Role of patent ductus arteriosus in preterms in long-term outcome.

OBJECTIVE: This study aimed to determine long-term neurodevelopmental outcome and cerebral oxygenation in extremely preterm infants, comparing those with a hemodynamic significant patent ductus arteriosus (hsPDA) to those without. STUDY DESIGN: We included infants born before 28 weeks of gestation from 2008 to 2010 with routine echocardiography. Prior to echocardiography, regional cerebral oxygen saturation was measured. At 5 years of age, we evaluated neurodevelopmental outcomes using the Movement Assessment Battery for Children 2nd Dutch edition for motor skills and the Wechsler Preschool and Primary Scale of Intelligence 3rd Dutch edition for cognition. RESULTS: A total of 66 infants (gestational age 26.6 ± 0.9 weeks, birth weight 912 ± 176 g) were included, 34 infants with a hsPDA (including treatment). The group infants with hsPDA showed lower pre-closure cerebral saturation levels (58.2 % ±7.8 % versus 62.8 % ±7.0 %; p = 0.01). At 5 years, impaired motor outcome occurred more often in infants with hsPDA (17 (53 %) vs. 7 (23 %); p = 0.01). In multivariate analysis existence of hsPDA remained unfavourably related to the motor subdomain "aiming and catching". There were no potential effects of hsPDA on cognitive performance at 5 years of age. CONCLUSION: Treatment-receiving infants with hsPDA appear to exhibit motor deficits, specifically in "aiming and catching", by the age 5. Persistent ductal patency could be a contributing factor.

GT-00AxIL15, a Novel Tumor-Targeted IL-15-Based Immunocytokine for the Treatment of TA-MUC1-Positive Solid Tumors: Preclinical In Vitro and In Vivo Pharmacodynamics and Biodistribution Studies.

GT-00AxIL15 is a novel interleukin-15-based immunocytokine targeting a tumor-specific, glycosylated epitope of MUC1 (TA-MUC1). We characterized mode of action, pharmacokinetic (PK) and pharmacodynamic (PD) properties and investigated the relevance of TA-MUC1 binding for the concept of delivering IL-15 to solid tumors. In vitro pharmacology was analyzed in binding and cell-based assays. The in vivo PK profile and IL-15-mediated PD effects of GT-00AxIL15 were investigated in tumor-free mice. Tumor accumulation, immune infiltration and anti-tumor activity were assessed in TA-MUC1+ syngeneic and xenogeneic murine tumor models. GT-00AxIL15 was shown to specifically bind TA-MUC1 on tumor cells via its mAb moiety, to IL-15 receptors on immune cells via its IL-15 fusion modules and to FcγRs via its functional Fc-part. In vitro, NK, NKT and CD8+ T cells were activated and proliferated, leading to anti-tumor cytotoxicity and synergism with antibody-dependent cellular cytotoxicity (ADCC)-mediating mAbs. In vivo, GT-00AxIL15 exhibited favorable PK characteristics with a serum half-life of 13 days and specifically accumulated in TA-MUC1+ tumors. In the tumor microenvironment, GT-00AxIL15 induced robust immune activation and expansion and mediated anti-metastatic and anti-tumor effects in syngeneic and xenograft tumor models. These results support the rationale to improve PK and anti-tumor efficacy of IL-15 by increasing local concentrations at the tumor site via conjugation to a TA-MUC1 binding mAb. The tumor-selective expression pattern of TA-MUC1, powerful immune activation and anti-tumor cytotoxicity, long serum half-life and tumor targeting properties, render GT-00AxIL15 a promising candidate for treatment of solid tumors with high medical need, e.g., ovarian, lung and breast cancer.

[Invasive group A streptococcal infections in the Netherlands]. / Invasieve groep A-streptokokkeninfecties in Nederland.

Group A streptococcal (GAS) infections are caused by the Gram-positive bacterium Streptococcus pyogenes. Infection can occur via droplet infection from the throat and via (in)direct contact with infected people. GAS can cause a wide variety of diseases, ranging from superficial skin infections, pharyngitis and scarlet fever, to serious invasive diseases such as puerperal sepsis, pneumonia, necrotising soft tissue infections (NSTI) (also known as necrotising fasciitis/myositis), meningitis and streptococcal toxic shock syndrome (STSS). In invasive GAS infections, the bacteria has penetrated into a sterile body compartment (such as the bloodstream, deep tissues, or the central nervous system). Invasive GAS infections are rare but serious, with high morbidity and mortality. Since March 2022, the National Institute for Public Health and the Environment (RIVM) reported a national increase in notifiable invasive GAS infections (NSTI, STSS and puerperal fever). Particularly NSTI has increased compared to the years before the SARS-CoV-2 pandemic. Remarkably, the proportion of children aged 0 to 5 years with invasive GAS-infections is higher in 2022 than in the previous years (12% compared to 4%). While seasonal peaks occur, the current elevation exceeds this variation. To promote early recognition and diagnosis of invasive GAS infections different clinical cases are presented.

Provision of cervical screening for transmasculine patients: a review of clinical and programmatic guidelines.

BACKGROUND: Most cervical cancer can be prevented through routine screening. Disparities in uptake of routine screening therefore translate into disparities in cervical cancer incidence and outcomes. Transmasculine people including transgender men experience multiple barriers to cervical screening and their uptake of screening is low compared with cisgender women. Comprehensive evidence-based guidelines are needed to improve cervical screening for this group. METHODS: We searched for and synthesised clinical and programmatic guidelines for the provision of cervical screening for transmasculine patients. FINDINGS: The guidelines offer recommendations addressing: (1) reception, check-in and clinic facilities; (2) patient data and invitation to screening; (3) improving inclusion in screening programmes; and (4) sexual history taking, language and identity. Guidelines offer strategies for alleviating physical and psychological discomfort during cervical screening and recommendations on what to do if the screening procedure cannot be completed. Most of the guidelines were from and for high-income countries. DISCUSSION: The evidence base is limited, but existing guidelines provide recommendations to ensure life-saving screening services are available to all who need them. We were only able to identify one set of guidelines for a middle-income country, and none for low-income countries. We encourage the involvement of transmasculine people in the development of future guidelines.

Pseudomonas aeruginosa left ventricular assist device (LVAD) driveline infection acquired from the bathroom at home.

We describe a patient with a left ventricular assist device (LVAD) infection by Pseudomonas aeruginosa acquired at home. The Pseudomonas from the driveline was similar to several surface cultures of the patient's home shower. This case illustrates the potential and importance of infection prevention measures at home.

The Cerebral Hemodynamic Response to Pain in Preterm Infants With Fetal Growth Restriction.

Background: Preterm infants undergoing intensive care often experience painful procedures such as heel lance for blood sampling. Knowledge of the cerebral hemodynamic response to painful stimuli contributes to understanding of cortical pain processing and the neurovascular network in the preterm brain. Previous research has demonstrated cerebral hemodynamic responses using near-infrared spectroscopy (NIRS) after noxious stimuli in infants appropriately grown for age (AGA). But this has not been studied in infants born small for gestational age after fetal growth restriction (FGR). FGR infants differ in brain development due to utero-placental insufficiency leading to the intrauterine growth restriction, and cerebral response to pain may be altered. Objectives: We aimed to compare the cerebral hemodynamic response to painful stimuli (heel lance) in FGR and AGA infants. Methods: Preterm FGR infants (n = 20) and AGA infants (n = 15) born at 28-32 weeks' gestation were studied at mean ± SD postnatal age of 11.5 ± 2.4 and 10.5 ± 2.4 days, respectively. Infants had baseline echocardiographic assessment of ductus arteriosus and stroke volume. They were monitored with NIRS for changes in tissue oxygenation index (TOI, %), and oxygenated, deoxygenated, and total hemoglobin (ΔO2Hb, ΔHHb, and ΔTHb) in contralateral and ipsilateral cerebral hemispheres, during a heel lance. Results: At baseline, FGR infants had significantly lower TOI, higher heart rate, and lower stroke volume compared to AGA infants. Most infants in both groups showed increase in each of the NIRS parameters in the contralateral hemisphere following heel lance. However, more AGA infants (6/15) showed decreased ΔTHb compared to FGR infants (1/20) (p = 0.016). The magnitude of cerebral hemodynamic response and time to response did not differ between FGR and AGA infants. FGR infants showed larger ΔO2Hb in the contralateral compared to ipsilateral cortex (p = 0.05). Conclusion: Preterm FGR infants have reduced stroke volume and lower cerebral oxygenation compared to AGA infants in the second to third week of life. FGR infants show similar cerebral hemodynamic responses to noxious stimuli compared to AGA infants. However, FGR infants are less likely to have a cerebral vasoconstrictive response, possibly due to cerebrovascular changes following placental insufficiency and brain sparing in-utero.

Effects of caffeine on the preterm brain: An observational study.

BACKGROUND AND AIM: Caffeine improves neurodevelopmental outcome of preterm infants. This study analyses the effects of caffeine on the neonatal brain. We hypothesized that caffeine has a neuroprotective effect through an increase in oxygen metabolism; reflected by increased cerebral oxygen extraction, electrical function, and perfusion. METHODS: Preterm infants <32 weeks gestation (GA) receiving their primary dose caffeine-base (10 mg/kg) were included. Ten minutes of stable monitoring were selected before, during, and every hour up to 6 h after caffeine. Near-infrared spectroscopy monitored regional cerebral oxygenation (rScO2) and extraction (FTOE). Amplitude-integrated electroencephalogram (aEEG) monitored minimum, mean and maximum amplitudes. Spontaneous activity transients (SAT) rate and the interval between SATs (ISI) were calculated. Mean arterial blood pressure (MABP), heart rate (HR) and arterial oxygen saturation (SaO2) were monitored. Arterial pCO2's were collected before and 4 h after caffeine. Brain perfusion was assessed 1 h before and 3 h after caffeine by Doppler-measured resistance-index (RI), peak systolic velocity (PSV) and end-diastolic velocity (EDV), in the anterior cerebral artery (ACA) and internal carotid artery (ICA). Results were presented in mean ±â€¯SD. RESULTS: 34 infants, mean GA 28.8 ±â€¯2.1 wk, were included. rScO2 significantly decreased from 69 ±â€¯11 to 63 ±â€¯12 1 h after caffeine, and recovered at 6 h (66 ±â€¯10). FTOE increased correspondingly. MABP and HR increased significantly. PSV in the ACA decreased slightly. Other Doppler variables, aEEG parameters, and SaO2 were unaffected. CONCLUSION: Caffeine increases oxygen extraction, suggesting a (transient) stimulating effect on brain metabolism. However, no substantial changes were found in brain perfusion and in electrical brain activity.

Corrigendum: Monitoring Cerebral Oxygenation in Neonates: An Update.

[This corrects the article on p. 46 in vol. 5, PMID: 28352624.].

Carbon Dioxide Fluctuations Are Associated with Changes in Cerebral Oxygenation and Electrical Activity in Infants Born Preterm.

OBJECTIVES: To evaluate the effects of acute arterial carbon dioxide partial pressure changes on cerebral oxygenation and electrical activity in infants born preterm. STUDY DESIGN: This retrospective observational study included ventilated infants born preterm with acute fluctuations of continuous end-tidal CO2 (etCO2) as a surrogate marker for arterial carbon dioxide partial pressure, during the first 72 hours of life. Regional cerebral oxygen saturation and fractional tissue oxygen extraction were monitored with near-infrared spectroscopy. Brain activity was monitored with 2-channel electroencephalography. Spontaneous activity transients (SATs) rate (SATs/minute) and interval between SATs (in seconds) were calculated. Ten-minute periods were selected for analysis: before, during, and after etCO2 fluctuations of ≥5 mm Hg. RESULTS: Thirty-eight patients (mean ± SD gestational age of 29 ± 1.8 weeks) were included, with 60 episodes of etCO2 increase and 70 episodes of etCO2 decrease. During etCO2 increases, brain oxygenation increased (regional cerebral oxygen saturation increased, fractional tissue oxygen extraction decreased; P < .01) and electrical activity decreased (SATs/minute decreased, interval between SATs increased; P < .01). All measures recovered when etCO2 returned to baseline. During etCO2 decreases, brain oxygenation decreased (regional cerebral oxygen saturation decreased, fractional tissue oxygen extraction decreased; P < .01) and brain activity increased (SATs/minute increased, P < .05), also with recovery after return of etCO2 to baseline. CONCLUSION: An acute increase in etCO2 is associated with increased cerebral oxygenation and decreased brain activity, whereas an acute decrease is associated with decreased cerebral oxygenation and slightly increased brain activity. Combining continuous CO2 monitoring with near-infrared spectroscopy may enable the detection of otherwise undetected fluctuations in arterial carbon dioxide partial pressure that may be harmful to the neonatal brain.

Monitoring Cerebral Oxygenation in Neonates: An Update.

Cerebral oxygenation is not always reflected by systemic arterial oxygenation. Therefore, regional cerebral oxygen saturation (rScO2) monitoring with near-infrared spectroscopy (NIRS) is of added value in neonatal intensive care. rScO2 represents oxygen supply to the brain, while cerebral fractional tissue oxygen extraction, which is the ratio between rScO2 and systemic arterial oxygen saturation, reflects cerebral oxygen utilization. The balance between oxygen supply and utilization provides insight in neonatal cerebral (patho-)physiology. This review highlights the potential and limitations of cerebral oxygenation monitoring with NIRS in the neonatal intensive care unit.

Severe hypercapnia causes reversible depression of aEEG background activity in neonates: an observational study.

INTRODUCTION: Elevated carbon dioxide (CO2) blood levels have a depressant effect on the central nervous system and can lead to coma in adults. Less is known about the effect of CO2 on the neurological function of infants. OBJECTIVE: To describe the effect of acute severe hypercapnia (PaCO2 >70 mm Hg) on amplitude-integrated electroencephalography (aEEG) and cerebral oxygenation in newborn infants. STUDY DESIGN: Observational study of full-term and preterm infants with acute severe hypercapnia (identified by arterial blood gas measurements), monitored with aEEG. Visual analysis of the aEEG was performed in all infants. In preterm infants <32 weeks postmenstrual age (PMA), analysis of two-channel EEG was performed. Mean spontaneous activity transients (SAT) rate (SATs/min), interval between SATs (ISI in seconds) and the ISI percentage (ISP) were calculated for 10-min periods before, during and after hypercapnia. Mean regional cerebral oxygen saturation (rScO2) and fractional tissue oxygen extraction (FTOE) measured with near-infrared spectroscopy were also calculated for these periods. RESULTS: Twenty-five infants (21 preterm, 4 full-term) comprising 32 episodes of acute severe hypercapnia were identified. Twenty-seven episodes were accompanied by a transient aEEG depression. Twenty-two episodes in 15 preterm infants <32 weeks PMA were quantitatively analysed. During hypercapnia, SAT rate decreased and ISI and ISP increased significantly. No significant change occurred in rScO2 or FTOE during hypercapnia. CONCLUSION: Profound depression of brain activity due to severe hypercapnia is also seen in infants. It can be recognised by an acute depression of the aEEG, without clinically detectable changes in cerebral oxygenation.

Reduction in Cerebral Oxygenation due to Patent Ductus Arteriosus Is Pronounced in Small-for-Gestational-Age Neonates.

BACKGROUND: A haemodynamically significant patent ductus arteriosus (hsPDA) reduces cerebral oxygenation in appropriate-for-gestational-age (AGA) preterm neonates. Reduced cerebral oxygenation has been associated with brain injury. Preterm small-for-gestational-age (SGA) neonates show higher cerebral oxygenation than AGA peers throughout the first postnatal days. To date, no studies have investigated the effect of hsPDA on cerebral oxygenation in preterm SGA neonates. OBJECTIVE: We aimed to assess the effect of hsPDA on cerebral oxygenation in preterm SGA neonates compared to AGA peers. We hypothesised that higher baseline cerebral oxygenation would reduce the impact of hsPDA on cerebral oxygenation in preterm SGA neonates. METHODS: We monitored regional cerebral oxygen saturation (rScO2) with near-infrared spectroscopy and calculated the cerebral fractional tissue oxygen extraction (cFTOE) for 72 h after birth. Retrospective analysis compared 36 preterm SGA neonates (birth weight <10th percentile, 18 with hsPDA) to 36 preterm AGA neonates (birth weight 20th to 80th percentile, 18 with hsPDA). RESULTS: In contrast to the other groups, SGA-hsPDA neonates demonstrated a significant fall in rScO2 [69% (SEM 2.5) at 4-8 h to 61% (2.7) at 68-72 h, p < 0.001] with a concurrent rise in cFTOE [0.26 (0.026) at 4-8 h to 0.34 (0.030) at 68-72 h, p < 0.001]. CONCLUSIONS: Contrary to our hypothesis, hsPDA had a significant negative effect on cerebral oxygenation in preterm SGA neonates. Future studies should explore the potential benefits of early screening and treatment for hsPDA on long-term neurodevelopmental outcome in preterm SGA neonates.

Cerebral oxygenation and echocardiographic parameters in preterm neonates with a patent ductus arteriosus: an observational study.

BACKGROUND: A haemodynamically significant patent ductus arteriosus (hsPDA) is clinically suspected and confirmed by echocardiographic examination. A hsPDA decreases cerebral blood flow and oxygen saturation by the ductal steal phenomenon. AIM: To determine the relationship between echocardiographic parameters, cerebral oxygenation and a hsPDA in preterm infants. METHODS: 380 preterm infants (<32 weeks gestational age) born between 2008 and 2010 were included. Blinded echocardiographic examination was performed on the second, fourth and sixth day after birth. Examinations were deblinded when hsPDA was clinically suspected. Regional cerebral oxygen saturation (rScO2) was continuously monitored by near-infrared spectroscopy during 72 h after birth, and afterwards for at least 1 h before echocardiography. Echocardiographic parameters included ductal diameter, end-diastolic flow in the left pulmonary artery, left atrium/aorta ratio and ductal flow pattern. RESULTS: rScO2 was significantly related only to ductal diameter over time. Mixed modelling analysed the course of rScO2 over time, where infants were divided into four groups: a closed duct, an open haemodynamically insignificant duct (non-sPDA), a hsPDA, which was successfully closed during study period (SC hsPDA) or a hsPDA, which was unsuccessfully closed during study period (UC hsPDA). SC hsPDA infants showed the highest rScO2 on day 6, while UC hsPDA infants had the lowest rScO2 values. CONCLUSIONS: Ductal diameter is the only echocardiographic parameter significantly related to cerebral oxygenation over time. Cerebral oxygenation takes a different course over time depending on the status of the duct. Low cerebral oxygenation may be suggestive of a hsPDA.

Reference values of regional cerebral oxygen saturation during the first 3 days of life in preterm neonates.

BACKGROUND: Currently, reliable reference values of regional cerebral oxygen saturation (rScO2) for different gestational age (GA) groups are lacking, which hampers the implementation of near-infrared spectroscopy (NIRS) alongside monitoring arterial oxygen saturation (SaO2) and blood pressure in neonatal intensive care. The aim of this study was to provide reference values for rScO2 and cerebral fractional tissue oxygen extraction (cFTOE; (SaO2 - rScO2)/SaO2) for small adult and neonatal NIRS sensors. METHODS: In this study, 999 infants born preterm (GA <32 wk) were monitored with NIRS during the first 72 h of life. Mixed modeling was used to generate reference curves grouped per 2 wk of GA. In addition, the influence of a hemodynamically significant patent ductus arteriosus, gender, and birth weight were explored. RESULTS: Average rScO2 was ~65% at admission, increased with GA (1% per week) and followed a parabolic curve in relation to postnatal age with a peak at ~36 h. The cFTOE showed similar but inverse effects. On average, the neonatal sensor measured 10% higher than the adult sensor. CONCLUSION: rScO2 and cFTOE reference curves are provided for the first 72 h of life in preterm infants, which might support the broader implementation of NIRS in neonatal intensive care.

Early end-tidal carbon monoxide levels, patency of the ductus arteriosus and regional cerebral oxygenation in preterm infants.

BACKGROUND: Carbon monoxide (CO), a relaxant regulator of muscle tone and marker of oxidative stress and inflammation, can be measured in exhaled air by determination of end-tidal CO corrected for CO in ambient air (ETCOc). OBJECTIVE: Increased endogenous production of CO may influence patency of the ductus arteriosus, cerebral perfusion and, subsequently, cerebral oxygenation. The aim was to study the relation between early ETCOc levels, hemodynamically significant patent ductus arteriosus (hsPDA) and cerebral oxygenation (rScO2) in preterm infants <32 weeks' gestational age and determine predictive values of ETCOc for hsPDA. METHODS: ETCOc was measured in 91 infants within the first 24 h after birth. A hsPDA was diagnosed according to echocardiographic indices. In 78/91 infants, rScO2 was monitored with near-infrared spectroscopy to assess cerebral oxygenation. RESULTS: ETCOc values were significantly higher in infants who subsequently developed hsPDA (2.3 ± 0.7 ppm) vs. no-hsPDA (1.7 ± 0.6 ppm), p < 0.001. With a cut-off value of 2.5 ppm, positive and negative predictive values of ETCOc for hsPDA were 55 and 88%, respectively. rScO2 values were not different between the two groups (64 ± 1 vs. 65 ± 3%, NS). CONCLUSIONS: The higher ETCOc values in hsPDA infants early after birth reflect the early relaxant state of ductal muscular tone. ETCOc <2.5 ppm within 24 h after birth may predict the subsequent absence of hsPDA. ETCOc showed no correlation with cerebral oxygenation in both groups.

Comparing near-infrared spectroscopy devices and their sensors for monitoring regional cerebral oxygen saturation in the neonate.

BACKGROUND: Near-infrared spectroscopy (NIRS) is an upcoming clinical method for monitoring regional cerebral oxygen saturation (rScO2) in neonates. There is a growing market offering different devices and sensors. Even though this technique is increasingly clinically applied, little is known about the similarities and/or differences in rScO2 values between the different devices and sensors. The aim of this study was to compare the rScO2 values obtained in (preterm) neonates with all available sensors of three frequently used NIRS devices. METHODS: Fifty-five neonates admitted to our neonatal intensive care unit (NICU) were included in this study. rScO2 was simultaneously monitored bilaterally with two different NIRS sensors (left and right frontoparietal) for at least 1 h. Then, the sensors were switched, and measurements were collected for at least another hour. RESULTS: We detected a rather close correlation between all investigated sensors from the three different NIRS devices, but absolute rScO2 values showed substantial differences: Bland-Altman analysis showed average differences from 10 to 15%. CONCLUSION: Although the rScO2 values correlated well between different NIRS sensors, sometimes there were substantial differences between the absolute rScO2 values, which may complicate clinical application.