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Purpose: To evaluate the results of a modified technique of creating a defunctioning end ileostomy. Methods: Medical records of all consecutive patients with a defunctioning end ileostomy with buried efferent limb operated at our hospital between January 2000 and December 2007 were reviewed. The defunctioning end ileostomy with buried efferent limb is created by closing the distal limb and positioning it in the subcutis. Parameters studied were: stomal and reversal related complications. Results: 66 patients were included. Between construction and closure of the stoma, a total of 21 patients (31.8%) developed stoma-related complications. In 1 patient (1.5%) high output occurred, in 6 (9%) stomal retraction and in 4 (6.1%) a parastomal hernia occurred. Peristomal skin problems were observed in 14 patients (21.2%) in the early postoperative period, decreasing to 6 patients (9.1%) after 3 weeks. In 1 patient, stoma closure could not be performed through a local approach and formal laparotomy was necessary. Complications of loop ileostomy as reported in the literature show relatively high rates of peristomal skin and leakage problems. Conclusions: Our results suggest that end ileostomy with subcutaneous buried efferent limb offers advantages over loop ileostomy with regard to the risk of developing peristomal skin and leakage problems.

Faculty members in the Department of Electrical Engineering at the U.S. Air Force Academy have been experimenting with methods to evaluate and improve our students’ technical presentation skills without sacrificing excessive class time or subject content. Three specific techniques and the observed results are discussed. 1 Introduction Just as technical writing differs from other forms of writing, presenting technical subjects to an audience requires specialized skills, different from other forms of public speaking. Many engineering curricula require some sort of speech class, typically administered by the English Department, which usually doesn’t address this form of verbal communication. Therefore, this important skill for successful engineers can be lacking in many graduates. The following sections describe three methods to improve and evaluate students’ technical presentations. Each of these methods gives the students an opportunity to formulate a technical presentation and present it to an engineering audience. The first method requires the student to make impromptu presentations of example problems given in class. Students are divided into small groups and asked to work on a particular problem. A representative is chosen from each group to present part of the solution to the problem. This method tests the linkage between quick thinking and verbal skills. The second method requires students to derive and present solutions to selected homework problems. This method allows the student to research a particular problem and develop an informal presentation following a logical problem-solution format. Presentations are evaluated for technical content and clarity. Fellow students provide critiques of each presentation. This method tests both technical presentation skills and the ability to logically organize complex information.

Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13–3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14–3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69–1·21]) and unfractionated heparin (0·81 [0·61–1·08]) led to a non-significant shift towards worse modified Rankin Scale scores. Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Many undergraduate engineering students have difficulty understanding the connections between the different engineering courses they are required to take. Too many of them focus on learning just the details of a specific course without any consideration of how the concepts fit with those of other courses. The integrated approach to teaching engineering involves a “systems view” to the curriculum. In this approach, one or more systems are presented to the students early in their engineering program. Throughout their courses, the students are reminded of where they are in the system. A specific example is discussed of how this approach is being used as a test case with five courses in the electrical engineering curriculum at the United States Air Force Academy. The resulting improvement in student performance is also discussed. The typical undergraduate engineering student sees most of his or her courses as a collection of facts and formulas. Most students focus on memorizing these facts and formulas and how to use them to solve specific problems. The focus of their efforts tends to be the problems presented through examples in assigned readings, homework, and laboratory exercises. They concentrate on learning very specific applications of the concepts and ideas presented in the course. This approach to learning gives the students a very narrow view of the material presented in a particular course. This problem is of particular concern in an environment where the student has a limited amount of time to devote to a particular course. In this case, the student will prioritize the focus of his/her study efforts to concentrate on those areas that seem most likely to appear on an examination. In essence, the students are learning in a vacuum: learning to pass an examination, rather than to understand the broader applications of the material. The motivation to use the integrated approach described in this paper came from a desire on the part of the authors to improve the understanding of students in senior-level electrical engineering courses. At this level, students should have a rudimentary understanding of how the major concepts presented in an undergraduate engineering curriculum “fit” together. For example, they should see that a fundamental understanding of linear systems is a key to understanding the basics of analog communications. 1

Current guidelines for ischaemic stroke treatment recommend a strict, but arbitrary, upper threshold of 185/110 mm Hg for blood pressure before endovascular thrombectomy. Nevertheless, whether admission blood pressure influences the effect of endovascular thrombectomy on outcome remains unknown. Our aim was to study the influence of admission systolic blood pressure (SBP) on functional outcome and on the effect of endovascular thrombectomy. We used individual patient data from seven randomised controlled trials (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, PISTE, and THRACE) that randomly assigned patients with anterior circulation ischaemic stroke to endovascular thrombectomy (predominantly using stent retrievers) or standard medical therapy (control) between June 1, 2010, and April 30, 2015. We included all patients for whom SBP data were available at hospital admission. The primary outcome was functional outcome (modified Rankin Scale) at 90 days. We assessed the association of SBP with outcome in both the endovascular thrombectomy group and the control group using multilevel regression analysis and tested for non-linearity and for interaction between SBP and effect of endovascular thrombectomy, taking into account treatment with intravenous thrombolysis. We included 1753 patients (867 assigned to endovascular thrombectomy, 886 assigned to control) after excluding 11 patients for whom SBP data were missing. We found a non-linear association between SBP and functional outcome with an inflection point at 140 mm Hg (732 [42%] of 1753 patients had SBP <140 mm Hg and 1021 [58%] had SBP ≥140 mm Hg). Among patients with SBP of 140 mm Hg or higher, admission SBP was associated with worse functional outcome (adjusted common odds ratio [acOR] 0·86 per 10 mm Hg SBP increase; 95% CI 0·81–0·91). We found no association between SBP and functional outcome in patients with SBP less than 140 mm Hg (acOR 0·97 per 10 mm Hg SBP decrease, 95% CI 0·88–1·05). There was no significant interaction between SBP and effect of endovascular thrombectomy on functional outcome (p=0·96). In our meta-analysis, high admission SBP was associated with worse functional outcome after stroke, but SBP did not seem to negate the effect of endovascular thrombectomy. This finding suggests that admission SBP should not form the basis for decisions to withhold or delay endovascular thrombectomy for ischaemic stroke, but randomised trials are needed to further investigate this possibility. Medtronic.

Objectives To investigate whether a new magnetic resonance image (MRI) technique called T2*-weighted fluid attenuation inversion recovery (FLAIR*) can differentiate between multiple sclerosis (MS) and vascular brain lesions, at 7 Tesla (T). Methods We examined 16 MS patients and 16 age-matched patients with (risk factors for) vascular disease. 3D-FLAIR and T2*-weighted images were combined into FLAIR* images. Lesion type and intensity, perivascular orientation and presence of a hypointense rim were analysed. Results In total, 433 cerebral lesions were detected in MS patients versus 86 lesions in vascular patients. Lesions in MS patients were significantly more often orientated in a perivascular manner: 74 % vs. 47 % ( P  < 0.001). Ten MS lesions (2.3 %) were surrounded by a hypointense rim on FLAIR*, and 24 MS lesions (5.5 %) were hypointense on T2*. No lesions in vascular patients showed any rim or hypointensity. Specificity of differentiating MS from vascular lesions on 7-T FLAIR* increased when the presence of a central vessel was taken into account (from 63 % to 88 %), most obviously for deep white matter lesions (from 69 % to 94 %). High sensitivity remained (81 %). Conclusion 7-T FLAIR* improves differentiation between MS and vascular lesions based on lesion location, perivascular orientation and presence of hypointense (rims around) lesions. Key Points • A new MRI technique T2*-weighted fluid attenuation inversion recovery (FLAIR*) was investigated. • FLAIR* at 7-T MRI combines FLAIR and T2* images into a single image. • FLAIR* at 7 T does not require enhancement with contrast agents. •High-resolution 7-T FLAIR* improves differentiation between MS and vascular brain lesions. • FLAIR* revealed a central vessel more frequently in MS than vascular lesions.

Jaundice caused by hyperbilirubinaemia is a common phenomenon during the neonatal period. Population-based studies evaluating assessment, management, and incidence of jaundice and need for phototherapy among otherwise healthy neonates are scarce. We prospectively explored these aspects in a primary care setting via assessing care as usual during the control phase of a stepped wedge cluster randomised controlled trial. We conducted a prospective cohort study embedded in the Screening and TreAtment to Reduce Severe Hyperbilirubinaemia in Infants in Primary care (STARSHIP) Trial. Healthy neonates were included in seven primary care birth centres (PCBCs) in the Netherlands between July 2018 and March 2020. Neonates were eligible for inclusion if their gestational age was ≥ 35 weeks, they were admitted in a PCBC for at least  2 days during the first week of life, and if they did not previously receive phototherapy. Outcomes were the findings of visual assessment to detect jaundice, jaundice incidence and management, and the need for phototherapy treatment in the primary care setting. 860 neonates were included of whom 608 (71.9%) were visibly jaundiced at some point during admission in the PCBC, with 20 being ‘very yellow’. Of the latter, four (20%) did not receive total serum bilirubin (TSB) quantification. TSB levels were not associated with the degree of visible jaundice (p = 0.416). Thirty-one neonates (3.6%) received phototherapy and none received an exchange transfusion. Five neonates did not receive phototherapy despite having a TSB level above phototherapy threshold. Jaundice is common in otherwise healthy neonates cared for in primary care. TSB quantification was not always performed in very jaundiced neonates, and not all neonates received phototherapy when indicated. Quality improvement initiatives are required, including alternative approaches to identifying potentially severe hyperbilirubinaemia. Trial registration: NL6997 (Dutch Trial Register; Old NTR ID 7187), registered 3 May 2018.

Aida Bertoli-Avella and colleagues report the identification of SMAD3 mutations in individuals with a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. The mutations cause increased aortic expression of components of the TGF-β signaling pathway. Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2–24.2 and show that the disease is caused by mutations in SMAD3 . This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission 1 , 2 , 3 . SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.

Kidney organoids derived from human induced pluripotent stem cells lack a proper vasculature, hampering their applicability. Transplantation prevents the loss of organoid endothelial cells (ECs) observed in vitro, and promotes vascularization. In this study, we transplanted kidney organoids in chicken embryos and deployed single-cell RNA sequencing of ~12,000 organoid ECs to delineate their molecular landscape and identify key changes associated with transplantation. Transplantation significantly altered EC phenotypic composition. Consistent with angiogenesis, proliferating EC populations expanded 8 days after transplantation. Importantly, ECs underwent a major vein-to-arterial phenotypic shift. One of the transplantation-specific arterial EC populations, characterized by laminar shear stress response and Notch signalling, showed a similar transcriptome as human fetal kidney arterial/afferent arteriolar ECs. Consistently, transplantation-induced transcriptional changes involved proangiogenic and arteriogenic SOX7 transcription factor upregulation and regulon enrichment. These findings point to blood flow and candidate transcription factors such as SOX7 as possible targets to enhance kidney organoid vascularization.

Background Preoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure. Methods We have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with locally advanced, nonmetastatic GISTs who received neoadjuvant imatinib. OS was calculated from start of imatinib therapy for locally advanced disease until death or last follow-up (FU) after resection of the GIST. DFS was calculated from date of resection to date of disease recurrence or last FU. Median FU time was 46 months. Results The primary tumor was located in the stomach (55 %), followed by rectum (20 %), duodenum (10 %), ileum/jejunum/other (11 %), and esophagus (3 %). The tumor resection after preoperative imatinib (median time on therapy, 40 weeks) was R0 in 83 %. Only two patients have demonstrated disease progression during neoadjuvant therapy. Five-year DSS/DFS rates were 95/65 %, respectively, median OS was 104 months, and median DFS was not reached. There were 56 % of patients who continued imatinib after resection. Thirty-seven GIST recurrences were diagnosed (only 5 local relapses). The most common mutations affected exon 11 KIT (65 %). Poorer DFS was related to primary tumor location in small bowel and lack of postoperative therapy with imatinib. Conclusions Our analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.