Search

Study Design: Retrospective chart review., Objective: To determine the effect of conservative measures on radiographic outcomes in those with isolated spondylolysis., Summary of Background Data: Spondylolysis is a common cause of low back pain in pediatric patients, affecting between 4.4% and 4.7% of all pediatric patients. This rate is even higher in high-level athletes, with recent studies suggesting a rate of 47% in this population. Conservative measures are recommended for treating symptomatic spondylolysis and are effective in controlling symptoms, but there is little evidence regarding their effect on radiographic outcomes., Methods: A retrospective review was conducted of patients diagnosed with spondylolysis who were treated at a single academic institution between January 1, 2012, and January 1, 2022. Data collected included demographics, presentation characteristics, pretreatment and post-treatment radiologic findings, types of treatments employed, and final symptomatic status at follow-up. The Student t test and the Wilcoxon rank sum test were used to compare continuous variables. The χ 2 test was used to compare categorical variables., Results: A total of 119 patients were included in the study. There was an 81.5% rate of healing on advanced imaging for those treated with conservative measures. When comparing those with healing on advanced imaging to those without, those with healing were more likely to have an acute fracture ( P= 0.04), have symptomatic improvement ( P <0.01), and return-to-play ( P= 0.02) compared with those without. Those with healing also had an odds ratio of 6.9 ( P <0.01) and 4.5 ( P =0.02) to achieve symptomatic improvement and return to their sport, respectively, compared with those who did not., Conclusion: Our study found those with isolated spondylolysis who were treated with conservative measures had a high healing rate on advanced imaging and those with healing had significantly higher odds of having symptomatic improvement and returning to play compared with those without., Level of Evidence: 4., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Umbilical vascular catheterization remains an important technique in case a newly born infant requires resuscitation. Most textbooks recommend a complete transection of the umbilical cord and subsequent opening of vessel lumen with an iris forceps to place the catheter. That method, however, is challenging in emergencies. Here we present an easy, quick and safe method of placing the umbilical catheters. The side-entry method could be an alternative to the conventional approach and is worth to enter pediatric textbooks and neonatal resuscitation guidelines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: In Germany, the 12-month prevalence of methamphetamine use among persons aged 15 to 34 is 1.9%. An increasing number of newborns are being born after a prenatal methamphetamine exposure (PME). In 2014, in the German state of Saxony, approximately four out of 1000 newborns were affected., Methods: This systematic review (Prospero registration number CRD42017060536) includes publications that were published between January 1990 and November 2019. The purpose was to determine the effects of PME on the peri- and neonatal condition of the affected children and on their further long-term development. Observational studies with a control group were included in the review and examined for their methodological quality., Results: 31 publications, which dealt with two prospective and six retrospective cohort studies, were included in the review. The studies involved a total of 4446 mother-child pairs with PME, compared with 43 778 pairs without PME. A metaanalysis revealed that PME was associated with, among other findings, lower birth weight (SMD = -0.348; 95% confidence interval [-0.777; 0.081]), shorter body length (SMD= -0.198 [-0.348; -0.047]), and smaller head circumference (SMD= -0.479 [-1.047; 0.089]). Some differences between the groups with and without PME persist into the toddler years. Moreover, children with PME much more commonly display psychological and neurocognitive abnormalities, which are more severe in children growing up in problematic surroundings (discord, violence, poverty, low educational level of the parent or caregiver). A limitation of this review is that not all studies employed an objective or quantitative measure of methamphet - amine use., Conclusion: The documented effects of PME on child development necessitate early treatment of the affected expectant mothers, children, and families. Emphasis should be placed on structured and interdisciplinary preventive measures for methamphetamine use.

Objectives: To estimate the real-use contraceptive effectiveness of the combined oral contraceptive (COC) containing dienogest and oestradiol valerate (DNG/oEV) compared to other combined oral contraceptives (oCOC) and particularly, levonorgestrel-containing OCs (LNG). Methods: Prospective, non-interventional cohort study with two main exposure groups and one exposure subgroup: new users of DNG/oEV and oCOC, with the subgroup, LNG. In a planned secondary analysis, pregnancy outcomes were investigated, including contraceptive failure. The influence of age, parity and OC-type were assessed. Results: 30,098 COC users were followed for a total oral contraceptive exposure time of 68,362 woman-years (WY) and 287 unintended pregnancies were reported. The overall contraceptive failure rate in the European population was 0.4 events/100 WY (95% CI, 0.4-0.5). DNG/oEV showed lower contraceptive failure rates compared to the comparators. This difference was maintained when the study population was restricted to women aged 18-35 years; the pearl index (PI) for this demographic for DNG/oEV was 0.37 (95% CI 0.24-0.54) and 0.76 (95% CI 0.56-1.01) for LNG. The hazard ratios (HRs) adjusted for age, parity, smoking and BMI were 0.7 (95% CI, 0.5-0.98, p  = .04) and 0.5 (95% CI, 0.3-0.8, p  < .01) for DNG/oEV versus oCOC and LNG, respectively. The corresponding adjusted HRs in women aged 25 years or younger were 0.6 (95% CI 0.4-1.1) and 0.4 (95% CI, 0.2-0.8), respectively. Conclusions/discussion: DNG/oEV showed improved contraceptive effectiveness compared with oCOC and particularly LNG-COC when adjusted for age, parity, user status and smoking.

Background: Wilson disease is an autosomal recessive genetic disorder affecting copper transport leading to hepatic and/or neuropsychiatric manifestation. Untreated Wilson disease in females may cause sub fertility or spontaneous miscarriage. Although the literature shows an increasing number of successful outcomes after treatment, pregnant patients with Wilson disease still need close monitoring and interdisciplinary management., Methods: In a retrospective study patient charts of 32 pregnancies in 22 women with Wilson disease were reviewed retrospectively for the initial clinical manifestation, medical treatment prior and during pregnancy, maternal and fetal course and outcome., Results: A total of 32 pregnancies in 22 patients were analyzed. The majority of our patients did not have any deterioration of symptoms of Wilson disease prior to and during pregnancy. One pregnant patient decided to stop her anticopper medications while pregnant with fatal outcome for both, mother and foetus. None of our newborns showed major birth defects or side effects in this cohort after maternal chelation treatment., Conclusions: Reproductive status and pregnancies of women with Wilson disease may be problematic. Pregnant women need close monitoring and multidisciplinary management. Anticopper therapy during pregnancy and breast feeding are safe. Treatment should be maintained during pregnancy and the pregnant women should be treated by a multi-disciplinary team. With adequate medical treatment and close monitoring before and during pregnancy, a successful outcome of mother and newborn can be achieved., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Sepsis is a leading cause of mortality in the critically ill, characterized by life-threatening organ dysfunctions due to dysregulation of the host response to infection. Using mass spectrometry, we identified a C-terminal fragment of alpha-1-antitrypsin, designated CAAP48, as a new sepsis biomarker that actively participates in the pathophysiology of sepsis. It is well-known that liver dysfunction is an early event in sepsis-associated multi-organ failure, thus we analyzed the pathophysiological function of CAAP48 in a microfluidic-supported in vitro liver-on-chip model. Hepatocytes were stimulated with synthetic CAAP48 and several control peptides. CAAP48-treatment resulted in an accumulation of the hepatocyte-specific intracellular enzymes aspartate- and alanine-transaminase and impaired the activity of the hepatic multidrug resistant-associated protein 2 and cytochrome P450 3A4. Moreover, CAAP48 reduced hepatic expression of the multidrug resistant-associated protein 2 and disrupted the endothelial structural integrity as demonstrated by reduced expression of VE-cadherin, F-actin and alteration of the tight junction protein zonula occludens-1, which resulted in a loss of the endothelial barrier function. Furthermore, CAAP48 induced the release of adhesion molecules and pro- and anti-inflammatory cytokines. Our results show that CAAP48 triggers inflammation-related endothelial barrier disruption as well as hepatocellular dysfunction in a liver-on-chip model emulating the pathophysiological conditions of inflammation. Besides its function as new sepsis biomarker, CAAP48 thus might play an important role in the development of liver dysfunction as a consequence of the dysregulated host immune-inflammatory response in sepsis.

The liver is a central organ in the metabolization of nutrition, endogenous and exogenous substances, and xenobiotic drugs. The emerging organ-on-chip technology has paved the way to model essential liver functions as well as certain aspects of liver disease in vitro in liver-on-chip models. However, a broader use of this technology in biomedical research is limited by a lack of protocols that enable the short-term preservation of preassembled liver-on-chip models for stocking or delivery to researchers outside the bioengineering community. For the first time, this study tested the ability of hypothermic storage of liver-on-chip models to preserve cell viability, tissue morphology, metabolism and biotransformation activity. In a systematic study with different preservation solutions, liver-on-chip function can be preserved for up to 2 d using a derivative of the tissue preservation solution TiProtec, containing high chloride ion concentrations and the iron chelators LK614 and deferoxamine, supplemented with polyethylene glycol (PEG). Hypothermic storage in this solution represents a promising method to preserve liver-on-chip function for at least 2 d and allows an easier access to liver-on-chip technology and its versatile and flexible use in biomedical research., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Methamphetamine abuse during pregnancy represents an emerging health care problem. The consequences are not only of relevance to the pregnant women, but also their unborn child. It is associated with an increased risk of preeclampsia and hypertension, fetal demise, preterm delivery, and intrauterine growth restriction. The deleterious effects of prenatal methamphetamine exposure on the developing fetal brain may lead to long-term neuro-developmental and behavioral problems.Given the current evidence, abuse of methamphetamine during pregnancy must be of utmost concern to health care professionals and to policy-makers. As it has been described for neonatal abstinence syndrome, a multi-professional team is required to improve care of affected women and families. A multi-disciplinary approach is needed, including good prenatal care of pregnant women, perinatal care by specialized obstetricians and neonatologists, and psychiatric treatment by an addiction specialist. Furthermore, families should be integrated into appropriate social support networks.For the development of a structured support program for pregnant women with methamphetamine consumption, methamphetamine use disorder should be considered as a disease that requires medical treatment as well as psychological and social support. The pregnancy should be considered as a window of opportunity to provide the required help., (© Georg Thieme Verlag KG Stuttgart · New York.)

Over the past several years, the number of first-time users of methamphetamine considerably increased within the Free State of Saxony. This number also, and especially, includes women of child-bearing age and young mothers. A supportive intervention aimed at reducing the effects of drug abuse should begin in a timely way - during pregnancy at latest, but better before it. To develop an optimal care protocol for both the mother and her child, more knowledge regarding the personal conditions of the women as well as the specific features of later child development after prenatal methamphetamine exposure (PME) is vital. In this study, the data of 129 women and their newborns with PME who were admitted to a Level-1 perinatal center between 2007 and 2015 were analyzed. At delivery, two-thirds of the women were aged 20-30 years. Only 48% attended their first preventive examination in pregnancy within the first 12 weeks. Their children subsequently presented with heterogeneous withdrawal symptoms, and pathological findings of the heart, urogenital and central nervous system. The present data aims to sensitize pediatric and obstetric health professionals to the need for timely and adequate care and support. A pathway model of detoxification treatment for mother and child - "The Dresden Crystal Path" - is presented. It combines public and voluntary youth welfare organizations, public health authorities, a public drugs advisory service as well as medical care facilities. Moreover, it describes the coordination of different medical subspecialties such as pediatrics, obstetrics/gynecology and psychiatry., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: To estimate the real-use contraceptive effectiveness of the combined oral contraceptive containing dienogest and estradiol valerate (DNG/EV) and whether DNG/EV compared to other combined oral contraceptives (oCOC) has a negative effect on return to fertility., Methods: Transatlantic, prospective, non-interventional cohort study conducted in the USA and seven European countries with two main exposure groups and one exposure subgroup: new users of DNG/EV and other COC (oCOC), particularly levonorgestrel-containing COCs (LNG). In a planned secondary analysis, pregnancy outcomes were investigated including contraceptive effectiveness and pregnancy following contraceptive cessation. The influence of age, parity and OC-type were assessed., Results: 50,203 COC users were followed for 105,761 woman-years (WY). There were 677 unintended pregnancies reported: 451 in the USA and 226 in Europe. The contraceptive failure rate in Europe was 0.5 events/100 WY (95% CI: 0.4-0.5) and in the USA 1.9 events/100 WY (95% CI: 1.7-2.1). Differences in compliance (1.3 pregnancies/100 WY) accounted for 90% of the geographical difference seen between Europe and the USA. DNG/EV showed lower contraceptive failure rates compared to the comparators; 0.9% DNG/EV, 2.1% oCOC and 2.8% LNG after 4 years. Overall, 1167 (2.3%) of women stopped contraceptive use with the intention of becoming pregnant with 89% conceiving within 2 years. No significant differences were seen between groups after adjusting for age., Conclusion/discussion: DNG/EV is associated with similar contraceptive effectiveness in typical-use settings when compared to oCOC and LNG. There was no difference observed between cohorts in fertility following OC use.

Objectives: The International Active Surveillance study "Safety of Contraceptives: Role of Estrogens" (INAS-SCORE) investigated the cardiovascular risks associated with the use of a combined oral contraceptive (COC) containing dienogest and estradiol valerate (DNG/EV) compared to established COCs in a routine clinical setting., Study Design: Transatlantic, prospective, noninterventional cohort study conducted in the United States and seven European countries with two main exposure groups and one exposure subgroup: new users of DNG/EV and other COC (oCOC), particularly levonorgestrel-containing COCs (LNG). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious cardiovascular events (SCE), particularly venous thromboembolic (VTEs) events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models., Results: A total of 50,203 new COC users were followed up for up to 5.5years (mean value, 2.1years). Overall 20.3% and 79.7% of these women used DNG/EV and oCOC (including 11.5% LNG users), respectively. A low loss to follow-up of 3.1% was achieved. Based on 47 (VTE) and 233 (SCE) events, the primary analysis (European data set) yielded adjusted hazard ratios for DNG/EV vs. oCOC of 0.4 and 0.5, respectively. The upper bounds of the 95% confidence intervals were 0.98 (VTE) and 0.96 (SCE). The corresponding hazard ratios for DNG/EV vs. LNG showed similar point estimates but the confidence intervals included unity., Conclusion: DNG/EV is associated with similar or even lower cardiovascular risk compared to oCOC and LNG., Implication Statement: A COC containing DNG and EV is associated with similar or even lower cardiovascular risk compared to COCs containing levonorgestrel or other progestogens., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Over the past years, research on neonatal resuscitation has focused on single interventions. The present study was performed to analyze the process quality of delivery room management of preterm infants born by c-section in our institution., Methods: We performed a cross-sectional study of videos of preterm infants born by c-section. Videos were analyzed according to time point, duration and number of performed medical interventions. The study period occurred between January 2012 and December 2013. Infants were caterogized in 3 groups according to their gestational age., Results: One hundred eleven videos were analyzed. 100 (90 %) of the infants were transferred to NICU and 91 (83 %) received respiratory support after a median of 0.5 min. All infants were auscultated after 8 (5-16) seconds median (IQR) and an oxygen saturation sensor was placed after 37 (28-52) seconds. 23 infants were intubated after 9 (6-17) minutes and 17 received exogenous surfactant; 29 % according to INSURE (intubation-surfactant-extubation) technique. The duration of intubation attempts was 47 (25-60) seconds. 51 % of the newborns received a sustained inflation for 8 (6-9) seconds. A successful IV-line placement occurred after 15 (12-20) minutes. 4 % of the infants were transported to the NICU without an IV-line after 3 (difference range: 2-5) unsuccessful attempts., Conclusions: Using video analysis as a tool to study process quality, we conclude that interventions differ not only between but also within similar age groups. This data can be used for benchmarking with current guidelines and practice in other centers.

Primary microcephaly and severe developmental delay are complex but unspecific signs pointing to various genetic or acquired diseases. A concomitant finding of hematological failure may lead to the differential diagnosis of rare genetic diseases such as chromosome breakage disorders or diseases associated with telomere dysfunction. X-linked Hoyeraal-Hreidarsson syndrome (HHS) is a rare heterogenic disorder characterized by severe neurological impairment and progressive bone marrow failure. The latter represents the main cause of mortality, usually in early childhood. We report on the clinical course of an infant with HHS due to a novel mutation in the DKC1 gene and the particular finding of pontocerebellar hypoplasia., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: The "Long-term Active Surveillance Study for Oral Contraceptives" investigated the risks of long-term use of a 21-day regimen of drospirenone and ethinylestradiol (DRSP) compared to established oral contraceptives (OCs) in a routine clinical setting., Study Design: Prospective, controlled, non-interventional cohort study conducted in seven European countries with three main exposure groups: new users of DRSP, levonorgestrel-containing OCs (LNG), and OCs containing other progestogens (Other OCs). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular cardiovascular events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models., Results: A total of 1,113 study centers enrolled 59,510 women. Overall 28%, 26% and 45% of these women used DRSP, LNG and Other OCs, respectively. Study participants were followed for up to ten years (mean value, 5.4years), which generated 318,784 woman-years (WY) of observation. Low loss to follow-up and drop-out rates of 2.9% and 16.8% were achieved. DRSP, LNG, and Other OCs showed similar incidence rates of venous thromboembolism. Corresponding hazard ratios (HRs) were close to unity. For arterial thromboembolic events (ATE) and initiation of antihypertensive treatment statistically significant lower risks were found for DRSP compared to LNG and Other OCs., Conclusion: DRSP use was associated with similar general health risks and a low risk of ATE compared to OCs containing other progestogens., Implication Statement: The 21-day regimen of drospirenone-containing combined oral contraceptives is associated with similar risk of VTE compared to other combined oral contraceptives as well as potentially with a lower risk of ATE., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Liver dysfunction is an early event in sepsis-related multi-organ failure. We here report the establishment and characterization of a microfluidically supported in vitro organoid model of the human liver sinusoid. The liver organoid is composed of vascular and hepatocyte cell layers integrating non-parenchymal cells closely reflecting tissue architecture and enables physiological cross-communication in a bio-inspired fashion. Inflammation-associated liver dysfunction was mimicked by stimulation with various agonists of toll-like receptors. TLR-stimulation induced the release of pro- and anti-inflammatory cytokines and diminished expression of endothelial VE-cadherin, hepatic MRP-2 transporter and apolipoprotein B (ApoB), resulting in an inflammation-related endothelial barrier disruption and hepatocellular dysfunction in the liver organoid. However, interaction of the liver organoid with human monocytes attenuated inflammation-related cell responses and restored MRP-2 transporter activity, ApoB expression and albumin/urea production. The cellular events observed in the liver organoid closely resembled pathophysiological responses in the well-established sepsis model of peritoneal contamination and infection (PCI) in mice and clinical observations in human sepsis. We therefore conclude that this human liver organoid model is a valuable tool to investigate sepsis-related liver dysfunction and subsequent immune cell-related tissue repair/remodeling processes.

Background: This study examined the association of 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) with postoperative medical complications and one year mortality of elderly patients sustaining a low-energy cervical hip fracture scheduled for surgery. We hypothesized that vitamin D deficiency and CRP in these patients might be associated with an increased 1-year mortality., Methods: The prospective single-center cohort study included 209 patients with a low-energy medial femoral neck fracture; 164 women aged over 50 years and 45 men aged over 60 years. Referring to 1-year mortality and postoperative medical complications multiple logistic regression analysis including 10 co-variables (age, sex, BMI, ASA, creatinine, CRP, leukocytes hemoglobin, 25(OH)D, vitamin D supplementation at follow-up) was performed., Results: Vitamin D deficiency was prevalent in 87 % of all patients. In patients with severe (<10 ng/ml) and moderate (10-20 ng/ml) vitamin D deficiency one year mortality was 29 % and 13 %, respectively, compared to 9 % in patients with > 20 ng/ml 25(OH)D levels (p =0.027). Patients with a mild (CRP 10-39.9 mg/l) or active inflammatory response (CRP ≥ 40 mg/l) showed a higher one year mortality of 33 % and 40 % compared to 16 % in patients with no (CRP < 10 mg/l) inflammatory response (p = 0.002). Multiple logistic regression analysis identified CRP (OR 1.01, 95 % CI 1.00-1.02; p = 0.007), but not 25(OH)D (OR 0.97, 95 % CI 0.89-1.05; p = 0.425) as an independent predictor for one year mortality. 20 % of patients suffered in-hospital postoperative medical complications (i.e. pneumonia, thromboembolic events, etc.). 25(OH)D (OR 0.89, 95 % CI 0.81-0.97; p = 0.010), but not CRP (OR 1.01, 95 % CI 1.00-1.02; p = 0.139), was identified as an independent risk factor., Conclusion: In elderly patients with low-energy cervical hip fracture, 25(OH)D is independently associated with postoperative medical complications and CRP is an independent predictor of one year mortality.

In vitro cytochrome P450 (CYP) inhibition assays are common approaches for testing the inhibition potential of drugs for predicting potential interactions. In contrast to marketed medicaments, drugs of abuse, particularly the so-called novel psychoactive substances, were not tested before distribution and consumption. Therefore, the inhibition potential of methylenedioxy-derived designer drugs (MDD) of different drug classes such as aminoindanes, amphetamines, benzofurans, cathinones, piperazines, pyrrolidinophenones, and tryptamines should be elucidated. The FDA-preferred test substrates, split in two cocktails, were incubated with pooled human liver microsomes and analysed after protein precipitation using LC-high-resolution-MS/MS. IC50 values were determined of MDD showing more than 50 % inhibition in the prescreening. Values were calculated by plotting the relative metabolite concentration formed over the logarithm of the inhibitor concentration. All MDD showed inhibition against CYP2D6 activity and most of them in the range of the clinically relevant CYP2D6 inhibitors quinidine and fluoxetine. In addition, the beta-keto compounds showed inhibition of the activity of CYP2B6, 5,6-MD-DALT of CYP1A2 and CYP3A, and MDAI of CYP2A6, all in the range of clinically relevant inhibitors. In summary, all MDD showed inhibition of the activity of CYP2D6, six of CYP1A2, three of CYP2A6, 13 of CYP2B6, two of CYP2C9, six of CYP2C19, one of CYP2E1, and six of CYP3A. These results showed that the CYP inhibition by MDD might be clinically relevant, but further studies are needed for final conclusions.

New psychoactive substances (NPS) are not tested for their cytochrome P450 (CYP) inhibition potential before consumption. Therefore, this potential was explored for tryptamine-derived NPS (TDNPS) including alpha-methyl tryptamines (AMTs), dimethyl tryptamines (DMTs), diallyl tryptamines (DALTs), and diisopropyl tryptamines (DiPTs) using test substrates preferred by the Food and Drug Administration in a cocktail assay. All tested TDNPS with the exception of DMT inhibited CYP2D6 activity with IC50 values below 100μM. DALTs inhibited CYP2D6 activity similar to paroxetine and quinidine and CYP1A2 activity comparable to fluvoxamine. 5-Methoxy-N,N-diallyltryptamine reduced in vivo the caffeine metabolism in rats consistent with in vitro results. Five of the AMTs also inhibited CYP1A2 activity comparable to amiodarone. AMT and 6-F-AMT inhibited CYP2A6 activity in the range of the test inhibitor tranylcypromine. CYP2B6 activity was inhibited by 19 tryptamines, but weakly compared to efavirenz. CYP2C8 activity was inhibited by five of the tested TDNPS and three showed values comparable to trimethoprim and gemfibrozil. Six tryptamines inhibited CYP2C9 and seven CYP2C19 activities comparable to fluconazole and chloramphenicol, respectively. Nineteen compounds showed inhibition of CYP2E1 and 18 of CYP3A activity, respectively. These results showed that the CYP inhibition by TDNPS might be clinically relevant, but clinical studies are needed to explore this further., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Within the liver, non-parenchymal cells (NPCs) are critically involved in the regulation of hepatocyte polarization and maintenance of metabolic function. We here report the establishment of a liver organoid that integrates NPCs in a vascular layer composed of endothelial cells and tissue macrophages and a hepatic layer comprising stellate cells co-cultured with hepatocytes. The three-dimensional liver organoid is embedded in a microfluidically perfused biochip that enables sufficient nutrition supply and resembles morphological aspects of the human liver sinusoid. It utilizes a suspended membrane as a cell substrate mimicking the space of Disse. Luminescence-based sensor spots were integrated into the chip to allow online measurement of cellular oxygen consumption. Application of microfluidic flow induces defined expression of ZO-1, transferrin, ASGPR-1 along with an increased expression of MRP-2 transporter protein within the liver organoids. Moreover, perfusion was accompanied by an increased hepatobiliary secretion of 5(6)-carboxy-2',7'-dichlorofluorescein and an enhanced formation of hepatocyte microvilli. From this we conclude that the perfused liver organoid shares relevant morphological and functional characteristics with the human liver and represents a new in vitro research tool to study human hepatocellular physiology at the cellular level under conditions close to the physiological situation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aims: To determine how often infants are suctioned during delivery and how it affects the neonate., Methods: Single-center analysis of video-recorded delivery room management after c-section from January 2012 until April 2013. Time point, duration, and frequency of suctioning in term and preterm newborns were analyzed along with vital parameters (heart rate (HR) and saturation values)., Results: Three hundred forty-six videos were analyzed. Twenty-three percent of term and 66% of preterm newborns were suctioned. Newborns were suctioned up to 14 times; total duration spent for suctioning was between 2 and 154 s. Suctioning before face mask application occurred in 31% of the suctioned newborns requiring respiratory support. No severe bradycardia (<60 bpm) was noticed. Suctioning did not have an effect on HR and saturation in preterm infants but was associated with significantly higher HR in term infants requiring respiratory support. Term infants who did not require respiratory support showed significantly higher saturation values at 3, 5, 6, 7, 8, 9, and 10 min if they were not suctioned., Conclusions: Suctioning of newborns in the delivery room does not adhere to recommendations of international guidelines. However, previously described side effects of suctioning could not be confirmed.

Drugs of abuse are not tested for cytochrome P450 (CYP) inhibition potential before distribution. Therefore, a cocktail assay should be developed for testing the inhibition potential for all relevant CYPs. The following CYP test substrates and selective inhibitors were incubated in pooled human liver microsomes: phenacetin (alpha-naphthoflavone for CYP1A2), coumarin (tranylcypromine, CYP2A6), bupropion (sertraline, CYP2B6), amodiaquine (trimethoprim, CYP2C8), diclofenac (sulfaphenazole, CYP2C9), omeprazole (fluconazole, CYP2C19), dextromethorphan (quinidine, CYP2D6), chlorzoxazone (clomethiazole, CYP2E1), testosterone (verapamil, CYP3A). Samples were analyzed after protein precipitation using a Thermo Fisher Q-Exactive LC-high-resolution-MS/MS. The IC50 values were calculated by plotting the concentration of the formed metabolite, relative to the control sample, over the logarithm of the inhibitor concentration. They were determined either for single substrate or the cocktail incubation. Unfortunately, the cocktail assay had to be split because of interferences during incubation caused by substrates or metabolites, but the mixture of both incubates could be analyzed in one analytical run. The IC50 values determined in the single substrate or both cocktail incubations were comparable among themselves and with published data. In conclusion, the new inhibition cocktail assay was reproducible and applicable for testing the inhibition potential of drugs of abuse as exemplified for 2,5-dimethoxy-4-iodo-amfetamine (DOI)., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)