Dissecting embryonic and extraembryonic lineage crosstalk with stem cell co-culture.

Embryogenesis necessitates harmonious coordination between embryonic and extraembryonic tissues. Although stem cells of both embryonic and extraembryonic origins have been generated, they are grown in different culture conditions. In this study, utilizing a unified culture condition that activates the FGF, TGF-ß, and WNT pathways, we have successfully derived embryonic stem cells (FTW-ESCs), extraembryonic endoderm stem cells (FTW-XENs), and trophoblast stem cells (FTW-TSCs) from the three foundational tissues of mouse and cynomolgus monkey (Macaca fascicularis) blastocysts. This approach facilitates the co-culture of embryonic and extraembryonic stem cells, revealing a growth inhibition effect exerted by extraembryonic endoderm cells on pluripotent cells, partially through extracellular matrix signaling. Additionally, our cross-species analysis identified both shared and unique transcription factors and pathways regulating FTW-XENs. The embryonic and extraembryonic stem cell co-culture strategy offers promising avenues for developing more faithful embryo models and devising more developmentally pertinent differentiation protocols.

Primate gastrulation and early organogenesis at single-cell resolution.

Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, nonhuman primates are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we collected six Carnegie stage 8-11 cynomolgus monkey (Macaca fascicularis) embryos and performed in-depth transcriptomic analyses of 56,636 single cells. Our analyses show transcriptomic features of major perigastrulation cell types, which help shed light on morphogenetic events including primitive streak development, somitogenesis, gut tube formation, neural tube patterning and neural crest differentiation in primates. In addition, comparative analyses with mouse embryos and human embryoids uncovered conserved and divergent features of perigastrulation development across species-for example, species-specific dependency on Hippo signalling during presomitic mesoderm differentiation-and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the nonhuman primate research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.

Blastocyst-like structures generated from human pluripotent stem cells.

Limited access to embryos has hampered the study of human embryogenesis and disorders that occur during early pregnancy. Human pluripotent stem cells provide an alternative means to study human development in a dish1-7. Recent advances in partial embryo models derived from human pluripotent stem cells have enabled human development to be examined at early post-implantation stages8-14. However, models of the pre-implantation human blastocyst are lacking. Starting from naive human pluripotent stem cells, here we developed an effective three-dimensional culture strategy with successive lineage differentiation and self-organization to generate blastocyst-like structures in vitro. These structures-which we term 'human blastoids'-resemble human blastocysts in terms of their morphology, size, cell number, and composition and allocation of different cell lineages. Single-cell RNA-sequencing analyses also reveal the transcriptomic similarity of blastoids to blastocysts. Human blastoids are amenable to embryonic and extra-embryonic stem cell derivation and can further develop into peri-implantation embryo-like structures in vitro. Using chemical perturbations, we show that specific isozymes of protein kinase C have a critical function in the formation of the blastoid cavity. Human blastoids provide a readily accessible, scalable, versatile and perturbable alternative to blastocysts for studying early human development, understanding early pregnancy loss and gaining insights into early developmental defects.

[Structured ABEV Exercises for the Treatment of vestibular dysfunction]. / Strukturierte ABEV-Übungen zur Behandlung vestibulärer Funktionsstörungen.

INTRODUCTION: In addition to medication, the standard clinical treatment for vestibular vertigo primarily includes physical therapy in the form of regular exercises. Vertidisan is a future digital health application (DiGA) for structured dizziness therapy. Its content is multimodal and consists of Adaptive Balance and Eye Movements and Visual Stimulation (ABEV) exercises, which are expected to have an anti-vertigo effect through neural learning. METHODS: A cohort study with 104 patients with intra-individual control was conducted to examine the clinical efficacy of solely 16 ABEV exercises for the treatment of peripheral vestibulopathies which are also used digitally in the future DiGA Vertidisan. Using the short version vertigo symptom scale short form1 vertigo and related symptoms (VSS-sf1-VER) of the vertigo-specific and validated VSS rating scale (Vertigo Symptom Scale) as the primary outcome variable, the vertigo scores before therapy (time T0) were compared with the corresponding data at the end of a period of 12-16 weeks (time T1). RESULTS: Complete datasets on T0 and T1 were available for N=104 patients. The mean VSS-sf1-V score decreased from 3.80 (median 4, SD 0.47) to 0.92 (median 1, SD 1.19) from T0 to T1 (weeks 12-16). The result is statistically significant (p=0.001) and shows a high clinical effect size. CONCLUSION: In summary, the analysis of the dizziness score shows a statistically and clinically significant reduction in dizziness through the use of the 16 ABEV exercises.

The Geriatrics at Risk Score (GeRi-Score) for mortality prediction in geriatric patients with proximal femur fracture - a development and validation study from the Registry for Geriatric Trauma (ATR-DGU).

This study developed an easy-to-use mortality prediction tool, which showed an acceptable discrimination and no significant lack of fit. The GeRi-Score was able to predict mortality and could distinguish between mild, moderate and high risk groups. Therefore, the GeRi-Score might have the potential to distribute the intensity of medical care. PURPOSE: Several mortality-predicting tools for hip fracture patients are available, but all consist of a high number of variables, require a time-consuming evaluation and/or are difficult to calculate. The aim of this study was to develop and validate an easy-to-use score, which depends mostly on routine data. METHODS: Patients from the Registry for Geriatric Trauma were divided into a development and a validation group. Logistic regression models were used to build a model for in-house mortality and to obtain a score. Candidate models were compared using Akaike information criteria (AIC) and likelihood ratio tests. The quality of the model was tested using the area under the curve (AUC) and the Hosmer-Lemeshow test. RESULTS: 38,570 patients were included, almost equal distributed to the development and to the validation dataset. The AUC was 0.727 (95% CI 0.711 - 0.742) for the final model, AIC resulted in a significant reduction in deviance compared to the basic model, and the Hosmer-Lemeshow test showed no significant lack of fit (p = 0.07). The GeRi-Score predicted an in-house mortality of 5.3% vs. 5.3% observed mortality in the development dataset and 5.4% vs. 5.7% in the validation dataset. The GeRi-Score was able to distinguish between mild, moderate and high risk groups. CONCLUSIONS: The GeRi-Score is an easy-to-use mortality-predicting tool with an acceptable discrimination and no significant lack of fit. The GeRi-Score might have the potential to distribute the intensity of perioperative medical care in hip fracture surgery and can be used in quality management programs as benchmark tool.

Correction: The Effect of an App-Based Home Exercise Program on Self-reported Pain Intensity in Unspecific and Degenerative Back Pain: Pragmatic Open-label Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/41899.].

Association of GPS-Based Logging and Manual Confirmation of the First Responders' Arrival Time in a Smartphone Alerting System: An Observational Study.

The latest guidelines for cardiopulmonary resuscitation recommend that in case of suspected cardiac arrest first responders, who are close to the emergency location, should be notified by a smartphone app or text message. Smartphone Alerting Systems (SAS) aim to reduce the resuscitation-free interval. Thus, there is a need for uniform reporting of process times. Objective: To compare the response times in a SAS either by using global positioning system (GPS) data or by manual confirmation of first responders arriving at the scene. Methods: In the region of Freiburg (Southern Germany, 1,531 km2, 493,000 inhabitants), a SAS is activated when the emergency dispatch center receives a call regarding suspected cardiac arrest. First responders who accept a mission are tracked using GPS. GPS-based times are logged for each responder when their position is within a radius of 100, 50, or 10 meters around the geographical position of the reported emergency. When arriving at the patient location, the first responders manually confirm "arrived" via their app. GPS-based and manually confirmed response arrival times were compared for all cases between 1 October and 31 March. Results: 192 missions with correct manual logging of the arrival time were included. GPS-based times were available in 175 (91%), 100 (52%), and 30 (16%) cases within radii of 100, 50, and 10 meters, respectively. GPS arrival times were approximately 1.5 minutes shorter when using a 100-meter radius and significantly longer when using a 10-meter radius. No difference was found for a 50-meter radius, but this would result in a lack of data in nearly half of the cases. Conclusion: GPS-based logging of arrival times leads to missing data. A 100-meter circle is associated with a low number of missing values, but 1.5 minutes must be added for the last 100 meters the first responder has to move. A wide range of the difference in response times (GPS vs. manual confirmation) must be regarded as a disadvantage. Manual confirmation reveals precise response times, but first responders may forget to confirm when they arrive. Trial registration: DRKS00016625 (14 April 2019).

The Effect of an App-Based Home Exercise Program on Self-reported Pain Intensity in Unspecific and Degenerative Back Pain: Pragmatic Open-label Randomized Controlled Trial.

BACKGROUND: The recommended first-line treatment for unspecific and degenerative back pain consists of movement exercises and patient education. OBJECTIVE: Using a pragmatic, randomized controlled trial, we evaluated the effectiveness of a digital home exercise program on self-reported pain intensity compared with the standard of care for physiotherapy. METHODS: Participant recruitment was based on newspaper advertisements and a consecutive on-site assessment for eligibility and enrollment. Participants with unspecific and degenerative back pain aged ≥18 years were randomly assigned in a 1:1 ratio to receive a 12-week stand-alone digital home exercise program or physiotherapy. The digital home exercise program included 4 exercises daily, while physiotherapy included 6 to 12 sessions, depending on the severity of symptoms. The primary outcome was pain, which was assessed using a verbal numerical rating scale. The clinical relevance of pain reduction was assessed using the following thresholds: improvement of at least 1.4 points on the verbal numerical rating scale and a pain reduction of at least 30%. RESULTS: During the study period, 108 participants were assigned to the intervention group and 105 participants to the control group. The mean difference in pain scores between the 2 groups at 12 weeks was -2.44 (95% CI -2.92 to -1.95; P<.01) in favor of the intervention group. The group receiving the digital therapeutic achieved a clinically relevant reduction in pain over the course of the study (baseline vs 12 weeks), with a mean change of -3.35 (SD 2.05) score points or -53.1% (SD 29.5). By contrast, this change did not reach clinical relevance in the control group (mean -0.91, SD 1.5; -14.6%, SD 25.3). Retention rates of 89.9% in the intervention group and 97.3% in the control group were maintained throughout the study. CONCLUSIONS: The use of the app-based home exercise program led to a significant and clinically relevant reduction in pain intensity throughout the 12-week duration of the program. The intervention studied showed superior improvement in self-reported pain intensity when compared with the standard of care. Given the great demand for standard physiotherapy for unspecific and degenerative back pain, digital therapeutics are evolving into a suitable therapeutic option that can overcome the limitations of access and availability of conventional modes of health care delivery into this spectrum of indications. However, further independent evaluations are required to support the growing body of evidence on the effectiveness of digital therapeutics in real-world care settings. TRIAL REGISTRATION: German Clinical Trials Register DRKS00022781; https://tinyurl.com/hpdraa89.

Observational study on implications of the COVID-19-pandemic for cardiopulmonary resuscitation in out-of-hospital cardiac arrest: qualitative and quantitative insights from a model region in Germany.

BACKGROUND: The city of Freiburg has been among the most affected regions by the COVID-19 pandemic in Germany. In out of hospital cardiac arrest (OHCA) care, all parts of the rescue system were exposed to profound infrastructural changes. We aimed to provide a comprehensive overview of these changes in the resuscitation landscape in the Freiburg region. METHODS: Utstein-style quantitative data on OHCA with CPR initiated, occurring in the first pandemic wave between February 27th, 2020 and April 30th, 2020 were compared to the same time periods between 2016 and 2019. Additionally, qualitative changes in the entire rescue system were analyzed and described. RESULTS: Incidence of OHCA with attempted CPR did not significantly increase during the pandemic period (11.1/100.000 inhabitants/63 days vs 10.4/100.000 inhabitants/63 days, p = 1.000). In witnessed cases, bystander-CPR decreased significantly from 57.7% (30/52) to 25% (4/16) (p = 0.043). A severe pre-existing condition (PEC) was documented more often, 66.7% (16/24) vs 38.2% (39/102) there were longer emergency medical services (EMS) response times, more resuscitation attempts terminated on scene, 62.5% (15/24) vs. 34.3% (35/102) and less patients transported to hospital (p = 0.019). Public basic life support courses, an app-based first-responder alarm system, Kids Save Lives activities and a prehospital extracorporeal CPR (eCPR) service were paused during the peak of the pandemic. CONCLUSION: In our region, bystander CPR in witnessed OHCA cases as well as the number of patients transported to hospital significantly decreased during the first pandemic wave. Several important parts of the resuscitation landscape were paused. The COVID-19 pandemic impedes OHCA care, which leads to additional casualties. Countermeasures should be taken.

KRAS/GNAS-testing by highly sensitive deep targeted next generation sequencing improves the endoscopic ultrasound-guided workup of suspected mucinous neoplasms of the pancreas.

Pancreatic cysts or dilated pancreatic ducts are often found by cross-sectional imaging, but only mucinous lesions can become malignant. Therefore, distinction between mucinous and non-mucinous lesions is crucial for adequate patient management. We performed a prospective study including targeted next generation sequencing (NGS) of cell-free DNA in the diagnostic endoscopic ultrasound (EUS)-guided workup. Pancreatic cyst(s) or main duct fluid obtained by EUS-guided FNA was analysed by carcinoembryonic antigen (CEA), cytology and deep targeted NGS of 14 known gastrointestinal cancer genes (AKT1, BRAF, CTNNB1, EGFR, ERBB2, FBXW7, GNAS, KRAS, MAP2K1, NRAS, PIK3CA, SMAD4, TP53, APC) with a limit of detection down to variant allele frequency of 0.01%. Results were correlated to histopathology and clinical follow-up. One hundred and thirteen patients with pancreatic cyst(s) and/or a dilated pancreatic main duct (≥5 mm) were screened. Sixty-six patients had to be excluded, mainly due to inoperability or small cyst size (≤10 mm). Forty-seven patients were enrolled for further analysis. A final diagnosis was available in 27 cases including 8 negative controls. In 43/47 (91.5%) of patients a KRAS- and/or GNAS-mutation was diagnosed by NGS. 27.0% of the KRAS-mutated and 10.0% of the GNAS-mutated lesions harbored multiple mutations. KRAS/GNAS-testing by NGS, cytology, and CEA had a sensitivity and specificity of 94.7/100%, 38.1/100%, and 42.1/75.0%, respectively. KRAS/GNAS-testing was significantly superior to CEA (P = .0209) and cytology (P = .0016). In conclusion, KRAS/GNAS-testing by deep targeted NGS is a suitable method to distinguish mucinous from non-mucinous pancreatic lesions, suggesting its usage as a single diagnostic test. Results must be confirmed in a larger cohort.

Next generation sequencing of the cellular and liquid fraction of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts and reveals cases with multiple mutated driver clones: First findings from the prospective ZYSTEUS biomarker study.

Approximately half of all pancreatic cysts are neoplastic, mainly comprising intraductal papillary mucinous neoplasms (IPMN), which can progress to invasive carcinoma. Current Fukuoka guidelines have limited sensitivity and specificity in predicting progression of asymptomatic pancreatic cysts. We present first results of the prospective ZYSTEUS biomarker study investigating (i) whether detection of driver mutations in IPMN by liquid biopsy is technically feasible, (ii) which compartment of IPMN is most suitable for analysis, and (iii) implications for clinical diagnostics. Twenty-two patients with clinical inclusion criteria were enrolled in ZYSTEUS. Fifteen cases underwent endoscopic ultrasound (EUS)-guided fine-needle aspiration and cytological diagnostics. Cellular and liquid fraction of the cysts of each case were separated and subjected to deep targeted next generation sequencing (NGS). Clinical parameters, imaging findings (EUS and MRI), and follow-up data were collected continuously. All IPMN cases (n = 12) showed at least one mutation in either KRAS (n = 11) or GNAS (n = 4). Three cases showed both KRAS and GNAS mutations. Six cases harbored multiple KRAS/GNAS mutations. In the three cases with pseudocysts, no KRAS or GNAS mutations were detected. DNA yields were higher and showed higher mutation diversity in the cellular fraction. In conclusion, mutation detection in pancreatic cyst fluid is technically feasible with more robust results in the cellular than in the liquid fraction. Current results suggest that, together with imaging, targeted sequencing supports discrimination of IPMN from pseudocysts. The prospective design of ZYSTEUS will provide insight into diagnostic value of NGS in preoperative risk stratification. Our data provide evidence for an oligoclonal nature of IPMN.

Patient radiation dose in percutaneous biliary interventions: recommendations for DRLs on the basis of a multicentre study.

OBJECTIVE: Percutaneous biliary interventions (PBIs) can be associated with a high patient radiation dose, which can be reduced when national diagnostic reference levels (DRLs) are kept in mind. The aim of this multicentre study was to investigate patient radiation exposure in different percutaneous biliary interventions, in order to recommend national DRLs. METHODS: A questionnaire asking for the dose area product (DAP) and the fluoroscopy time (FT) in different PBIs with ultrasound- or fluoroscopy-guided bile duct punctures was sent to 200 advanced care hospitals. Recommended national DRLs are set at the 75th percentile of all DAPs. RESULTS: Twenty-three facilities (9 interventional radiology depts. and 14 gastroenterology depts.) returned the questionnaire (12%). Five hundred sixty-five PBIs with 19 different interventions were included in the analysis. DAPs (range 4-21,510 cGy·cm2) and FTs (range 0.07-180.33 min) varied substantially depending on the centre and type of PBI. The DAPs of initial PBIs were significantly (p < 0.0001) higher (median 2162 cGy·cm2) than those of follow-up PBIs (median 464 cGy·cm2). There was no significant difference between initial PBIs with ultrasound-guided bile duct puncture (2162 cGy·cm2) and initial PBIs with fluoroscopy-guided bile duct puncture (2132 cGy·cm2) (p = 0.85). FT varied substantially (0.07-180.33 min). CONCLUSIONS: DAPs and FTs in percutaneous biliary interventions showed substantial variations depending on the centre and the type of PBI. PBI with US-guided bile duct puncture did not reduce DAP, when compared to PBI with fluoroscopy-guided bile duct puncture. National DRLs of 4300 cGy·cm2 for initial PBIs and 1400 cGy·cm2 for follow-up PBIs are recommended. KEY POINTS: • DAPs and FTs in percutaneous biliary interventions showed substantial variations depending on the centre and the type of PBI. • PBI with US-guided bile duct puncture did not reduce DAP when compared to PBI with fluoroscopy-guided bile duct puncture. • DRLs of 4300 cGy·cm2for initial PBIs (establishing a transhepatic tract) and 1400 cGy·cm2for follow-up PBIs (transhepatic tract already established) are recommended.

Comparison of Metal Artifact Reduction in Dual- and Single-Source CT: A Vertebral Phantom Study.

OBJECTIVE: The objective of this study was to compare the capability of two algorithms for metal artifact reduction and virtual monoenergetic imaging (VME), a metal artifact reduction application for dual-source CT. MATERIALS AND METHODS: A bovine vertebra phantom with 16 artificial osteolyses and two 20 × 4.5 mm stainless steel screws was scanned on two single-source CT scanner and one dual-source CT scanner at a dose identical to the single-source acquisitions. Datasets were reconstructed with a metal artifact reduction algorithm for orthopedic implants (O-MAR, Philips Healthcare), an iterative metal artifact reduction algorithm (iMAR, Siemens Healthineers), and VME. Blinded to the method used for artifact reduction, three independent observers evaluated datasets regarding the extent of metal artifacts using a 4-point scale. Depicted osteolyses were counted and screw diameters measured for each reconstruction. Interobserver variability was evaluated using the Kendall coefficient of concordance for ordinal variables and the intraclass correlation coefficient for continuous data. RESULTS: VME showed the best metal artifact reduction capability among evaluated methods; overall artifacts were rated 1.08 ± 0.29 for VME, 3.33 ± 0.65 for iMAR, and 3.91 ± 0.29 for O-MAR (p < 0.01). VME resulted in better representation of the cortical bone, trabecular structure, and soft tissue compared with the other two algorithms. VME provided the most realistic reconstruction of screw diameter. However, VME missed osteolyses. Good to almost perfect agreement was achieved for nearly all evaluated attributes. CONCLUSION: In our vertebral phantom, VME led to the most detailed representation of the osteosynthesis screw, caused the lowest amount of artifact, and represented the adjacent tissue best. Thus, VME should be considered as an alternative method to evaluate implants when other algorithms fail.

Gender-specific differences in therapy and laboratory parameters and validation of mortality predictors in severely injured patients--results of a German level 1 trauma center.

PURPOSE: Gender-specific differences in trauma patients have been reported in several studies. There is a lack of knowledge about differences in therapy and laboratory parameters. The objective of this study is to analyze differences between genders, confirming the therapy and laboratory parameters. Additionally, predictors for mortality were validated. METHODS: Patients on primary admission to the hospital between 2002 and 2012 with an Injury Severity Score (ISS) ≥ 16 were included. 1073 patients met the inclusion criteria. Comparisons and matched-pair analyses between deceased and survived females, males, and between deceased females and males were conducted. RESULTS: The analyzed laboratory parameters differed between genders, especially the base excess, lactate, and coagulation parameters. In particular, females presented values that were normal or only slightly pathological. The prothrombin ratio was 75.3% in female and 63.2% in male (p = 0.027) and lactate 2.5 mmol/l in female and 3.8 mmol/l in male (p = 0.049). No differences between genders could be found in the initial treatment of severely injured patients. Only the infused volume differed between genders with 1178.2 ml in male and 793.6 ml in female (p = 0.02). The known predictors for mortality, lactate, and prothrombin ratio could not be validated in female trauma patients. CONCLUSIONS: No gender differences, except the infused volume, in the treatment of severely injured patients could be found. Differences in laboratory tests, especially base excess, lactate, and coagulation parameters were found. As these parameters are also used as predictors of mortality in trauma patients, gender-specific cut-offs of these laboratory tests might be necessary to avoid underestimating injured women.

Quantification of myo-inositol, 1,5-anhydro- D-sorbitol, and D-chiro-inositol using high-performance liquid chromatography with electrochemical detection in very small volume clinical samples.

Inositol is a six-carbon sugar alcohol and is one of nine biologically significant isomers of hexahydroxycyclohexane. Myo-inositol is the primary biologically active form and is present in higher concentrations in the fetus and newborn than in adults. It is currently being examined for the prevention of retinopathy of prematurity in newborn preterm infants. A robust method for quantifying myo-inositol (MI), D-chiro-inositol (DCI) and 1,5-anhydro- D-sorbitol (ADS) in very small-volume (25 µL) urine, blood serum and/or plasma samples was developed. Using a multiple-column, multiple mobile phase liquid chromatographic system with electrochemical detection, the method was validated with respect to (a) selectivity, (b) accuracy/recovery, (c) precision/reproducibility, (d) sensitivity, (e) stability and (f) ruggedness. The standard curve was linear and ranged from 0.5 to 30 mg/L for each of the three analytes. Above-mentioned performance measures were within acceptable limits described in the Food and Drug Administration's Guidance for Industry: Bioanalytical Method Validation. The method was validated using blood serum and plasma collected using four common anticoagulants, and also by quantifying the accuracy and sensitivity of MI measured in simulated urine samples recovered from preterm infant diaper systems. The method performs satisfactorily measuring the three most common inositol isomers on 25 µL clinical samples of serum, plasma, milk, and/or urine. Similar performance is seen testing larger volume samples of infant formulas and infant formula ingredients. MI, ADS and DCI may be accurately tested in urine samples collected from five different preterm infant diapers if the urine volume is greater than 2-5 mL.

An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. Highlights: AIRIM variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.

Gender-specific differences in severely injured patients between 2002 and 2011: data analysis with matched-pair analysis.

INTRODUCTION: Previous studies reported divergent results concerning the effect of gender on patient outcome after severe injury. Results suggest that women have better outcomes because they have lower rates of sepsis and multi-organ failure. The objective of this analysis was to study gender differences in a Level 1 trauma center in Germany. METHODS: Patients who were admitted to hospital between 2002 and 2011 with an Injury Severity Score (ISS) ≥16 were included. Data were collected from the Trauma Registry of the German Society for Trauma Surgery and from hospital records. The effects of gender on a variety of parameters were investigated. To eliminate the influence of differences in ISS, an analysis of groups with similar ISS was performed. Also, a matched-pair analysis of 422 patients was performed. RESULTS: A total of 962 patients met the inclusion criteria. The mortality rate was lower in male patients (25.4% versus 36.59%). Female patients had more severe head injuries, received less fluid volume and had a lower rate of sepsis. Men were more frequently involved in motorcycle accidents and sustained more penetrating trauma. Women were more frequently involved in pedestrian accidents and sustained more falls from under 3 m. The effects of gender were reduced when the data were analyzed by matching ISS. The mortality rate was significantly different in the ISS 26 to 35 group but in mostly all groups, the mortality rate was higher in women. In the matched-pair analysis, the rate of sepsis and the length of the ICU stay were significantly lower in women and the mortality rate showed no significant difference (28.1% for male patients versus 33.01% for female patients). Women died after an average of 5.22 days, and men died after an average of 9.02 days. CONCLUSIONS: Gender-based differences in patient outcome after severe trauma were observed in this study. Women are more likely to die in the first days after trauma. Upon extended hospital stay, women had a better survival rate because they had a lower rate of sepsis. No significant differences in mortality rate could be found, but there was a trend towards a higher rate in female patients.

Bipolar haemostatic forceps versus standard therapy by haemoclip + / - epinephrine injection as initial endoscopic treatment in active non-variceal upper GI bleeding: study protocol for a prospective, randomized multicentre trial (BeBop-Trial).

BACKGROUND: Patients with active nonvariceal upper gastrointestinal bleeding (NVUGIB) usually require urgent endoscopic treatment. Standard therapy (ST) using haemoclip + / - epinephrine injection is not always successful. Bipolar haemostatic forceps (HemoStat/Pentax®) are an approved medical device for the treatment of gastrointestinal bleeding. However, their use as a primary endoscopic treatment for active NVUGIB has not yet been proven in a randomized prospective study. METHODS: This is a prospective, randomized, multicentre superiority trial (n ≥ 5). Patients with active NVUGIB will be randomized (1:1) to ST and to experimental therapy (ET) by application of bipolar haemostatic forceps. In the case of failed initial treatment within 15 min, crossover treatment will be attempted first. Rescue treatment (e.g. via over-the-scope-clip) will then be allowed after 30 min. All patients will also receive standard therapy with proton pump inhibitors. Forty-five patients per treatment arm are required to demonstrate an absolute difference of 25.4% with a power of 80% and a significance level of 0.05. DISCUSSION: The hypothesis of the study is that bipolar haemostatic forceps are superior to ST in terms of successful primary haemostasis and the absence of recurrent bleeding within 30 days (combined endpoint). The 1:1 randomization is also ethically justifiable for this study, as both procedures are approved for the intervention in question. To further increase the safety of the patients in the study, crossover treatment and rescue treatment are planned. The prospective design seems feasible in a reasonable time frame (recruitment period of 12 months), as nonvariceal upper gastrointestinal bleeding is common. Anticoagulants and/or antiplatelet drugs could be an important confounding factor in the statistical analysis that needs to be taken into account and calculated if necessary. In conclusion, this randomized, prospective, multicentre study could make an important contribution to answering the question of whether bipolar haemostatic forceps could be the first-line therapy in the endoscopic treatment of stage Forrest I a + b NVUGIB. TRIAL REGISTRATION: ClinicalTrials.gov NCT05353062. Registered on April 30 2022.