App-based assessment of patient-reported outcomes in the Molecular Tumor Board in the Center for Personalized Medicine-(TRACE).

Background: Biomarker-based therapies are increasingly used in cancer patients outside clinical trials. Systematic assessment of patient-reported outcomes (PRO) is warranted to take patients' perspectives during biomarker-based therapies into consideration. We assessed the feasibility of an electronic PRO assessment via a smartphone application. Methods: An interdisciplinary expert panel developed a smartphone application based on symptom burden and health-related quality of life (HRQoL) metrics reported in a retrospective analysis of 292 neuro-oncological patients. The app included validated assessments of health-related quality of life (HRQoL), the burden of symptoms, and psychological stress. Feasibility and usability were tested in a pilot study. Semi-structured interviews with patients and health care professionals (HCP) were conducted, transcribed, and analyzed according to Mayring´s qualitative content analysis. Furthermore, we assessed compliance and descriptive data of ePROs. Results: A total of 14 patients have been enrolled, (9 female, 5 male). A total of 4 HCPs, 9 patients, and 1 caregiver were interviewed regarding usability/feasibility. The main advantages were the possibility to complete questionnaires at home and comfortable implementation in daily life. Compliance was high, for example, 82% of the weekly distributed NCCN distress thermometer questionnaires were answered on time, however, with interindividual variability. We observed a median distress score of 5 (range 0-10, 197 results, n = 12, weekly assessed) and a median Global health score of 58.3 according to the EORTC QLQ-C30 instrument (range 16.7-100, 77 results, n = 12, monthly assessed). Conclusions: This pilot study proved the feasibility and acceptance of the app. We will therefore expand its application during biomarker-guided therapies to enable systematic PRO assessments.

Implementation and Evaluation of a Breast Cancer Disease Model Using Real-World Claims Data in Germany from 2010 to 2020.

Breast cancer is the leading cause of cancer-related mortality among women in Germany and worldwide. This retrospective claims data analysis utilizing data from AOK Baden-Wuerttemberg, a major statutory German health insurance provider, aimed to construct and assess a real-world data breast cancer disease model. The study included 27,869 female breast cancer patients and 55,738 age-matched controls, analyzing data from 2010 to 2020. Three distinct breast cancer stages were analyzed: Stage A (early breast cancer without lymph node involvement), Stage B (early breast cancer with lymph node involvement), and Stage C (primary distant metastatic breast cancer). Tumor subtypes were estimated based on the prescription of antihormonal or HER2-targeted therapy. The study established that 77.9% of patients had HR+ breast cancer and 9.8% HER2+; HR+/HER2- was the most common subtype (70.9%). Overall survival (OS) analysis demonstrated significantly lower survival rates for stages B and C than for controls, with 5-year OS rates ranging from 79.3% for stage B to 35.4% for stage C. OS rates were further stratified by tumor subtype and stage, revealing varying prognoses. Distant recurrence-free survival (DRFS) analysis showed higher recurrence rates in stage B than in stage A, with HR-/HER2- displaying the worst DRFS. This study, the first to model breast cancer subtypes, stages, and outcomes using German claims data, provides valuable insights into real-world breast cancer epidemiology and demonstrates that this breast cancer disease model has the potential to be representative of treatment outcomes.

Using an Electronic Mindfulness-based Intervention (eMBI) to improve maternal mental health during pregnancy: Results from a randomized controlled trial.

Prevalence rates of peripartum depression and anxiety are high and correlate with adverse maternal and neonatal outcomes. Mindfulness-based interventions (MBI) have been shown to reduce mental distress during pregnancy. A multicenter, randomized controlled study was conducted after screening for depressive symptoms. The intervention group (IG) was given access to an 8-week supervised eMBI between weeks 29 and 36 of pregnancy and followed up to 5 months postpartum. Psychometric data were collected using the Edinburgh Postnatal Depression Scale (EPDS), the State-Trait Anxiety Inventory (STAI), the Pregnancy-Related Anxiety Questionnaire (PRAQ-R), the Freiburg Mindfulness Inventory (FMI-14) as well as the Patient Health Questionnaire (PHQ). Out of 5299 pregnant women, 1153 scored >9 on the EPDS and N = 460 were included in the RCT. No significant interaction effects for depressive symptoms and anxiety were found. Pregnancy- and birth-related anxiety decreased significantly in the IG and 6 weeks after birth, the rate of women at risk for adverse mental outcome was significantly lower compared to the CG. Mindfulness scores improved significantly in the IG. The eMBI program did not show effective regarding general depressive or anxiety symptoms, however, positive results were demonstrated regarding pregnancy and birth-related anxiety and the prevention of postpartum depression.

Full Profiling of GE81112A, an Underexplored Tetrapeptide Antibiotic with Activity against Gram-Negative Pathogens.

After the first total synthesis combined with structure revision, we performed thorough in vitro and in vivo profiling of the underexplored tetrapeptide GE81112A. From the determination of the biological activity spectrum and physicochemical and early absorption-distribution-metabolism-excretion-toxicity (eADMET) properties, as well as in vivo data regarding tolerability and pharmacokinetics (PK) in mice and efficacy in an Escherichia coli-induced septicemia model, we were able to identify the critical and limiting parameters of the original hit compound. Thus, the generated data will serve as the basis for further compound optimization programs and developability assessments to identify candidates for preclinical/clinical development derived from GE81112A as the lead structure. IMPORTANCE The spread of antimicrobial resistance (AMR) is becoming a more and more important global threat to human health. With regard to current medical needs, penetration into the site of infection represents the major challenge in the treatment of infections caused by Gram-positive bacteria. Considering infections associated with Gram-negative bacteria, resistance is a major issue. Obviously, novel scaffolds for the design of new antibacterials in this arena are urgently needed to overcome this crisis. Such a novel potential lead structure is represented by the GE81112 compounds, which inhibit protein synthesis by interacting with the small 30S ribosomal subunit using a binding site distinct from that of other known ribosome-targeting antibiotics. Therefore, the tetrapeptide antibiotic GE81112A was chosen for further exploration as a potential lead for the development of antibiotics with a new mode of action against Gram-negative bacteria.

Machine learning and patient-reported outcomes for longitudinal monitoring of disease progression in metastatic breast cancer: a multicenter, retrospective analysis.

BACKGROUND: Assessments of health-related quality of life (HRQoL) play an important role in transition to palliative care for women with metastatic breast cancer. We developed machine learning (ML) algorithms to analyse longitudinal HRQoL data and identify patients who may benefit from palliative care due to disease progression. METHODS: We recruited patients from two institutions and administered the EuroQoL Visual Analog Scale (EQ-VAS) via an online platform over a 6-month period. We trained a regularised regression algorithm using 10-fold cross-validation to determine if a patient was at high or low risk of disease progression based on changes in the EQ-VAS scores using data of one institution and validated the performance on data of the other institution. Progression-free survival (PFS) was the end-point. We conducted Kaplan-Meier and Cox regression analysis adjusted for clinical risk factors. RESULTS: Of 179 patients, 98 (54.7%) had progressive disease after a median follow-up of 14weeks. Using EQ-VAS scores collected at weeks 1-6 to predict disease progression at week 12, in the validation set (n = 63), PFS was significantly lower in the intelligent EQ-VAS high-risk versus low-risk group: median PFS 7 versus 10weeks, log-rank P < 0.038). Intelligent EQ-VAS had the strongest association with PFS (adjusted hazard ratio 2.69, 95% confidence interval 1.17-6.18, P = 0.02). CONCLUSION: ML algorithms can analyse changes in longitudinal HRQoL data to identify patients with disease progression earlier than standard follow-up methods. Intelligent EQ-VAS scores were identified as independent prognostic factor. Future studies may validate these results to remotely monitor patients.

Total Synthesis of GE81112A: An Orthoester-Based Approach.

The GE81112 series, consisting of three naturally occurring tetrapeptides and synthetic derivatives, is evaluated as a potential lead structure for the development of a new antibacterial drug. Although the first total synthesis of GE81112A reported by our group provided sufficient amounts of material for an initial in depth biological profiling of the compound, improvements of the routes toward the key building blocks were needed for further upscaling and structure-activity relationship studies. The major challenges identified were poor stereoselectivity in the synthesis of the C-terminal ß-hydroxy histidine intermediate and a concise access to all four isomers of the 3-hydroxy pipecolic acid. Herein, we report a second-generation synthesis of GE81112A, which is also applicable to access further representatives of this series. Based on Lajoie's ortho-ester-protected serine aldehydes as key building blocks, the described route provides both a satisfactory improvement in stereoselectivity of the ß-hydroxy histidine intermediate synthesis and a stereoselective approach toward both orthogonally protected cis and trans-3-hydroxy pipecolic acid.

Long-term effects of preeclampsia on maternal cardiovascular health and postpartum utilization of primary care: an observational claims data study.

PURPOSE: Preeclampsia occurs in up to 15% of pregnancies and constitutes a major risk factor for cardiovascular disease. This observational cohort study aimed to examine the association between preeclamptic pregnancies and cardiovascular outcomes as well as primary and specialized care utilization after delivery. METHODS: Using statutory claims data we identified women with singleton live births between 2010 and 2017. Main outcomes included the occurrence of either hypertension or cardiovascular disease after one or more preeclamptic pregnancies, number of contacts to a general practitioner or cardiologist after delivery and prescribed antihypertensive medication. Data were analyzed using Cox proportional hazard regression models adjusted for maternal age, diabetes, dyslipidemia, and obesity. RESULTS: The study cohort consisted of 181,574 women with 240,698 births. Women who experienced preeclampsia once had an increased risk for cardiovascular (hazard ratio, HR = 1.29) or hypertensive (HR = 4.13) events. In women affected by recurrent preeclampsia, risks were even higher to develop cardiovascular disease (HR = 1.53) or hypertension (HR = 6.01). In the following years after delivery, general practitioners were seen frequently, whereas cardiologists were consulted rarely (0.3 and 2.4%). CONCLUSION: Women affected by preeclampsia experience an increased risk of developing chronic hypertension and cardiovascular disease, especially those with recurrent preeclampsia. Future medical guidelines should take this potential risk into account.

Observational database study on preeclampsia and postpartum medical care up to 7.5 years after birth.

Preeclampsia is associated with a substantially increased long-term risk for cardiovascular, cerebrovascular and renal disease. It remains unclear whether and to which extent specialized medical postpartum care is sought. We aimed to assess current utilization of postpartum primary and specialized care and medication prescription behavior in women who experienced preeclampsia. This retrospective observational study based on statutory claims data included 193,205 women with 258,344 singleton live births between 2010 and 2017 in Southern Germany. Postpartum care was evaluated by analyzing and comparing the frequency of medical consultations in primary and specialized care and prescriptions for antihypertensive medication among women with and without preeclampsia up to 7.5 years after delivery. Gynecologists and general practitioners were the main health care providers for all women. Although specialized postpartum care was sought by more women after preeclampsia, the effect size indices revealed no considerable association between a history of preeclampsia and the utilization of specialized outpatient aftercare (e.g. 2% vs. 0.6% of patients with and without preeclampsia who consulted a nephrologist during the first year postpartum, r = 0.042). Preeclampsia was associated with an increased risk to take any antihypertensive medication after delivery (HR 2.7 [2.6; 2.8]). Postpartum referral to specialized outpatient care and quarterly prescriptions of antihypertensives following preeclampsia failed to match the early and rapidly increased incidence and risk of hypertension. These data highlight the missed opportunity to implement a reasonable follow-up strategy and prevention management in order to achieve long-term clinical benefits.

Aldehyde-catalysed carboxylate exchange in α-amino acids with isotopically labelled CO2.

The isotopic labelling of small molecules is integral to drug development and for understanding biochemical processes. The preparation of carbon-labelled α-amino acids remains difficult and time consuming, with established methods involving label incorporation at an early stage of synthesis. This explains the high cost and scarcity of C-labelled products and presents a major challenge in 11C applications (11C t1/2 = 20 min). Here we report that aldehydes catalyse the isotopic carboxylate exchange of native α-amino acids with *CO2 (* = 14, 13, 11). Proteinogenic α-amino acids and many non-natural variants containing diverse functional groups undergo labelling. The reaction probably proceeds via the trapping of *CO2 by imine-carboxylate intermediates to generate iminomalonates that are prone to monodecarboxylation. Tempering catalyst electrophilicity was key to preventing irreversible aldehyde consumption. The pre-generation of the imine carboxylate intermediate allows for the rapid and late-stage 11C-radiolabelling of α-amino acids in the presence of [11C]CO2.

Structure Elucidation, Total Synthesis, Antibacterial In Vivo Efficacy and Biosynthesis Proposal of Myxobacterial Corramycin.

Herein, we describe the myxobacterial natural product Corramycin isolated from Corallococcus coralloides. The linear peptide structure contains an unprecedented (2R,3S)-γ-N-methyl-ß-hydroxy-histidine moiety. Corramycin exhibits anti-Gram-negative activity against Escherichia coli (E. coli) and is taken up via two transporter systems, SbmA and YejABEF. Furthermore, the Corramycin biosynthetic gene cluster (BGC) was identified and a biosynthesis model was proposed involving a 12-modular non-ribosomal peptide synthetase/polyketide synthase. Bioinformatic analysis of the BGC combined with the development of a total synthesis route allowed for the elucidation of the molecule's absolute configuration. Importantly, intravenous administration of 20 mg kg-1 of Corramycin in an E. coli mouse infection model resulted in 100 % survival of animals without toxic side effects. Corramycin is thus a promising starting point to develop a potent antibacterial drug against hospital-acquired infections.

Probing Factor Xa Protein-Ligand Interactions: Accurate Free Energy Calculations and Experimental Validations of Two Series of High-Affinity Ligands.

The accurate prediction of protein-ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen-π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots.

Genomic and Chemical Decryption of the Bacteroidetes Phylum for Its Potential to Biosynthesize Natural Products.

With progress in genome sequencing and data sharing, 1,000s of bacterial genomes are publicly available. Genome mining-using bioinformatics tools in terms of biosynthetic gene cluster (BGC) identification, analysis, and rating-has become a key technology to explore the capabilities for natural product (NP) biosynthesis. Comprehensively, analyzing the genetic potential of the phylum Bacteroidetes revealed Chitinophaga as the most talented genus in terms of BGC abundance and diversity. Guided by the computational predictions, we conducted a metabolomics and bioactivity driven NP discovery program on 25 Chitinophaga strains. High numbers of strain-specific metabolite buckets confirmed the upfront predicted biosynthetic potential and revealed a tremendous uncharted chemical space. Mining this data set, we isolated the new iron chelating nonribosomally synthesized cyclic tetradeca- and pentadecalipodepsipeptide antibiotics chitinopeptins with activity against Candida, produced by C. eiseniae DSM 22224 and C. flava KCTC 62435, respectively. IMPORTANCE The development of pipelines for anti-infectives to be applied in plant, animal, and human health management are dried up. However, the resistance development against compounds in use calls for new lead structures. To fill this gap and to enhance the probability of success for the discovery of new bioactive natural products, microbial taxa currently underinvestigated must be mined. This study investigates the potential within the bacterial phylum Bacteroidetes. A combination of omics-technologies revealed taxonomical hot spots for specialized metabolites. Genome- and metabolome-based analyses showed that the phylum covers a new chemical space compared with classic natural product producers. Members of the Bacteroidetes may thus present a promising bioresource for future screening and isolation campaigns.

Identification, Characterization, and Synthesis of Natural Parasitic Cysteine Protease Inhibitors: Pentacitidins Are More Potent Falcitidin Analogues.

Protease inhibitors represent a promising therapeutic option for the treatment of parasitic diseases such as malaria and human African trypanosomiasis. Falcitidin was the first member of a new class of inhibitors of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum. Using a metabolomics dataset of 25 Chitinophaga strains for molecular networking enabled identification of over 30 natural analogues of falcitidin. Based on MS/MS spectra, they vary in their amino acid chain length, sequence, acyl residue, and C-terminal functionalization; therefore, they were grouped into the four falcitidin peptide families A-D. The isolation, characterization, and absolute structure elucidation of two falcitidin-related pentapeptide aldehyde analogues by extensive MS/MS spectrometry and NMR spectroscopy in combination with advanced Marfey's analysis was in agreement with the in silico analysis of the corresponding biosynthetic gene cluster. Total synthesis of chosen pentapeptide analogues followed by in vitro testing against a panel of proteases revealed selective parasitic cysteine protease inhibition and, additionally, low-micromolar inhibition of α-chymotrypsin. The pentapeptides investigated here showed superior inhibitory activity compared to falcitidin.

The Discovery and Structure-Activity Evaluation of (+)-Floyocidin B and Synthetic Analogs.

Tuberculosis represents one of the ten most common courses of death worldwide and the emergence of multidrug-resistant M. tuberculosis makes the discovery of novel anti-tuberculosis active structures an urgent priority. Here, we show that (+)-floyocidin B representing the first example of a novel dihydroisoquinoline class of fungus-derived natural products, displays promising antitubercular hit properties. (+)-Floyocidin B was identified by activity-guided extract screening and its structure was unambiguously determined by total synthesis. The absolute configuration was deduced from a key synthesis intermediate by single crystal X-ray diffraction analysis. A hit series was generated by the isolation of further natural congeners and the synthesis of analogs of (+)-floyocidin B. Extensive biological and physicochemical profiling of this series revealed first structure-activity relationships and set the basis for further optimization and development of this novel antitubercular scaffold.

An observational claims data analysis on the risk of maternal chronic kidney disease after preterm delivery and preeclampsia.

Women with complications of pregnancy such as preeclampsia and preterm birth are at risk for adverse long-term outcomes, including an increased future risk of chronic kidney disease (CKD) and end-stage kidney disease (ESKD). This observational cohort study aimed to examine the risk of CKD after preterm delivery and preeclampsia in a large obstetric cohort in Germany, taking into account preexisting comorbidities, potential confounders, and the severity of CKD. Statutory claims data of the AOK Baden-Wuerttemberg were used to identify women with singleton live births between 2010 and 2017. Women with preexisting conditions including CKD, ESKD, and kidney replacement therapy (KRT) were excluded. Preterm delivery (< 37 gestational weeks) was the main exposure of interest; preeclampsia was investigated as secondary exposure. The main outcome was a newly recorded diagnosis of CKD in the claims database. Data were analyzed using Cox proportional hazard regression models. The time-dependent occurrence of CKD was analyzed for four strata, i.e., births with (i) neither an exposure of preterm delivery nor an exposure of preeclampsia, (ii) no exposure of preterm delivery but exposure of at least one preeclampsia, (iii) an exposure of at least one preterm delivery but no exposure of preeclampsia, or (iv) joint exposure of preterm delivery and preeclampsia. Risk stratification also included different CKD stages. Adjustments were made for confounding factors, such as maternal age, diabetes, obesity, and dyslipidemia. The cohort consisted of 193,152 women with 257,481 singleton live births. Mean observation time was 5.44 years. In total, there were 16,948 preterm deliveries (6.58%) and 14,448 births with at least one prior diagnosis of preeclampsia (5.61%). With a mean age of 30.51 years, 1,821 women developed any form of CKD. Compared to women with no risk exposure, women with a history of at least one preterm delivery (HR = 1.789) and women with a history of at least one preeclampsia (HR = 1.784) had an increased risk for any subsequent CKD. The highest risk for CKD was found for women with a joint exposure of preterm delivery and preeclampsia (HR = 5.227). These effects were the same in magnitude only for the outcome of mild to moderate CKD, but strongly increased for the outcome of severe CKD (HR = 11.90). Preterm delivery and preeclampsia were identified as independent risk factors for all CKD stages. A joint exposure or preterm birth and preeclampsia was associated with an excessive maternal risk burden for CKD in the first decade after pregnancy. Since consequent follow-up policies have not been defined yet, these results will help guide long-term surveillance for early detection and prevention of kidney disease, especially for women affected by both conditions.

Total synthesis and mechanism of action of the antibiotic armeniaspirol A.

Emerging antimicrobial resistance urges the discovery of antibiotics with unexplored, resistance-breaking mechanisms. Armeniaspirols represent a novel class of antibiotics with a unique spiro[4.4]non-8-ene scaffold and potent activities against Gram-positive pathogens. We report a concise total synthesis of (±) armeniaspirol A in six steps with a yield of 20.3% that includes the formation of the spirocycle through a copper-catalyzed radical cross-coupling reaction. In mechanistic biological experiments, armeniaspirol A exerted potent membrane depolarization, accounting for the pH-dependent antibiotic activity. Armeniaspirol A also disrupted the membrane potential and decreased oxygen consumption in mitochondria. In planar lipid bilayers and in unilamellar vesicles, armeniaspirol A transported protons across membranes in a protein-independent manner, demonstrating that armeniaspirol A acted as a protonophore. We provide evidence that this mechanism might account for the antibiotic activity of multiple chloropyrrole-containing natural products isolated from various origins that share a 4-acylphenol moiety coupled to chloropyrrole as a joint pharmacophore. We additionally describe an efflux-mediated mechanism of resistance against armeniaspirols.

Effectiveness and cost-effectiveness of an electronic mindfulness-based intervention (eMBI) on maternal mental health during pregnancy: the mindmom study protocol for a randomized controlled clinical trial.

BACKGROUND: Mental disorders are common during the peripartum period and may have far-reaching consequences for both mother and child. Unfortunately, most antenatal care systems do not provide any structured screening for maternal mental health. As a consequence, mental illnesses are often overlooked and not treated adequately. If correctly diagnosed, cognitive behavioral therapy is currently the treatment of choice for mental illnesses. In addition, mindfulness-based interventions (MBIs) seem to represent a promising treatment option for anxiety and depression during the peripartum period. Considering the internet's increasing omnipresence, MBIs can also be offered electronically via a (tablet) computer or smartphone (electronically based MBI = eMBI). OBJECTIVE: The current study aims to examine the clinical effectiveness and cost-effectiveness of an eMBI (the mindmom application) developed by an interdisciplinary team of gynecologists, psychologists, and midwives, teaching pregnant women how to deal with stress, pregnancy-related anxiety, and depressive symptoms. The study sample consists of pregnant women in their third trimester who screened positive for emotional distress. The mindmom study is a bicentric prospective randomized controlled trial (RCT), which is currently conducted at the University women's hospitals of Heidelberg and Tübingen, Germany. METHODS: Within the scope of the routine prenatal care, pregnant women attending routine pregnancy care in Baden-Wuerttemberg, Germany, are invited to participate in a screening for mental distress based on the Edinburgh Postnatal Depression Scale (EPDS). Women with an EPDS screening result > 9 will be referred to one of the mindmom coordinating study centers and are offered counseling either face-to-face or via videotelephony. After an initial psychological counseling, women are invited to participate in an eMBI in their last pregnancy trimester. The study will enroll N = 280 study participants (N = 140 per group), who are randomized 1:1 into the intervention (IG) or control group (treatment as usual = TAU). All participants are requested to complete a total of 7 digital assessments (5 visits pre- and 2 follow-up visits postpartum), involving self-report questionnaires, sociodemographic and medical data, physiological measures, and morning cortisol profiles. The primary outcome will be depressive and anxiety symptoms, measured by the Edinburgh Postnatal Depression Scale, the State Trait Anxiety Questionnaire, and the Pregnancy-Related Anxiety Questionnaire. Secondary outcomes include mindfulness, satisfaction with birth, quality of life, fetal attachment, bonding, mode of delivery, and cost-effectiveness. DISCUSSION: This is the first German RCT to examine the (cost-)effectiveness of an eMBI on maternal mental health during pregnancy. If successful, the mindmom app represents a low-threshold and cost-effective help for psychologically distressed women during pregnancy, thereby reducing the negative impact on perinatal health outcome. TRIAL REGISTRATION: Deutsches Register Klinischer Studien, German Clinical Trials Register DRKS00017210 . Registered on 13 January 2020. Retrospectively registered.

Total Synthesis and Structure Revision of (-)-Avicennone C.

All four possible stereoisomers of the natural product (-)-avicennone C were synthesized using two different methods for ring closure. The absolute stereochemistry was elucidated unambiguously by comparison of the analytical data with those of the reported natural product and by single X-ray crystal diffraction of synthetic intermediates. The proposed structure needed to be revised with regard to the absolute configuration of the stereogenic center bearing the secondary hydroxyl group. The reported synthesis offers a flexible, selective, and efficient access to all possible stereoisomers and may be of value for the stereoselective synthesis of other epoxyquinone natural products.

Molecular Networking-Guided Discovery and Characterization of Stechlisins, a Group of Cyclic Lipopeptides from a Pseudomonas sp.

Increasingly sensitive analytical instruments and robust downstream data processing tools have revolutionized natural product research over the past decade. A molecular networking-guided survey led to the identification of 33 new cyclic lipopeptides (CLPs) from the culture broth of the proteobacterium Pseudomonas sp. FhG100052. The compound family resembles members of the amphisin group of CLPs that possess a 3-hydroxy fatty acid linked to the N-terminus of an undecapeptide core. Culture optimization led to the isolation and subsequent structure elucidation of one known and five new derivatives by extensive MS/MS and NMR experiments in combination with Marfey's analysis. The data were in agreement with in silico analysis of the corresponding biosynthetic gene cluster. Most strikingly, the length of the incorporated fatty acid defined the growth inhibitory effects against Moraxella catarrhalis FH6810, as observed by MIC values ranging from no inhibition (>128 µg/mL) to 4 µg/mL.

Effects of a Brief Electronic Mindfulness-Based Intervention on Relieving Prenatal Depression and Anxiety in Hospitalized High-Risk Pregnant Women: Exploratory Pilot Study.

BACKGROUND: Peripartum depression and anxiety disorders are highly prevalent and are correlated with adverse maternal and neonatal outcomes. Antenatal care in Germany does not yet include structured screening and effective low-threshold treatment options for women facing peripartum depression and anxiety disorders. Mindfulness-based interventions (MBIs) are increasingly becoming a focus of interest for the management of such patients. Studies have shown a decrease in pregnancy-related stress and anxiety in expectant mothers following mindfulness programs. OBJECTIVE: The aim of this study was to explore the clinical effectiveness of a 1-week electronic course of mindfulness on prenatal depression and anxiety in hospitalized, high-risk pregnant women. We hypothesized that participating in a 1-week electronic MBI (eMBI) could alleviate symptoms of depression and anxiety during the hospital stay. METHODS: A prospective pilot study with an explorative study design was conducted from January to May 2019 in a sample of 68 women hospitalized due to high-risk pregnancies. After enrolling into the study, the participants were given access to an eMBI app on how to deal with stress, anxiety, and symptoms of depression. Psychometric parameters were assessed via electronic questionnaires comprising the Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI-S), and abridged version of the Pregnancy-Related Anxiety Questionnaire (PRAQ-R). RESULTS: We observed a high prevalence of peripartum depression and anxiety among hospitalized high-risk pregnant women: 39% (26/67) of the study participants in the first assessment and 41% (16/39) of the participants in the second assessment achieved EPDS scores above the cutoff value for minor/major depression. The number of participants with anxiety levels above the cutoff value (66% [45/68] of the participants in the first assessment and 67% [26/39] of the participants in the second assessment) was significantly more than that of the participants with anxiety levels below the cutoff value, as measured with the STAI-S. After completing the 1-week electronic course on mindfulness, the participants showed a significant reduction in the mean state anxiety levels (P<.03). Regarding pregnancy-related anxiety, participants who completed more than 50% of the 1-week course showed lower scores in PRAQ-R in the second assessment (P<.05). No significant changes in the EPDS scores were found after completing the intervention. CONCLUSIONS: Peripartum anxiety and depression represent a relevant health issue in hospitalized pregnant patients. Short-term eMBIs could have the potential to reduce anxiety levels and pregnancy-related anxiety. However, we observed that compliance to eMBI seems to be related to lower symptoms of pregnancy-related stress among high-risk patients. eMBIs represent accessible mental health resources at reduced costs and can be adapted for hospitalized patients during pregnancy.