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Diabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

Objectives To evaluate clinical presentation, imaging features, embolization techniques and their outcome for acquired uterine vascular anomalies (UVA) related to obstetric events. Materials and methods Thirteen women (mean age = 34; range = 20–40 years) who had undergone interventional radiological treatment of UVAs between 2013 and 2024 were retrospectively analyzed. All patients had a history of an obstetric event. They presented with ongoing postpartal vaginal blood losses ( n  = 11) or were asymptomatic ( n  = 2). Fertilization had been performed by intracytoplasmic sperm injection (ICSI) in 3/13 women. 7/13 women had delivered healthy babies. 6 women had surgical, drug-induced or missed abortions. Postpartum dilatation and curettage had been performed in 4 women. The delay between the obstetric/gynecological event and the radiological intervention ranged from 19 to 193 days (median = 49 days). Long-term follow-up was available in 12/13 patients (median FU = 2.4 years). Unilateral selective transcatheter embolization was performed in 7/12 patients (n-Butyl-Cyanoacrylate-Lipiodol mixture [BCAL], n  = 5; trisacryl gelatine particles, n  = 2); Bilateral uterine artery embolization was performed in 5/12 women (unilateral BCAL combined with contralateral particles in 3/12, or bilateral gelatine sponge slurry in 2/12). In one patient percutaneous direct injection of BCAL into a uterine artery branch pseudoaneurysm was performed. Results Primary clinical success without complications was achieved in 10/13 interventions. Re-embolization was successful in the 3 patients with ongoing bleeding despite uterine artery embolization. Follow-up information was available in 12/13 patients (median FU = 2.4 yrs). The pregnancy rate after embolization was 8/12women with a birth rate of 6/8 pregnancies. Conclusion Embolization of acquired UVAs is an effective and safe treatment. Preservation of uterine function for future pregnancy after uterine transarterial embolization seems warranted.

Introduction Our objective was to assess non‐inferiority of the unique approach used in our institution of combined 10 IU IM (intramyometrial) and 10 IU IV (intravenous) oxytocin to carbetocin IV in preventing severe postpartum blood loss in elective cesarean sections. The design was a prospective controlled phase IV non‐inferiority interventional trial. The setting was a tertiary center at University Hospital, Zurich, Switzerland. Material and Methods The population consisted of 550 women undergoing elective cesarean section after 36 completed weeks of gestation at low risk for postpartum hemorrhage (PPH). Participants were assigned to either combined oxytocin regimen (10 IU IM and 10 IU IV) or carbetocin (100 μg IV). Non‐inferiority for oxytocin for severe PPH was assessed with a 0.05 margin using the Newcombe–Wilson score method. The main outcome measures were severe postpartum blood loss defined as delta hemoglobin (∆Hb, Hb prepartum—Hb postpartum) ≥30 g/L. Results Non‐inferiority of combined oxytocin (IM/IV) in preventing severe postpartum blood loss was not shown (17 women in the oxytocin group vs. 7 in the carbetocin group). The number needed to treat when using carbetocin was 28. The risk difference for ∆Hb ≥30 g/L was 0.04 (oxytocin 0.06 vs. 0.03), 95% confidence interval (CI) (0.00–0.08). No significant difference was observed for ∆Hb (median 12 [IQR 7.0–19.0] vs. 11 [5.0–17.0], p = 0.07), estimated blood loss (median 500 [IQR 400–600] vs. 500 [400–575], p = 0.38), or the PPH rate defined as estimated blood loss ≥1000 mL (12[4.5] vs. 5 [2.0], risk difference 0.03, 95% CI (−0.01 to 0.06), p = 0.16). More additional uterotonics were administered in the oxytocin group compared to the carbetocin group (15.2% vs. 5.9%, p = 0.001). Total case costs were non‐significantly different in the oxytocin group (US $ 10 146 vs. 9621, mean difference 471.4, CI (−476.5 to 1419.3), p = 0.33). Conclusions Combined (IM/IV) oxytocin is not non‐inferior to carbetocin regarding severe postpartum blood loss defined as postpartum Hb decrease ≥30 g/L in elective cesarean sections. We recommend carbetocin for use in clinical practice for elective cesarean sections. The risk difference comparing the proportions of combined Oxytocin IM and IV to the carbetocin IV group is 0.04 [90% CI: 0.01 0.07]. The figure shows the computed risk difference with 90%‐Newcombe–Wilson‐Score‐Interval alongside the non‐inferiority margin of 0.05. The upper confidence limit is larger than the prespecified margin and thus we cannot conclude that combined oxytocin is non‐inferior to carbetocin based on these results. (The results are inconclusive in the sense that it is plausible that the true risk difference is less than the non‐inferiority margin but the new treatment is statistically significantly worse than the standard)

Background Guillain-Barré syndrome (GBS) during pregnancy can be a very severe and life-threatening condition for both mother and child. GBS due to cytomegalovirus (CMV) in pregnancy is even rarer and may be associated with more respiratory insufficiency, cranial nerve involvement and sensory loss in the mother. Case presentation A 29-year-old secondparous woman at 25 weeks of gestation (WG) presented with a rapid ascending tetraparesis, bulbar paralysis, bilateral facial palsy, right-sided abducens paresis within 72 h of symptom onset and respiratory failure after 12 days. She needed intubation and mechanical ventilation for cumulative 42 days. GBS due to CMV primo-infection was diagnosed. A multidisciplinary team was involved to monitor and manage patient and fetus. In the electrodiagnostic studies, the patient presented severe primarily demyelinating features consistent with an acute inflammatory demyelinating (AIDP) GBS form treated with repeated plasma exchanges and administration of intravenous immunoglobulins. At 34 + 1 WG a cesarean delivery was performed, the newborn was healthy without intrauterine CMV-transmission. Conclusion The optimal time of delivery for intubated pregnant GBS patients is unknown. The mother’s respiratory and medical conditions should be assessed in relation to premature-associated morbidity of the newborn.

IntroductionThe primary objective of this trial is to evaluate the effect of replenishing coagulation factor XIII (FXIII) in women with postpartum haemorrhage (PPH) on measured blood loss (MBL). Based on earlier research, we hypothesise that the administration of FXIII leads to a significant reduction in postpartum blood loss.Methods and analysisThis is a randomised, controlled trial that will allocate eligible patients in the event of a PPH and after receiving tranexamic acid either to the treatment group, receiving FXIII, or to the control group (standard of care). The primary endpoint is the MBL within 24 hours using a standardised method. For the primary analysis, estimation of the OR under a proportional odds assumption is conducted simultaneously for all possible cut-off points. A corresponding estimate, along with a two-sided 95% CI and two-sided p value against the null hypothesis OR=1, is obtained from the Continuous Outcome Logistic Regression model. More than 7000 patients will be screened in order to include a total of 988 eligible patients into the trial. Secondary outcomes include the rate of adverse maternal outcomes related to PPH, the rate of women breastfeeding after PPH and the safety of the administration of FXIII in women with PPH. Dynamics of blood coagulation factors in women with PPH and their association with MBL will be assessed in specific centres. A preliminary overview on costs and potential savings through early treatment of PPH with FXIII is included in the analysis as well as a patient and public involvement report, asking for patients’ personal experience during PPH in the main study centre.Ethics and disseminationEthics approval was granted by the central ethics committee (Kantonale Ethikkommission Zürich/Switzerland) on 16 June 2024, reference number: BASEC 2024-00374. Results will be disseminated via open-access publication in a relevant medical journal.Trial registration numberClinicalTrials.gov ID NCT06481995.

Alterations in metabolic pathways were recently recognized as potential underlying drivers of idiopathic pulmonary fibrosis (IPF), translating into novel therapeutic targets. However, knowledge of metabolic and lipid regulation in fibrotic lungs is limited. To comprehensively characterize metabolic perturbations in the bleomycin mouse model of IPF, we analyzed the metabolome and lipidome by mass spectrometry. We identified increased tissue turnover and repair, evident by enhanced breakdown of proteins, nucleic acids and lipids and extracellular matrix turnover. Energy production was upregulated, including glycolysis, the tricarboxylic acid cycle, glutaminolysis, lactate production and fatty acid oxidation. Higher eicosanoid synthesis indicated inflammatory processes. Because the risk of IPF increases with age, we investigated how age influences metabolomic and lipidomic changes in the bleomycin-induced pulmonary fibrosis model. Surprisingly, except for cytidine, we did not detect any significantly differential metabolites or lipids between old and young bleomycin-treated lungs. Together, we identified metabolomic and lipidomic changes in fibrosis that reflect higher energy demand, proliferation, tissue remodeling, collagen deposition and inflammation, which might serve to improve diagnostic and therapeutic options for fibrotic lung diseases in the future.

Background To analyze blood loss after delivery in women with induction of labor compared to women with spontaneous onset of labor. Methods In this secondary analysis of a prospective cohort study investigating postpartum hemorrhage, 965 deliveries were analyzed including 380 women with induction of labor (39%) between 2015 and 2016. Primary outcome parameters were rate of postpartum hemorrhage, estimated blood loss and post-partum decrease in hemoglobin. Results Rates of postpartum hemorrhage and estimated blood loss were not significantly different in women with induction of labor. Women with induction of labor had a significantly reduced decrease in hemoglobin after delivery. In the multivariate linear regression analysis, induction of labor remained associated with reduced decrease in hemoglobin. Secondary maternal and neonatal outcomes were unaffected. Conclusions Induction of labor is not associated with increased blood loss after delivery and should not be regarded as a risk factor for postpartum hemorrhage.

Background Post-mortem imaging has been suggested as an alternative to conventional autopsy in the prenatal and postnatal periods. Noninvasive autopsies do not provide tissue for histological examination, which may limit their clinical value, especially when infection-related morbidity and mortality are suspected. Methods We performed a prospective, multicentre, cross-sectional study to compare the diagnostic performance of post-mortem magnetic resonance imaging with computed tomography-guided biopsy (Virtopsy®) with that of conventional autopsy in foetuses and infants. Cases referred for conventional autopsy were eligible for enrolment. After post-mortem imaging using a computed tomography scanner and a magnetic resonance imaging unit, computed tomography-guided tissue sampling was performed. Virtopsy results were compared with conventional autopsy in determining the likely final cause of death and major pathologies. The primary outcome was the proportion of cases for which the same cause of death was determined by both methods. Secondary outcomes included the proportion of false positive and false negative major pathological lesions detected by virtopsy and the proportion of computed tomography-guided biopsies that were adequate for histological examination. Results Overall, 101 cases (84 fetuses, 17 infants) were included. Virtopsy and autopsy identified the same cause of death in 91 cases (90.1%, 95% CI 82.7 to 94.5). The sensitivity and specificity of virtopsy for determining the cause of death were 96.6% (95% CI 90.6 to 98.8) and 41.7% (95% CI 19.3 to 68.0), respectively. In 32 cases (31.7%, 95% CI 23.4 to 41.3), major pathological findings remained undetected by virtopsy, and in 45 cases (44.6%, 95% CI 35.2 to 54.3), abnormalities were diagnosed by virtopsy but not confirmed by autopsy. Computed tomography-guided tissue sampling was adequate for pathological comments in 506 of 956 biopsies (52.7%) and added important diagnostic value in five of 30 cases (16.1%) with an unclear cause of death before autopsy compared with postmortem imaging alone. In 19 of 20 infective deaths (95%), biopsies revealed infection-related tissue changes. Infection was confirmed by placental examination in all fetal cases. Conclusions Virtopsy demonstrated a high concordance with conventional autopsy for the detection of cause of death but was less accurate for the evaluation of major pathologies. Computed tomography-guided biopsy had limited additional diagnostic value. Trial registration ClinicalTrials.gov (NCT01888380).

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, has attracted interest as a target for pharmacological intervention in malignant diseases. Here, we describe BI 853520, a novel ATP-competitive inhibitor distinguished by high potency and selectivity. In vitro, the compound inhibits FAK autophosphorylation in PC-3 prostate carcinoma cells with an IC50 of 1 nmol/L and blocks anchorage-independent proliferation of PC-3 cells with an EC50 of 3 nmol/L, whereas cells grown in conventional surface culture are 1000-fold less sensitive. In mice, the compound shows long half-life, high volume of distribution and high oral bioavailability; oral dosing of immunodeficient mice bearing subcutaneous PC-3 prostate adenocarcinoma xenografts resulted in rapid, long-lasting repression of FAK autophosphorylation in tumor tissue. Daily oral administration of BI 853520 to nude mice at doses of 50 mg/kg was well tolerated for prolonged periods of time. In a diverse panel of 16 subcutaneous adenocarcinoma xenograft models in nude mice, drug treatment resulted in a broad spectrum of outcomes, ranging from group median tumor growth inhibition values >100% and tumor regression in subsets of animals to complete lack of sensitivity. Biomarker analysis indicated that high sensitivity is linked to a mesenchymal tumor phenotype, initially defined by loss of E-cadherin expression and subsequently substantiated by gene set enrichment analysis. Further, we obtained microRNA expression profiles for 13 models and observed that hsa-miR-200c-3p expression is strongly correlated with efficacy (R2 = 0.889). BI 853520 is undergoing evaluation in early clinical trials.

B cell chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course. Recurrent chromosomal imbalances provide significant prognostic markers. Risk-adapted therapy based on genomic alterations has become an option that is currently being tested in clinical trials. To supply a robust tool for such large scale studies, we developed a comprehensive DNA microarray dedicated to the automated analysis of recurrent genomic imbalances in B-CLL by array-based comparative genomic hybridization (matrix-CGH). Validation of this chip in a series of 106 B-CLL cases revealed a high specificity and sensitivity that fulfils the criteria for application in clinical oncology. This chip is immediately applicable within clinical B-CLL treatment trials that evaluate whether B-CLL cases with distinct chromosomal abnormalities should be treated with chemotherapy of different intensities and/or stem cell transplantation. Through the control set of DNA fragments equally distributed over the genome, recurrent genomic imbalances were discovered: trisomy of chromosome 19 and gain of the MYCN oncogene correlating with an elevation of MYCN mRNA expression.