Wenzhou Shi, China

Continuous Non-invasive Electrophysiological Monitoring in High Risk Pregnancies

Pregnant women in need for maternal and/or fetal monitoring are hospitalized at the obstetric high care (OHC) of Máxima Medical Center (MMC). They are monitored for up to three times a day with conventional cardiotocography (CTG). In the meantime they reside at the OHC, but the status of the fetus and uterine activity (UA) is not monitored. Nemo Healthcare developed a wireless abdominal electrode patch for measuring fetal heart rate (FHR) and UA: The Nemo Fetal Monitoring System (NFMS). Previous research on non-invasive electrophysiological CTG (eCTG) has yielded promising results in monitoring FHR and UA both during pregnancy and labor. With the use of eCTG technology, safe continuous 24/7 monitoring is possible, which is not possible with conventional cardiotocography. The investigators hypothesize that by introducing continuous antepartum eCTG monitoring perinatal and maternal outcomes will improve. The investigators aim to include 1911 pregnant women ≥18 years old with a singleton pregnancy between 23+0 and 32+0 weeks of gestation requiring hospitalization on the OHC for maternal or fetal surveillance (including 1400 historical controls). Additional objectives: The collected NFMS and demographic data will be used to develop and verify a mathematical model for the prediction of time until (preterm) birth, which may be used in clinical practice to reduce unnecessary OHC admissions and facilitate a better timing of interventions. Furthermore, data collected in this study (NFMS, accelerometric, annotated ultrasound) will be used for the development and verification of a mathematical model for the automated detection of fetal movements in NFMS data. This latter model might provide new opportunities in non-invasive monitoring of fetal health.

ASIA-Mesh: a Pilot Study for Diagnostics and Treatment on ASIA Syndrome Caused by Polypropylene Mesh Implantation

Worldwide there is a lot of commotion about the effects and complications of various implants. In analogy to patients with silicone breast implants, some patients report various systemic complaints following inguinal polypropylene (PP) mesh implantation, suggesting 'Autoinflammatory/Autoimmunity Syndrome Induced by Adjuvants' (ASIA; Shoenfeld's syndrome) or some other suspected systemic auto-immune/inflammatory response. Although an evidence-based and causal relationship is lacking, patients report serious complaints. Therefore, the investigators recently started seeing these patients at the outpatient clinic and developed a diagnostic workup, including an elaborate anamnesis, conventional immunologic analyses and mesh allergy testing (MAT). Further, in case the implant is removed as part of the treatment due to a persistent wish of the patient, the PP explant will be histologically examined to find additional cues for an auto-immune/inflammatory response (and thus ASIA). So far, evidence on the optimal diagnostic workup for patients with suspected ASIA syndrome is lacking completely.

A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a) - ACCLAIM-Lp(a)

A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF)

Intrapartum Non-invasive Electrophysiological Monitoring

Prospective RegIstration Of the peRformance of the IoTa ADNEX Model in Dutch gYnaecological Practice

Rationale: Correct pre-operative classification of ovarian tumors is critical for optimal treatment of both women with benign and malignant ovarian tumors. The International Ovarian Tumor Analysis (IOTA) consortium developed several risk-assessment strategies, including the Assessment of Different NEoplasias in the adneXa (ADNEX) model. This is a polytomous model that estimates the risk of malignancy in women with an ovarian tumor and can help differentiate benign from malignant ovarian tumors. Recent validation studies have shown superior diagnostic accuracy of the ADNEX model compared with previously developed risk-assessment strategies. However, the diagnostic accuracy of this model in daily clinical practice is still unknown. Furthermore, expertise is necessary to use this model before the results are reliable. With the recently published Dutch guideline on risk-assessment strategies of ovarian tumors, in which it is advised to use the ADNEX model, clinical data on diagnostic performance of the ADNEX model in daily Dutch gynaecological practice are necessary. Lower sensitivity and/or specificity of the model will have significant influence on the referral practice in The Netherlands. Objective: To determine the diagnostic accuracy of the IOTA ADNEX model in the discrimination between benign and malignant ovarian tumors in daily gynaecological practice in The Netherlands. Study design: Multicentre prospective cohort study. Hospitals from three oncologic networks in the Netherlands will participate in this trial. Ultrasound data will be prospectively recorded in a database for a duration of five years by means of an electronic case report form (eCRF). With these data, the diagnostic accuracy of the IOTA ADNEX model will be calculated. Study population: All women ≥ 18 years with an ovarian tumor for which ultrasound assessment in accordance with the IOTA definitions has been performed and the ADNEX model has been applied. Women with a tumor that meets the IOTA criteria of a benign 'easy descriptor' will be excluded. Data collection: All patients eligible for this study will be asked for informed consent and clinical data will be collected through eCRFs. Data will be collected in a cloud-based database by the treating physician. Main study parameters/endpoints: The sensitivity, specificity and area under the curve of the IOTA ADNEX model. Secondary analysis: Secondary endpoints include the influence of practice variation (eg type of center, volume per center, prevalence of malignancy, availability of consultation time specifically aimed at performing ultrasounds according to IOTA criteria) and the experience of the ultrasound performer on the diagnostic accuracy of the IOTA ADNEX model.

High-Risk prostatE Cancer radiatiOn Versus surgERy

Detailed description: Robot assisted radical prostatectomy (RARP) and external beam radiotherapy (EBRT) combined with Androgen Deprivation Therapy (ADT) are widely used treatment modalities for high-risk non-metastatic prostate cancer (HR-PCa). Both treatments are associated with adverse effects and can have a great impact on health-related quality of life (HRQoL). To date there is no consensus on which of both is the optimal treatment for men with HR-PCa, as it is unclear which treatment is superior in terms of HRQoL, cost-effectiveness, progression-free survival (PFS) and distant metastases-free survival (DMFS). This is reflected in substantial variation between individual hospitals in the utilization of both treatment options that is not explained by patient- and tumor characteristics or patient preferences. In the RECOVER study we aim to address this knowledge gap. The insights gained can be used to tailor recommendations in (national) guidelines and in shared decision-making tools. This allows healthcare professionals to better inform their patients and allows patients to make well-informed choices.

Optimal Postoperative Chest Tube and Pain Management in Patients Surgically Treated for Primary Spontaneous Pneumothorax (Pneumotrial)

Molecular Culture for the Diagnosis of Neonatal Sepsis

Newborns often receive antibiotics for a suspicion of sepsis. Sepsis has high morbidity and mortality in newborns. Around 5% of all newborns and over 85% of very preterm born infants receive antibiotics empirically. Postnatally, antibiotics are often prescribed for presumed bacterial infections on neonatal wards, but in approximately 90-96% of these patients bacterial infection is not proven. Rapid diagnosis of sepsis in newborns is problematic because clinical signs start subtle and are non-specific. The gold standard for diagnosis of bacterial neonatal sepsis is a conventional blood culture. Unfortunately, bacterial culture is time-consuming (time to result up to 36-72 hours) and lacks sensitivity in this population. For this reason, neonates with risk factors for infection or clinical signs and symptoms of infection are treated with antibiotics empirically at initial sepsis suspicion, awaiting results of the conventional blood culture. Currently more than 85% of very preterm born infants (gestational age <30 weeks) receive antibiotics for the risk of early-onset sepsis in the Netherlands. There is increasing evidence that, apart from antibiotic resistance, the use of antibiotics in the neonatal period and during childhood alters the microbiome with an increased risk of immediate and long-term adverse effects, such as increased risk for asthma, obesity, allergies and inflammatory bowel diseases (IBD). To avoid unnecessary treatment of non-infected infants, an early, quick, sensitive and specific laboratory test would be helpful to guide clinicians to decide when to discontinue antibiotics as soon as possible. A promising technique to detect neonatal sepsis quickly and in an earlier stage compared to conventional blood culture is Molecular Culture (MC). MC is an advanced, rapid molecular based culturing technique that is able to identify bacteria within 4 hours after blood sampling. In short, MC is a DNA-based profiling technique, differentiating between bacterial species based on species-specific differences in 16S-23S rDNA interspacer (IS) region nucleotide length by using phylum-specific fluorescently labelled polymerase chain reaction (PCR) primers. A standard IS-pro procedure consists of two separate PCRs. In the first PCR two different primers are added, one primer fluorescently labeling members of the phyla Firmicutes, Actinobacter, Fusobacteria and Verrucomicrobia (FAFV), whereas the second primer labels members of the Bacteroidetes phylum. In the second PCR, a third labeled primer is added targeting members of the phylum Proteobacteria. Subsequently, these PCR products can be amplified and DNA fragments can be separated based on their nucleotide length. Eventually, a typical IS-pro microbial profile will be created, consisting of a set of color-labeled peaks. Each peak representing an individual bacterial operational taxonomic unit (OTU) depending on the nucleotide length of the IS-pro fragment, length of these peaks demonstrating the concentration of this particular OTU, whereas peak colors provides information about the present phyla (FAFV, Bacteroidetes or Proteobacteria). Figure 3 shows a schematic representation of the concept of how the IS-pro procedure works. Figure 3. Schematic representation of the concept behind the IS-pro procedure. (A) All bacterial species contain at least one IS region in their chromosome. However, many species contain multiple alleles of the IS region. These regions may vary between different alleles. Depicted here is the schematic situation in E. faecalis that contains four alleles of the IS region. Two alleles have a length of 275 nt, and the other two have a length of 377 nt. When amplified, a profile specific for E. faecalis is obtained. (B) IS profiles are highly diverse between different species. The fact that species commonly have multiple alleles with different lengths dramatically increases the differential potential between species. (C) By amplifying IS fragments with phylum-specific fluorescently labeled primers, a next layer of information is added. (D) When an IS profile is made of a sample containing multiple species from different phyla, peaks with different lengths, height, and color are found. These correspond to species, abundance, and phylum. A peak profile may be translated to a list of bacterial species by a software algorithm linked to a database of IS profiles of known bacterial species. The whole IS-pro procedure from unprocessed sample to analyzed data can be performed in 4 h. In bacterial sepsis, a bacteria has reached the otherwise sterile bloodstream causing sepsis. Both blood culture and MC can detect bacteria and give a positive result (in case a bacteria has been cultured) or a negative result (in case no bacteria was detected). In case the tests are positive, both techniques also show which bacteria was found, which could be used to change antibiotic regimen to target that specific cultured bacteria. However, the process of MC can be finished within 4 hours, which is much shorter than the incubation period of the gold standard blood culture which is 36-72 hours. When there is no sepsis (and thus no bacteria in the bloodstream), the MC will turn out negative also within 4 hours and thus may guide clinicians to stop antibiotics in uninfected infants much faster compared to the conventional blood culture. Blood cultures are still gold standard, but are generally assumed to have a low sensitivity for the diagnosis of sepsis in newborns and are time consuming. Cases of sepsis may be missed by cultures and a more sensitive diagnostic test such as molecular tests as the MC may be useful. Advances in microbial technology have led to the development of rapid molecular methods, that may be more sensitive than culture. Multiple novel molecular techniques, such as quantitative PCR, broad range conventional PCR and multiplex PCR, have been studied to detect neonatal sepsis. However, these techniques, are directed at specific species which makes it impossible to detect all bacterial species. Thus, anything that is not explicitly searched for will be missed. In contrast, MC had the ability to detect every bacterial species that can cause bacterial neonatal sepsis. The MC technique has been externally validated to detect bacteria. A series of papers validating all aspects of the MC technique have been published last years. Furthermore, MC is already being used in some hospitals on the intensive care unit to detect bacteria in otherwise sterile specimens like blood, but also on samples obtained from abscesses. In a previous cohort, the investigators from this research group demonstrated that MC may be a useful tool to diagnose sepsis in neonates using cord blood. However, this was a small cohort and no large studies have been performed to analyze the suitability of MC in detecting bacterial sepsis in neonates. Results from other studies using the MC technique to detect bacteria in human body fluid are promising. In one of these studies 66 samples were collected and tested by conventional culture and MC. In 100% of samples with a positive culture, the MC was also positive. In five samples, the conventional culture turned out to be negative, whereas the MC was positive. The case histories of these five patients were obtained and suggested that the MC findings were highly clinically relevant, and thus may have higher sensitivity compared to conventional blood culture. In summary, the quick detection makes MC a very promising technique to detect sepsis in newborns using cord blood. However, the suitability of MC in this specific population has not been investigated previously. Therefore, a large, high quality study should be performed to determine the diagnostic accuracy of the MC for sepsis in neonates using cord blood.

Cerclage for the Reduction of Extreme Preterm Birth in Twin Pregnancies With a Short Cervix or Dilatation

Rationale: In the Netherlands, 250 women with a twin pregnancy deliver at < 28 weeks per year, resulting in 157 perinatal deaths. A vaginal cerclage could be an effective surgical method to reduce cervical insufficiency and with that preterm birth, but the evidence regarding its effectiveness on extreme preterm birth and (long term) neonatal outcome is lacking. Objective: To assess the effectiveness of a cerclage in women with a twin pregnancy with a midpregnancy short cervix or cervical dilatation compared to standard treatment (no cerclage) in the prevention of extreme preterm birth < 28 weeks of gestational age. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: A vaginal cerclage is a minor and safe surgical procedure commonly performed in singleton pregnancies with a short cervix and a previous preterm birth in all the participating centers, thus there is experience in the participating hospitals. The results of this study will show whether a vaginal cerclage reduces extreme preterm birth in women with twin pregnancy and a short cervix, and its accompanying perinatal complications. If proven effective, the implementation of this intervention will have a huge impact on the lifelong health of these children and their families.