Supplementary Material for: Introduction of Hypothermia for Neonates with Perinatal Asphyxia in the Netherlands and Flanders

Background: Therapeutic hypothermia was introduced in the Netherlands and Flanders, Belgium, in 2008. Since then, an increasing number of patients has been treated - up to 166 in 2010. Complications and outcome were registered in an online database. Objectives: The aim of this study was to analyse complications and outcome after implementation. Methods: Data were retrieved from an online database to which all centres had contributed. Results: In 3 years, 332 patients were treated. Excluding 24 patients with congenital abnormalities or metabolic disorders, mortality was 31.8%. Of the 210 survivors without congenital malformations, 21 had cerebral palsy, another 19 a developmental delay of more than 3 months at the age of at least 24 months, and 2 had severe hearing loss. The total adverse outcome, combining death and adverse neurodevelopment, in 308 patients without congenital malformations is 45.5%, which is similar to that of the large trials. Conclusions: The introduction of therapeutic hypothermia for neonates with perinatal asphyxia in the Netherlands and Flanders has been rapid and successful, with results similar to findings in the randomised controlled trials

Supplementary Material for: Predictive Intelligent Control of Oxygenation in Preterm Infants: A Two-Center Feasibility Study

Introduction: Supplemental oxygen therapy is a mainstay of modern neonatal intensive care for preterm infants. However, both insufficient and excess oxygen delivery are associated with adverse outcomes. Automated or closed loop FiO2 control has been developed to keep SpO2 within a predefined target range more effectively. Methods: The aim of this study was to investigate the feasibility of closed loop FiO2 control by Predictive Intelligent Control of Oxygenation (PRICO) on the Fabian ventilator in maintaining SpO2 within a target range (88/89-95%) in preterm infants on different modes of invasive and noninvasive respiratory support. In two tertiary neonatal intensive care units, preterm infants with an FiO2 >0.21 were included and received an 8 h nonblinded treatment period of closed loop FiO2 control by PRICO, flanked by two 8 h control periods of routine manual control (RMC1 and RMC2). Results: 32 preterm infants were included (median gestational age 26 + 5 weeks [IQR 25 + 5–27 + 6], median birthweight 828 grams [IQR 704–930]). Six patients received invasive respiratory support, while 26 received noninvasive respiratory support (18 CPAP, 4 DuoPAP, and 4 nasal IMV). The time percentage within the SpO2 target range was increased with PRICO (74.4% [IQR 67.8–78.5]) compared to RMC1 (65.8% [IQR 51.1–77.8]; p = 0.011) and RMC2 (60.6% [IQR 56.2–66.6]; p < 0.001) with an estimated median difference of 6.0% (95% CI 1.2–11.5) and 9.8% (95% CI 6.0–13.0), respectively. Conclusion: In preterm infants on invasive and noninvasive respiratory supports, closed loop FiO2 control by PRICO compared to RMC is feasible and superior in maintaining SpO2 within target ranges

Limited evidence for return to sport testing after ACL reconstruction in children and adolescents under 16 years: a scoping review

Abstract Specific return to sport criteria for children and adolescents after anterior cruciate ligament injury and reconstruction are unknown. The aim of this scoping review is to provide an overview of current tests regarding return to sport for children and adolescents. This scoping review was performed according to the PRISMA statement. A systematic search was performed on PubMed and EMBASE. The inclusion criteria were diagnostic and prognostic studies evaluating tests regarding return to sport after ACL injury and reconstruction in children/adolescents (ag

Additional file 2 of Identifying potential patient-specific predictors for anterior cruciate ligament reconstruction outcome – a diagnostic in vitro tissue remodeling platform

Additional file 2: Figure S2. Western blot protein bands. (A) Protein bands in Western blot for αSMA and tubulin (housekeeping protein). (B) Protein bands in Western blot for tenomodulin and tubulin (housekeeping protein). (C) Protein bands in Western blot for tubulin to check cell lysate content of ELISA-samples. (D) Boxplot of semi-quantified tubulin protein band intensities, with identified outliers

Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls

Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer. Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines. A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17–121) months, survivors scored significantly lower on physical (83.7 vs. 89.8, difference (diff) = −5.80, p=.005), role (83.5 vs. 90, diff = −5.97, p=.02), cognitive (83.7 vs. 91.9, diff = −8.05, p=.001), and social functioning (86.5 vs. 95.1, diff = −8.49, p= vs. 15.5, diff = 7.48, p=.004), dyspnea (13.3 vs. 6.7, diff = 6.47 p=.02), diarrhea (7.9 vs. 4.0, diff = 3.78, p=.04), and financial impact (10.5 vs. 2.5, diff = 8.07, p=.001) than matched controls. Group differences were indicated as clinically relevant. Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care

Oncogenic TYK2P760L kinase is effectively targeted by combinatorial TYK2, mTOR and CDK4/6 kinase blockade

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase/signal transducer and activator of transcription pathway, which is central in cytokine signaling. Previously, germline TYK2 mutations have been described in two patients developing de novo T-cell acute lymphoblastic leukemias (T-ALL) or precursor B-ALL. The mutations (P760L and G761V) are located within the regulatory pseudokinase domain and lead to constitutive activation of TYK2. We demonstrate the transformation capacity of TYK2 P760L in hematopoietic cell systems including primary bone marrow cells. In vivo engraftment of TYK2 P760L-expressing cell lines led to development of leukemia. A kinase inhibitor screen uncovered that oncogenic TYK2 acts synergistically with the PI3K/AKT/mTOR and CDK4/6 pathways. Accordingly, the TYK2-specific inhibitor deucravacitinib (BMS986165) reduces cell viability of TYK2 P760L-transformed cell models and ex vivo cultured TYK2 P760L-mutated patient- derived xenograft cells most efficiently when combined with mTOR or CDK4/6 inhibitors. Our study thereby pioneers novel treatment options for patients suffering from TYK2-driven acute leukemia

Additional file 4 of Identifying potential patient-specific predictors for anterior cruciate ligament reconstruction outcome – a diagnostic in vitro tissue remodeling platform

Additional file 4: Table S1. Patient data

Identifying potential patient-specific predictors for anterior cruciate ligament reconstruction outcome – a diagnostic in vitro tissue remodeling platform

Abstract Purpose Upon anterior cruciate ligament (ACL) rupture, reconstruction is often required, with the hamstring tendon autograft as most widely used treatment. Post-operative autograft remodeling enhances graft rupture risk, which occurs in up to 10% of the patient population, increasing up to 30% of patients aged under 20 years. Therefore, this research aimed to identify potential biological predictors for graft rupture, derived from patient-specific tissue remodeling-related cell properties in an in vitro micro-tissue platform. Methods Hamstring tendon-derived cells were obtained from remnant autograft tissue after ACL reconstructions (36 patients, aged 12–55 years), and seeded in collagen I gels on a micro-tissue platform. Micro-tissue compaction over time – induced by altering the boundary constraints – was monitored. Pro-collagen I expression was assessed using ELISA, and protein expression of tenomodulin and α-smooth muscle actin were measured using Western blot. Expression and activity of matrix metalloproteinase 2 were determined using gelatin zymography. Results Only micro-tissues corresponding to younger patients occasionally released themselves from the constraining posts. Pro-collagen I expression was significantly higher in younger patients. Differences in α-smooth muscle actin and tenomodulin expression between patients were found, but these were age-independent. Active matrix metalloproteinase 2 expression was slightly more abundant in younger patients. Conclusions The presented micro-tissue platform exposed patient-specific remodeling-related differences between tendon-derived cells, with the micro-tissues that released from constraining posts and pro-collagen I expression best reflecting the clinical age-dependency of graft rupture. These properties can be the starting point in the quest for potential predictors for identifying individual patients at risk for graft rupture

Intrauterine resuscitation during the second stage of term labour by maternal hyperoxygenation versus conventional care: study protocol for a randomised controlled trial (INTEREST O2)

Abstract Background Perinatal asphyxia is, even in developed countries, one the major causes of neonatal morbidity and mortality. Therefore, if foetal distress during labour is suspected, one should try to restore foetal oxygen levels or aim for immediate delivery. However, studies on the effect of intrauterine resuscitation during labour are scarce. We designed a randomised controlled trial to investigate the effect of maternal hyperoxygenation on the foetal condition. In this study, maternal hyperoxygenation is induced for the treatment of foetal distress during the second stage of term labour. Methods/design This study is a single-centre randomised controlled trial being performed in a tertiary hospital in The Netherlands. From among cases of a suboptimal or abnormal foetal heart rate pattern during the second stage of term labour, a total of 116 patients will be randomised to the control group, where normal care is provided, or to the intervention group, where before normal care 100% oxygen is supplied to the mother by a non-rebreathing mask until delivery. The primary outcome is change in foetal heart rate pattern. Secondary outcomes are Apgar score, mode of delivery, admission to the neonatal intensive care unit and maternal side effects. In addition, blood gas values and malondialdehyde are determined in umbilical cord blood. Discussion This study will be the first randomised controlled trial to investigate the effect of maternal hyperoxygenation for foetal distress during labour. This intervention should be recommended only as a treatment for intrapartum foetal distress, when improvement of the foetal condition is likely and outweighs maternal and neonatal side effects. Trial registration EudraCT, 2015-001654-15; registered on 3 April 2015. Dutch Trial Register, NTR5461; registered on 20 October 2015

Study protocol training for life: a stepped wedge cluster randomized trial about emergency obstetric simulation-based training in a low-income country

Abstract Background Globally perinatal and maternal mortality rates remain unacceptably high. There is increasing evidence that simulation-based training in obstetric emergencies is associated with improvement in clinical outcomes. However, the results are not entirely consistent. The need for continued research in a wide variety of clinical settings to establish what works, where and why was recommended. The aim of this study is to investigate the effectiveness of an emergency obstetric simulation-based training program with medical technical and teamwork skills on maternal and perinatal mortality in a low-income country. Methods A stepped wedge cluster randomized trial will be conducted at the medium to high-risk labour ward at Mulago Hospital, Kampala, Uganda, with an annual delivery rate of over 23,000. The training will be performed using a train-the-trainers model in which training is cascaded down from master trainers to local facilitators (gynaecologists) to learners (senior house officers). Local facilitators will be trained during a four-day train-the-trainers course with an annual repetition. The senior house officers will be naturally divided in seven clusters and randomized for the moment of training. The training consists of a one-day, monodisciplinary, simulation-based training followed by repetition training sessions. Scenarios are based on the main local causes of maternal and neonatal mortality and focus on both medical technical and crew resource management skills. Kirkpatrick’s classification will be used to evaluate the training program. Primary outcome will be the composite of maternal and neonatal mortality ratios. Secondary outcome will comprise course perception, evaluation of the instructional design of the training, knowledge, technical skills, team performance, percentage of ventouse deliveries, percentage of caesarean sections, and a Weighted Adverse Outcome Score. Discussion This stepped wedge cluster randomized trial will investigate the effect of a monodisciplinary simulation-based obstetric training in a low-income country, focusing on both medical technical skills and crew resource management skills, on patient outcome at one of the largest labour wards worldwide. We will use a robust study design which will allow us to better understand the training effects, and difficulties in evaluating training programs in low-income countries. Trial registration ISRCTN98617255 , retrospectively registered July 23, 2018