Persistent Mycobacterium tuberculosis bioaerosol release in a tuberculosis-endemic setting.

Pioneering studies linking symptomatic disease and cough-mediated release of Mycobacterium tuberculosis (Mtb) established the infectious origin of tuberculosis (TB), simultaneously informing the pervasive notion that pathology is a prerequisite for Mtb transmission. Our prior work has challenged this assumption: by sampling TB clinic attendees, we detected equivalent release of Mtb-containing bioaerosols by confirmed TB patients and individuals not receiving a TB diagnosis, and we demonstrated a time-dependent reduction in Mtb bioaerosol positivity during six-months' follow-up, irrespective of anti-TB chemotherapy. Now, by extending bioaerosol sampling to a randomly selected community cohort, we show that Mtb release is common in a TB-endemic setting: of 89 participants, 79.8% (71/89) produced Mtb bioaerosols independently of QuantiFERON-TB Gold status, a standard test for Mtb infection; moreover, during two-months' longitudinal sampling, only 2% (1/50) were serially Mtb bioaerosol negative. These results necessitate a reframing of the prevailing paradigm of Mtb transmission and infection, and may explain the current inability to elucidate Mtb transmission networks in TB-endemic regions.

Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status.

Potential Mycobacterium tuberculosis (Mtb) transmission during different pulmonary tuberculosis (TB) disease states is poorly understood. We quantified viable aerosolized Mtb from TB clinic attendees following diagnosis and through six months' follow-up thereafter. Presumptive TB patients (n=102) were classified by laboratory, radiological, and clinical features into Group A: Sputum-Xpert Ultra-positive TB (n=52), Group B: Sputum-Xpert Ultra-negative TB (n=20), or Group C: TB undiagnosed (n=30). All groups were assessed for Mtb bioaerosol release at baseline, and subsequently at 2 wk, 2 mo, and 6 mo. Groups A and B were notified to the national TB program and received standard anti-TB chemotherapy; Mtb was isolated from 92% and 90% at presentation, 87% and 74% at 2 wk, 54% and 44% at 2 mo and 32% and 20% at 6 mo, respectively. Surprisingly, similar numbers were detected in Group C not initiating TB treatment: 93%, 70%, 48% and 22% at the same timepoints. A temporal association was observed between Mtb bioaerosol release and TB symptoms in all three groups. Persistence of Mtb bioaerosol positivity was observed in ~30% of participants irrespective of TB chemotherapy. Captured Mtb bacilli were predominantly acid-fast stain-negative and poorly culturable; however, three bioaerosol samples yielded sufficient biomass following culture for whole-genome sequencing, revealing two different Mtb lineages. Detection of viable aerosolized Mtb in clinic attendees, independent of TB diagnosis, suggests that unidentified Mtb transmitters might contribute a significant attributable proportion of community exposure. Additional longitudinal studies with sputum culture-positive and -negative control participants are required to investigate this possibility.

Consensus statement on the interhospital transfer of patients with acute aortic syndrome: TRAVERSING Delphi study.

BACKGROUND: Standardisation of referral pathways and the transfer of patients with acute aortic syndromes (AAS) to regional centres are recommended by NHS England in the Acute Aortic Dissection Toolkit. The aim of the Transfer of Thoracic Aortic Vascular Emergencies to Regional Specialist INstitutes Group study was to establish an interdisciplinary consensus on the interhospital transfer of patients with AAS to specialist high-volume aortic centres. METHODS: Consensus on the key aspects of interhospital transfer of patients with AAS was established using the Delphi method, in line with Conducting and Reporting of Delphi Studies guidelines. A national patient charity for aortic dissection was involved in the design of the Delphi study. Vascular and cardiothoracic surgeons, emergency physicians, interventional radiologists, cardiologists, intensivists and anaesthetists in the United Kingdom were invited to participate via their respective professional societies. RESULTS: Three consecutive rounds of an electronic Delphi survey were completed by 212, 101 and 58 respondents, respectively. Using predefined consensus criteria, 60 out of 117 (51%) statements from the survey were included in the consensus statement. The study concluded that patients can be taken directly to a specialist aortic centre if they have typical symptoms of AAS on the background of known aortic disease or previous aortic intervention. Accepted patients should be transferred in a category 2 ambulance (response time <18 min), ideally accompanied by transfer-trained personnel or Adult Critical Care Transfer Services. A clear plan should be agreed in case of a cardiac arrest occurring during the transfer. Patients should reach the aortic centre within 4 hours of the initial referral from their local hospital. CONCLUSIONS: This consensus statement is the first set of national interdisciplinary recommendations on the interhospital transfer of patients with AAS. Its implementation is likely to contribute to safer and more standardised emergency referral pathways to regional high-volume specialist aortic units.

National action plans for antimicrobial resistance and variations in surveillance data platforms.

Objective: To assess how national antimicrobial susceptibility data used to inform national action plans vary across surveillance platforms. Methods: We identified available open-access, supranational, interactive surveillance platforms and cross-checked their data in accordance with the World Health Organization's (WHO's) Data Quality Assurance: module 1. We compared platform usability and completeness of time-matched data on the antimicrobial susceptibilities of four blood isolate species: Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae from WHO's Global Antimicrobial Resistance and Use Surveillance System, European Centre for Disease Control's (ECDC's) network and Pfizer's Antimicrobial Testing Leadership and Surveillance database. Using Bland-Altman analysis, paired t-tests, and Wilcoxon signed-rank tests, we assessed susceptibility data and number of isolate concordances between platforms. Findings: Of 71 countries actively submitting data to WHO, 28 also submit to Pfizer's database; 19 to ECDC; and 16 to all three platforms. Limits of agreement between WHO's and Pfizer's platforms for organism-country susceptibility data ranged from -26% to 35%. While mean susceptibilities of WHO's and ECDC's platforms did not differ (bias: 0%, 95% confidence interval: -2 to 2), concordance between organism-country susceptibility was low (limits of agreement -18% to 18%). Significant differences exist in isolate numbers reported between WHO-Pfizer (mean of difference: 674, P-value: < 0.001, and WHO-ECDC (mean of difference: 192, P-value: 0.04) platforms. Conclusion: The considerable heterogeneity of nationally submitted data to commonly used antimicrobial resistance surveillance platforms compromises their validity, thus undermining local and global antimicrobial resistance strategies. Hence, we need to understand and address surveillance platform variability and its underlying mechanisms.

Female naïve human pluripotent stem cells carry X chromosomes with Xa-like and Xi-like folding conformations.

Three-dimensional (3D) genomics shows immense promise for studying X chromosome inactivation (XCI) by interrogating changes to the X chromosomes' 3D states. Here, we sought to characterize the 3D state of the X chromosome in naïve and primed human pluripotent stem cells (hPSCs). Using chromatin tracing, we analyzed X chromosome folding conformations in these cells with megabase genomic resolution. X chromosomes in female naïve hPSCs exhibit folding conformations similar to the active X chromosome (Xa) and the inactive X chromosome (Xi) in somatic cells. However, naïve X chromosomes do not exhibit the chromatin compaction typically associated with these somatic X chromosome states. In H7 naïve human embryonic stem cells, XIST accumulation observed on damaged X chromosomes demonstrates the potential for naïve hPSCs to activate XCI-related mechanisms. Overall, our findings provide insight into the X chromosome status of naïve hPSCs with a single-chromosome resolution and are critical in understanding the unique epigenetic regulation in early embryonic cells.

Scalable production of tissue-like vascularized liver organoids from human PSCs.

The lack of physiological parity between 2D cell culture and in vivo culture has led to the development of more organotypic models, such as organoids. Organoid models have been developed for a number of tissues, including the liver. Current organoid protocols are characterized by a reliance on extracellular matrices (ECMs), patterning in 2D culture, costly growth factors and a lack of cellular diversity, structure, and organization. Current hepatic organoid models are generally simplistic and composed of hepatocytes or cholangiocytes, rendering them less physiologically relevant compared to native tissue. We have developed an approach that does not require 2D patterning, is ECM independent, and employs small molecules to mimic embryonic liver development that produces large quantities of liver-like organoids. Using single-cell RNA sequencing and immunofluorescence, we demonstrate a liver-like cellular repertoire, a higher order cellular complexity, presenting with vascular luminal structures, and a population of resident macrophages: Kupffer cells. The organoids exhibit key liver functions, including drug metabolism, serum protein production, urea synthesis and coagulation factor production, with preserved post-translational modifications such as N-glycosylation and functionality. The organoids can be transplanted and maintained long term in mice producing human albumin. The organoids exhibit a complex cellular repertoire reflective of the organ and have de novo vascularization and liver-like function. These characteristics are a prerequisite for many applications from cellular therapy, tissue engineering, drug toxicity assessment, and disease modeling to basic developmental biology.

Staged surgically created type B aortic dissection model with endovascular reintervention for different morphological features.

OBJECTIVES: Understanding morphology and how this relates to treatment strategy is critical for achieving remodelling in aortic dissection. A controllable and reproducible large animal model is required for investigating new therapeutic devices and interventions. METHODS: Our experimental protocol involved the development of surgically created type B aortic dissection (TBAD) and endovascular reintervention-induced TBAD porcine models. The sample was randomly divided into 2 groups: 1 underwent a secondary tear creation (STC) procedure and the other underwent a false lumen extension (FLE) procedure. Anatomical features were observed at 1 and 3 months, and 2 animals in each group were euthanized at 3 months after the procedures. The aorta and main branches were harvested en bloc, cross-sectioned and prepared for histological examination. RESULTS: All surgically created TBAD models were successfully generated, and no unintended complications occurred. The endovascular reintervention-induced TBAD model was successfully created in 11 of 12 animals, with 6 in the STC group and 5 in the FLE group. In the STC group, the intraoperative mean diameter of the new secondary tear was 7.23 mm, and a slight increase was observed at first 30 days (P = 0.0026). In the FLE group, the intraoperative new propagation length was (235.80 ± 84.94) mm. The FL propagation length at the 1-month follow-up was significantly longer than that measured intraoperatively (P = 0.0362). Histological evaluation demonstrated that the elastic fibres in the media layer of the aortic wall were disrupted and appeared to be significantly stretched on the adventitial side of the false lumen. CONCLUSIONS: Our endovascular reintervention is a reliable, minimally invasive approach for producing specific TBAD models with different morphologies.

Does surgical companionship modify the learning curve for fenestrated and branched endovascular aortic repair?

OBJECTIVES: The goal of this study was to describe the learning curve of an operator trained in an aortic centre during the first years of performing fenestrated/branched endovascular aortic repairs independently. METHODS: Patients electively treated with fenestrated/branched stent grafts from January 2013 to March 2020 were included retrospectively. Groups were defined according to the treating operator: experienced operator (group 1), early-career operator (group 2) or both during a 14-month surgical companionship period (group 3). The early-career operator's learning curve was assessed using a cumulative sum analysis. A composite criterion including technical failure, death and/or any major adverse event was evaluated in a logistic regression model. RESULTS: Overall, 437 patients (93% male; median 69 (63, 77) years old) were included (group 1: n = 240; group 2: n = 173; group 3: n = 24). There were significantly more extended thoraco-abdominal aneurysms (extent I, II, III and V) in group 1 compared to group 2 [n = 68 (28%) vs 19 (11%), P<0.001]. The technical success rate was 94% (P=0.874). The 30-day mortality and/or major adverse event rates in juxta-/pararenal aneurysms or extent IV thoraco-abdominal aneurysms were 8.1% in group 1 and 9.7% in group 2 (P = 0.612), whereas they were 10% (group 1) and 0 (group 2) for extended thoraco-abdominal aneurysms (P=0.339). The adjusted cumulative sum analysis highlighted satisfactory results from the beginning of the experience. The operator's experience was not predictive of the composite criterion [adjusted OR 0.77; 95% (0.42, 1.40); P=0.40]. CONCLUSIONS: This study demonstrated favourable outcomes in patients treated with a fenestrated/branched aortic stent graft performed by an early-career operator trained in a high-volume centre from the beginning of independent practice.

Aortic dissection: results of the invasive treatment in France between 2012 and 2018 according to the French national database.

BACKGROUND: To evaluate results of the invasive repair in the management of acute aortic dissection (AoD) in France. METHODS: Patients admitted to hospital with acute AoD from 2012 to 2018 were identified. Patient demographics, severity score at admission, treatment strategy and in-hospital mortality were described. For patients undergoing intervention, perioperative complications rate was reported. A secondary analysis evaluating patients' outcome as regards of the annual caseload per center was conducted. RESULTS: Overall, 14,706 patients with acute AoD were identified (male 64%, mean age 67, median modified Elixhauser score 5). The overall incidence increased during the study period (from 3.8 in 2012 to 4.4/100,000 in 2018) associated with a North-South gradient (respectively 3.6 vs. 4.7/100,000) and a winter peak; 45.5% (N.=6697) of patients received medical treatment alone. Among those with invasive repair, 6276 (78.3%) were defined as type A AoD (TAAD), whereas type B AoD (TBAD) accounted for 1733 patients (21.7%), of whom 1632 (94%) had TEVAR and 101 (6%) had other arterial procedures; 30-day mortality was respectively 18.9% in TAAD and 9.5% for TBAD. In high-volume centers (i.e. >20 AoD/year), a lower 3-month mortality of 22.3% was noted compared to 31.4% in the low-volume centres (P<0.001); 47% of patients reported ≥1 early major complication. TEVAR exhibited less complication (P<0.001) compared to other arterial reconstructions in TBAD. CONCLUSIONS: The incidence of acute AoD increased in France over the period of the study and was associated with stable postoperative early mortality. Early postoperative mortality is significantly reduced in high-volume centers.

Benefits of Prehabilitation before Complex Aortic Surgery.

The purpose of this narrative review was to detail and discuss the underlying principles and benefits of preoperative interventions addressing risk factors for perioperative adverse events in open aortic surgery (OAS). The term "complex aortic disease" encompasses juxta/pararenal aortic and thoraco-abdominal aneurysms, chronic aortic dissection and occlusive aorto-iliac pathology. Although endovascular surgery has been increasingly favored, OAS remains a durable option, but by necessity involves extensive surgical approaches and aortic cross-clamping and requires a trained multidisciplinary team. The physiological stress of OAS in a fragile and comorbid patient group mandates thoughtful preoperative risk assessment and the implementation of measures dedicated to improving outcomes. Cardiac and pulmonary complications are one of the most frequent adverse events following major OAS and their incidences are correlated to the patient's functional status and previous comorbidities. Prehabilitation should be considered in patients with risk factors for pulmonary complications including advanced age, previous chronic obstructive pulmonary disease, and congestive heart failure with the aid of pulmonary function tests. It should also be combined with other measures to improve postoperative course and be included in the more general concept of enhanced recovery after surgery (ERAS). Although the current level of evidence regarding the effectiveness of ERAS in the setting of OAS remains low, an increasing body of literature has promoted its implementation in other specialties. Consequently, vascular teams should commit to improving the current evidence through studies to make ERAS the standard of care for OAS.

Evaluation of Arterial and Venous Allografts in Subinguinal Bypasses.

BACKGROUND: Autologous saphenous vein is the preferred conduit for below-the-knee bypasses in patients with critical limb-threatening ischemia. Alternative graft must be considered for patients without (autologous saphenous vein). The aim of this article is to evaluate the mid-term performance of arterial allograft (AA) and venous allograft (VA) used as alternative conduits. METHODS: This retrospective study included patients with critical limb-threatening ischemia, with or without a history of homolateral femoropopliteal bypass, and no autologous veins were available who underwent infrainguinal arterial reconstructions using VA or AA from 2008 to 2018. Patients undergoing revision operations for infected bypasses were excluded. Primary patency (PP), primary assisted patency, secondary patency, major amputation, and death from any cause were the endpoints. For each event, a set of analyses were performed. RESULTS: Overall, 111 patients (63 VAs and 48 AAs) were included, with 108 having below-the-knee bypass. The median follow-up time was 27.8 months (15.6-37.4). The difference in PP between the 2 allograft types was significant (P = 0.049), with 65.9% (43.7-81.0), 44.1% (24.2-62.3), and 44.1% (24.2-62.3) in the AA group, respectively, at 6, 12, and 18 months, whereas 55.6% (40.0-68.6), 46.0% (30.6-60.2), and 33.2% (18.2-49.0) in the VA group. The choice of an AA over a VA was an independent factor associated with patency (for PP: hazard ratio [HR] = 0.43 [0.24-0.75], P = 0.003); primary assisted patency: HR = 0.52 (0.30-0.89], P = 0.018; and secondary patency: HR = 0.49 (0.27-0.88), P = 0.016. The allograft type did not affect either the incidence of major amputation or death from any cause (respectively, HR = 1.20 [0.49-2.93], and 0.88 [0.37-2.14]). CONCLUSIONS: The nature of the allograft appears to influence the patency of infrainguinal reconstruction, but not the course of the disease. Performant alternative grafts answering infectious issues are needed.

Early Institutional Experience with One-Piece Bifurcated-Fenestrated Stentgraft in the Treatment of Abdominal Aortic Aneurysms.

PURPOSE: To review the early experience of the use of a bifurcated-fenestrated endograft (Bif-FEVAR) to treat abdominal aortic aneurysms (AAA) in a high-volume aortic center. METHODS: A retrospective single-center analysis was conducted between March 2019 and April 2021 including consecutive patients that underwent Bif-FEVAR. Only patients without a proper infrarenal neck and a distance <70 mm between the lowest target artery and the native or prosthetic aortic bifurcation were considered. All Bif-FEVAR custom-made devices were manufactured by Cook Medical (Inc., Bloomington, Indiana). Demographics, anatomical features, technical success, major adverse events, 30-day mortality, and survival according to Kaplan-Meier were analyzed according to Society for Vascular Surgery standards. RESULTS: Overall, 10 patients (100% male with median age 78) were included. The median preoperative maximal aneurysm diameter was 68 mm [51-84]. Eight patients were treated for a proximal type I endoleak after endovascular aneurysm repair. A total of 36 fenestrations were planned. The median operative time was 144 min [127-168], with a median fluoro time of 40.5 min [34-54] and a median dose area product of 73 Gy cm2 [61-89]. Technical success rate was 100%. No patients experienced a major postoperative adverse event. Median follow-up time was 8 months [6-13]. CONCLUSION: Bif-FEVAR is technically feasible when there is a short distance below the lowest target artery and the aortic bifurcation, with favorable short-term results. CLINICAL IMPACT: This study assessed the use of an innovative one-piece bifurcated fenestrated stent-graft as a primary procedure or in the treatment of proximal endoleak after standard infrarenal EVAR. We demonstrated these custom-made devices can be used safely with favorable short-term results. One-piece bifurcated fenestrated stent-grafts extend the indications of FEVAR for patients with an unusually short distance between the lowest renal artery and the aorto-iliac bifurcation or the diverter flow of a preexisting bifurcated infrarenal stent-graft.

Dyslexia associated gene KIAA0319 regulates cell cycle during human neuroepithelial cell development.

Dyslexia, also known as reading disability, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of dyslexia is between 5 and 17%, and the heritability ranges from 44 to 75%. Genetic linkage analysis and association studies have identified several genes and regulatory elements linked to dyslexia and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. The association of KIAA0319 with reading performance has been replicated in independent studies and different languages. Rodent models suggest that kiaa0319 is involved in neuronal migration, but its role throughout the cortical development is largely unknown. In order to define the function of KIAA0319 in human cortical development, we applied the neural developmental model of a human embryonic stem cell. We knocked down KIAA0319 expression in hESCs and performed the cortical neuroectodermal differentiation. We found that neuroepithelial cell differentiation is one of the first stages of hESC differentiation that are affected by KIAA0319 knocked down could affect radial migration and thus differentiation into diverse neural populations at the cortical layers.

Do fluoroquinolones increase aortic aneurysm or dissection incidence and mortality? A systematic review and meta-analysis.

Objective: The aim of this study was to determine the association between fluoroquinolones (FQs) use, the risk of de novo aortic aneurysm or dissection (AAD), and the prognosis of patients with pre-existing AAD. Materials and methods: We searched PubMed, EMBASE, CENTRAL, Scopus, and Web of Science on 31 March 2022. Observational studies that evaluated the association of FQs with AAD risk in the general population or FQs with the prognosis of patients with preexisting AAD and presented adjusted effect estimates were included. Two reviewers assessed study eligibility, extracted data, and assessed the risk of bias and certainty of evidence using GRADE. Results: Of the 13 included studies, 11 focused on the association of FQs with de novo AAD incidence, and only one study investigated the association of FQs with the patient with AAD prognosis. FQ use was associated with an increased risk of de novo AAD within 30 days (RR: 1.42; 95% CI: 1.11-1.81; very low certainty) and 60 days (RR: 1.44; 95% CI: 1.26-1.64; low certainty). Specifically, the association was significant when compared with amoxicillin, azithromycin, doxycycline, or no antibiotic use. Furthermore, patients with preexisting AAD exposure to FQ had an increased risk of all-cause mortality (RR: 1.61; 95% CI: 1.50-1.73; moderate certainty) and aortic-specific mortality (RR: 1.80; 95% CI: 1.50-2.15; moderate certainty), compared to the non-exposed FQ group within a 60-day risk period. Conclusion: FQs were associated with an increased incidence of AAD in the general population and a higher risk of adverse outcomes in patients with preexisting AAD. Nevertheless, the results may be affected by unmeasured confounding factors. This should be considered by physicians contemplating using FQs in patients with aortic dilation and those at high risk of AAD. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42021230171].

Iliac branch device to treat type Ib endoleak with a brachial access or an "up-and-over" transfemoral technique.

OBJECTIVE: In the present study, we reviewed the results of secondary iliac branch device (IBD) implantation for patients with a type Ib endoleak after prior fenestrated and/or branched (F/B) or infrarenal endovascular aortic aneurysm repair (EVAR) using either brachial access or an "up-and-over" transfemoral technique. METHODS: We performed a retrospective, single-center analysis between January 2016 and October 2021 of consecutive patients who had undergone IBD to correct a type Ib endoleak after prior EVAR or F/B-EVAR. The groups were defined by arterial access, which was either brachial (group 1) or transfemoral (group 2). All implanted IBDs had been manufactured by Cook Medical, Inc (Bloomington, IN). The demographics, anatomic features, technical success, and 30-day major adverse events were recorded in accordance with the current Society for Vascular Surgery standards. The survival curves using the Kaplan-Meier method were calculated. Branch instability was a composite end point of any internal iliac artery (IIA) branch-related complication or reintervention indicated to treat endoleak, kink, disconnection, stenosis, occlusion, or rupture. RESULTS: Overall, 28 patients (93% male; median age, 74 years), who had received 32 IBDs, were included, with 14 patients in each group. The prior endovascular aortic repairs included 23 cases of EVAR and 5 cases of F/B-EVAR, with an interval from the initial repair of 58 months (interquartile range [IQR], 48-70 months). The median pre-IBD maximal aneurysm diameter was 63.5 mm (IQR, 59.0-78.0 mm). The baseline characteristics were similar between the two groups, except for pulmonary status. All procedures were performed in a hybrid operative room. The median total operating time, fluoroscopy time, and dose area product was 120 minutes (IQR, 86-167 minutes), 23 minutes (IQR, 15-32 minutes), and 54 Gyccm2 (IQR, 40-62 Gyccm2), respectively. The total operating time was shorter for group 2 (P = .006). The technical success rate was 100%, and no early deaths occurred. One 30-day major adverse event, medically treated colonic ischemia, had occurred in one patient in group 2. Aortic-related secondary interventions had been required for seven patients (five in group 1 and two in group 2), including three cases of surgical explantation. The median follow-up was 31 months (IQR, 24-42 months) and 6 months (IQR, 3-10 months) for groups 1 and 2, respectively. For group 1, the 2-year freedom from aortic-related secondary intervention and IIA branch instability was 84.6% (IQR, 67.1%-100%) and 92.3% (IQR, 78.9%-100%), respectively. For group 2, the 6-month freedom from aortic-related secondary intervention and IIA branch instability was 87.5% (IQR, 67.3%-100%) and 91.7% (IQR, 77.3%-100%), respectively. CONCLUSIONS: The results from the present study have shown that secondary implantation of an IBD to correct a distal type I endoleak from a previous aortic stent graft is safe with a high technical success rate. The "up-and-over" technique can be considered an alternative to brachial access for patients with suitable anatomy.

Expression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids.

Microglia play a role in the emergence and preservation of a healthy brain microenvironment. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative disorders. Investigating the function of human microglia in health and disease has been challenging due to the limited models of the human brain available. Here, we develop a method to generate functional microglia in human cortical organoids (hCOs) from human embryonic stem cells (hESCs). We apply this system to study the role of microglia during inflammation induced by amyloid-ß (Aß). The overexpression of the myeloid-specific transcription factor PU.1 generates microglia-like cells in hCOs, producing mhCOs (microglia-containing hCOs), that we engraft in the mouse brain. Single-cell transcriptomics reveals that mhCOs acquire a microglia cell cluster with an intact complement and chemokine system. Functionally, microglia in mhCOs protect parenchyma from cellular and molecular damage caused by Aß. Furthermore, in mhCOs, we observed reduced expression of Aß-induced expression of genes associated with apoptosis, ferroptosis, and Alzheimer's disease (AD) stage III. Finally, we assess the function of AD-associated genes highly expressed in microglia in response to Aß using pooled CRISPRi coupled with single-cell RNA sequencing in mhCOs. In summary, we provide a protocol to generate mhCOs that can be used in fundamental and translational studies as a model to investigate the role of microglia in neurodevelopmental and neurodegenerative disorders.

Intraoperative cone beam computed tomography to improve outcomes after infrarenal endovascular aortic repair.

OBJECTIVE: We evaluated whether a combination of intraoperative contrast-enhanced cone beam computed tomography (ceCBCT) and postoperative contrast-enhanced ultrasound (CEUS) after infrarenal endovascular abdominal aortic aneurysm repair (EVAR) could reduce late stent graft-related complications and, consequently, reintervention. METHODS: All consecutive patients who had received infrarenal bifurcated stent grafts in our hybrid room (IGS 730; GE Healthcare, Île-de-France, France) during two discrete periods were included in the present study. From November 2012 to September 2013, two-dimensional completion angiography was performed after each EVAR, followed by computed tomography angiography (CTA) before discharge (group 1). From October 2013 to January 2015, intraoperative ceCBCT was performed, followed by CEUS within the first postoperative days (group 2). Comparative analyses of the outcomes were performed. The primary endpoint was late stent graft-related complications, a composite factor incorporating aneurysm-related death, type I or III endoleaks, kink or occlusion of the iliac limb, and aortic sac enlargement after the first 30 postoperative days. The secondary endpoint was all stent graft-related reinterventions. All-cause and aneurysm-related deaths were also recorded. RESULTS: Overall, 100 consecutive patients (50 each in groups 1 and 2) were enrolled, with a median follow-up of 60 months (interquartile range, 41-69 months). At 60 months after the index procedure, the freedom from late stent graft-related complications in each group was 61.6% (95% confidence interval [CI], 47.0%-80.6%) for group 1 and 81.7% (95% CI, 70.1%-95.2%) for group 2 (P = .033). The use of intraoperative ceCBCT was independently associated with a reduced rate of late stent graft-related complications on multivariate analysis (hazard ratio, 0.39; 95% CI, 0.16-0.95; P = .038) but did not appear to significantly protect against stent graft-related reinterventions (hazard ratio, 0.53; 95% CI, 0.20-1.39; P = .198) or all-cause death (P = .47). CONCLUSIONS: To the best of our knowledge, the present study is the first to report the influence of routine ceCBCT on late outcomes after EVAR. The use of ceCBCT shows the potential for reducing late stent graft-related complications associated.

Hybrid Room: Does it Offer Better Accuracy in the Proximal Deployment of Infrarenal Aortic Endograft?

BACKGROUND: This work aims to evaluate the impact of hybrid rooms and their advanced tools on the accuracy of proximal deployment of infrarenal bifurcated endograft (EVAR). METHODS: A retrospective single center analysis was conducted between January 2015 and March 2019 including consecutive patients that underwent EVAR. Groups were defined whether the procedure was performed in a hybrid operating room (HOR group) or using a mobile 2D fluoroscopic imaging system (non-HOR group). The accuracy of the proximal deployment was estimated by the distance (mm) between the bottom of the lowest renal artery (LwRA) origin and the endograft radiopaque markers parallax (LwRA/EDG distance) after curvilinear reconstruction. The impact of HOR on the LwRA/EDG distance was investigated using a multiple linear regression model. A composite "proximal neck"-related complications event was studied (Cox models). RESULTS: Overall, 93 patients (87 %male, median age 73 years) were included with 49 in the HOR group and 44 in the non-HOR group. Preoperative CTA analysis of the proximal neck exhibited similar median length, but different median aortic diameter (P = 0.012) and median beta angulation (P = 0.027) between groups. The median LwRA/EDG distance was shorter in the HOR group (multivariate model, P = 0.022). No difference in "proximal neck"-related complications was evidenced between the HOR and non-HOR groups (univariate analysis, P = 0.620). Median follow-up time was respectively 25 [14-28] and 36 months [23-44] in the HOR group and in the non-HOR group (P < 0.001). CONCLUSION: HOR offer more accurate proximal deployment of infrarenal endografts, with however no difference in "proximal neck"-related complications between groups.