Marine Proteobacteria metabolize glycolate via the ß-hydroxyaspartate cycle.

One of the most abundant sources of organic carbon in the ocean is glycolate, the secretion of which by marine phytoplankton results in an estimated annual flux of one petagram of glycolate in marine environments1. Although it is generally accepted that glycolate is oxidized to glyoxylate by marine bacteria2-4, the further fate of this C2 metabolite is not well understood. Here we show that ubiquitous marine Proteobacteria are able to assimilate glyoxylate via the ß-hydroxyaspartate cycle (BHAC) that was originally proposed 56 years ago5. We elucidate the biochemistry of the BHAC and describe the structure of its key enzymes, including a previously unknown primary imine reductase. Overall, the BHAC enables the direct production of oxaloacetate from glyoxylate through only four enzymatic steps, representing-to our knowledge-the most efficient glyoxylate assimilation route described to date. Analysis of marine metagenomes shows that the BHAC is globally distributed and on average 20-fold more abundant than the glycerate pathway, the only other known pathway for net glyoxylate assimilation. In a field study of a phytoplankton bloom, we show that glycolate is present in high nanomolar concentrations and taken up by prokaryotes at rates that allow a full turnover of the glycolate pool within one week. During the bloom, genes that encode BHAC key enzymes are present in up to 1.5% of the bacterial community and actively transcribed, supporting the role of the BHAC in glycolate assimilation and suggesting a previously undescribed trophic interaction between autotrophic phytoplankton and heterotrophic bacterioplankton.

Time for "code ICH"? - Workflow metrics of hyperacute treatments and outcome in patients with intracerebral haemorrhage.

INTRODUCTION: Knowledge about uptake and workflow metrics of hyperacute treatments in patients with non-traumatic intracerebral haemorrhage (ICH) in the emergency department are scarce. METHODS: Single centre retrospective study of consecutive patients with ICH between 01/2018-08/2020. We assessed uptake and workflow metrics of acute therapies overall and according to referral mode (stroke code, transfer from other hospital or other). RESULTS: We enrolled 332 patients (age 73years, IQR 63-81 and GCS 14 points, IQR 11-15, onset-to-admission-time 284 minutes, IQR 111-708minutes) of whom 101 patients (35%) had lobar haematoma. Mode of referral was stroke code in 129 patients (38%), transfer from other hospital in 143 patients (43%) and arrival by other means in 60 patients (18%). Overall, 143 of 216 (66%) patients with systolic blood pressure >150mmHG received IV antihypertensive and 67 of 76 (88%) on therapeutic oral anticoagulation received prothrombin complex concentrate treatment (PCC). Forty-six patients (14%) received any neurosurgical intervention within 3 hours of admission. Median treatment times from admission to first IV-antihypertensive treatment was 38 minutes (IQR 18-72minutes) and 59 minutes (IQR 37-111 minutes) for PCC, with significant differences according to mode of referral (p<0.001) but not early arrival (≤6hours of onset, p=0.92). The median time in the emergency department was 139 minutes (IQR 85-220 minutes) and among patients with elevated blood pressure, only 44% achieved a successful control (<140mmHG) during ED stay. In multivariate analysis, code ICH concordant treatment was associated with significantly lower odds for in-hopsital mortality (aOR 0.30, 95%CI 0.12-0.73, p=0.008) and a non-significant trends towards better functional outcome measured using the modified Rankin scale score at 3 months (aOR for ordinal shift 0.54 95%CI 0.26-1.12, p=0.097). CONCLUSION: Uptake of hyperacute therapies for ICH treatment in the ED is heterogeneous. Treatment delays are short but not all patients achieve treatment targets during ED stay. Code ICH concordant treatment may improve clinical outcomes. Further improvements seem achievable advocating for a "code ICH" to streamline acute treatments.

Physical activity and its impact on cardiovascular health in pediatric kidney transplant recipients.

BACKGROUND: Cardiovascular (CV) morbidity after kidney transplantation (KTx) in childhood is of increasing importance. In light of a high prevalence of CV risk factors, protective measures such as physical activity (PA) come into focus. Our aim was to comprehensively assess PA in pediatric KTx recipients and evaluate its impact on CV health. METHODS: Forty-eight patients were assessed for frequency, duration, intensity, and setting of PA using the "Motorik-Modul" PA questionnaire. Walking-based activity was measured by accelerometer in a subgroup (n = 23). CV risk factors and subclinical CV organ damage were determined. The impact of PA on CV parameters was analyzed using linear regression models. RESULTS: Fifty-two percent of pediatric KTx recipients did not reach WHO recommended PA level; 54% did not engage in PA with vigorous intensity (VPA). Twenty-nine percent indicated an extremely inactive lifestyle (< 120 min/week of moderate to vigorous intensity PA, MVPA). Compared to the healthy German KiGGS cohort, KTx recipients specifically lacked engagement in sport activities (KTx: 129 min/week; 95%CI, 97-162 vs. KiGGS, 242 min/week; 95%CI, 230-253). VPA was associated with lower systolic blood pressure (p = 0.024) and resting heart rate (p = 0.005), MVPA with fewer components of the post-transplant metabolic syndrome (p = 0.037), and better left ventricular diastolic function (p = 0.006). CONCLUSIONS: A considerable lack of PA, especially VPA, exists in young KTx recipients. PA was positively associated with important parameters of CV health. While long-term CV protection through PA seems promising in pediatric KTx recipients, specific educational approaches are most likely needed to increase patients' engagement in sport activities.

Oxygen accumulation and associated dangers in rescue helicopters.

BACKGROUND: At the time of the COVID-19 pandemic, devastating incidents increased due to frequent oxygen administration to patients. The dangers associated with the use of oxygen, especially through local enrichments and formation of "oxygen clouds", have been well understood for years. Nevertheless, dramatic incidents continue to occur, since fire hazard increases exponentially with oxygen concentrations above 23%. Rescue helicopters are at a particular high risk, because of technical reasons such as oxygen use in a very small space, surrounded by kerosene lines, electronic relays and extremely hot surfaces. METHODS: In this study three different sized rescue helicopter models (Airbus H135, H145 and MD902) were examined. Oxygen enrichment in the cabin was measured with an oxymeter during a delivery rate of 15 l/min constant flow for 60 min. Furthermore, the clearance of the enriched atmosphere was tested in different situations and with different ventilation methods. To make the airflow visible, a fog machine was used to fill the helicopter cabin. RESULTS: Oxygen accumulation above 21% was detected in every helicopter. After 10-15 min, the critical 23% threshold was exceeded in all three aircrafts. The highest concentration was detected in the smallest machine (MD902) after 60 min with 27.4%. Moreover, oxygen clouds persisted in the rear and the bottom of the aircrafts, even when the front doors were opened. This was most pronounced in the largest aircraft, the H145 from Airbus Helicopters. Complete and rapid removal of elevated oxygen concentrations was achieved only by cross-ventilation within 1 min. CONCLUSIONS: Oxygen should be handled with particular care in rescue helicopters. Adapted checklists and precautions can help to prevent oxygen accumulation, and thus, fatal incidents. To our knowledge, this is the first study, which analyzed oxygen concentrations in different settings in rescue helicopters.

Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (Pinteraction=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02866838.

Comparative analysis of EpCAM high-expressing and low-expressing circulating tumour cells with regard to their clonal relationship and clinical value.

BACKGROUND: Circulating tumour cells (CTCs) are mainly enriched based on the epithelial cell adhesion molecule (EpCAM). Although it was shown that an EpCAM low-expressing CTC fraction is not captured by such approaches, knowledge about its prognostic and predictive relevance and its relation to EpCAM-positive CTCs is lacking. METHODS: We developed an immunomagnetic assay to enrich CTCs from metastatic breast cancer patients EpCAM independently using antibodies against Trop-2 and CD-49f and characterised their EpCAM expression. DNA of single EpCAM high expressing and low expressing CTCs was analyzed regarding chromosomal aberrations and predictive mutations. Additionally, we compared CTC-enrichment on the CellSearch system using this antibody mix and the EpCAM based enrichment. RESULTS: Both antibodies acted synergistically in capturing CTCs. Patients with EpCAM high-expressing CTCs had a worse overall and progression-free survival. EpCAM high- and low-expressing CTCs presented similar chromosomal aberrations and mutations indicating a close evolutionary relationship. A sequential enrichment of CTCs from the EpCAM-depleted fraction yielded a population of CTCs not captured EpCAM dependently but harbouring predictive information. CONCLUSIONS: Our data indicate that EpCAM low-expressing CTCs could be used as a valuable tumour surrogate material-although they may be prognostically less relevant than EpCAM high-expressing CTCs-and have particular benefit if no CTCs are detected using EpCAM-dependent technologies.

Efficacy of CytoSorb®: a systematic review and meta-analysis.

INTRODUCTION: Cytokine adsorption using the CytoSorb® adsorber has been proposed in various clinical settings including sepsis, ARDS, hyperinflammatory syndromes, cardiac surgery or recovery after cardiac arrest. The aim of this analysis is to provide evidence for the efficacy of the CytoSorb® adsorber with regard to mortality in various settings. METHODS: We searched PubMed, Cochrane Library database and the database provided by Cytosorbents™ (01.1.2010-29.5.2022). We considered randomized controlled trials and observational studies with control groups. The longest reported mortality was defined as the primary endpoint. We computed risk ratios and 95%-confidence intervals and used DerSimonian and Lairds random effects model. We analysed all studies combined and divided them into the subgroups: sepsis, cardiopulmonary bypass surgery (CPB), other severe illness, SARS-CoV-2 infection and recovery from cardiac arrest. The meta-analysis was registered in advance (PROSPERO: CRD42022290334). RESULTS: Of an initial 1295 publications, 34 studies were found eligible, including 1297 patients treated with CytoSorb® and 1314 controls. Cytosorb® intervention did not lower mortality (RR [95%-CI]: all studies 1.07 [0.88; 1.31], sepsis 0.98 [0.74; 1.31], CPB surgery 0.91 [0.64; 1.29], severe illness 0.95 [0.59; 1.55], SARS-CoV-2 1.58 [0.50; 4.94]). In patients with cardiac arrest, we found a significant survival advantage of the untreated controls (1.22 [1.02; 1.46]). We did not find significant differences in ICU length of stay, lactate levels, or IL-6 levels after treatment. Of the eligible 34 studies only 12 were randomized controlled trials. All observational studies showed moderate to serious risk of bias. INTERPRETATION: To date, there is no evidence for a positive effect of the CytoSorb® adsorber on mortality across a variety of diagnoses that justifies its widespread use in intensive care medicine.

Arterial stiffness and blood pressure increase in pediatric kidney transplant recipients.

BACKGROUND: Pulse wave velocity (PWV) is a measure of arterial stiffness. We investigated PWV and blood pressure (BP) to determine to what extent BP changes contribute to arterial stiffness, and secondly, to identify influencing factors on BP in children after kidney transplantation. METHODS: Seventy children ≥ 2.5 years post-transplantation with at least two PWV measurements were included. Changes of systolic (Δ SBP) and diastolic BP (Δ DBP) were classified into "stable/decreasing," "1-10 mmHg increase," and " > 10 mmHg increase." Linear mixed modeling for PWV z-score (PWVz) adjusted either for Δ SBP or Δ DBP was performed. An extended dataset with monthly entries of BP, immunosuppression, and creatinine was obtained in 35 participants over a median of 74 months to perform linear mixed modeling for SBP and DBP. RESULTS: PWVz increased with a rate of 0.11/year (95% CI 0.054 to 0.16). Compared to participants with stable BP, those with 1-10-mmHg SBP and DBP increase showed a higher PWVz of 0.59 (95% CI 0.046 to 1.13) and 0.86 (95% CI 0.43 to 1.30), respectively. A > 10-mmHg BP increase was associated with an even higher PWVz (SBP ß = 0.78, 95% CI 0.22 to 1.34; DBP ß = 1.37, 95% CI 0.80 to 1.94). Female sex and participants with lower eGFR showed higher PWVz. In the extended analysis, DBP was positively associated with cyclosporin A and everolimus trough levels. CONCLUSIONS: A higher increase of PWV is seen in patients with greater BP increase, with higher cyclosporin A and everolimus trough levels associated with higher BP. This emphasizes the role of BP as a modifiable risk factor for the improvement of cardiovascular outcome after transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Intraoperative suggestions to prevent postoperative delirium in patients undergoing transaortic valvular replacement: a randomized placebo-controlled trial.

BACKGROUND: Postoperative delirium (POD) is a serious complication following anaesthesia and surgery and significantly influences postoperative outcome especially in the elderly population. Intraoperative music and positive suggestions influence postoperative outcomes by attenuating analgesic demand and increasing patient satisfaction. AIMS: Here, we examined the effect of intraoperative music and positive suggestions on the development of POD in aged patients undergoing transcatheter aortic valve replacement (TAVR) procedure under general anaesthesia. METHODS: For this randomized placebo-controlled study, eligible patients without cognitive deficit, indicated by a MMSE < 10 points, were anesthetized using remifentanil and sevoflurane. Anaesthetic depth was guide with bispectral index. An audiotape with positive suggestions was applied from a MP3 player via headphones. POD, pain and PONV was assessed. CAM-ICU and Nu-DESC were done twice daily for the first 5 days. RESULTS: Of 140 patients 118 patients could be analysed (57 male, 80.6 ± 5.1 years). POD was diagnosed in 16 patients (12.7%). POD was significantly more often observed in male (12, 21.1%) than in female (4, 6.6%, p = 0.02) and in patients with a low MMSE (23.6 ± 4.5 vs. 26.8 ± 2.8, p = 0.001). Anaesthetic depth did not influence the incidence of POD. Intraoperative music and suggestions did not affect the rate of POD, pain, analgesic requirement or PONV. DISCUSSION: In patients undergoing TAVR male sex and low MMSE scoring are associated with an increase in POD. CONCLUSIONS: Intraoperative music and positive suggestions do not influence the incidence of POD in this patient group. STUDY REGISTRATION: DRKS: 00024444, start of registration: 4.02.202, final registration: 17.09.2021.

Long-term effects of retrograde approach on the knee after motorized femoral limb lengthening.

BACKGROUND AND PURPOSE: The retrograde femoral approach is an established technique for implantation of nails for leg lengthening and correction and in cases of distal femoral fractures. The purpose of this study was to determine the 10-year outcome of this technique by analyzing the clinical long-term effects and radiological status of the knee after leg lengthening via a retrograde femoral approach. PATIENTS AND METHODS: This retrospective single-center study included 13 patients (median age at surgery 17 [range 15-20] years) who underwent unilateral, retrograde, femoral lengthening with a motorized nail. Outcome measurements were graded variables of the SF-36, ISKD score, and Lysholm score. MRI of both knees was performed in all patients. MRI was evaluated for the presence of degenerative changes and compared with the healthy contralateral knee. Cartilage condition was graded according to the International Cartilage Repair Society (ICRS) scoring system. RESULTS: All patients were pain-free and had a full range of motion 10 (range 10.0-12.2) years after surgery. All postoperative knees showed fibrosis of Hoffa's fat pad and moderate to severe cartilage defects (ICRS Grade 2-4) of the trochlear groove (nail entry site). 6 out of 13 operated knees exhibited retropatellar cartilage defects. CONCLUSION: Our study showed that patients were pain-free, but cartilage defects at the entry point and arthrofibrosis at Hoffa's fat pad were observed without causing clinical impairment.

Ophthalmologic Care of Former Preterm and Full-Term Infants during Their Childhood and Adolescence - A Retrospective View of Their Parents. / Augenärztliche Versorgung früh- und reifgeborener Personen in deren Kindheit und Jugend ­ eine retrospektive Sicht der Eltern.

BACKGROUND: The aim of the present study was to evaluate the ophthalmologic care in childhood and adolescence of infants born preterm and full-term from the retrospective point of view of their parents. METHODOLOGY: The Gutenberg Prematurity Eye Study (GPES) is a retrospective cohort study with a prospective ophthalmologic examination of persons born preterm and full-term between 1969 and 2002 (now aged 18 to 52 years), and asks their parents about the ophthalmologic care received by their children in childhood and adolescence from their retrospective perspective. Participants and their parents were grouped into those with normal gestational age (GA) ≥ 37 (control group), preterm born infants without retinopathy of prematurity (ROP) and gestational age (GA) 33 - 36 (group 2), GA 29 - 32 (group 3), GA ≤ 28 weeks (group 4), and those with ROP without treatment (group 5) and with ROP with treatment (group 6). Parents of participants were interviewed about the ophthalmic care received by their children. RESULTS: In total, data from 57 full-term and 131 preterm infants and their parents were included in the present study. The parents of the participants reported that ophthalmologic examination had taken place until 6 years of age in the respective groups 1 to 6 in 22/57 (38.6%), 33/58 (56.9%), 22/38 (57.9%), 3/6 (50%), 19/21 (90.5%), and 7/8 (87.5%). Overall, between 83% and 100% of parents in the different groups reported that ophthalmologic care had been adequate. A change of ophthalmologist due to dissatisfaction with treatment was reported by a total of 4/57 (7%), 9/58 (15.5%), 8/38 (21.1%), 1/6 (16.7%), 1/21 (4.8%) and 2/8 (25%) in the respective groups. DISCUSSION: The present study demonstrates adequate satisfaction and good treatment regarding ophthalmologic care of former preterm children from the parents' perspective. Especially parents of children with ROP rated the treatment positively.

Findings from 4C-T Study demonstrate an increased cardiovascular burden in girls with end stage kidney disease and kidney transplantation.

Mortality in children with kidney failure is higher in girls than boys with cardiovascular complications representing the most common causes of death. Pulse wave velocity (PWV), a measure of vascular stiffness, predicts cardiovascular mortality in adults. Here, PWV in children with kidney failure undergoing kidney replacement therapy was investigated to determine sex differences and potential contributing factors. Two-hundred thirty-five children (80 girls; 34%) undergoing transplantation (150 pre-emptive, 85 with prior dialysis) having at least one PWV measurement pre- and/or post-transplantation from a prospective cohort were analyzed. Longitudinal analyses (median/maximum follow-up time of 6/9 years) were performed for PWV z-scores (PWVz) using linear mixed regression models and further stratified by the categories of time: pre-kidney replacement therapy and post-transplantation. PWVz significantly increased by 0.094 per year and was significantly higher in girls (PWVz +0.295) compared to boys, independent of the underlying kidney disease. During pre-kidney replacement therapy, an average estimated GFR decline of 4 ml/min/1.73 m2 per year was associated with a PWVz increase of 0.16 in girls only. Higher diastolic blood pressure and low density lipoprotein were independently associated with higher PWVz during pre-kidney replacement therapy in both sexes. In girls post-transplantation, an estimated GFR decline of 4ml/min/1.73m2 per year pre-kidney replacement therapy and a longer time (over 12 months) to transplantation were significantly associated with higher PWVz of 0.22 and of 0.57, respectively. PWVz increased further after transplantation and was positively associated with time on dialysis and diastolic blood pressure in both sexes. Thus, our findings demonstrate that girls with advanced chronic kidney disease are more susceptible to develop vascular stiffening compared to boys, this difference persist after transplantation and might contribute to higher mortality rates seen in girls with kidney failure.

Anticoagulation after stroke: persistent uncertainties.

PURPOSE OF REVIEW: Direct oral anticoagulants (DOAC) are the mainstay of anticoagulant therapy for stroke prevention in patients with nonvalvular atrial fibrillation. Persistent uncertainties remain in different areas, and this review discusses current dilemmas based on selected studies. RECENT FINDINGS: Optimal timing of DOAC initiation after a recent ischaemic stroke in patients with atrial fibrillation is currently unknown and subject of ongoing randomized controlled trials. Ischaemic stroke despite anticoagulant therapy in patients with atrial fibrillation is frequent, constitutes heterogeneous causes (competing stroke cause, medication error and cardioembolism despite anticoagulation) and optimal treatment is currently unknown. Thorough etiological work-up is justified. Recent randomized controlled trials found no beneficial effect of DOAC therapy in unselected patients with embolic stroke of undetermined source (ESUS). Currently ongoing trials targeting subgroup of ESUS patients with additional atrial cardiopathy will provide novel data. Cerebral mircobleeds combined in a novel risk score (MICON score) provide good predictive value to stratify the risk of intracranial haemorrhage in patients taking anticoagulants. Use of DOAC after intracerebral haemorrhage in patients with atrial fibrillation is subject of ongoing trials. SUMMARY: There are still significant uncertainties in anticoagulant management in patients with stroke. Ongoing trials will soon provide novel data to improve management of these patients.

Strong seasonal differences of bacterial polysaccharide utilization in the North Sea over an annual cycle.

Marine heterotrophic bacteria contribute considerably to global carbon cycling, in part by utilizing phytoplankton-derived polysaccharides. The patterns and rates of two different polysaccharide utilization modes - extracellular hydrolysis and selfish uptake - have previously been found to change during spring phytoplankton bloom events. Here we investigated seasonal changes in bacterial utilization of three polysaccharides, laminarin, xylan and chondroitin sulfate. Strong seasonal differences were apparent in mode and speed of polysaccharide utilization, as well as in bacterial community compositions. Compared to the winter month of February, during the spring bloom in May, polysaccharide utilization was detected earlier in the incubations and a higher portion of all bacteria took up laminarin selfishly. Highest polysaccharide utilization was measured in June and September, mediated by bacterial communities that were significantly different from spring assemblages. Extensive selfish laminarin uptake, for example, was detectible within a few hours in June, while extracellular hydrolysis of chondroitin was dominant in September. In addition to the well-known Bacteroidota and Gammaproteobacteria clades, the numerically minor verrucomicrobial clade Pedosphaeraceae could be identified as a rapid laminarin utilizer. In summary, polysaccharide utilization proved highly variable over the seasons, both in mode and speed, and also by the bacterial clades involved.

Telomere length is associated with intima-media thickness in pediatric liver transplant patients: A prospective cohort study.

Leukocyte telomere length (LTL) is a marker for biological age. Pediatric liver transplant recipients show a high rate of subclinical atherosclerosis, indicated by elevated intima-media thickness (IMT). We hypothesized that atherosclerosis is associated with biological age in these patients and investigated the course of LTL over time. We measured LTL from peripheral blood leukocytes by quantitative polymerase chain reaction and IMT from 97 pediatric patients after liver transplantation in a prospective cohort study. Of the patients, 71% (n = 69) had two or more assessments (total, 228 observations; median follow-up, 1.1 years). Lower LTL was associated with higher IMT (ß = -0.701, p = 0.01) and higher aspartate aminotransferase (ß = -0.001, p = 0.02), adjusted for age, sex, and age at transplantation. Of the patients, 45% showed decreasing LTL over time, whereas 55% exhibited stable LTL. Patients with stable LTL showed a decrease in IMT (median, -0.02 mm/year) and a decrease of tacrolimus trough levels (median, -0.08 µg/L/year). LTL is associated with IMT independent of age in pediatric liver transplant patients, suggesting that early aging contributes to the high burden of subclinical cardiovascular damage and may furthermore negatively affect the graft.

Plant PhysioSpace: a robust tool to compare stress response across plant species.

Generalization of transcriptomics results can be achieved by comparison across experiments. This generalization is based on integration of interrelated transcriptomics studies into a compendium. Such a focus on the bigger picture enables both characterizations of the fate of an organism and distinction between generic and specific responses. Numerous methods for analyzing transcriptomics datasets exist. Yet, most of these methods focus on gene-wise dimension reduction to obtain marker genes and gene sets for, for example, pathway analysis. Relying only on isolated biological modules might result in missing important confounders and relevant contexts. We developed a method called Plant PhysioSpace, which enables researchers to compute experimental conditions across species and platforms without a priori reducing the reference information to specific gene sets. Plant PhysioSpace extracts physiologically relevant signatures from a reference dataset (i.e. a collection of public datasets) by integrating and transforming heterogeneous reference gene expression data into a set of physiology-specific patterns. New experimental data can be mapped to these patterns, resulting in similarity scores between the acquired data and the extracted compendium. Because of its robustness against platform bias and noise, Plant PhysioSpace can function as an inter-species or cross-platform similarity measure. We have demonstrated its success in translating stress responses between different species and platforms, including single-cell technologies. We have also implemented two R packages, one software and one data package, and a Shiny web application to facilitate access to our method and precomputed models.

Fused Bis(hemi-indigo): Broad-Range Wavelength-Independent Photoswitches.

Wavelength-independent conversion of organic photoswitches in the photostationary state is a rare phenomenon that opens up a way for many practical applications. In this work, three fused bis(hemi-indigo) derivatives with different substitution patterns were synthesized and their photoswitching was investigated by optical spectroscopy, real-time NMR spectroscopy and TD-DFT calculations. We disclosed that the Z-E photoisomerization of the meta-bis(hemi-indigo) derivative was remarkably independent of the irradiation wavelength from UV up to yellow light. The wavelength-independent forward photoswitching together with the inhibited backward photoisomerization, high thermal stability of the photoinduced isomers as well as significant overlap between the photoswitch absorption and the solar spectrum allows to suggest bis(hemi-indigo) derivatives as promising candidates for molecular solar thermal energy storage (MOST) systems.

Renal events in patients receiving neprilysin inhibitors: a systematic review and meta-analysis.

BACKGROUND: While it is well known that angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) increase the risk of acute renal failure, the role of neprilysin inhibition (NEPi) is unclear and some physicians are reluctant to prescribe sacubitril/valsartan because of safety concerns. This meta-analysis aimed to examine the risk for renal events, progression of chronic kidney disease (CKD) or progression to dialysis on combined NEPi and ACEi/ARBs compared with ACEi or ARBs. METHODS: We performed a systematic meta-analysis including 17 randomized controlled trials (study drug sacubitril/valsartan or omapatrilat), involving a total of 23 569 patients, after searching PubMed, Cochrane, ClinicalTrials.org and Embase for eligible studies. From the included trials, all renal endpoints, including long- and short-term outcomes and hyperkalemia, were extracted. Pooled odds ratios (ORs) were calculated using the DerSimonian and Laird method. The study was registered at PROSPERO. RESULTS: Overall, treatment with sacubitril/valsartan or omapatrilat showed a slightly lower risk of any renal event [OR 0.82 (0.7-0.97)] compared with treatment with an ACEi or ARB alone. Also, there was a decreased risk of severe acute renal events [OR 0.8 (0.69-0.93)] and a decrease in estimated glomerular filtration rate decline [mean difference -0.58 mL/min (-0.83 to -0.33 mL/min)]. There was no difference in chronic renal events [OR 0.92 (0.8-1.05)] or hyperkalemia [OR 1.02 (0.84-1.23)]. CONCLUSION: NEPi + ACEi/ARBs are safe in terms of renal adverse events. Longer trials focusing on CKD are needed to evaluate the effect of NEPi on decreasing progression of CKD.

Brain morphometry and connectivity differs between adolescent- and adult-onset major depressive disorder.

BACKGROUND: Early-onset (EO) major depressive disorder (MDD) patients experience more depressive episodes and an increased risk of relapse. Thus, on a neurobiological level, adult EO patients might display brain structure and function different from adult-onset (AO) patients. METHODS: A total of 103 patients (66 females) underwent magnetic resonance imaging. Structural measures of gray matter volume (GMV) and functional connectivity networks during resting state were compared between EO (≤19 years) and AO groups. Four residual major depression symptoms, mood, anxiety, insomnia, and somatic symptoms, were correlated with GMV between groups. RESULTS: We found comparatively increased GMV in the EO group, namely the medial prefrontal and insular cortex, as well as the anterior hippocampus. Functional networks in EO patients showed a comparatively weaker synchronization of the left hippocampus with the adjacent amygdala, and a stronger integration with nodes in the contralateral prefrontal cortex and supramarginal gyrus. Volumetric analysis of depression symptoms associated the caudate nuclei with symptoms of insomnia, and persisting mood symptoms with the right amygdala, while finding no significant clusters for somatic and anxiety symptoms. CONCLUSIONS: The study highlights the important role of the hippocampus and the prefrontal cortex in EO patients as part of emotion-regulation networks. Results in EO patients demonstrated subcortical volume changes irrespective of sleep and mood symptom recovery, which substantiates adolescence as a pivotal developmental phase for MDD. Longitudinal studies are needed to differentiate neural recovery trajectories while accounting for age of onset.

Design and synthesis of a tetracyclic tripeptide mimetic frozen in a polyproline type II (PP2) helix conformation.

A synthesis of the new tetracyclic scaffold ProM-19, which represents a XPP tripeptide unit frozen in a PPII helix conformation, was developed. As a key building block, N-Boc-protected ethyl (1S,3S,4R)-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate was prepared through a diastereoselective aza-Diels-Alder reaction and subsequent hydrogenolytic removal of the chiral N-1-phenylethyl substituent under temporary protection of the double bond through dihydroxylation and reconstitution by Corey-Winter olefination. The target compound Boc-[ProM-19]-OMe was then prepared via subsequent peptide coupling and Ru-catalyzed ring-closing metathesis steps employing (S)-N-Boc-allylgylcine and cis-5-vinyl-proline methyl ester as additional building blocks. In addition, Ac-[2-Cl-Phe]-[Pro]-[ProM-19]-OMe was prepared by solution phase peptide synthesis as a potential ligand for the ena-VASP EVH1 domain.