Association of placental and umbilical cord characteristics with cerebral palsy: national cohort study.

OBJECTIVES: Cerebral palsy (CP) is a group of movement disorders usually diagnosed in childhood. A substantial proportion are thought to be caused by antenatal events. Abnormalities of the umbilical cord and placenta are associated with an increased risk of adverse neonatal outcomes, but it is unclear whether these conditions also carry an increased risk of CP. We aimed to determine whether abnormalities of the umbilical cord or placenta are associated with CP and assess if these associations differ by sex of the child or gestational age at birth. METHODS: We performed a national cohort study by linking data from The Medical Birth Registry of Norway with other national registries. All liveborn singletons born between 1999 and 2017 (n = 1 087 486) were included and followed up until the end of 2019. Diagnoses of CP were provided by the Norwegian National Insurance Scheme and the Norwegian Patient Register. We used generalized estimating equations and multilevel log binomial regression to calculate relative risks (RR), adjusted for year of birth, and stratified analyses were carried out based on sex and gestational age at birth. Exposures were abnormal umbilical cord (velamentous or marginal insertion, single umbilical artery (SUA), knots and entanglement), and placental abnormalities (retained placenta, placental abruption and previa). RESULTS: A total of 2443 cases with CP (59.8% males) were identified. Velamentous cord insertion (adjusted RR (aRR), 2.11 (95% CI, 1.65-2.60)), cord knots (aRR, 1.53 (95% CI, 1.15-2.04)) and placental abnormalities (placenta previa (aRR, 3.03 (95% CI, 2.00-4.61)), placental abruption (aRR, 10.63 (95% CI, 8.57-13.18)) and retained placenta (aRR, 1.71 (95% CI, 1.32-2.22))) carried an increased risk of CP. Velamentous cord insertion was associated with CP regardless of gestational age or sex. A retained placenta was associated with a 2-fold increased risk for CP in males, while the associations of SUA and cord knot with CP were significant only among females. CONCLUSIONS: The detection of placental and umbilical cord abnormalities may help identify children at increased risk of CP. The associations between placental or umbilical cord abnormalities and the risk of CP do not vary substantially with gestational age at birth or sex of the child. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[O-DEM: a new cognitive screening in patients with hearing loss]. / O-DEM: ein neues kognitives Screening bei Schwerhörigkeit.

BACKGROUND: Hearing loss is a significant risk factor for dementia. To date, cognitive impairment and dementia in patients with hearing impairment (HI) cannot be adequately diagnosed by commonly administered cognitive screening tests due to sensory impairments. Therefore, an adapted screening is needed. The aim of the present study was to develop and evaluate a cognitive screening for people with HI. MATERIALS AND METHODS: The new cognitive screening, called O­DEM, entails a word fluency test, the Trail Making Test A (TMT-A), and a subtraction task. First, the O­DEM was tested in a large clinical sample (N = 2837) of people without subjective HI. In a second step, the O­DEM was evaluated in 213 patients with objectively assessed HI and compared with the Hearing-Impaired Montreal Cognitive Assessment (HI-MoCA). RESULTS: The results indicate that the O­DEM subtests significantly discriminate between participants with no, mild, and moderate to severe cognitive impairment. Based on the mean and standard deviation of the participants without cognitive impairment, a transformation of the raw scores was performed and a total score with a maximum value of 10 was determined. In the second part of the study, the O­DEM was shown to be as sensitive as the HI-MoCA in differentiating between people with and without cognitive impairment. CONCLUSION: Compared to other screenings, the O­DEM is a quickly administrable screening for the detection of mild and moderate cognitive impairment in people with HI.

Single umbilical artery and risk of congenital malformation: population-based study in Norway.

OBJECTIVES: Single umbilical artery (SUA) is associated with congenital malformations in most organ systems, but reported findings have not been consistent. While it has been suggested that genetic and persisting environmental factors influence the development of SUA, it is not known whether there is an increased risk of recurrence in a subsequent pregnancy of the same woman. The aims of this study were to investigate the occurrence of, and risk factors for, SUA in Norway, to assess its association with congenital malformations and trisomies 13, 18 and 21 and to study the risk of recurrence of SUA in subsequent pregnancies. METHODS: This was a population-based study of all (n = 918 933) singleton pregnancies of > 16 weeks' gestation recorded in the Medical Birth Registry of Norway from 1999 to 2014. To identify risk factors and congenital malformations associated with SUA, generalized estimating equations and logistic regression were used to calculate odds ratios (OR) with 95% CIs. ORs were also calculated for the recurrence of SUA in subsequent pregnancy. RESULTS: The occurrence of SUA in our population was 0.46% (4241/918 933). Parity ≥ 4, smoking, maternal pregestational diabetes, epilepsy, chronic hypertension, previous Cesarean delivery and conception by assisted reproductive technology increased the odds of having SUA. There was a particularly strong association between SUA and gastrointestinal atresia or stenosis in the neonate, with ORs of 25.8 (95% CI, 17.0-39.1) and 20.3 (95% CI, 13.4-30.9) for esophageal and anorectal atresia or stenosis, respectively, followed by an OR of 5.9 (95% CI, 1.9-18.5) for renal agenesis. SUA was associated with an up to 7-8 times increased risk of congenital heart defects. There was an association with microcephaly, congenital hydrocephalus and other congenital malformations of the brain and spinal cord. Diaphragmatic hernia, limb reductions and cleft lip or palate had a weaker association with SUA, with ORs ranging from 4.8 to 2.8. The associations with trisomy 18 and 13 were equally strong (OR 14.4 (95% CI, 9.3-22.4) and OR 13.6 (95% CI, 6.7-27.8), respectively), and the risk of trisomy 21 was doubled (OR 2.1 (95% CI, 1.2-3.6)). Pregnancies with SUA, with or without an associated malformation, had a 2-fold increased risk for SUA in a subsequent pregnancy. CONCLUSIONS: SUA is associated strongly with gastrointestinal atresia or stenosis, suggesting common developmental mechanisms. The increased risk of recurrence of SUA suggests that genetic and/or persisting environmental factors influence the risk. We found that SUA had equally strong associations with trisomies 13 and 18. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.

Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.

[Conversions of cognitive screenings : Mini-Mental State Examination vs. Montreal Cognitive Assessment vs. DemTect]. / Konversionen von kognitiven Screenings : Mini-Mental-Status-Test vs. Montreal Cognitive Assessment vs. DemTect.

BACKGROUND: For a comprehensive specification and quantification of neuropsychological deficits, extensive neuropsychological assessment is needed. Due to its time intensiveness, this cannot be accomplished in every clinical setting and is not always necessary. Therefore, screening instruments provide a first step. Because the selection differs between and sometimes even within clinics, a comparison of results for different screening procedures would be helpful. The current study aimed at achieving this in the German-speaking area, i.e. conversions between sum scores of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Dementia Detection Test (DemTect) can be accomplished. METHOD: In the Department of Neurology at the University Hospital of Cologne, 8240 patients with different neurological diseases were examined between 2008 and 2017. Conversion scores using the results in the MMSE, MoCA and DemTect were computed by using the equipercentile equating method. RESULTS: The calculated bidirectional conversion tables enable a quick and easy comparison between the three most commonly used screening instruments. They are also similar to those from previous studies in English-speaking countries. CONCLUSION: The results enable an enhanced longitudinal assessment of cognitive functions in different clinical settings, provide comparability, and offer more flexibility for determination of patient status. An extension of the current study might be the transfer of the method presented to other cognitive or affective domains, such as memory and depression.

[Establishment of the new cross-sectional field of pain medicine : An application example at the medical faculty of Heidelberg]. / Etablierung des neuen Querschnittsbereichs Schmerzmedizin : Ein Anwendungsbeispiel der Medizinischen Fakultät Heidelberg.

Studies from recent years paint a picture of qualitatively deficient treatment in pain medicine. In order to improve the situation knowledge on targeted diagnostics and effective therapy should be imparted at an early stage during undergraduate studies. For this reason the cross-sectional field Q14 - pain medicine was newly created in the revision of the medical physician licencing regulations. The Q14 was then established in a longitudinal, multidisciplinary form at the medical faculty in Heidelberg, whereby the complete Kern cycle was run through. The present project report describes and discusses the establishment. The results of the first multiple choice examination and an online-based evaluation by the students are presented. The latter show that the students recognized the relevance of the teaching program for their future professional career; however, the presentation of the interdisciplinary aspect must still be improved. The students were critical of the longitudinal structure and this does indeed involve a great deal of organization for the faculty and students. On the other hand this corresponds to the basic conception of a cross-sectional field and gives a good depiction of the multidisciplinary character. The first evaluation results set the precedent for further fine adjustments of the cross-sectional field. A continuous further development is generally needed with respect to the Kern cycle.

[Interprofessional symptom management at the end of life]. / Interprofessionelle Symptomkontrolle am Lebensende.

At the end of life patients often show distressful symptoms which significantly reduce their quality of life. The goal of all healthcare professionals should be to recognize the beginning of this end of life period in order to provide good symptom management. For this purpose, existing symptoms have to be recorded, suitable therapeutic goals have to be defined for the current situation and potential therapeutic strategies have to be individually formulated. Besides the identification of underlying causes with the possibility of causal treatment, a symptom-based therapy is often necessary. Therapeutic approaches of different professions should be equally considered and should additionally be used for the benefit of the patient.

Incentivizing Authorization for Deceased Organ Donation With Organ Allocation Priority: The First 5 Years.

The allocation system of donor organs for transplantation may affect their scarcity. In 2008, Israel's Parliament passed the Organ Transplantation Law, which grants priority on waiting lists for transplants to candidates who are first-degree relatives of deceased organ donors or who previously registered as organ donors themselves. Several public campaigns have advertised the existence of the law since November 2010. We evaluated the effect of the law using all deceased donation requests made in Israel during the period 1998-2015. We use logistic regression to compare the authorization rates of the donors' next of kin in the periods before (1998-2010) and after (2011-2015) the public was made aware of the law. The authorization rate for donation in the period after awareness was substantially higher (55.1% vs. 45.0%, odds ratio [OR] 1.43, p = 0.0003) and reached an all-time high rate of 60.2% in 2015. This increase was mainly due to an increase in the authorization rate of next of kin of unregistered donors (51.1% vs. 42.2%). We also found that the likelihood of next-of-kin authorization for donation was approximately twice as high when the deceased relative was a registered donor rather than unregistered (89.4% vs. 44.6%, OR 14.27, p < 0.0001). We concluded that the priority law is associated with an increased authorization rate for organ donation.

Cognitive screening in Parkinson's disease: Comparison of the Parkinson Neuropsychometric Dementia Assessment (PANDA) with 3 other short scales.

BACKGROUND: Cognitive screening is crucial in Parkinson's disease (PD). However, there is still a lack of short tools in French. In this study, we aimed to compare the Parkinson Neuropsychometric Dementia Assessment (PANDA) with the Mini Mental Parkinson (MMP), the Mini Mental State Examination (MMSE) and the Clock Test in French-speaking patients. We also aimed to propose cut-off scores for cognitive impairment and dementia for the French language version of the PANDA. METHOD: Fifty-one patients with PD took the PANDA, the MMSE, the MMP, and the Clock Test. They also underwent extensive neuropsychological testing by a neuropsychologist who was blinded to the above-mentioned screening test results. Patients were classified as either having normal cognition (n=15), mild cognitive impairment (n=20) or dementia (n=16). RESULTS: When compared with the three other screening tools, the PANDA exhibited the highest area under the curve (AUC) for both cognitive disorders and dementia. Using the cut-off scores proposed for the German version, the PANDA had 94% specificity and 100% sensitivity for dementia and 100% and 72%, respectively for cognitive disorders. CONCLUSIONS: In our study, the PANDA exhibited a higher discriminative power than the three other tests in detecting cognitive disorders and dementia. In PD patients, the PANDA should thus be considered for the detection of cognitive impairment in routine clinical practice.

[A New Diagnostic Tool for Apraxia in Patients with Right-Hemisphere Stroke: The Revised Cologne Apraxia Screening (KAS-R)]. / Das revidierte Kölner Apraxie-Screening (KAS-R) als diagnostisches Verfahren für Patienten mit rechtshemisphärischem Schlaganfall.

The Cologne Apraxia Screening (KAS) was developed to diagnose apraxia following left-hemisphere (LH) stroke. The present study aims at developing a diagnostic tool for patients with right-hemisphere (RH) stroke (KAS-R) by modifying the test material of the KAS and reducing the test items based on psychometric analyses.A total of 100 patients with RH stroke and 77 healthy control participants were tested. Psychometric analyses led to the exclusion of 8 KAS items. The final KAS-R, consisting of 12 items, shows good internal consistency (α = 0.795) as well as high sensitivity (79.4 %) and specificity (84.4 %). Applying a cut-off value of ≤ 46 (out of 48) points, 39 RH stroke patients were diagnosed with apraxia. Significant correlations were found between the KAS-R and an imitation test as well as expert ratings, indicating high construct validity. The results suggest that the KAS-R is a reliable and valid diagnostic tool for apraxic deficits after RH stroke.

Cognitive training in Parkinson's disease reduces cognitive decline in the long term.

BACKGROUND AND PURPOSE: Patients with Parkinson's disease (PD) are at high risk for cognitive dysfunction. Non-pharmacological interventions have attracted increasing interest for enhancing PD patients' cognitive functions. METHODS: One-year follow-up data (T2 ) of a randomized controlled trial evaluating two 6-week cognitive trainings - a structured (NEUROvitalis, NV) and an unstructured (mentally fit, MF) program - compared with a waiting list control group (CG) in non-demented PD patients (Hoehn and Yahr I-III) are presented. Forty-seven PD patients were examined at T2 . Effects on overall cognitive functions (Mini-Mental State Examination and DemTect) were compared between all groups with repeated measurement analyses of variance. A combined score of the percentage change value from baseline (T0 ) to T2 was calculated to identify patients who retained or improved their cognitive state (responders). The risk of developing mild cognitive impairment (MCI) was analyzed. RESULTS: Significant time × treatment effects on overall cognitive functions were found for both training groups, each compared separately to the CG (DemTect, P < 0.05). Nine patients (56.3%) of the NV group, seven (41.2%) of the MF group and three (21.4%) of the CG were responders. Comparing NV to CG the odds ratio was 4.7 [95% confidence interval (0.8; 33.3)], and comparing MF to CG it was 2.6 [95% confidence interval (0.4; 17.4)]. MCI risk for patients without prior MCI was 40.0% in CG, 18.2% in MF and 18.2% in NV. The odds ratio was 3 comparing NV to CG, MF to CG. DISCUSSION: This study gives evidence that cognitive training may be effective to prevent cognitive decline and onset of MCI in PD patients.

Intrapartum monitoring with cardiotocography and ST-waveform analysis in breech presentation: an observational study.

OBJECTIVE: To determine the electrocardiographic performance and neonatal outcome of pregnancies with breech presentation and planned vaginal delivery monitored with ST-waveform analysis (STAN). DESIGN: Prospective observational study. SETTING: University hospital, Norway; 2004-2008. POPULATION: Singleton pregnancies with a gestational age above 35 + 6 weeks, breech presentation, selected for vaginal delivery and monitored with STAN. METHODS: Common clinical guidelines for STAN monitoring were used. An experienced neonatologist graded the symptoms of neonatal encephalopathy. The outcome was compared with STAN-monitored high-risk deliveries in a vertex presentation (n = 5569) using logistic regression analysis. MAIN OUTCOME MEASURE: Frequency of ST events, indications of intervention for fetal distress, and neonatal morbidity and mortality. RESULTS: Breech presentation occurred in 750 of 23,219 (3.2%) deliveries, 625 (83%) of which were selected for vaginal delivery. Intrapartum monitoring by STAN was performed in 433 (69%). Compared with vertex presentations, fetuses in breech presentation had a lower risk of baseline T/QRS rise during labour [odds ratio (OR) = 0.7, 95% confidence interval (95% CI) = 0.7-0.9, P = 0.003] and a higher risk for intervention as a result of preterminal cardiotocogram (OR = 2.9, 95% CI = 1.6-5.9, P = 0.001). The risks of perinatal mortality (OR = 1.8, 95% CI = 0.2-15, P = 0.6), cord metabolic acidosis (OR = 0.8, 95% CI = 0.2-3.2, P = 0.7) and moderate or severe neonatal encephalopathy (OR = 1.8, 95% CI = 0.5-6.2, P = 0.3) did not differ significantly between breech and vertex deliveries. CONCLUSION: STAN can be used for the surveillance of breech presentations selected for vaginal delivery with an acceptable neonatal outcome. The electrocardiogram (ECG) pattern during labour varies with the fetal presentation.

Peripheral regional anaesthesia and outcome: lessons learned from the last 10 years.

BACKGROUND: Our aim was to review the recent evidence for the efficacy of peripheral regional anaesthesia. METHODS: Following a systematic literature search and selection of publications based on prospectively agreed upon criteria, we produced a narrative review of the most commonly performed peripheral regional anaesthetic blocks for surgery on the upper limb, the lower limb, and the trunk. We considered short-term and longer-term benefits and complications among the outcomes of interest. RESULTS: Where good quality evidence exists, the great majority of the blocks reviewed were associated with one or any combination of reduced postoperative pain, reduced opioid consumption, or increased patient satisfaction. For selected surgical procedures, the use of blocks avoided general anaesthesia and was associated with increased efficiency of the surgical pathway. The exceptions were supraclavicular block, where there was insufficient evidence, and transversus abdominis plane block, where the evidence for efficacy was conflicting. The evidence for the impact of the blocks on longer-term outcomes was, in general, inadequate to inform clinical decision making. Permanent complications are rare. CONCLUSIONS: The majority of peripheral regional anaesthetic techniques have been shown to produce benefits for patients and hospital efficiency. Further interventional trials are required to clarify such benefits for supraclavicular block and transversus abdominis plane block and to ascertain any longer-term benefits for almost all of the blocks reviewed. Permanent complications of peripheral regional anaesthetic blocks are rare but accurate estimates of their incidence are yet to be determined.

Foetal Doppler abnormality is associated with increased risk of sepsis and necrotising enterocolitis in preterm infants.

AIM: Fetoplacental Doppler abnormalities have been associated with increased neonatal mortality and morbidity. This study evaluated the associations between prenatal Doppler assessments and neonatal mortality and morbidity in premature infants born small for gestational age or after pre-eclampsia. METHODS: This was a population-based study of infants born alive at 22(0) -33(6) weeks of gestation, a birthweight <10th percentile for gestational age and/or maternal pre-eclampsia. Doppler assessments of the umbilical artery, middle cerebral artery and ductus venosus were evaluated in 127, 125 and 95 cases, respectively. Circulatory compromise was defined as absent or reversed end-diastolic velocity in the umbilical artery (AREDF), middle cerebral artery pulsatility index <2.5 percentile for gestational age and ductus venosus pulsatility index for veins >97.5 percentile. RESULTS: AREDF was present in 28% of the infants. This was associated with increased frequencies of neonatal sepsis and necrotising enterocolitis after adjusting for gestational age. Abnormal ductus venosus pulsatility index for veins was associated with increased risk of neonatal sepsis, but only in combination with AREDF. These associations were only present when gestational age was <28 weeks. CONCLUSION: AREDF was associated with increased neonatal morbidity in premature infants born small for gestational age or after pre-eclampsia.

[DemTect 40- and DemTect 80+: New scoring routines for these age groups]. / DemTect 40- und DemTect 80+: Neue Auswertungsroutinen für diese Altersgruppen.

The DemTect, a frequently used cognitive screening tool for the German-speaking population, has been proven to be age-, but not education-dependent. To date, scoring routines for persons under and over 60 years of age have been available. In order to describe the age-effect more specifically, the DemTect was administered to persons under 40 (n = 105; median 33 years [18 - 39]) and over 80 years of age [n = 68; median 83 years [80 - 93}). After transformation of the raw scores, which are based on the mean and standard deviation of the respective reference group, an adequate attribution of scores could be achieved and no differences between the groups can be observed in the total score or the subtest scores. The median of the transformed total score was 16 [5 ­ 18] for the younger and 15 [5 ­ 18] for the older age group. The new scoring routines supplement the scoring procedures of the DemTect for these age groups.

A treadmill exercise reduced cardiac fibrosis, inflammation and vulnerability to ischemia-reperfusion in rat pristane-induced arthritis.

AIMS: To explore cardiac structural and functional parameters and myocardial sensitivity to ischemia in a rat model of chronic arthritis, pristane-induced arthritis (PIA), and to investigate the effects of a running exercise protocol on cardiac disorders related to rheumatoid arthritis (RA). MAIN METHODS: 3 groups of male Dark Agouti rats were formed: Controls, PIA and PIA-Exercise. The PIA-Exercise group was subjected to an individualized treadmill running protocol during the remission phase. At acute and chronic phases of PIA, cardiac structure was analyzed by histology. Cardiac function was explored in isolated hearts to measure left ventricular developed pressure (LVDP), cardiac compliance and infarct size before and after ischemia/reperfusion. Cardiac inflammation was evaluated through VCAM-1 mRNA expression by RT-qPCR. Plasma irisin levels were measured by ELISA. KEY FINDINGS: PIA rats exhibited myocardial hypertrophy fibrosis and inflammation at the 2 inflammatory phases of the model. At chronic phase only, LVDP and cardiac compliance were lower in PIA compared to controls. As compared to sedentary PIA, exercise did not change cardiac function but reduced fibrosis, inflammation, infarct size, and arthritis severity and increased irisin levels. Cardiac inflammation positively correlated with fibrosis, while irisin levels negatively correlated with cardiac inflammation and fibrosis. SIGNIFICANCE: In the PIA model that recapitulated most cardiac disorders of RA, a daily program of treadmill running alleviated cardiac fibrosis and inflammation and improved resistance to ischemia. These data provide arguments to promote the practice of exercise in RA patients for cardiac diseases prevention.

Measurement of the 13C/12C of atmospheric CH4 using near-infrared (NIR) cavity ring-down spectroscopy.

A near-infrared (NIR) continuous-wave-cavity ring-down spectrometry (CW-CRDS) device was developed with the goal of measuring seasonal changes in the isotopic composition of atmospheric CH4 on Earth and eventually on Mars. The system consisted of three distributed feedback laser diodes (DFB-LDs), two of which were tuned to the absorption line peaks of (12)CH4 and (13)CH4 at 6046.954 cm(-1) and 6049.121 cm(-1), respectively, and a third that measured the baseline at 6050.766 cm(-1). The multiple laser design improved the long-term stability of the system and increased the data acquisition rate. The acquisition frequency was further increased by utilizing a semiconductor optical amplifier (SOA) to initiate cavity ring-down events. The high repetition rate combined with the superhigh reflectivity mirrors yielded precise isotopic measurements in this NIR region, even though the line strengths of CH4 in this region are 200 times weaker than those of the strongest mid-IR absorption bands. The current system has a detection limit of 1.9 × 10(-12) cm(-1), corresponding to 10 pptv of CH4 at 100 Torr. For ambient air samples that contained 1.9 ppmv CH4, the δ(13)C of the CH4 was determined to be -48.7 ± 1.7‰ (1σ).

The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H.

The application of patient-derived (PD) in vitro tumor models represents the classical strategy for clinical translational oncology research. Using these cellular heterogeneous cultures for the isolation of cancer stem cells (CSCs), suggested to be the main driver for disease malignancy, relies on the use of surrogate biomarkers or is based on CSC-enriching culture conditions. However, the ability of those strategies to exclusively and efficiently enrich for CSC pool has been questioned. Here we present an alternative in vitro CSC model based on the oncogenic transformation of single clone-derived human induced pluripotent stem cells (hiPSC). Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) and codon R175 of p53 are commonly occurring molecular features of different tumors and were selected for our transformation strategy. By choosing p53 mutant glial tumors as our model disease, we show that in vitro therapy discovery tests on IDH1-engineered synthetic CSCs (sCSCs) can identify kinases-targeting chemotherapeutics that preferentially target tumor cells expressing corresponding genetic alteration. In contrast, neural stem cells (NSCs) derived from the IDH1R132H overexpressing hiPSCs increase their resistance to the tested interventions indicating glial-to-neural tissue-dependent differences of IDH1R132H. Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

Molecular iodine is not responsible for cytotoxicity in iodophors.

BACKGROUND: Ten percent povidone-iodine (PVP-I) was initially promoted as 'tamed iodine' as the chemical activity of the active biocide, uncomplexed or free molecular iodine (I2), is reduced 30- to 50-fold compared with Lugol's solution. The idea that I2 is responsible for topical iodine staining and irritation remains widely held. However, there are no controlled studies that characterize the cytotoxicity and staining of the hydrophobic I2 species compared with the other hydrophilic iodine species that comprise over 99.9% of the total iodine in topical iodine disinfectants. AIMS: To compare the staining properties of the I2 species with other topical iodine disinfectants; to evaluate if the concentrations of I2 in diluted PVP-I used to reduce severe acute respiratory syndrome coronavirus-2 in the nasal cavity are potentially cytotoxic; and to determine if high concentrations of I2 can be delivered beyond the stratum corneum into the hypodermis, which could provide a mechanistic rationale for I2 out-gassing. METHODS: Five liquid compositions that contained complexed and uncomplexed (free) I2 in aqueous and non-aqueous carriers were used to evaluate the interaction of I2 with mammalian cells in culture as well as human and pig skin. FINDINGS: Concentrations of I2 (7800 ppm) that are 1500 times higher than that found in PVP-I can be applied to skin without irritation and staining. I2 is not cytotoxic at concentrations >100 times higher than that found in PVP-I, and does not contribute materially to staining of skin at concentrations found in Lugol's solution (approximately 170 ppm). I2 can partition into hypodermis tissue, remain there for hours and out-gas from skin. PVP-I and Lugol's solution are highly effective topical disinfectants, but do not facilitate diffusion of I2 through the stratum corneum. CONCLUSION: The maximum concentration of I2 found in diluted PVP, approximately 25 ppm, is not cytotoxic or irritating. The potential clinical utility of I2 has been limited by incorporating this broad-spectrum biocide into acidic aqueous formulations that contain numerous chemical species that contribute toxicity but not biocidal activity. I2 can be delivered topically into hypodermis tissue without irritation.