, department workload for selected radionuclides (99mTc, 18F, 68Ga, 177Lu, 90Y) and protective measures. RESULTS: A total of 106 replies were received, 92% of which were from Europe. About half of the respondents were from academic hospitals. Ninety-nine departments implement extremity dose monitoring for a total of 1335 workers. Most workers (95%) wear a ring dosimeter, generally on the non-dominant hand, and 44% on the index finger. Monthly doses were generally low (median values at different ring position: 0.4-1.8 mSv), although higher doses were reported (20.8-38.8 mSv). About 1/3 of workers performed the full task range (preparation, dispensing, and administration). Administration is associated with significantly lower extremity doses. Interestingly, no correlation between department workload and collective dose was found. The adoption of vial and syringe shielding, as well as distance tools, was common. The workers dispensing 99mTc without syringe shielding or PET nuclides without automated system received a significantly higher dose. Handling 68Ga, 177Lu and 90Y did not appear to have an impact on the reported doses. CONCLUSIONS: Protective measures play a significant role in lowering extremity doses, while department workload and more recently introduced radionuclides seem not to be major dose determinants.

ObjectiveObservational studies in preterm infants suggest that systemic hydrocortisone improves pulmonary condition but may also lead to systemic adverse effects. We report the short-term pulmonary and systemic effects of hydrocortisone initiated in the second week.DesignRandomised placebo-controlled trial.SettingDutch and Belgian neonatal intensive care units.PatientsInfants born InterventionInfants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190).Main outcome measuresData on extubation, ventilator settings, glucose levels, and blood pressure were recorded daily and analysed during the first 7 days of treatment using linear mixed-effects models.ResultsInfants in the hydrocortisone group (24.3%) failed extubation less often compared with placebo (38.6%, crude risk difference: −14.3% (95% CI: −23.4% to −4.8%)). The estimated difference in daily rate of change between hydrocortisone and placebo was −0.42 cmH2O (95% CI: −0.48 to −0.36) for mean airway pressure, −0.02 (95% CI: −0.02 to −0.01) for fraction of inspired oxygen, −0.37 (95% CI: −0.44 to −0.30) for respiratory index, 0.14 mmol/L (95% CI: 0.08 to 0.21) for blood glucose levels and 0.83 mm Hg (95% CI: 0.58 to 1.09) for mean blood pressure.ConclusionsSystemic hydrocortisone initiated between 7 and 14 days after birth in ventilated preterm infants improves pulmonary condition, thereby facilitating weaning and extubation from invasive ventilation. The effects of hydrocortisone on blood glucose levels and blood pressure were mild and of limited clinical relevance.Trial registration numberNetherlands Trial Register (NTR2768;https://www.trialregister.nl/trial/2640) and European Union Clinical Trials Register (EudraCT, 2010-023777-19).

Objectives To study the presence of viral RNA in follicular fluid, cumulus cells and endometrial tissue samples in SARS-CoV-2 positive women undergoing assisted reproductive technologies (ART). Design Prospective, single-center, observational study. Setting Tertiary hospital, University Hospital UZ Brussel, Belgium. Patients Sixteen patients undergoing transvaginal oocyte retrieval who had a positive SARS-CoV-2 RNA test less than 48 hours before the procedure. All cases were done between September 2020 and June 2021 and used in-vitro fertilization or intracytoplasmic sperm injection. All embryos were vitrified to avoid conception during SARS-CoV-2 infection. Intervention Follicular fluid aspirated during oocyte retrieval, cumulus cells and endometrial samples were analyzed for SARS-CoV-2 RNA using RealStar® SARS-CoV-2 RT-PCR-Kit1.0 (Altona-Diagnostics). Main outcome measures The primary outcome parameter was the detection of viral RNA in follicular fluid, cumulus cells and endometrial cells. Fertilization rate, embryo developmental potential and clinical outcome after frozen embryo transfer were secondary outcome parameters. Results Samples from sixteen patients were analyzed. Cycle threshold (Ct) values < 40 were considered positive. All samples were negative for SARS-CoV-2 viral RNA. No inflammatory lesions of the endometrium were identified histologically. Fertilization rate, embryo development and clinical outcomes after embryo transfer were reassuring. Conclusions In women infected with SARS-CoV-2 who underwent ART, viral RNA was undetectable in follicular fluid, cumulus cells and endometrium. Caution is warranted in view of the small sample size, and the risk of SARS-CoV-2 affecting the embryo via ART cannot be ruled out. Adequate counselling of women and couples undergoing ART is crucial in parallel with further research on the effect of exposure of the early human embryo to SARS-CoV-2., In patients with a SARS-CoV-2 infection, viral RNA was undetectable in follicular fluid, cumulus cells and endometrial biopsies. Additionally, embryological data and clinical outcomes are reported.

Humans present remarkable diversity in their mitochondrial DNA (mtDNA) in terms of variants across individuals as well as across tissues and even cells within one person. We have investigated the timing of the first appearance of this variant-driven mosaicism. For this, we deep-sequenced the mtDNA of 254 oocytes from 85 donors, 158 single blastomeres of 25 day-3 embryos, 17 inner cell mass and trophectoderm samples of 7 day-5 blastocysts, 142 bulk DNA and 68 single cells of different adult tissues. We found that day-3 embryos present blastomeres that carry variants only detected in that cell, showing that mtDNA mosaicism arises very early in human development. We classified the mtDNA variants based on their recurrence or uniqueness across different samples. Recurring variants had higher heteroplasmic loads and more frequently resulted in synonymous changes or were located in non-coding regions than variants unique to one oocyte or single embryonic cell. These differences were maintained through development, suggesting that the mtDNA mosaicism arising in the embryo is maintained into adulthood. We observed a decline in potentially pathogenic variants between day 3 and day 5 of development, suggesting early selection. We propose a model in which closely clustered mitochondria carrying specific mtDNA variants in the ooplasm are asymmetrically distributed throughout the cell divisions of the preimplantation embryo, resulting in the earliest form of mtDNA mosaicism in human development.

Although research on sociodemographic correlates of internet use in older adults without and with pronounced cognitive impairment is already quite extensive, much less is known about the relationship between cognitive frailty (CF) and this behaviour. As CF is associated to multidimensional frailty aspects, this study explored the relationship between internet use and CF, operationalised as Subjective Cognitive Impairment, in older adults by means of a comprehensive explanatory model including sociodemographic factors and multiple frailty measures. The dataset included a sample of community-dwelling 60 + older adults that were included in the Belgian Ageing Studies (BAS) and that completed survey questions on (i) internet use frequency and (ii) internet activities. Multidimensional frailty was measured with the CFAI-Plus. The analysis comprised a structural equation modelling (SEM) procedure. Internet use was frequent; however, it became less frequent with higher CF. Moreover, the latter used less tablets as compared to the no-low CF group. Navigating the web, sharing email and online banking were the most frequently reported activities. Tele-communicating with Skype, online shopping and using e-government services were the least frequent. Age, female gender, lower income and living with a partner were also negatively associated with internet use. To conclude, CF, along with other frailty and sociodemographic factors, was negatively related to internet use in older adults. Future research should focus, amongst others, on the dynamic processes underlying internet use in the population of older adults affected by CF.The online version contains supplementary material available at 10.1007/s10433-022-00686-2.

Research question Do cumulative live birth rates (CLBR) differ between polycystic ovary syndrome (PCOS) phenotypes when a freeze-all strategy is used to prevent ovarian hyperstimulation syndrome (OHSS) after ovarian stimulation (OS)? Design This is a single-centre, retrospective cohort study including 422 women with PCOS as defined by Rotterdam criteria or with PCO-like ovarian morphology-only (PCOM) in whom, between January 2015 and December 2019, a freeze-all strategy was applied after GnRH agonist triggering in the context of hyper-response defined as ≥18 follicles of ≥11 mm in their first or second IVF/ICSI cycle in a tertiary referral hospital. The primary outcome was CLBR resulting from the transfer of all cryopreserved embryos from the same IVF/ICSI cycle. Analysis was performed by multivariate logistic regression analysis adjusting for confounders. Results In total, 91/422 (21.6%) patients had PCOS phenotype A (hyperandrogenism + ovulation disorder + PCOM = HOP), 33/422 (7.8%) had phenotype C (hyperandrogenism + PCOM = HP), 161/422 (38.2%) had phenotype D (ovulation disorder + PCOM = OP) and 137/422 (32.5%) had PCOM. Unadjusted CLBR was similar among the groups (69.2%, 69.7%, 79.5% and 67.9%, respectively; p= 0.11). The multivariate logistic regression model adjusting for age, BMI, number of oocytes, fertilization rate and embryo stage at vitrification confirmed that the PCOS/PCOM phenotype did not have any impact on CLBR [OR 0.72, CI 0.24-2.14 (phenotype C); OR 1.55, CI 0.71-3.36 (phenotype D); OR 0.84, CI 0.39-1.83 (PCOM); p= 0.2, with phenotype A as reference]. Conclusions In subfertile women with PCOS eligible for ART, hyper-response after OS confers excellent cumulative live birth rates of ∼70%, irrespective of the phenotype, when a freeze-all strategy is used. This contrasts with the unfavourable clinical outcomes that have previously been observed in hyperandrogenic PCOS women who underwent mild OS targeting normal ovarian response and fresh embryo transfer. The data should however be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. The results cannot be generalized to all ART cycles in women with polycystic ovaries as they pertain to those cycles in which hyper-response is observed after OS.

AIM: The direct oral anticoagulants (DOACs) are increasingly used for stroke prevention in atrial fibrillation (AF). However, little is known about the association between medication adherence, patient satisfaction and treatment knowledge. The objective was to determine patients' DOAC adherence and their treatment satisfaction over time. Furthermore, we respectively investigated possible associations of treatment satisfaction and treatment knowledge in relation to adherence. METHODS: Longitudinal study conducted in AF patients hospitalized in 2019 in a tertiary university hospital. DOAC adherence, treatment satisfaction and knowledge were assessed with validated questionnaires. Mixed effects logistic regression was modelled to investigate the effect of both treatment satisfaction and knowledge on DOAC adherence over time. RESULTS: In total, 164 patients participated of which 128 and 101 patients could be recontacted after a period of respectively 3 (first contact) and 6 months (second contact) to assess adherence and treatment satisfaction. Suboptimal adherence was observed in 40.6% of the patients after 3 months and in 42.6% after 6 months (p=0.78). There was no significant difference (p=0.29) in the total score for treatment satisfaction between the first (79.2%) and the second contact (80.6%). DOAC adherence was not affected by time (p=0.71) nor by total knowledge score (p=0.61) or treatment satisfaction score (p=0.34). Nonetheless, a strong correlation between treatment satisfaction and knowledge was found (p=0.004). CONCLUSION: DOAC adherence was suboptimal. Treatment satisfaction and knowledge were not associated with DOAC adherence over a 6 month period. Knowledge gaps were identified that could be remediated through patient education and follow-up.

Objectives Patients eligible for spinal cord stimulation (SCS) generally experience excruciating pain, requiring more opioid consumption, which is usually an indication for SCS implantation. After final implantation, SCS has the ability to stabilize or decrease opioid usage in half of the patients. In this study, opioids were actively eliminated prior to implantation of any neuromodulation device with a standardized detoxification protocol. This pilot study aims to explore the feasibility, effectiveness, and safety of this opioid detoxification protocol prior to neuromodulation techniques. Materials and methods In this retrospective pilot study, 70 patients who were taking opioids and who were eligible for neuromodulation techniques, underwent the detoxification program. A combined in- and out-patient clinic protocol was applied, whereby clonidine was the main component of both parts of the program. A multidisciplinary team with pain physicians and psychologists was responsible for performing this detoxification program. Safety and feasibility were systematically recorded during the hospitalization. Results No serious safety issues were reported. At the start of the program, patients reported a mild sedative effect of clonidine. Additionally, most patients presented mild symptoms of opioid withdrawal, which were partially countered by the sedative effect of clonidine. Both patients and the medical staff found this protocol feasible in clinical practice. Concerning the effectiveness, a statistically significant decrease in median morphine milligram equivalents (MMEs) was found with a MME of 175 (Q1-Q3: 118.1-240) at baseline and at the last available follow-up visit the MME was 0 (Q1-Q3: 0-16.88). Conclusions This standardized detoxification program has proven its effectiveness, safety, and feasibility in this single-center experience pilot study in patients eligible for neuromodulation techniques.

About half of testicular sperm extraction (TESE) procedures in men with non-obstructive azoospermia (NOA), including men with Klinefelter syndrome (KS), are unsuccessful. To avoid unnecessary invasive surgery, biomarkers for spermatozoa were studied. In addition, markers for spermatogonia in testis tissue were explored. This study aimed to find biomarkers in the semen and/or urine of NOA patients to predict the presence of spermatogonia in the testis. Differentially expressed miRNAs were identified (1) between samples from patients with and without a positive TESE procedure as well as (2) between TESE-negative patients with and without spermatogonia. A total of thirteen upregulated miRNAs (ten in seminal plasma and three in urine) were found in the TESE-negative/spermatogonia-positive group compared to the TESE-negative/spermatogonia-negative group. These miRNAs could be potential biomarkers for spermatogonia; however, more research is necessary to validate their predictive power.

Fatigue, pain, headache, brain fog, anosmia, ageusia, mood symptoms, and sleep disorders are symptoms commonly experienced by people with post-COVID-19 condition. These symptoms could be considered as manifestations of central sensitization. The aim of this study is to evaluate whether there are indicators of central sensitization by using experimental pain measurements and to determine their association with patient-reported outcome measures (PROMs). A cross-sectional study including 42 patients after COVID-19 infection was conducted. The central sensitization inventory (CSI) was administered as a PROM to evaluate central-sensitization-associated symptoms. Pressure pain thresholds (PPT), temporal summation, and descending nociceptive pain inhibition (CPM) were assessed as experimental pain measurements. The median score on the CSI was 46.5 (Q1–Q3: 33–54). The presence of central-sensitization-associated symptoms was seen in 64.3% of patients based on the CSI (≥40/100 points). A deficient CPM was seen in 12% and 14% of patients when measured at the trapezius and rectus femoris, respectively. A negative correlation between pressure sensitivity on the rectus femoris and the CSI score (r = −0.36, 95%CI −0.13 to −0.65, p = 0.007) was observed. Central-sensitization-associated symptoms were present in up to 64.3% of patients post-COVID-19 infection, based on a PROM, i.e., the CSI. A more objective evaluation of nociceptive processing through experimental pain measurements was less suggestive of indicators of central sensitization. Only a small negative correlation between pressure sensitivity and the CSI was observed, thereby pointing towards the discrepancy between the CSI and experimental pain measurements and presumably the complementary need for both to evaluate potential indicators of central sensitization in this population.

Item does not contain fulltext Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T(>MIC)) (for efficacy purposes and 100% T(>4×MIC) and 100% T(>5×MIC) to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T(>MIC) during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T(>MIC) during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T(>4×MIC) and 100% T(>5×MIC) are desired.

Florence Talrich,1,2 Astrid Van Damme,1,2 Hilde LA Bastiaens,3 Jochen Bergs,4 Marlies EB Rijnders,5 Katrien Beeckman1,2,6 1Department of Public Health, Vrije Universiteit Brussel (VUB), Jette, Belgium; 2Department of Nursing and Midwifery Research Group (NUMID), Universitair Ziekenhuis Brussel (UZ Brussel), Jette, Belgium; 3Department Family Medicine and Population Health, Universiteit Antwerpen, Antwerp, Belgium; 4Department of Healthcare, Universiteit Hasselt, Hasselt, Belgium; 5Department of Child Health, TNO, Leiden, the Netherlands; 6Department Nursing and Midwifery, Universiteit Antwerpen, Antwerp, BelgiumCorrespondence: Florence Talrich, Laarbeeklaan 103, Brussel, Jette, 1090, Belgium, Tel +324749853, Email florence.talrich@vub.be

OBJECTIVES: To date, pain relief in general continues to be the most prominent outcome measurement in daily routine care and clinical research. Nevertheless, the awareness of a shift toward more functional outcomes and/or emotional and cognitive outcomes has been raised. The interplay between bodily functions (such as pain intensity) and emotional or cognitive factors, however, has not yet been fully elucidated. The aim of this study was to systematically review the evidence for associations between bodily functions and cognitive and emotional factors in patients with chronic pain who are treated with neuromodulation. MATERIALS AND METHODS: Four data bases were consulted for this systematic literature review: PubMed, Web of Science, Scopus, and Embase. The Downs and Black Checklist (modified) was used to assess the risk of bias. The study protocol was prospectively registered at the International prospective register of systematic reviews (PROSPERO, CRD42021226803). If two or more studies reported correlation coefficients for a specific association, a meta-analysis based on correlation coefficients was performed for that specific association. RESULTS: The initial data base search identified a total of 1432 studies, of which 19 studies were eventually included in the systematic review. Evidence was found for two associations: 1) a positive correlation between pain intensity and anxiety (r = 0.42; 95% CI, 0.34 to 0.50) and 2) a positive correlation between pain intensity and depression (r = 0.32; 95% CI, 0.10 to 0.51). The association between pain intensity and catastrophizing was not statistically significant (r = 0.23; 95% CI, -0.36 to 0.69). CONCLUSIONS: On the basis of the associations between pain intensity and anxiety/depression, a biopsychosocial approach might be the most suitable in clinical practice to properly address all aspects of the International Classification of Functioning, Disability, and Health framework in patients who are treated with neuromodulation.

OBJECTIVES: Spinal cord stimulation (SCS) can reduce the need for opioids; however, the influence on the full spectrum of pain medication is less known. The aims of this study were to explore general prescription practices for patients scheduled for SCS, potential differences in prescriptions between Belgium and United Kingdom, and the influence of SCS on pain medication. MATERIALS AND METHODS: Individual patient data from the TRIAL-STIM study in the United Kingdom and DISCOVER in Belgium were pooled. Medication use was collected before SCS and three months after SCS from 180 chronic pain patients. The Medication Quantification Scale III (MQS) was used to calculate a total score for medication use, as well as subscores for several classes. Differences in prescription practices between United Kingdom and Belgium were evaluated with two-sided Wilcoxon tests. To evaluate differences in medication use after three months of SCS between United Kingdom and Belgium, Tweedie-generalized linear models were calculated.RESULTS: There was a statistically significant difference (-6.40 [95% CI from -3.40 to -9.10]) between the median total MQS score in United Kingdom and Belgium before SCS. Additionally, a significant difference was found for nonsteroidal anti-inflammatory drugs (NSAIDs) (-3.40 [95% CI -3.40 to -6.80]), neuropathic agents (-2.30 [95% CI -0.40 to -3.80]), and benzodiazepines (1.83e-05 [95% CI 2.64-05 to 7.45-05 ]) between United Kingdom and Belgium, before SCS. Tweedie-generalized models revealed a statistically significant interaction between country and time for MQS, neuropathic agents, and opioids. CONCLUSIONS: Our combined analysis revealed differences in prescription practice in patients scheduled for SCS implantation between Belgium and United Kingdom. NSAIDs and neuropathic mood agents are more frequently used in the United Kingdom, presumably due to easier access to repeat prescriptions and over the counter medications. After three months of SCS, a decrease in medication use is observed in both countries, with higher reductions in Belgium, presumably due to strict regulations concerning reimbursement criteria.

AIM: After preterm birth, supine head midline position is supported for stable cerebral blood flow (CBF) and prevention of intraventricular haemorrhage (IVH), while prone position supports respiratory function and enables skin-to-skin care. The prone compared to supine position could lead to a change in near-infrared derived cerebral tissue oxygen saturation (rScO2), which is a surrogate for cerebral blood flow (CBF). By monitoring rScO2 neonatologists aim to stabilise CBF during intensive care and prevent brain injury. In this systematic review and meta-analysis, we investigate the effect of the body position on rScO2. METHODS: A comprehensive literature search was performed to identify all trials that included preterm infants in the first 2 weeks after birth and compared rScO2 in the prone versus supine head in midline position of the infant. A meta-analysis, including two subgroup analyses based on postnatal age (PNA) and gestational age (GA), was performed. RESULTS: Six observational cohort studies wereincluded. In the second, but not the first week after birth, a significant higher rScO2 in the prone position was found with a mean difference of 1.97% (95% CI 0.87-3.07). No rScO2 difference was observed between positions in the extremely preterm nor the preterm group. CONCLUSION: No consistent evidence was found that body position influences rScO2 in the first 2 weeks after preterm birth. Subgroup analysis suggests that in the second week after birth, the prone position might result in higher cerebral rScO2 than the supine position with head in midline. Multiple factors determine the best body position in preterms.

Background Drug-disease interactions are situations where pharmacotherapy may have a negative effect on patients' comorbidities. In these cases, it can be necessary to avoid that drug, adjust its dose or monitor therapy. In the Netherlands, pharmacists have developed a best practice how to systematically evaluate drug-disease interactions based on pharmacological considerations and implement recommendations for specific drug-disease interactions. Aim To describe the development of recommendations for drug-disease interactions and the implementation in prescribing and dispensing practice in the Netherlands. Setting Pharmacies and physicians' practices in primary care and hospitals in the Netherlands. Development A multi-disciplinary expert panel assessed if diseases had clinically relevant drug-disease interactions and evaluated drug-disease interactions by literature review and expert opinion, and subsequently developed practice recommendations. Implementation The recommendations were implemented in all clinical decision support systems in primary care and hospitals throughout the Netherlands. Evaluation Recommendations were developed for 57 diseases and conditions. Cardiovascular diseases have the most drug-disease interactions (n = 12, e.g. long QT-syndrome, heart failure), followed by conditions related to the reproductive system (n = 7, e.g. pregnancy). The number of drugs with recommendations differed between 6 for endometriosis and tympanostomy tubes, and up to 1171 in the case of porphyria or even all drugs for pregnancy. Conclusion Practice recommendations for drug-disease interactions were developed, and implemented in prescribing and dispensing practice. These recommendations support both pharmacists and physicians by signalling clinically relevant drug-disease interactions at point of care, thereby improving medication safety. This practice may be adopted and contribute to safer medication use in other countries as well.

Background: Klinefelter syndrome (KS; 47,XXY) affects 1-2 in 1000 males. Most KS men suffer from an early germ cell loss and testicular fibrosis from puberty onwards. Mechanisms responsible for these processes remain unknown. Previous genomics studies on KS tissue focused on germ cell loss, while a transcriptomic analysis focused on testicular fibrosis has not yet been performed. This study aimed to identify factors involved in the fibrotic remodelling of KS testes by analysing the transcriptome of (non-)fibrotic testicular tissue.Material and methods: RNA sequencing was performed to compare the genetic profile of testicular samples with (KS and testis atrophy) and without (Sertoli cell-only syndrome and fertile controls) fibrosis (n=5, each). Additionally, differentially expressed genes (DEGs) between KS and testis atrophy samples were studied to reveal KS-specific fibrotic genes. DEGs were considered significant when p2. Next, downstream analyses (GO and KEGG) were performed. Lastly, RNA scope was performed to validate the results.Results: The first analysis (fibrotic vs non-fibrotic) resulted in 734 significant DEGs (167 up- and 567 down-regulated). Genes involved in the extracellular structure organization (e.g. VCAM1) were found upregulated. KEGG analysis showed an up-regulation of genes involved in the TGF-β pathway.The KS vs TA analysis resulted in 539 significant DEGs (59 up- and 480 down-regulated). Chronic inflammatory response genes were found upregulated. The overlap of X-linked DEGs from the two analyses revealed three genes: matrix-remodelling associated 5 (MXRA5), doublecortin (DCX) and variable charge X-Linked 3B (VCX3B). RNA in situ hybridization showed an overexpression of VCAM1, MXRA5 and DCX within the fibrotic group compared with the non-fibrotic group.Conclusion: In this study, DEGs between fibrotic and non-fibrotic tissue were first compared, revealing fibrotic genes, including VCAM1. Secondly, DEGs between KS and TA samples were studied and the analysis revealed KS-specific, fibrotic genes. When comparing X-linked genes of the first analysis (fibrotic versus non-fibrotic) with those of the second analysis (KS versus TA), KS-related X-linked fibrotic genes were revealed, i.e. MXRA5, DCX and VCX3B. Their potential role in KS-related testicular fibrosis needs further study.

Background For patients with therapy-refractory persistent spinal pain syndrome type II (PSPS-T2), spinal cord stimulation (SCS) may serve as an effective minimally invasive treatment. Despite the evidence that SCS can improve return to work (RTW), only 9.5 to 14% of patients implanted with SCS are effectively capable of returning to work. Thus, it seems that current post-operative interventions are not effective for achieving RTW after SCS implantation in clinical practice. The current objective is to examine whether a personalised biopsychosocial rehabilitation programme specifically targeting RTW alters the work ability in PSPS-T2 patients after SCS implantation compared to usual care. Methods A two-arm, parallel-group multicentre randomised controlled trial will be conducted including 112 patients who will be randomised (1:1) to either (a) a personalised biopsychosocial RTW rehabilitation programme of 14 weeks or (b) a usual care arm, both with a follow-up period until 12 months after the intervention. The primary outcome is work ability. The secondary outcomes are work status and participation, pain intensity, health-related quality of life, physical activity and functional disability, functional capacities, sleep quality, kinesiophobia, self-management, anxiety, depression and healthcare expenditure. Discussion Within the OPERA project, we propose a multidisciplinary personalised biopsychosocial rehabilitation programme specifically targeting RTW for patients implanted with SCS, to tackle the high socio-economic burden of patients that are not re-entering the labour market. The awareness is growing that the burden of PSPS-T2 on our society is expected to increase over time due to the annual increase of spinal surgeries. However, innovative and methodologically rigorous trials exploring the potential to decrease the socio-economic burden when patients initiate a trajectory with SCS are essentially lacking. Trial registration ClinicalTrials.gov NCT05269212. Registered on 7 March 2022.

Background In order to acquire accurate drug pharmacokinetic information, which is required for tissue dosimetry, micro-SPECT must be quantitative to allow for an accurate assessment of radioligand activity in the relevant tissue. This study investigates the feasibility of deriving accurate mouse-specific time-integrated drug pharmacokinetic data in mouse kidneys from activity measurements using micro-SPECT. Methods An animal experiment was carried out to evaluate the accuracy of 131I activity quantification in mouse kidneys (mean tissue volume of 0.140 mL) using a micro-SPECT system against conventional ex vivo gamma counting (GC) in a NaI(Tl) detector. The imaging setting investigated was that of the mouse biodistribution of a 131I-labelled single-domain antibody fragment (sdAb), currently being investigated for targeted radionuclide therapy of HER2-expressing cancer. SPECT imaging of 131I 365-keV photons was done with a VECTor/CT system (MILabs, Netherlands) using a high-energy mouse collimator with 1.6-mm-diameter pinholes. For both activity quantification techniques, the pharmacokinetic profile of the radioligand from approximately 1–73 h p.i. was derived and the time-integrated activity coefficient per gram of tissue (ã/M) was estimated. Additionally, SPECT activity recovery coefficients were determined in a phantom setting. Results SPECT activities underestimate the reference activities by an amount that is dependent on the 131I activity concentration in the kidney, and thus on the time point of the pharmacokinetic profile. This underestimation is around − 12% at 1.5 h (2.89 MBq mL−1 mean reference activity concentration), − 13% at 6.6 h (149 kBq mL−1), − 40% at 24 h (17.6 kBq mL−1) and − 46% at 73 h (5.2 kBq mL−1) p.i. The ã/M value estimated from SPECT activities is, nevertheless, within − 14% from the reference (GC) ã/M value. Furthermore, better quantitative accuracy (within 2% from GC) in the SPECT ã/M value is achieved when SPECT activities are compensated for partial recovery with a phantom-based recovery coefficient of 0.85. Conclusion The SPECT imaging system used, together with a robust activity quantification methodology, allows an accurate estimation of time-integrated pharmacokinetic information of the 131I-labelled sdAb in mouse kidneys. This opens the possibility to perform mouse-specific kidney-tissue dosimetry based on pharmacokinetic data acquired in vivo on the same mice used in nephrotoxicity studies.

Background Group care (GC) improves the quality of maternity care, stimulates women’s participation in their own care and facilitates growth of women’s social support networks. There is an urgent need to identify and disseminate the best mechanisms for implementing GC in ways that are feasible, context appropriate and sustainable. This protocol presents the aims and methods of an innovative implementation research project entitled Group Care in the first 1000 days (GC_1000), which addresses this need. Aims The aim of GC_1000 is to co-create and disseminate evidence-based implementation strategies and tools to support successful implementation and scale-up of GC in health systems throughout the world, with particular attention to the needs of ‘vulnerable’ populations. Methods By working through five inter-related work packages, each with specific tasks, objectives and deliverables, the global research team will systematically examine and document the implementation and scale-up processes of antenatal and postnatal GC in seven different countries. The GC_1000 project is grounded theoretically in the consolidated framework for implementation research (CFIR), while the process evaluation is guided by ‘Realistic Evaluation’ principles. Data are gathered across all research phases and analysis at each stage is synthesized to develop Context-Intervention-Mechanism-Outcome configurations. Discussion GC_1000 will generate evidence-based knowledge about the integration of complex interventions into diverse health care systems. The 4-year project also will pave the way for sustained implementation of GC, significantly benefitting populations with adverse pregnancy and birthing experiences as well as poor outcomes.

Background: In real-life settings, guidelines frequently cannot be followed since many patients are multimorbid and/or elderly or have other complicating conditions which carry an increased risk of drug-drug interactions. This document aimed to adapt recommendations from existing clinical practice guidelines (CPGs) to assist physicians' decision-making processes concerning specific and complex scenarios related to acute CAP.Methods: The process for the adaptation procedure started with the identification of unsolved clinical questions (PICOs) in patients with CAP and continued with critically appraising the updated existing CPGs and choosing the recommendations, which are most applicable to these specific scenarios.Results: Seventeen CPGs were appraised to address five PICOs. Twenty-seven recommendations were endorsed based on 7 high, 9 moderate, 10 low, and 1 very low-quality evidence. The most valid recommendations applicable to the clinical practice were the following ones: Respiratory virus testing is strongly recommended during periods of increased respiratory virus activity. Assessing the severity with a validated prediction rule to discriminate where to treat the patient is strongly recommended along with reassessing the patient periodically for improvement as expected. In adults with multiple comorbidities, polypharmacy, or advanced age, it is strongly recommended to check for possible drug interactions before starting treatment. Strong graded recom-mendations exist on antibiotic treatment and its duration. Recommendations on the use of biomarkers such as C -reactive protein or procalcitonin to improve severity assessment are reported.Conclusion: This document provides a simple and reliable updated guide for clinical decision-making in the management of complex patients with multimorbidity and CAP in the real-life setting.

Background End-of-life decisions with potential life-shortening effect in neonates and infants are common. We aimed to evaluate how often and in what manner neonatologists consult with parents and other healthcare providers in these cases, and whether consultation is dependent on the type of end-of-life decision made. Methods Based on all deaths under the age of one that occurred between September 2016 and December 2017 in Flanders, Belgium, a nationwide mortality follow-back survey was performed. The survey asked about different types of end-of-life decisions, and whether and why parents and/or other healthcare providers had or had not been consulted. Results Response rate was 83% of the total population. End-of-life decisions in neonates and infants were consulted both with parents (92%) and other healthcare providers (90%), and agreement was reached between parents and healthcare providers in most cases (96%). When medication with an explicit life-shortening intent was administered parents were always consulted prior to the decision; however when medication without explicit life-shortening intention was administered parents were not consulted in 25% of the cases. Conclusions Shared decision-making between parents and physicians in case of neonatal or infant end-of-life decision-making is the norm in daily practice. All cases without parental consultation concerned non-treatment decisions or comfort medication without explicit life-shortening intention where physicians deemed the medical situation clear and unambiguous. However, we recommend to at least inform parents of medical options, and to explore other possibilities to engage parents in reaching a shared decision. Physicians consult other healthcare providers before making an end-of-life decision in most cases.

Virtual reality has proven to be an effective approach to decrease pain in acute settings, both in adults and children. The aim of this study is to evaluate whether virtual reality (VR) could reduce pain during an intrathecal pump refill procedure in children receiving intrathecal drug delivery, compared to a standard refill procedure. This is a three-arm crossover randomized controlled trial, evaluating the effect of VR on pain in children with cerebral palsy undergoing an intrathecal pump refill compared to a standard refill and a refill with distraction (watching a video). Pain was evaluated using the Wong–Baker Faces Scale. Secondary outcomes were procedural pain, fear, state anxiety, the incidence of adverse events and satisfaction. Six children participated in this study, whereby all children underwent the three conditions. Five children indicated an equal of lower pain score during VR, compared to a standard refill. This finding of an equal or lower pain intensity score for the VR condition compared to the control condition was also revealed by the ratings of the parents, physician and the researcher. The influence of VR on anxiety and fear seem to be in line with the influence of watching a video. In terms of satisfaction, all children and parents agreed with the statement that they would like to use VR again for a next refill. Due to the lack of adverse events, the high degree of satisfaction of children with VR and the decreased pain levels after a refill with VR, physicians may aim to explore the implementation of VR during intrathecal pump refill procedures in children in a daily clinical routine care setting.

BACKGROUND As in other domains of medicine, high-throughput sequencing methods have led to the identification of an ever-increasing number of gene variants in the fields of both male and female infertility. The increasing number of recently identified genes allows an accurate diagnosis for previously idiopathic cases of female infertility and more appropriate patient care. However, robust evidence of the gene–disease relationships (GDR) allowing the proper translation to clinical application is still missing in many cases. OBJECTIVE AND RATIONALE An evidence-based curation of currently identified genes involved in female infertility and differences in sex development (DSD) would significantly improve both diagnostic performance and genetic research. We therefore performed a systematic review to summarize current knowledge and assess the available GDR. SEARCH METHODS PRISMA guidelines were applied to curate all available information from PubMed and Web of Science on genetics of human female infertility and DSD leading to infertility, from 1 January 1988 to 1 November 2021. The reviewed pathologies include non-syndromic as well as syndromic female infertility, and endocrine and reproductive system disorders. The evidence that an identified phenotype is caused by pathogenic variants in a specific gene was assessed according to a standardized scoring system. A final score (no evidence, limited, moderate, strong, or definitive) was assigned to every GDR. OUTCOMES A total of 45 271 publications were identified and screened for inclusion of which 1078 were selected for gene and variant extraction. We have identified 395 genes and validated 466 GDRs covering all reported monogenic causes of female infertility and DSD. Furthermore, we present a genetic diagnostic flowchart including 105 genes with at least moderate evidence for female infertility and suggest recommendations for future research. The study did not take into account associated genetic risk factor(s) or oligogenic/polygenic causes of female infertility. WIDER IMPLICATIONS We have comprehensively reviewed the existing research on the genetics of female infertility and DSD, which will enable the development of diagnostic panels using validated genes. Whole genome analysis is shifting from predominantly research to clinical application, increasing its diagnostic potential. These new diagnostic possibilities will not only decrease the number of idiopathic cases but will also render genetic counselling more effective for infertile patients and their families.

In clinical practice, many drug therapies are associated with prolongation of the QT interval. In literature, estimation of the risk of prescribing drug-induced QT prolongation is mainly executed by means of logistic regression; only one paper reported the use of machine learning techniques. In this paper, we compare the performance of both techniques on the same dataset. High risk for QT prolongation was defined as having a corrected QT interval (QTc) ≥ 450 ms or ≥ 470 ms for respectively male and female patients. Both conventional statistical methods (CSM) and machine learning techniques (MLT) were used. All algorithms were validated internally and with a hold-out dataset of respectively 512 and 102 drug-drug interactions with possible drug-induced QTc prolongation. MLT outperformed the best CSM in both internal and hold-out validation. Random forest and Adaboost classification performed best in the hold-out set with an equal harmonic mean of sensitivity and specificity (HMSS) of 81.2% and an equal accuracy of 82.4% in a hold-out dataset. Sensitivity and specificity were both high (respectively 75.6% and 87.7%). The most important features were baseline QTc value, C-reactive protein level, heart rate at baseline, age, calcium level, renal function, serum potassium level and the atrial fibrillation status. All CSM performed similarly with HMSS varying between 60.3% and 66.3%. The overall performance of logistic regression was 62.0%. MLT (bagging and boosting) outperform CSM in predicting drug-induced QTc prolongation. Additionally, 19.2% was gained in terms of performance by random forest and Adaboost classification compared to logistic regression (the most used technique in literature in estimating the risk for QTc prolongation). Future research should focus on testing the classification on fully external data, further exploring potential of other (new) machine and deep learning models and on generating data pipelines to automatically feed the data to the classifier used.

Representatives of neuromodulation device manufacturers are expected to facilitate the relationship between patients and healthcare providers. Nevertheless, the goals, expectations, and definition of success for neuromodulation for pain have not yet been explored. Representatives present at the 2nd Joint Congress of the INS European Chapters in September 2021 completed a survey to ascertain their opinions about the goals to achieve with neuromodulation, the factors that they expect to change, and their definition of success for neuromodulation. In total, 39 representatives completed the survey. To provide excellent service for patients (22.4%), to become a trusted partner for physicians (21.5%), and to provide excellent service for physicians (20.7%) were the highest ranked goals. The most frequently reported factors that were expected to change were pain intensity (23.1%), patient satisfaction (19.7%), mobility/functioning (14.5%), and capacity to return to work (13.7%). Within the definitions of success, increased quality of life of the patient was stated in 21% of the definitions, closely followed by pain control (19.3%) and happiness/patient satisfaction (15.8%). The goals of representatives of neuromodulation device manufacturers seem to focus on ensuring a good relationship with physicians on the one hand and providing good service towards patients on the other hand, whereby pain control, quality of life, and patient satisfaction seem to be important for company representatives.

Intracytoplasmic sperm injection (ICSI), developed 30 years ago in our Center, allowed men with low to extremely low sperm quality to become the genetic father of their child. Overall, ICSI is now applied in up to 70% of all ART cycles and has resulted in the birth of millions of children worldwide. ICSI circumvents natural sperm selection mechanisms and concerns related to transgenerational inheritance of male infertility following ICSI could not be fully answered till today, given the young age of the offspring born after ICSI. Since genetic abnormalities account for one third of all cases of male factor infertility, it is essential to identify these genetic abnormalities because of the potential risk of their transmission to the offspring through the use of ART. As ICSI is nowadays performed even in couples with normal semen parameters, the disentanglement of procedure-related and parental background-related factors on the health of the offspring is important. Due to the safety concerns regarding the health of children born after ART, a longitudinal follow-up program was set up in our Center in the 80’s, resulting in data of more than 50 000 pregnancies. To date, more than 25 000 children are conceived after ICSI in our Center. We have not only the worldwide eldest cohort of ICSI offspring but also a uniform cohort of children and young adults conceived by ICSI because of (severe) male factor infertility. We present the results of these prospective studies with focus on the reproductive health in ICSI children between 8 and 22 years and compare these with available data from others. First of all, we will show data on the gonadal function assessed both clinically and by means of biomarkers at pre-pubertal and pubertal ages in ICSI boys. Secondly, we will present findings on the reproductive status of young adult men and women conceived after ICSI between 1992 and 1996: results of hormonal work-up, physical examination and semen parameters for ICSI men and results of hormone levels and antral follicle counts for ICSI women. Finally, we will discuss the findings in these cohorts of children and young adults conceived because of male infertility in view of the available literature regarding reproductive function in offspring conceived following ICSI.

The current drug allergy documentation module in the electronic health record of our institution is in a free-text format. Two versions of a structured and coded drug allergy documentation module were developed. Twenty-five physicians tested the three interfaces via 3x5 test scenarios. The usability was measured for each interface with a system usability scale questionnaire. Both new versions scored significantly better than the current free-text version. User feedback will be used to further optimize the new module.

PURPOSE: To investigate whether treatment with commercially available ready-to-use A23187 ionophore (GM508-CultActive) improves embryo development outcome in patients with a history of embryo developmental problems. METHODS: This is a uni-center prospective study in which sibling oocytes of patients with embryos of poor quality on day 5 in the previous cycle were treated or not with CultActive. RESULTS: Two hundred forty-seven metaphase II (MII) oocytes from 19 cycles performed between 2016 and 2019 were included in the study. After ICSI, the sibling oocytes were assigned to the treatment group or to the control group, following an electronically generated randomization list. A number of 122 MII were treated with CultActive and 125 MII had no treatment and were assigned to the control group. No difference in fertilization rate (p = 0.255) or in the capacity of embryos to reach good quality on day 5 (p = 0.197) was observed between the two groups. The utilization rates defined as the number of embryos transferred or cryopreserved per mature oocyte (p = 0.438) or per fertilized oocytes (p = 0.299) were not significantly different between the treated group and the control group. CONCLUSION: The results of the current study do not support the use of CultActive in cases with embryo developmental problems.

Recently, Petersen provided in this journal a critical discussion of individualisation arguments in the context of social egg freezing. This argument underlines the idea that it is morally problematic to use individual technological solutions to solve societal challenges that women face. So far, however, there is a lack of empirical data to contextualise his central normative claim that individualisation arguments are implausible. This article discusses an empirical study that supports a contextualised reading of the normative work of Petersen. Based on a qualitative interview study, we found that most women could make sense of this argument but addressed other concerns that are overlooked in the premises of moral individualisation arguments, for instance, the influence of relationship formation on the demand of egg freezing. Furthermore, women did not experience social egg freezing as morally problematic. Nonetheless, the interviewees pointed to a need of more societal solutions and even actively advocated for efforts to increase accessibility such as a partial reimbursement and better quality of information. The implications of these findings for empirical bioethics are discussed. While more research is needed, we argue that, in order to better address individualisation arguments and related ethical concerns, we need to contextualise normative evaluations within women’s moral reasoning.

OBJECTIVES: High-dose spinal cord stimulation (HD-SCS) revealed positive results for obtaining pain relief in patients with failed back surgery syndrome (FBSS). However, it is less clear whether HD-SCS also is able to reduce pain medication use. The aim of this registry-based cohort study is to explore the impact of HD-SCS on pain medication use in FBSS patients. MATERIALS AND METHODS: Data from the Discover registry was used in which the effectiveness of HD-SCS was explored in neurostimulation-naïve FBSS patients as well as in rescue patients. All neurostimulation-naïve FBSS patients positively responded to a four-week SCS trial period in which at least 50% pain relief and 50% medication reduction were obtained. Medication use was measured with the Medication Quantification Scale III (MQS) in 259 patients at baseline and at 1, 3, and 12 months of HD-SCS. Additionally, defined daily doses (DDD) and morphine milligram equivalents (MME) were calculated as well. RESULTS: One hundred thirty patients reached thevisit at 12 months. In neurostimulation-naïve patients, a statistically significant decrease in MQS (χ2 = 62.92, p

The precise delivery of cytotoxic radiation to cancer cells through the combination of a specific targeting vector with a radionuclide for targeted radionuclide therapy (TRT) has proven valuable for cancer care. TRT is increasingly being considered a relevant treatment method in fighting micro-metastases in the case of relapsed and disseminated disease. While antibodies were the first vectors applied in TRT, increasing research data has cited antibody fragments and peptides with superior properties and thus a growing interest in application. As further studies are completed and the need for novel radiopharmaceuticals nurtures, rigorous considerations in the design, laboratory analysis, pre-clinical evaluation, and clinical translation must be considered to ensure improved safety and effectiveness. Here, we assess the status and recent development of biological-based radiopharmaceuticals, with a focus on peptides and antibody fragments. Challenges in radiopharmaceutical design range from target selection, vector design, choice of radionuclides and associated radiochemistry. Dosimetry estimation, and the assessment of mechanisms to increase tumor uptake while reducing off-target exposure are discussed.

Objectives: The number of electronic prescriptions (ePrescriptions) grows steadily in Belgium as in other European countries. In the future, Belgium wants to dematerialize the ePrescription flow, removing all paper trails. A quality check of the digital content and implementation of national ePrescription guidelines in the field was conducted, comparing the content at both prescription and pharmacy side. Methods: An explanatory mixed-methods design was applied. In a first phase, potential problems (warning flags) were identified by consulting stakeholders. Secondly, the warning flags were validated to problems (errors) in a random set of ePrescriptions collected in April 2019. In a third phase, explanatory interviews were held with various stakeholders in order to find explanations and to identify the initiators of these errors. Results: In the first phase, 15 warning flags were identified to evaluate the quality of an ePrescription. In the second phase, a random selection of 11,798 ePrescriptions was validated. The most prevalent errors found, were the digital construction of the messages (18.88%), combined with lots of necessarily deemed substitutions by the pharmacist (3.39%) not following what was prescribed originally. In the third phase, stakeholders indicated that software of the prescriber and the use of inconsistent databases between prescriber and pharmacy can often be seen as the cause and initiator of these problems. Conclusions: Use of authentic medication databases and well-designed software systems have the potential to solve ePrescription problems. Focus should go to prevention instead of detection.

Objectives: To analyze prefrailty’s relationship with limitations in activities of daily living (ADLs) and restrictions in social participation. Method: Robust (Fried 0/4; n = 214; Mage = 82.3 years [ SD ±2.1]) and prefrail (Fried 1–2/4; n = 191; Mage = 83.8 years [ SD ±3.2]) community-dwelling older individuals were included. Frailty scores were obtained from weight loss, exhaustion, gait speed, and grip strength. A total disability index (DI) expressed dependency for basic (b-), instrumental (i-), and advanced (a-)ADLs. Total participation score, being a member, total number of memberships, being a board member, level of participation, membership over time, volunteering, and formal participation represented social participation. Results: Logistic regression retained age (OR = 1.224; 95% CI = [1.122, 1.335]), sex (OR = 3.818; 95% CI = [2.437, 5.982]), and a-ADL-DI (OR = 1.230; 95% CI = [1.018, 1.486]) as variables significantly related to prefrailty (68.3%; χ2 = 68.25; df = 3; p < .001). Discussion: Subtle limitations in a-ADLs, higher age, and being a man were associated with prefrailty, revealing the possible role of personal and culturally related a-ADLs as red flags for (pre)frailty.