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The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

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. 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. 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). 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. 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.

Perinatal maternal mental health problems, such as depression and anxiety, are highly prevalent during pregnancy and post partum. Electronic mindfulness-based interventions (eMBIs) are a promising treatment option, which can be provided in a low-threshold, cost-effective manner. However, research underscores the fact that face-to-face coaching sessions are more effective than solely digital methods. A blended care approach (eMBI with direct face-to-face coaching) could amplify the therapeutic impact on maternal mental health and weight gain during the perinatal period. We investigated whether combining an eMBI intervention with face-to-face personal support significantly improves maternal mental health, and whether the intervention can influence weight gain in affected women during pregnancy. A community-based sample of 460 pregnant women with a singleton pregnancy who screened positive for depression was enrolled in a multicenter randomized controlled trial (RCT) including the University Hospitals of Heidelberg and Tübingen as well as more than 200 gynecological practices within the state of Baden-Württemberg in Germany between February 2019 and October 2020. Participating women were randomized 1:1 to the control group (CG) or intervention group (IG) that received access to an 8-week pregnancy-adapted eMBI between the 29th and 36th gestational week. In a subanalysis, we grouped participants in those receiving only the initial face-to-face coaching session at recruitment (no personal coaching) and those with ≥2 personal coaching sessions. Primary outcome measures were severity of depressive symptoms using the Edinburgh Postnatal Depression Scale, anxiety using the State-Trait Anxiety Inventory, the Pregnancy-Related Anxiety Questionnaire, the Freiburg Mindfulness Inventory, and the Patient Health Questionnaire; secondary outcome measure, BMI. In the final sample, 137 CG women and 102 IG women received only one coaching session, whereas 37 CG women and 40 IG women received at least 2 (mean 2.3, SD 0.7) coaching sessions. The analyses were adjusted for significant confounders. The IG's mindfulness scores increased significantly (F =4.560, P=.01, η²=0.024, ω²=0.012) regardless of coaching frequency. Both general anxiety (F =2.361, P=.01, η²=0.0180, ω²=0.100) and depression symptoms (F =3.033, P=.01, η²=0.020, ω²=0.009) were significantly lower in the group that received ≥2 coaching sessions than in the no-personal-coaching group. In the group receiving ≥2 coaching sessions, BMI generally was lower in the IG than in the CG (F =4.732, P=.002, η²=0.036, ω²=0.013). Adding a minimal amount of PC to the digital eMBI increased mindfulness and decreased birth-related anxiety, symptoms of depression, and anxiety in at-risk pregnant women. Favorable effects on gestational weight gain were found in the respective IGs, the strongest effect being within the PC group. This blended digital health approach amplifies the effectiveness of the digital intervention. German Clinical Trials Register DRKS00017210; https://www.drks.de/search/de/trial/DRKS00017210.

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.

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.

Introduction We aimed to develop a machine learning model for first-trimester prediction of gestational diabetes mellitus (GDM) in twin pregnancies using a prospective international, multi-center cohort and identify useful predictive markers. Methods Pregnant women with two live fetuses were enrolled at 11 + 0 to 13 + 6 weeks’ gestation and followed until delivery. GDM was diagnosed at 24–28 weeks’ gestation using the two-stage GCT and OGTT tests. Biochemical, biophysical, and blood assessments were conducted at three periods during pregnancy. Multiple machine learning models evaluated demographic, clinical, and laboratory parameters, including maternal factors (BMI, age, medical history), sonographic markers (crown rump length, estimated fetal weight, uterine artery pulsatility index), and blood and biochemical markers (placental growth factors, blood glucose, cell counts). LightGBM, XGBoost, and logistic regression models were compared using area under the curve (AUC) analysis. Results Among 596 women, 99 (16.6%) developed GDM. LightGBM demonstrated superior performance (AUC = 0.72, 95% CI 0.69–0.75). First-trimester high BMI was the strongest predictor, followed by elevated white blood cell counts and platelet levels. Detection rates (DR) were 28% and 42% at 10% and 20% false positive rates (FPR), respectively. Previous GDM was associated with an increased risk for GDM. Discussion GDM in twins is associated with certain characteristics of the first-trimester. Information from later trimesters has a limited impact. The GDM probability risk score increased with the severity of the treatment. An app to predict this score is available at: twin-pe.math.biu.ac.il.

Background/Objectives: With breast cancer (BC) survival improving due to optimized therapy, enhancing quality of life has become increasingly important. Both diagnosis and treatment, with their potential side effects, pose risks to mental well-being. Our study aimed to analyze the incidence and potential risk factors for mental disorders in BC patients. Methods: This retrospective analysis used claims data from AOK Baden-Wuerttemberg, including 11,553 BC patients diagnosed via ICD code C50 between 2010 and 2020 and 31,944 age-matched controls. Patients with mental disorders in the 12 months prior to diagnosis were excluded. Mental disorders were categorized into eight groups based on ICD codes: anxiety, obsessive compulsive disorder, adjustment disorder, dissociative disorder, hypochondriac disorder, affective disorder, mania, and other neuroses. Results: Mental disorders were significantly more common in BC patients than in controls (64.2% vs. 38.1%, p < 0.01, OR 2.91, 95%CI [2.79, 3.04]). In particular, hypochondriac, anxiety, affective, and adjustment disorders occurred significantly more often in BC patients. No differences were found for mania, bipolar disease, other neuroses, obsessive compulsive-, or dissociative disorders. Furthermore, endocrine therapy was associated with psychological comorbidities (OR 1.69, p < 0.001, 95%CI [1.53, 1.86]), while primarily metastasized patients (stage C) had a lower risk than adjuvant patients in stage A (OR 0.55, p < 0.0001, 95%CI [0.49, 0.61]). Regarding surgical treatment, mastectomy patients showed lower rates of mental illnesses (61.2%) than those with breast-conserving treatment (71.6%), or especially breast reconstruction (78.4%, p < 0.01). Breast reconstruction was also associated with more hypochondriac (p < 0.01) and adjustment disorders (p < 0.01). Conclusions: So, BC patients experience significantly more mental disorders than controls, particularly when treated with endocrine therapy and breast reconstructive surgery.

Background Anxiety and depression are the most prevalent psychiatric diseases in the peripartum period. They can lead to relevant health consequences for mother and child as well as increased health care resource utilization (HCRU) and related costs. Due to the promising results of mindfulness-based interventions (MBI) and digital health applications in mental health, an electronic MBI on maternal mental health during pregnancy was implemented and assessed in terms of transferability to standard care in Germany. The present study focused the health economic outcomes of the randomized controlled trial (RCT). Methods The analysis, adopting a payer’s and a societal perspective, included women of increased emotional distress at < 29 weeks of gestation. We applied inferential statistics (α = 0.05 significance level) to compare the intervention group (IG) and control group (CG) in terms of HCRU and costs. The analysis was primarily based on statutory health insurance claims data which covered the individual observational period of 40 weeks. Results Overall, 258 women (IG: 117, CG: 141) were included in the health economic analysis. The results on total health care costs from a payer’s perspective indicated higher costs for the IGi compared to the CG (Exp(ß) = 1.096, 95% CI: 1.006–1.194, p  = 0.037). However, the estimation was not significant after Bonferroni correction ( p  < 0.006). Even the analysis from a societal perspective as well as sensitivity analyses did not show significant results. Conclusions In the present study, the eMBI did neither reduced nor significantly increased health care costs. Further research is needed to generate robust evidence on eMBIs for women suffering from peripartum depression and anxiety. Trial registration German Clinical Trials Register: DRKS00017210. Registered on 13 January 2020. Retrospectively registered.

Background The risk of breast cancer patients for long-term side effects of therapy such as neurotoxicity and cardiotoxicity as well as late effects regarding comorbidities varies from individual to individual. Personalised follow-up care concepts that are tailored to individual needs and the risk of recurrences, side effects and late effects are lacking in routine care in Germany. Methods We describe the methodology of BETTER-CARE, a parallel-arm cluster-randomised controlled trial conducted at 15 intervention and 15 control centres, aiming to recruit 1140 patients, and the results of the pilot phase. The needs- and risk-adapted complex intervention, based on existing development frameworks, includes a multidisciplinary network and digital platforms for symptom and need documentation and just-in-time adaptive interventions. The control group comprises usual care according to clinical guidelines. The primary outcome is health-related quality of life (EORTC QLQ-C30 global health), and secondary outcomes include treatment adherence. Results The 2-month pilot phase comprising 16 patients in one intervention and one control pilot centre demonstrated the feasibility of the BETTER-CARE approach. Discussion BETTER-CARE is a feasible intervention and study concept, investigating individualised needs- and risk-adapted breast cancer follow-up care in Germany. If successful, the approach could be implemented in German routine care. Trial registration German Clinical Trial Register DRKS00028840. Registered on April 2022.

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.