Multimodal management of ectopic hepatic pregnancy: a systematic review of the literature.

PURPOSE: Ectopic pregnancies with implantation in the upper abdomen are exceptionally rare. Here we provide a systematic review of hepatic ectopic pregnancies and the corresponding management strategies. Furthermore, this report details a case of ectopic hepatic pregnancy, successfully treated with primary methotrexate (MTX) followed by a two-staged robotic-assisted resection. METHODS: Two independent investigators performed a systematic review using the online search engine PubMed and MEDLINE database. The search utilized the following terms: 'Hepatic Ectopic Pregnancy,' 'Hepatic Extrauterine Pregnancy,' 'Hepatic Abdominal Pregnancy,' and 'Ectopic Liver Pregnancy.' Cross-referencing was employed to identify possible additional publications. FINDINGS: Forty-seven case reports on hepatic pregnancies were identified. Of these, 40 provided manuscripts in the English language. Most patients with hepatic pregnancy presented with mild to moderate abdominal pain, while only a minority exhibited signs of hemodynamically relevant intraperitoneal hemorrhage. Most cases were managed through open surgical removal, although in recent years, there has been an increase in laparoscopically managed cases. Conservative approaches using methotrexate are seldom employed. CONCLUSION: Hepatic pregnancies present a rare and challenging clinical scenario. Until now, these cases have usually been treated primarily with open explorative surgery. As reported in this case, primary conservative treatment approaches with MTX before surgery hold promise as a strategy to reduce surgery-related bleeding and morbidity, particularly for asymptomatic or oligosymptomatic patients.

Prognostic Impact of Surgical Margin Status on Overall Survival of Patients with Early Breast Cancer: A Retrospective Analysis from the Department for Women's Medicine at Charité - University Hospital Berlin.

Introduction: The impact of surgical margins on the prognosis of early breast cancer remains uncertain, particularly in the context of modern treatment approaches. This study aimed to investigate whether involved margins after surgery for early breast cancer affect overall survival. Methods: We conducted a retrospective analysis of 3767 patients who underwent surgery for primary breast cancer or carcinoma in situ between 2006 and 2022 at Charité - University Hospital Berlin. Survival analysis based on margin status and a subsequent multivariate Cox regression analysis were conducted. Results: With a median follow-up of 72.2 months, clear margins were achieved in 81.4% of patients (n = 3068) after primary surgery, while 16.2% (n = 610) required re-excision. Only 2.4% of patients (n = 89) had definitively involved margins. Margin involvement was more common in hormone receptor-positive disease, lobular subtype, carcinoma in situ, or locally advanced tumors, but less frequent in patients with previous neoadjuvant chemotherapy or triple-negative breast cancer. The Kaplan-Meier survival curves showed a significant separation with worse outcomes for patients with definitive R1 resections. However, the multivariate Cox regression analysis detected no statistically significant difference in overall survival based on margin status. Breast conserving surgery (HR 0.66; 95% CI 0.54-0.81) and HER2 overexpression (HR 0.65; 95% CI 0.48-0.89) were associated with improved survival. Conclusion: Patients who underwent breast-conserving surgery in our study demonstrated favorable outcomes compared to patients after mastectomy. Although margin status did not significantly affect overall survival, larger multicenter studies are needed to evaluate the prognostic implications of margin involvement in breast cancer treatment in different tumor stages, tumor subtypes and local and systemic treatments.

Training in obstetrics and gynecology between reality and vision: results of a JAGO-NOGGO survey in 601 physicians (NOGGO-Monitor-12 trial).

PURPOSE: The primary objective of this study was to establish a benchmark by collecting baseline data on surgical education in obstetrics and gynecology in Germany, including factual number of operations performed. MATERIALS AND METHODS: A nationwide anonymous survey was conducted in Germany between January 2019 and July 2019 utilizing a specially designed questionnaire which addressed both residents and senior trainers. RESULTS: A total of 601 participants completed the survey, comprising 305 trainees and 296 trainers. The trainees reported performing a median of 125 non-obstetric surgeries (IQR: 41-332) and 75 obstetric procedures (IQR: 27-168) independently. While most last-year residents managed to meet the targeted numbers for minor surgical procedures outlined in the logbook, they fell short of achieving the required numbers for major operations, such as hysterectomies or more complex laparoscopies. Although both trainees and trainers emphasized the significance of surgical training, the overall quality of the training was rated poorly, particularly by trainees. This was attributed to a high proportion of administrative tasks and a deficiency in teaching time within the operating theater. External fellowship and mentoring programs, as well as the implementation of regular, centralized reviews of residency training, were identified as potentially beneficial by both trainees and trainers. CONCLUSION: The findings of this survey should serve as a wake-up call both within and outside of Germany, highlighting the importance of comprehensive and structured surgical training to enhance long-term patient care and increase satisfaction among obstetrics and gynecology trainees.

Accuracy of endometrial sampling in the diagnosis of endometrial cancer: a multicenter retrospective analysis of the JAGO-NOGGO.

BACKGROUND: Accurate preoperative molecular and histological risk stratification is essential for effective treatment planning in endometrial cancer. However, inconsistencies between pre- and postoperative tumor histology have been reported in previous studies. To address this issue and identify risk factors related to inaccurate histologic diagnosis after preoperative endometrial evaluation, we conducted this retrospective analysis. METHODS: We conducted a retrospective analysis involving 375 patients treated for primary endometrial cancer in five different gynaecological departments in Germany. Histological assessments of curettage and hysterectomy specimens were collected and evaluated. RESULTS: Preoperative histologic subtype was confirmed in 89.5% of cases and preoperative tumor grading in 75.2% of cases. Higher rates of histologic subtype variations (36.84%) were observed for non-endometrioid carcinomas. Non-endometrioid (OR 4.41) histology and high-grade (OR 8.37) carcinomas were identified as predictors of diverging histologic subtypes, while intermediate (OR 5.04) and high grading (OR 3.94) predicted diverging tumor grading. CONCLUSION: When planning therapy for endometrial cancer, the limited accuracy of endometrial sampling, especially in case of non-endometrioid histology or high tumor grading, should be carefully considered.

Real-World Evidence: How Long Do Our Patients Fast?-Results from a Prospective JAGO-NOGGO-Multicenter Analysis on Perioperative Fasting in 924 Patients with Malignant and Benign Gynecological Diseases.

BACKGROUND: Despite the key role of optimized fasting in modern perioperative patient management, little current data exist on perioperative fasting intervals in routine clinical practice. METHODS: In this multicenter prospective study, the length of pre- and postoperative fasting intervals was assessed with the use of a specifically developed questionnaire. Between 15 January 2021 and 31 May 2022, 924 gynecology patients were included, from 13 German gynecology departments. RESULTS: On average, patients remained fasting for about three times as long as recommended for solid foods (17:02 ± 06:54 h) and about five times as long as recommended for clear fluids (9:21 ± 5:48 h). The average perioperative fasting interval exceeded one day (28:23 ± 14:02 h). Longer fasting intervals were observed before and after oncological or extensive procedures, while shorter preoperative fasting intervals were reported in the participating university hospitals. Smoking, treatment in a non-university hospital, an increased Charlson Comorbidity Index and extensive surgery were significant predictors of longer preoperative fasting from solid foods. In general, prolonged preoperative fasting was tolerated well and quality of patient information was perceived as good. CONCLUSION: Perioperative fasting intervals were drastically prolonged in this cohort of 924 gynecology patients. Our data indicate the need for better patient education about perioperative fasting.

Development and validation of a 1-km cardio-trekking test to estimate cardiorespiratory fitness in healthy adults.

Maximum oxygen uptake (V̇O2max), the gold standard measure of cardiorespiratory fitness (CRF), supports cardiovascular risk assessment and is mainly assessed during maximal spiroergometry. However, for field use, submaximal exercise tests might be appropriate and feasible. There have been no studies attempting a submaximal test protocol involving uphill hiking. This study aimed to develop and validate a 1-km cardio-trekking test (CTT) controlled by heart rate monitoring and Borg's 6-20 rating of perceived exertion (RPE) scale to predict V̇O2max outdoors. Healthy participants performed a maximal incremental treadmill walking laboratory test and a submaximal 1-km CTT on mountain trails in Austria and Germany, and V̇O2max was assessed with a portable spirometry device. Borg's RPE scale was used to control the exercise intensity of the CTT. All subjects wore a chest strap to measure heart rate (HR). A total of 134 participants (median age: 56.0 years [IQR: 51.8-63.0], 43.3 % males) completed both testing protocols. The prediction model is based on age, gender, smoking status, weight, mean HR, altitude difference, duration, and the interaction between age and duration (R2 = 0.65, adj. R2 = 0.63). Leave-one-out cross-validation revealed small shrinkage in predictive accuracy (R2 = 0.59) compared to the original model. Submaximal exercise testing using uphill hiking allows for practical estimation of V̇O2max in healthy adults. This method may allow people to engage in physical activity while monitoring their CRF to avert unnecessary cardiovascular events.

Assessment of Exercise Intensity for Uphill Walking in Healthy Adults Performed Indoors and Outdoors.

BACKGROUND: Borg's rating of perceived exertion (BRPE) scale is a simple, but subjective tool to grade physical strain during exercise. As a result, it is widely used for the prescription of exercise intensity, especially for cardiovascular disease prevention. The purpose of this study was to assess and compare relationships between BRPE and physiological measures of exercise intensity during uphill walking indoors and outdoors. METHODS: 134 healthy participants [median age: 56 years (IQR 52-63)] completed a maximal graded walking test indoors on a treadmill using the modified Bruce protocol, and a submaximal 1 km outdoor uphill cardio-trekking test (1 km CTT). Heart rate (HR) and oxygen consumption (V̇O2) were continuously measured throughout both tests. BRPE was simultaneously assessed at the end of each increment on the treadmill, while the maximal BRPE value was noted at the end of the 1 km CTT. RESULTS: On the treadmill, BRPE correlated very high with relative HR (%HRmax) (ρ = 0.88, p < 0.001) and V̇O2 (%V̇O2max) (ρ = 0.89, p < 0.001). During the 1 km CTT, a small correlation between BRPE and %HRmax (ρ = 0.24, p < 0.05), respectively %V̇O2max was found (ρ = 0.24, p < 0.05). CONCLUSIONS: Criterion validity of BRPE during uphill walking depends on the environment and is higher during a treadmill test compared to a natural environment. Adding sensor-based, objective exercise-intensity parameters such as HR holds promise to improve intensity prescription and health safety during uphill walking in a natural environment.

Valorization of Natural Cardio Trekking Trails Through Open Innovation for the Promotion of Sustainable Cross-generational Health-Oriented Tourism in the Connect2Move Project: Protocol for a Cross-sectional Study.

BACKGROUND: Hiking is one of the most popular forms of exercise in the alpine region. However, besides its health benefits, hiking is the alpine activity with the highest incidence of cardiac events. Most incidents occur due to overexertion or underestimation of the physiological strain of hiking. OBJECTIVE: This project will establish a standardized cardio trekking test trail to evaluate the exercise capacity of tourists within hiking areas and deliver a tool for the prevention of hiking-associated cardiac incidents. Further, individual exercise intensity for a hiking tour will be predicted and visualized in digital maps. METHODS: This cooperation study between Austria and Germany will first validate a 1-km outdoor cardio trekking test trail at 2 different study sites. Then, exercise intensity measures on 8-km hiking trails will be evaluated during hiking to estimate overall hiking intensity. A total of 144 healthy adults (aged >45 years) will perform a treadmill test in the laboratory and a 1-km hiking test outdoors. They will wear a portable spirometry device that measures gas exchange, as well as heart rate, walking speed, ventilation, GPS location, and altitude throughout the tests. Estimation models for exercise capacity based on measured parameters will be calculated. RESULTS: The project "Connect2Move" was funded in December 2019 by the European Regional Development Fund (INTERREG V-A Programme Austria-Bavaria - 2014-2020; Project Number AB296). "Connect2Move" started in January 2020 and runs until the end of June 2022. By the end of April 2022, 162 participants were tested in the laboratory, and of these, 144 were tested outdoors. The data analysis will be completed by the end of June 2022, and results are expected to be published by the end of 2022. CONCLUSIONS: Individual prediction of exercise capacity in healthy individuals with interest in hiking aims at the prevention of hiking-associated cardiovascular events caused by overexertion. Integration of a mathematical equation into existing hiking apps will allow individual hiking route recommendations derived from individual performance on a standardized cardio trekking test trail. TRIAL REGISTRATION: ClinicalTrails.gov NCT05226806; https://clinicaltrials.gov/ct2/show/NCT05226806. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39038.

Targeting Gαi/s Proteins with Peptidyl Nucleotide Exchange Modulators.

Chemical probes that specifically modulate the activity of heterotrimeric G proteins provide excellent tools for investigating G protein-mediated cell signaling. Herein, we report a family of selective peptidyl Gαi/s modulators derived from peptide library screening and optimization. Conjugation to a cell-penetrating peptide rendered the peptides cell-permeable and biologically active in cell-based assays. The peptides exhibit potent guanine-nucleotide exchange modulator-like activity toward Gαi and Gαs. Molecular docking and dynamic simulations revealed the molecular basis of the protein-ligand interactions and their effects on GDP binding. This study demonstrates the feasibility of developing direct Gαi/s modulators and provides a novel chemical probe for investigating cell signaling through GPCRs/G proteins.

Subthalamic beta oscillations correlate with dopaminergic degeneration in experimental parkinsonism.

Excessive beta activity has been shown in local field potential recordings from the cortico-basal ganglia loop of Parkinson's disease patients and in its various animal models. Recent evidence suggests that enhanced beta oscillations may play a central role in the pathophysiology of the disorder and that beta activity may be directly linked to the motor impairment. However, the temporal evolution of exaggerated beta oscillations during the ongoing dopaminergic neurodegeneration and its relation to the motor impairment and histological changes are still unknown. We investigated motor behavioral, in-vivo electrophysiological (subthalamic nucleus, motor cortex) and histological changes (striatum, substantia nigra compacta) 2, 5, 10 and 20-30 days after a 6-hydroxydopamine injection into the medial forebrain bundle in Wistar rats. We found strong correlations between subthalamic beta power and motor impairment. No correlation was found for beta power in the primary motor cortex. Only subthalamic but not cortical beta power was strongly correlated with the histological markers of the dopaminergic neurodegeneration. Significantly increased subthalamic beta oscillations could be detected before this increase was found in primary motor cortex. At the latest observation time point, a significantly higher percentage of long beta bursts was found. Our study is the first to show a strong relation between subthalamic beta power and the dopaminergic neurodegeneration. Thus, we provide additional evidence for an important pathophysiological role of subthalamic beta oscillations and prolonged beta bursts in Parkinson's disease.

High-affinity binding and catalytic activity of His/Tyr-based sequences: Extending heme-regulatory motifs beyond CP.

BACKGROUND & MOTIVATION: Peptides and proteins can interact with heme through His, Tyr, or Cys in heme-regulatory motifs (HRMs). The Cys-Pro dipeptide is a well investigated HRM, but for His and Tyr such a distinct motif is currently unknown. In addition, many heme-peptide complexes, such as heme-amyloid ß, can display a peroxidase-like activity, albeit there is little understanding of how the local primary and secondary coordination environment influences catalytic activity. We thus systematically evaluated a series of His- and Tyr-based peptides to identify sequence features for high-affinity heme binding and their impact on the catalytic activity of heme. METHODS: We employed solid-phase peptide synthesis to produce 58 nonapeptides, which were investigated by UV/vis, resonance Raman, and 2D NMR spectroscopy. A chromogenic assay was used to determine the catalytic activity of the heme-peptide complexes. RESULTS: Heme-binding affinity and binding mode were found to be dependent on the coordinating amino acid and spacer length between multiple potential coordination sites in a motif. In particular, HXH and HXXXH motifs showed strong heme binding. Analysis of the peroxidase-like activity revealed that some of these peptides and also HXXXY motifs enhance the catalytic activity of heme significantly. CONCLUSIONS: We identify HXH, HXXXH, and HXXXY as potential new HRMs with functional properties. Several peptides displayed a strikingly high peroxidase-like activity. GENERAL SIGNIFICANCE: The identification of HRMs allows to discover yet unknown heme-regulated proteins, and consequently, enhances our current understanding of pathologies involving labile heme.

VEGF-A165b levels are reduced in breast cancer patients at primary diagnosis but increase after completion of cancer treatment.

The antiangiogenic splice variant VEGF-A165b is downregulated in a variety of cancer entities, but little is known so far about circulating plasma levels. The present analysis addresses this question and examines circulating VEGF-A/VEGF-A165b levels in a collective of female high-risk breast cancer patients over the course of treatment. Within the SUCCES-A trial 205 patients were recruited after having received primary breast surgery. Using ELISA VEGF-A/VEGF-A165b concentrations were determined and correlated to clinical characteristics (1) before adjuvant chemotherapy, (2) four weeks and (3) two years after therapy and compared to healthy controls (n = 107). VEGF165b levels were significantly elevated after completion of chemotherapy. Within the breast cancer cohort, VEGF-A165b levels increased two years after completion of chemotherapy. VEGF-A plasma concentrations were significantly elevated in the breast cancer cohort at all examined time points and decreased after treatment. VEGF-A levels two years after chemotherapy correlated with increased cancer related mortality, no such correlation could be found between VEGF-A165b and the examined clinical characteristics. Compared to controls, VEGF-A/VEGF-A165b ratios were decreased in patients before and after chemotherapy. Our data suggests that circulating VEGF-A165b is significantly reduced in women with primary breast cancer at time of diagnosis; furthermore, levels change during adjuvant treatment.

Differential effects of levodopa and apomorphine on neuronal population oscillations in the cortico-basal ganglia loop circuit in vivo in experimental parkinsonism.

The current pharmacotherapy of Parkinson's disease (PD) is primarily based on two classes of drugs: dopamine precursors, namely levodopa, and dopamine receptor agonists, such as apomorphine. Although both types of agents exert their beneficial clinical effects on motor and non-motor symptoms in PD via dopamine receptors, clinical efficiency and side effects differ substantially between levodopa and apomorphine. Levodopa can provide a greater symptomatic relief than dopamine receptor agonists. However, because long-term levodopa use is associated with early debilitating motor fluctuations, dopamine receptor agonists are often recommended in younger patients. The pharmacodynamic basis of these profound differences is incompletely understood. It has been hypothesized that levodopa and dopamine receptor agonists may have diverging effects on beta and gamma oscillations that have been shown to be of importance for the pathophysiology of PD. Here, we used electrophysiological recordings in anesthetized dopamine-intact and dopamine-depleted rats to systemically compare the impact of levodopa or apomorphine on neuronal population oscillations in three nodes of the cortico-basal ganglia loop circuit. Our results showed that levodopa had a higher potency than apomorphine to suppress the abnormal beta oscillations often associated with bradykinesia while simultaneously enhancing the gamma oscillations often associated with increased movement. Our data suggests that the higher clinical efficacy of levodopa as well as some of its side effects, as e.g. dyskinesias may be based on its characteristic ability to modulate beta-/gamma-oscillation dynamics in the cortico-basal ganglia loop circuit.

Acute In Vivo Electrophysiological Recordings of Local Field Potentials and Multi-unit Activity from the Hyperdirect Pathway in Anesthetized Rats.

Converging evidence shows that many neuropsychiatric diseases should be understood as disorders of large-scale neuronal networks. To better understand the pathophysiological basis of these diseases, it is necessary to precisely characterize in which way the processing of information is disturbed between the different neuronal parts of the circuit. Using extracellular in vivo electrophysiological recordings, it is possible to accurately delineate neuronal activity within a neuronal network. The application of this method has several advantages over alternative techniques, e.g., functional magnetic resonance imaging and calcium imaging, as it allows a unique temporal and spatial resolution and does not rely on genetically engineered organisms. However, the use of extracellular in vivo recordings is limited since it is an invasive technique that cannot be universally applied. In this article, a simple and easy to use method is presented with which it is possible to simultaneously record extracellular potentials such as local field potentials and multiunit activity at multiple sites of a network. It is detailed how a precise targeting of subcortical nuclei can be achieved using a combination of stereotactic surgery and online analysis of multi-unit recordings. Thus, it is demonstrated, how a complete network such as the hyperdirect cortico-basal ganglia loop can be studied in anesthetized animals in vivo.

Short- and long-term dopamine depletion causes enhanced beta oscillations in the cortico-basal ganglia loop of parkinsonian rats.

Abnormally enhanced beta oscillations have been found in deep brain recordings from human Parkinson's disease (PD) patients and in animal models of PD. Recent correlative evidence suggests that beta oscillations are related to disease-specific symptoms such as akinesia and rigidity. However, this hypothesis has also been repeatedly questioned by studies showing no changes in beta power in animal models using an acute pharmacologic dopamine blockade. To further investigate the temporal dynamics of exaggerated beta synchrony in PD, we investigated the reserpine model, which is characterized by an acute and stable disruption of dopamine transmission, and compared it to the chronic progressive 6-hydroxydopamine (6-OHDA) model. Using simultaneous electrophysiological recordings in urethane anesthetized rats from the primary motor cortex, the subthalamic nucleus and the reticulate part of the substantia, we found evidence for enhanced beta oscillations in the basal ganglia of both animal models during the activated network state. In contrast to 6-OHDA, reserpine treated animals showed no involvement of primary motor cortex. Notably, beta coherence levels between primary motor cortex and basal ganglia nuclei were elevated in both models. Although both models exhibited elevated beta power and coherence levels, they differed substantially in respect to their mean peak frequency: while the 6-OHDA peak was located in the low beta range (17Hz), the reserpine peak was centered at higher beta frequencies (27Hz). Our results further support the hypothesis of an important pathophysiological relation between enhanced beta activity and akinesia in parkinsonism.

Sobre o artigo de Beck: "a última fase da fenomenologia de Husserl"

Beck delimita uma acusação forçada. Se todas essas acusações pudessem ser comprovadas, o objetivo de Husserl seria inalcançável, suas problematizações fundamentais seriam falsas, seus métodos incongruentes, suas principais teorias seriam falsas e a sua própria coempreensão uma autoilusão. Para evidências detalhadas e presumidamente comprobatórias, nos referimos às publicações prévias de Beck, as quais não tive como consultar. Por si só, este artigo aborda a oposição de Beck frente a inúmeras teorias que, em sua opinião, foram mantidas por Edmund Husserl. A propósito, algumas delas foram contestadas por Husserl. De fato, muitas afirmações feitas por Beck, acreditando que estaria contradizendo Husserl são, na verdade, afirmações sobre seu ponto de vista. Já outras teorias contestadas são do próprio Husserl, mas nada do que consta neste artigo deve suscitar dúvidas quanto a sua validação. As outras teorias contestadas são realmente de Husserl, mas nada no presente artigo deve pôr em causa a sua validade.