Clinical Impact of Comprehensive Molecular Profiling in Adolescents and Young Adults with Sarcoma.

Sarcomas are a heterogenous group of tumours that commonly carry poor prognosis with limited therapeutic options. Adolescents and young adults (AYAs) with sarcoma are a unique and understudied patient population that have only achieved modest survival gains compared to other groups. We present our institutional experience of AYAs with sarcoma who underwent comprehensive molecular profiling (CMP) via either large-panel targeted DNA sequencing or whole genome and transcriptome sequencing and evaluated the feasibility and clinical impact of this approach. Genomic variants detected were determined to be clinically relevant and actionable following evaluation by the Molecular Tumour Board. Clinicians provided feedback regarding the utility of testing three months after reporting. Twenty-five patients who were recruited for CMP are included in this analysis. The median time from consent to final molecular report was 45 days (interquartile range: 37-57). Potentially actionable variants were detected for 14 patients (56%), and new treatment recommendations were identified for 12 patients (48%). Pathogenic germline variants were identified in three patients (12%), and one patient had a change in diagnosis. The implementation of CMP for AYAs with sarcoma is clinically valuable, feasible, and should be increasingly integrated into routine clinical practice as technologies and turnaround times continue to improve.

Clonal hematopoiesis related TET2 loss-of-function impedes IL1ß-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.

Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1ß is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1ß promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1ß administration, which is resisted by Tet2-deficient HSPCs, and thus IL1ß enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1ß-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.

Severe persistent neurotoxicity associated with CAR T therapy in children.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy is an important therapy for relapsed or refractory acute lymphoblastic leukaemia, but its use carries the risk of immune effector cell-associated neurotoxicity syndrome (ICANS). In children, severe ICANS is almost universally reported in association with cytokine release syndrome and is reversible. We describe two cases of severe, intractable neurotoxicity following CAR T-cell therapy in children with pre-existing central nervous system (CNS) vulnerabilities. The cases were atypical in their delayed onset and independence from cytokine release syndrome and did not respond to standard therapies.

Density of antibiotic use and infectious complications in pediatric allogeneic hematopoietic cell transplantation.

BACKGROUND: Antibiotics, while an essential component of supportive care in allogeneic hematopoietic cell transplantation (allo-HCT), can have adverse effects and select for antibiotic resistance. Understanding of patterns of use will inform antimicrobial stewardship (AMS) interventions. METHODS: Retrospective, single-center cohort of children undergoing first allo-HCT (n = 125). Antibiotic prescription and infection data were included from the date conditioning was commenced until 30 days post allo-HCT. Antibiotic use was reported as length of therapy (LOT) (number of days a patient received an antibiotic) and days of therapy DOT (aggregating all antibiotics prescribed per day). Infections were classified as microbiologically documented infection (MDI) or clinically documented infections. RESULTS: At least one course of antibiotics was administered to 124 (99%) patients. The LOT was 636 per 1000 patient days and DOT was 959 per 1000 patient days. The median duration of cumulative antibiotic exposure per patient was 24 days (interquartile range [IQR] 20-30 days). There were 131 days of fever per 1000 patient days with patients febrile for a median of 4 days (IQR 1-7 days). Piperacillin-tazobactam was used for 116 (94%) of patients with an LOT of 532 per 1000 patient days. A total of 119 MDI episodes occurred in 74 (59%) patients, including blood stream infection in 30 (24%) and a proven/probable invasive fungal infection in 4 (3%). CONCLUSION: Pediatric HCT patients receive prolonged courses of broad-spectrum antibiotics relative to the frequency of fever and bacterial infections. This study has identified opportunities for AMS intervention to improve outcomes for our HCT patients.

Increasing rates of ulnar collateral ligament repair outpace reconstruction in isolated injuries: review of a Texas surgical database.

Background: The gold standard of treatment for ulnar collateral ligament (UCL) injuries has been reconstruction. Despite early repair studies yielding less than satisfactory results, there has been recent renewed interest in UCL repair due to improved outcomes and new technologies. Data regarding clinical use of these procedures are lacking. The purpose of this study was to define the epidemiological trends of UCL repair and reconstruction surgery from 2010 to 2019, compare demographic characteristics of patients undergoing either procedure, and determine incidence of concomitant procedures in each surgical group as well as comparing respective patient-level charges. Methods: A retrospective database analysis of UCL surgeries was performed through the Texas Healthcare Information Collection database, a comprehensive and publicly available statewide billing dataset. Inclusion criteria were defined using Current Procedural Terminology billing codes for elbow UCL repair and reconstruction between 2010 through 2019, excluding patients who had concomitant elbow fractures or lateral collateral ligament tears indicative of high-energy trauma. Procedural volume changes, patient demographics, and commonly performed concomitant procedures including elbow arthroscopy, ulnar nerve surgery, and platelet-rich plasma injection were compared. Total patient-level charges were compared across groups. Results: A total of 1664 patients were included, consisting of 484 UCL repairs and 1180 reconstructions. Total UCL surgeries increased eleven-fold when corrected for population growth from 2010 (N = 25) to 2019 (N = 315). In 2010, repair constituted 23% of all UCL tear surgeries and increased to 40% by the end of 2019. The annual frequency of UCL repair increased at a 5.4% faster rate than UCL reconstruction from 2010 to 2019 (P < .001). There were no significant differences between any demographic data between UCL repair and reconstruction except for rural surgical settings which demonstrated 1.8 times greater odds of undergoing reconstruction (P = .05). There were no differences among commonly associated procedures including ulnar nerve surgery (P = .217), elbow arthroscopy (P = .092), and platelet-rich plasma injection (P = .837) with no differences in patient-level charges at any time point (P = .47). Conclusion: While reconstruction remains more common, the annual frequency of UCL repair is increasing at a faster rate. Since were no demographic differences aside from surgical setting, it can be inferred that patients who were previously receiving reconstruction are instead undergoing repair. This highlights the need for future studies to further identify surgical indications for the two interventions.

A pilot study to investigate the effect of topical microporous polysaccharide haemospheres on outcomes following robot-assisted radical prostatectomy.

INTRODUCTION: Controlling bleeding without disturbing the anatomy and function of the structures in the prostate bed remains a significant challenge during radical prostatectomy (RP). MATERIALS AND METHODS: Five grams of powdered microporous polysaccharide haemospheres (MPH) was applied to the prostate bed at the end of robot-assisted RP in 422 consecutive patients. Continence was defined as no pads and potency as the ability to have penetrative sex with or without PDE5 inhibitors in previously potent, non-diabetic men aged <70 years following bilateral intra- or inter-fascial neurovascular bundle (NVB) preservation. RESULTS: In total, 95.3% of patients had nerve preservation and the mean operating time and blood loss were 142 minutes and 200ml, respectively. There were no intraoperative complications, and the postoperative transfusion rate was 0.2%. The mean hospital stay was 1.7 nights, and duration of catheterisation was 12 days. Final pathology demonstrated a mean prostate weight of 40.0g and 14.5% replacement by cancer, most commonly Gleason 7. The positive surgical margin rate for pT2 tumours was 10.0%. Biochemical recurrence was 2.1% at a mean follow-up of 18.0 months. Continence and potency rates at 4 weeks and 1 year after surgery were 76.4% and 97.7% and 27.8% and 78.1%, respectively. The trifecta and pentafecta rates 1 year after surgery were 53.1% and 45.8%. DISCUSSION AND CONCLUSION: Powdered MPH applied to the prostate bed at the end of robot-assisted RP appears to be a safe, easily applied and useful adjunct to conventional haemostasis. The suggestion that it might also improve the functional outcomes of RP merits further investigation in the context of a randomised trial.

An international multidisciplinary peer-driven consensus on the optimal use of hemostatic powders in surgical practice.

Bleeding is a consequence of insufficient hemostasis and excessive bleeding at a surgical site is associated with an increased risk of post-operative infection, transfusion and re-operation, in addition to increased hospital length of stay and costs. Surgeons employ a range of methods to achieve hemostasis, including topical hemostatic agents of differing composition and properties. Hemostatic powders are a sub-group of topical hemostats, which can be used in helping as adjuncts to manage troublesome bleeding in a variety of situations. As this technology is relatively new and potentially not well known by the broad surgical community, no specific guidelines or recommendations for the optimal use of hemostatic powders in surgery currently exist. A steering group throughout Europe of multidisciplinary surgeons, expert in hemostasis and hemostatics, identified from literature and from personal experience, five key topics. When to use hemostatic powder, the evidence for use, benefits of use, safety remarks and considerations in various surgical specialties. Thirty-seven statements were subsequently drawn from these five key topics. An online survey was sent to 128 high-volume surgeons working in breast surgery, gynaecological and obstetric surgery, general and emergency surgery, thoracic surgery and urological surgery in Europe to assess agreement (consensus) with these statements. Consensus was defined as high if ≥ 75% and very high if ≥ 90% of respondents agreed with a statement. A total of 79 responses were received and consensus among the surgical experts was very high in 27 (73%) statements, high in 8 (22%) statements and was not achieved in 2 (5%) statements. Based on the consensus scores, the steering group produced 16 key recommendations which they considered could improve patient outcomes by reducing post-operative bleeding and its associated complications using hemostatic powder.

UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma.

INTRODUCTION: Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. METHODS: Microarray, real-time quantitative reverse transcription-polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. RESULTS: UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-sequencing experiments exhibited the pleiotropic effects of UHRF1 down-regulation and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. CONCLUSIONS: UHRF1 is an epigenetic driver in MPM. These findings support the efforts to target UHRF1 expression or activity for mesothelioma therapy.

Facilitators and barriers to implementation of the Pharmacy DOTS Initiative in selected project sites in the Philippines

@#<p style="text-align: justify;"><strong>Objectives:</strong> The Pharmacy DOTS Initiative (PDI) was relaunched on a larger scale in 2014 through the Innovations and Multi-Sectoral Partnerships to Achieve Control of Tuberculosis (IMPACT) project. This paper aimed to assess the PDI program through IMPACT by identifying the facilitating and hindering factors in its implementation. The identified factors are classified as to the affected stakeholders or processes.</p><p style="text-align: justify;"><strong>Methods:</strong> Semi-structured interviews were conducted with the PDI Program Manager and four NTP coordinators from selected project sites. Thematic analysis was done to determine the recurring facilitating and hindering factors as identified by the key informants.</p><p style="text-align: justify;"><strong>Results:</strong> Facilitating factors identified include cooperation of the stakeholders, capability-building and a good referral system. The barriers to the implementation were grouped into patient-related, pharmacy-related, health center-related, program-related as well as external factors.</p><p style="text-align: justify;"><strong>Conclusion:</strong> The referral system created through PDI facilitated the flow of referrals starting from the pharmacy. This enabled presumptive patients to have access to health facilities for TB. Hindering factors contributed to the inability of the engaged pharmacies to sustain their consistency and commitment in conducting the PDI interventions.</p><p style="text-align: justify;"><strong>Key Words:</strong> barriers, facilitators, tuberculosis, directly observed therapy, program evaluation, pharmacy</p>

Green tea (Camellia sinensis) extract inhibits biofilm formation in acyl homoserine lactone-producing, antibiotic-resistant Morganella morganii isolated from Pasig River, Philippines.

The drastic development of urban districts around the world has caused changes in the environment, specifically on metropolitan waterways such as the Pasig River in the Philippines. These significant changes resulted in diversity of microorganisms and their mechanisms employed such as antibiotic resistance and their communication system or quorum sensing (QS). In this study, four bacterial isolates from Pasig River, identified as Aeromonas salmonicida, Acinetobacter sp., Morganella morganii, and Citrobacter freundii, were observed to employ short-chain acyl homoserine lactone (AHL) as their signalling molecule based on in vitro assays using the biosensor strain Chromobacterium violaceum CV026. Furthermore, M. morganii isolate was shown to be resistant to chloramphenicol. This poses a significant threat not just to public health but also to the aquatic life present in the river. Thus, green tea (Camellia sinensis) extract was tested for its capability to inhibit in vitro biofilm formation in M. morganii, as well as the short-chain acyl homoserine lactone QS system using C. violaceum ATCC 12472. Results showed that the extract significantly (p < 0.05) inhibited biofilm formation in M. morganii at as low as 62.5 µg/mL (31.55%). Increasing the concentration (500 µg/mL) did not significantly (p > 0.05) enhance the activity (41.21%). Furthermore, the extract also inhibited pigmentation in C. violaceum ATCC 12472, suggesting QS inhibition. This study adds into record the production of short-chain AHLs by Aeromonas salmonicida, Acinetobacter sp., Morganella morganii, and Citrobacter freundii, as well as the potential of green tea extract as inhibitor of biofilm formation in antibiotic-resistant M. morganii possibly through QS inhibition.

The use of innominate artery cannulation for antegrade cerebral perfusion in aortic dissection.

BACKGROUND: Direct cannulation of the innominate artery for selective antegrade cerebral perfusion has been shown to be safe in elective proximal aortic reconstructions. We sought to evaluate the safety of this technique in acute aortic dissection. METHODS: A multi-institutional retrospective review was undertaken of patients who underwent proximal aortic reconstruction for Stanford type A dissection between 2006 and 2016. Those patients who had direct innominate artery cannulation for selective antegrade cerebral perfusion were selected for analysis. RESULTS: Seventy-five patients underwent innominate artery cannulation for ACP for Stanford Type A Dissections. Isolated replacement of the ascending aorta was performed in 36 patients (48.0%), concomitant aortic root replacement was required in 35 patients (46.7%), of whom 7 had a valve-sparing aortic root replacement, ascending aorta and arch replacement was required in 4 patients (5%). Other procedures included frozen elephant trunk (n = 11 (14.7%)), coronary artery bypass grafting (n = 20 (26.7%)), and peripheral arterial bypass (n = 4 (5.3%)). Mean hypothermic circulatory arrest time was 19 ± 13 min. Thirty-day mortality was 14.7% (n = 11). Perioperative stroke occurred in 7 patients (9.3%). CONCLUSIONS: This study is the first comprehensive review of direct innominate artery cannulation through median sternotomy for selective antegrade cerebral perfusion in aortic dissection. Our experience suggests that this strategy is a safe and effective technique compared to other reported methods of cannulation and cerebral protection for delivering selective antegrade cerebral perfusion in these cases.

Elective proximal aortic surgery in patients with renal insufficiency.

BACKGROUND: To evaluate preoperative risk factors and postoperative outcomes in patients with preoperative renal insufficiency undergoing open surgical repair of the aortic root, ascending aorta, or aortic arch. METHODS: Our institutional database was reviewed for all patients undergoing elective aortic root, ascending aorta, and aortic arch open repairs. Patients were separated into two groups based on renal function. Patients with preoperative renal insufficiency were compared to those with normal renal function. Regression analyses were used to identify independent predictors of short and long term postoperative outcomes. RESULTS: The cohort consisted of 2140 patients, of which 55 had preoperative renal insufficiency (PRI). Patients with PRI were older and had worse cardiovascular risk profiles. On presentation, PRI patients were more likely to have lower ejection fraction. There was no difference in operative mortality between the two groups. The most frequent major postoperative complications among renal insufficiency patients were reoperation for bleeding (9.1%, P = .02). Logistic regression analysis indicated that PRI and left ventricular ejection fraction were independent predictors of major adverse events. Long-term survival was significantly reduced in preoperative renal insufficiency patients in the unmatched cohort. CONCLUSIONS: Aortic patients with preoperative renal insufficiency have a higher risk profile of mortality. Renal insufficiency remains an independent predictor of adverse outcomes following aortic surgery and understanding this patient population can guide physicians to improve outcomes.

Pharmacy DOTS Initiative (PDI): A case study on integrating pharmacies in the tuberculosis directly observed treatment-short course (TB DOTS) network in the Philippines

Background@#Tuberculosis (TB) is a disease that has continuously burdened Filipinos. Various programs have been launched by public and private sectors to decrease the incidence of TB and to scale up TB prevention and control in the country. In line with this, pharmacists have been contributing in the campaign against TB since 2004 through the implementation of the Pharmacy DOTS Initiative (PDI). Through the project Innovations and Multi-Sectorial Partnerships to Achieve Control of TB (IMPACT), PDI was relaunched in the country in 2014. @*Objectives@#This case study aims to evaluate the impact of PDI on TB prevention and control by assessing the effectiveness of the technical assistance package rolled out during program implementation. @*Methods@#A review of documents was done to evaluate the achievement of the specific targets of PDI. @*Results@#Among the targets, the percentage of actively referring pharmacies and the number of referrals made throughout the program failed to meet the target. The remaining program targets such as the establishment of a referral system, training of pharmacy personnel, adoption of a TB DOTS curriculum in pharmacy schools, and presence of national legislation, policies, and guidelines relevant to PDI were satisfactorily met. @*Conclusion@#PDI had a good response at the start of its implementation, but several issues resulted in the inability to sustain the interventions and achieve set targets.

Pulmonary Mycobacterium abscessus complex in children with cystic fibrosis: A practical management guideline.

The treatment of Mycobacterium abscessus complex (MABSC) pulmonary infections is an emerging challenge in patients with cystic fibrosis (CF). Multidrug therapy for prolonged durations is required and carries the significant burden of drug-related toxicity, cost and selective pressure for multiresistant bacteria. International guidelines acknowledge that clinical and in vitro data to support treatment regimens are limited, particularly in children. As part of a collaboration between the infectious diseases and respiratory units at our institution, we have developed a modified treatment guideline that aims to balance the aims of MABSC eradication and slowing disease progression with minimising drug toxicity and resistance. The outcomes of this treatment approach will be monitored and reported. In this manuscript, we discuss the available evidence for treatment choices and present our treatment guideline for paediatric patients with CF and MABSC infection.

Outputs and Outcome of the Pharmacy Directly-Observed Treatment Short-Course (DOTS) Initiative in the Philippines

@#<p><strong>OBJECTIVE:</strong> This was an evaluation of the effectiveness of the technical assistance package for the Pharmacy DOTS Initiative (PDI) in the Philippines.</p><p><strong>METHODOLOGY:</strong> Five pre-identified implementation sites were included in the evaluation. A survey was conducted to ascertain pharmacies currently implementing PDI and the number of TB presumptive cases referred by these pharmacies. Data abstraction was performed to determine the change in the number of TB cases seen by local TB programs after its implementation.</p><p><strong>RESULTS:</strong> Findings revealed that the proportion of pharmacies actively referring presumptive TB patients is not significantly lower than 60% (p=0.1892). Furthermore, results showed that the average monthly referrals were not statistically lower than 20 clients per month (p=0.9159). Nevertheless, interrupted time series analysis found no statistically significant immediate effects (p=0.516) and long-term effects (p=0.3673) on the total number of new TB cases identified after the PDI was implemented in the year 2014.</p><p><strong>CONCLUSION:</strong> The PDI was able to achieve outputs related to pharmacy engagement and referral of TB presumptive clients. However, the PDI was unsuccessful in increasing the actual number of TB presumptive cases seen by local TB programs in its implementation sites.</p>

Adverse effects of amphotericin B in children; a retrospective comparison of conventional and liposomal formulations.

AIMS: Lipid formulations of amphotericin B, rather than conventional amphotericin (c-amB), are increasingly used despite limited data comparing these preparations in children. Data on the incidence of adverse effects with amphotericin B at standard doses are scarce. This study aimed to compare the adverse effects associated with standard doses of c-amB and liposomal amphotericin (l-amB) in children. METHODS: Children admitted to the Royal Children's Hospital Melbourne and treated with c-amB or l-amB between January 2010 and September 2013 were included. Clinical and laboratory data were retrospectively extracted from medical records to compare amphotericin-related infusion reactions, nephrotoxicity (glomerulotoxicity and tubulopathy) and hepatotoxicity. RESULTS: Seventy-six children received c-amB and 39 received l-amB. Standard drug administration (recommended dose and infusion time) occurred in 74% (56/76) of patients on c-amB and 85% (33/39) on l-amB. In these 89 children, infusion-related reactions were similar for both c-amB and l-amB (23% (13/56) vs. 9% (3/33); P = 0.15); none occurred in children aged <90 days. There was no difference in amphotericin-associated glomerulotoxicity (c-amB 14% (8/56) vs. l-amB 21% (7/33); P = 0.40) or in the median maximum potassium requirements (c-amB 3.1 vs. l-amB 2.3 mmol kg-1  d-1 ; P = 0.29). Hepatotoxicity occurred more frequently with l-amB than c-amB (83% (24/29) vs. 56% (20/36); P = 0.032). CONCLUSIONS: When appropriately administered, l-amB was associated with more hepatotoxicity than c-amB, with no difference in infusion-related reactions or nephrotoxicity. Differences in adverse effects between the preparations is not as marked in children as reported in adults.

ASXL3 Is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer.

In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSCs (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAECs. Of particular novelty, we identified the PRC2-associated protein, ASXL3, which was markedly upregulated in Lu-iPSCs and small cell lung cancer (SCLC) lines and clinical specimens. ASXL3 overexpression correlated with increased genomic copy number in SCLC lines. ASXL3 silencing inhibited proliferation, clonogenicity, and teratoma formation by Lu-iPSCs, and diminished clonogenicity and malignant growth of SCLC cells in vivo Collectively, our studies validate the utility of the Lu-iPSC model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and highlight ASXL3 as a novel candidate target for SCLC therapy. Cancer Res; 77(22); 6267-81. ©2017 AACR.

Undersized Stent Grafts for Acute Mesenteric Ischemia in Chronic Type B Dissection.

Acute ischemia in chronic type B dissections carries high rates of morbidity and mortality. A 29-year-old woman with a chronic type B dissection presented with acute abdominal pain. Imaging revealed a worsening dissection with pseudocoarctation causing near complete occlusion of the true lumen by the false lumen. We placed purposefully undersized stent grafts to treat acute mesenteric ischemia by improving true lumen flow. The patient was discharged on postoperative day 4 without adverse events. We suggest that endovascular rescue by placing undersized stent grafts can provide improved flow to the mesenteric vessels with continued false lumen flow to vital organs.

Broadly neutralizing antibodies suppress post-transcytosis HIV-1 infectivity.

Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection in humans. Immunoprophylaxis with potent bNAbs efficiently protects non-human primates from mucosal transmission even after repeated challenges. However, the precise mechanisms of bNAb-mediated viral inhibition in mucosal tissues are currently unknown. Here, we show that immunoglobulin (Ig)G and IgA bNAbs do not interfere with the endocytic transport of HIV-1 across epithelial cells, a process referred to as transcytosis. Instead, both viruses and antibodies are translocated to the basal pole of epithelial cells, possibly in the form of an immune complex. Importantly, as opposed to free virions, viral particles bound by bNAbs are no longer infectious after transepithelial transit. Post-transcytosis neutralization activity of bNAbs displays comparable inhibitory concentrations as those measured in classical neutralization assays. Thus, bNAbs do not block the transport of incoming HIV-1 viruses across the mucosal epithelium but rather neutralize the transcytosed virions, highlighting their efficient prophylactic and protective activity in vivo.