Advanced Therapy Research Articles

Damage control thoracic surgery: What you need to know.

Damage control surgery in trauma prioritizes patient stabilization through an initial temporizing surgical approach to rapidly control hemorrhage and contamination, minimizing intraoperative time to allow for resuscitation and the correction of hypothermia, coagulopathy, and acidosis in the intensive care unit. This is followed by definitive repair of injuries once physiological parameters have improved. While damage control techniques for traumatic intra-abdominal and extremity injuries are well established and frequently utilized, the same cannot be said for damage control thoracic surgery. The complexity of thoracic injuries, the intricate decision making process, the level of surgical expertise required, and potential complications make damage control thoracic surgery particularly challenging. However, advances in surgical techniques, improvements in perioperative care, and the emergence of adjuncts such as extracorporeal membrane oxygenation have significantly enhanced decision making and underscored the importance of timely and decisive intervention in damage control thoracic surgery to optimize patient outcomes. This review aims to provide a comprehensive overview of damage control thoracic surgery, detailing the principles, indications, operative techniques, perioperative management, and the integration of advanced therapies to improve outcomes in patients with severe thoracic injuries.

Interpreting modern randomized controlled trials of medical therapy in inflammatory bowel disease.

Treatment options for the medical management of inflammatory bowel disease (IBD) have expanded substantially over the past decade. Multiple classes of advanced therapies, including both monoclonal antibodies and novel oral small molecules, are now available for the treatment of moderately-to-severely active Crohn's disease and ulcerative colitis, highlighted by the approvals of the first IL23p19 antagonists, selective Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. These advances have been accompanied by the identification of novel targets and the rapid growth in both the number and size of IBD clinical trials. Over a dozen landmark randomized controlled trials (RCTs) have been completed in the past 5 years, including the first head-to-head biologic trials, the first combination biologic studies, and multiple phase III registrational trials of novel compounds with new co-primary and composite end points that will change the treatment landscape for years to come. Importantly, the methodology of RCTs in IBD has evolved substantially, with new trial designs, evaluation of unique patient populations, and different types of efficacy and safety end points being key innovations. In this Review, we provide a comprehensive evaluation of how modern RCTs of IBD medical therapies have evolved and the implications for their appraisal that will help guide the application of these data to clinical practice.

Single nucleus DNA sequencing of flow sorted archived frozen and formalin fixed paraffin embedded solid tumors.

Archived samples, including frozen and formalin fixed paraffin embedded (FFPE) tissues, are a vast resource of clinically annotated materials for the application of high-definition genomics to improve patient management and provide a molecular basis for the delivery of personalized cancer therapeutics. Notably, FFPE tissues are stable, provide repeat sampling of tissues of interest, and can be stored indefinitely at ambient temperature. The development of single cell DNA sequencing (scDNA-seq) technologies provides an unparalleled opportunity for the study of tumor heterogeneity and the identification of often rare subclonal cell populations that drive tumor evolution and progression to advanced therapy resistant disease. However, major limitations to the use of archived tissues for scDNA-seq include the low yields of intact cells in the presence of high levels of subcellular debris in biopsies, and the highly variable quantity and quality of the DNA extracted from samples of interest. The latter is of high significance for the use of FFPE tissues due to the presence of DNA-protein crosslinks. In addition, many samples, notably tumors arising in solid tissues, contain admixtures of reactive stroma, inflammatory cells, and necrosis in immediate contact with tumor cells. To expand their use for translational studies, we optimized flow sorting and sequencing of single nuclei from archived fresh frozen (FF) and FFPE tumor tissues. Our methods, which include isolation of intact nuclei suitable for library preparations, quality control (QC) metrics for each step, and a single cell sequencing bioinformatic processing and analysis pipeline, were validated with flow sorted nuclei from matching FF and FFPE ovarian cancer surgical samples and a sequencing panel of 553 amplicons targeting single nucleotide and copy number variants in genes of interest. Our flow sorting based protocol provides intact nuclei suitable for snDNA-seq from archival FF and FFPE tissues. Furthermore, we have developed QC steps that optimize the preparation and selection of samples for deep single cell clonal profiling. Our data processing pipeline captures rare subclones in tumors with highly variable genomes based on variants in genes of interest.

Network Meta-Analysis: Histologic and Histo-Endoscopic Improvement and Remission With Advanced Therapy in Ulcerative Colitis.

Histology has prognostic value in ulcerative colitis (UC). However, direct comparisons of histological endpoints are lacking. To perform a network meta-analysis (NMA) to compare histological endpoints with biologics and small molecules. We searched four databases up until July 2024 for randomised controlled trials (RCTs) on advanced therapies for moderate-to-severe UC reporting histological endpoints. Outcomes included histological improvement or remission, and histo-endoscopic improvement after induction or during maintenance. We used a random-effects frequentist model and have reported outcomes as relative risk and 95% confidence interval. We estimated relative drug efficacy with the P-score. We conducted subgroup analysis by trial phase and evaluated risk of bias and evidence certainty. We included 24 RCTs (15 therapies, 8874 patients). Nineteen provided data on induction and 10 on maintenance; outcome definitions were similar. Etrasimod 2 mg/day ranked highest in achieving histologic improvement (P-score 0.98) and remission (P-score 0.90) following induction. Globally, guselkumab 200-400 mg ranked first for histo-endoscopic improvement, while etrasimod 2 mg/day and upadacitinib 45 mg/day were superior in the subgroup analysis. During maintenance, upadacitinib 30 mg/day was superior in achieving histologic improvement and remission (P-score 0.88 for both) and histo-endoscopic improvement (P-score 0.94). Etrasimod 2 mg/day ranked second for histologic remission (P-score 0.70) and histo-endoscopic improvement (P-score 0.73), while mirikizumab 200 mg/month ranked second for histologic improvement. These results support the ability of small molecules to achieve stringent endpoints in moderate-to-severe UC. Histological outcome data for biologics was sparser, particularly during maintenance. Head-to-head RCTs are imperative to better inform clinical practice.

Development of Scaffolds with Chitosan Magnetically Activated with Cobalt Nanoferrite: A Study on Physical-Chemical, Mechanical, Cytotoxic and Antimicrobial Behavior.

Background/Objectives: This study investigates the development of 3D chitosan-x-cobalt ferrite scaffolds (x = 5, 7.5, and 10 wt%) with interconnected porosity for potential biomedical applications. The objective was to evaluate the effects of magnetic particle incorporation on the scaffolds' structural, mechanical, magnetic, and biological properties, specifically focusing on their biocompatibility and antimicrobial performance. Methods: Scaffolds were synthesized using freeze-drying, while cobalt ferrite nanoparticles were produced via a pilot-scale combustion reaction. The scaffolds were characterized for their physical and chemical properties, including porosity, swelling, and mechanical strength. Hydrophilicity was assessed through contact angle measurements. Antimicrobial efficacy was evaluated using time kill kinetics and agar diffusion assays, and biocompatibility was confirmed through cytotoxicity tests. Results: The incorporation of cobalt ferrite increased magnetic responsiveness, altered porosity profiles, and influenced swelling, biodegradation, and compressive strength, with a maximum value of 87 kPa at 7.5 wt% ferrite content. The scaffolds maintained non-toxicity and demonstrated bactericidal activity. The optimal concentration for achieving a balance between structural integrity and biological performance was found at 7.5 wt% cobalt ferrite. Conclusions: These findings suggest that magnetic chitosan-cobalt ferrite scaffolds possess significant potential for use in biomedical applications, including tissue regeneration and advanced healing therapies. The incorporation of magnetic properties enhances both the structural and biological functionalities, presenting promising opportunities for innovative therapeutic approaches in reconstructive procedures.

Defining mucosal healing in randomized controlled trials of inflammatory bowel disease: A systematic review and future perspective.

Mucosal healing (MH) is an established treatment goal in inflammatory bowel disease (IBD). However, various definitions of MH exist. We aimed to identify how MH is defined in randomized controlled trials (RCTs) in ulcerative colitis (UC) and Crohn's disease (CD). We searched MEDLINE, EMBASE, and the Cochrane library from inception to December 2023 for phase 2 and 3 RCTs of advanced therapies in IBD. One hundred forty-four studies were included, 72 in UC and 72 in CD, published between 1997 and 2023. In UC, 64% (46/72) RCTs reported MH as an endpoint. 12 definitions of MH were found, from endoscopic assessment alone (35/46; 76%) to the more recent combination of histology and endoscopy (10/46; 22%). 96% (44/46) of studies used the Mayo Endoscopic Subscore. In CD, reporting of MH lagged behind UC, with only 12% (9/72) of trials specifically defining MH as an endpoint, 7 as "absence of ulceration," 2 as Simplified Endoscopic Score for CD score ≤2 or 0. Histological assessment was performed in 3 RCTs of CD. Centralized reading of endoscopy was used in 48% (35/72) of RCTs of UC and 22% (16/72) of CD. Only 1 RCT included transmural healing as an endpoint. A standard definition of MH in IBD is lacking. Definitions have evolved particularly in UC, which now includes the addition of histological evaluation. Transmural healing holds promise as a future target in CD. We support a greater standardization of definitions as we expect endpoints to become increasingly stringent and multimodal with computers automating the assessment.

A Pilot Analysis of Capecitabine Plus PD‐1 Antibody as Maintenance Therapy in Advanced or Metastatic Gastric Cancer and the Prognostic Factors

A Pilot Analysis of Capecitabine Plus PD‐1 Antibody as Maintenance Therapy in Advanced or Metastatic Gastric Cancer and the Prognostic Factors

Ambulation in patients with peripheral veno-arterial extracorporeal membrane oxygenation and concomitant femoral intra-aortic balloon pump support.

The mobilization and ambulation of patients with severe cardiogenic shock supported with peripheral veno-arterial extracorporeal membrane oxygenation (pVA-ECMO) and concomitant femoral intra-aortic balloon pump (IABP) support is not well-described. This technical paper describes an ambulation protocol to prevent deconditioning in this critically ill patient population. A protocol for the ambulation of patients with pVA-ECMO and concomitant IABP support was created in December 2022 and implemented at a single center. To initiate ambulation, patients were initially placed in a vertical position utilizing the VitalGo Total Lift Bed (VitalGo Systems, Miramar, FL) with mechanical circulatory support device monitoring performed by a critical care multidisciplinary team. Retrospective analysis of successfully ambulated patients was performed from December 2022 to January 2024. A total of 35 patients out of 112 patients with ECMO support were ambulated in the study period. Four of these patients had pVA-ECMO with concomitant IABP support with this cohort completing a total of 11 sessions during the study period. Patients ambulated an average of 200 feet per session without any adverse events, including cannula and balloon pump migration or displacement. Three of the four patients studied were either bridged to an advanced therapy including orthotopic heart transplant or durable left ventricular assist device or were discharged. A protocol for ambulation of CS patients with pVA-ECMO support and concomitant femoral IABP support is feasible and can safely be implemented in this critically ill patient population. Further multicenter studies are necessary to determine the overall impact of ambulation on patient outcomes.

Bringing PERT to Pediatrics: Initial Experience and Outcomes of a Pediatric Multidisciplinary Pulmonary Embolism Response Team (PERT)

IntroductionMultidisciplinary Pulmonary Embolism Response Teams (PERTs) streamline care of adults with life-threatening pulmonary embolism (PE). Given rarity of pediatric PE, developing a clinical, educational, and research PERT paradigm is a novel and underutilized concept in pediatrics. Research QuestionIs PERT feasible in pediatrics, and does it improve PE care? Study Design and MethodsA strategy-to-execution proposal to launch a pediatric PERT was developed for institutional buy-in. Key stakeholders collectively implemented PERT. Data were collected for the two-year pre- and post-PERT eras, and outcomes were compared. ResultsPERT implementation took 12 months. Our PERT, led by hematology, comprises of pediatric experts in emergency medicine, critical care, interventional cardiology, anesthesiology, and interventional radiology. Data on 30 patients pre-PERT and 31 post-PERT were analyzed. Pre-PERT, 10%(3/30), 13%(4/30), 20%(6/30), and 57%(17/30), and post-PERT, 3%(1/31), 10%(3/31), 16%(5/31), and 71%(22/31) were categorized as high-risk, intermediate-LOW risk, intermediate-HIGH risk, and low-risk PE, respectively. Post-PERT, there were 13 unique PERT activations. PERT was activated on all eligible PE patients and, additionally, on four low-risk PEs. Time-to-echocardiogram was shorter post-PERT (4.7 hrs vs 2 hrs, P=0.0147). Anticoagulation was ordered (90 min vs 54 min, P=0.003) and given sooner (154 min vs 113 min, P=0.049) post-PERT. There were no differences in time-to-reperfusion therapies (12 hrs pre-PERT vs 8.7 hrs post-PERT, P=0.1). Five (83.3%) of six eligible (intermediate-HIGH and high-risk) patients received reperfusion therapies in the post-PERT era compared to three (37.5%) of eight eligible patients in the pre-PERT era (P=0.0001). There were no differences in major bleeding, mortality, or length of stay in either era. InterpretationThe pediatric PERT paradigm was successfully created and adopted locally. Our PERT enhanced access to experts, facilitated timely advanced therapies, and held value for low-risk PE. The University of Texas Southwestern Medical Center (UTSW) and Children’s Health System of Texas pediatric PERT may serve as a best-practice model for streamlining care for pediatric PE.

A dual-targeted small-molecule photosensitizer with enhanced dual antitumor and anti-vascular effect for metastatic advanced prostate cancer photodynamic therapy

Advanced prostate cancer is regarded as a fatal disease, characterized by limited treatment options, poor prognosis and considerable tumor metastasis closely related to angiogenesis. Photodynamic therapy emerges as a promising and safe therapeutic modality for advanced prostate cancer with high metastasis and high fatality rate due to its focal damage to tumor cells, as well as its anti-angiogenesis and antitumor immunity capabilities. Herein, a tumor-targeting vascular disrupting agent ASA-404 was introduced to conjugate with a photosensitizer ZnPc for targeted prostate cancer treatment and enhanced vascular-disrupting efficiency. Notably, this novel organic small-molecule photosensitizer Pc-ASA possess a well-defined chemical structure and purity, as well as good photophysical and photochemical properties, which are of benefit for clinical approval and application. Pc-ASA prefers to accumulate in both prostate cancer cells and vascular endothelial cells. Moreover, the conjugation of ASA-404 boosts the photodynamic anticancer effect of Pc-ASA towards both prostate cancer cells and vascular endothelial cells. Ultimately, PC-ASA can successfully inhibit the migration and metastasis of prostate cancer cells, offering significant advantages in advanced prostate cancer management. Our study might open a window in the development of the tumor and vascular dual-targeted small-molecule photosensitizers, with the potential to achieve safe and efficient treatment of metastatic advanced prostate cancer through dual mode of antitumor and anti-vascular action.

La magia de la Farmacobiotecnología: De las magistrales a los virus recombinantes en terapia génica

In the history of societies, in general, there is a progressive evolution, which runs parallel to the progress of science and, in particular, of Medicine. Perhaps it is necessary to consider, without fear of misunderstanding, that Pharmacology has allowed us to live longer and better. If we look back, especially those of us who have had the good fortune of having a very old apothecary’s shop, where perhaps our great-grandfather was a pharmacist, a lifelong pharmacist, in an almost lost village in the former Castilla La Vieja, around the second half of the 19th century, we can better appreciate the progress that has been made. But, in addition, if the great-grandson in question chose to follow a family tradition of being an apothecary, things take on a different dimension, especially when his vocation has been of university professor in Pharmacy and of researcher in Biotechnology. Knowing that we are facing an extraordinarily novel pharmacological reality, it would seem that we are moving in the world of magic and surprise. Because the therapeutic purposes that are being pursued at the present time were unimaginable decades ago, and even less so with the current techniques, pharmaceutical forms and procedures that are a combination of the multidisciplinary activity of many specialists. In this evolution that goes from magistral formulas, of empirical utility, to new advanced therapies, areas have been born that are the combination of different knowledge, such as Pharmacobiotechnology. We also control, in part, biology in its most intimate “soul”, which is the genome, and we are able to create animal models with a specific pathology to study new drugs. Pharmacobiotechnology has made it possible to obtain recombinant therapeutic proteins in the laboratory; recombinant mono- and bispecific antibodies for the treatment of cancer and other diseases and, through new therapies, gene therapy and cell therapy, it is possible to correct alterations in the genes that give rise to many hereditary diseases. However, in this new world of modern pharmacology, which will be largely individualized, the bioethics of healing must be kept in mind, lest the new high-cost procedures can further increase social inequity. Keywords: Advances in Biomedicine; History; Biotechnology; Advanced therapies; Rare diseases

Comparative Efficacy of Advanced Therapies for Management of Moderate-to-Severe Ulcerative Colitis: 2024 American Gastroenterological Association Evidence Synthesis

We performed an updated systematic review and network meta-analysis to inform the 2024 American Gastroenterological Association (AGA) Clinical Guidelines on the management of moderate-to-severe ulcerative colitis (UC). We searched multiple electronic databases through November 21, 2023, to identify randomized controlled trials in adults with moderate-to-severe UC, comparing different advanced therapies (tumor necrosis factor antagonists, vedolizumab, sphingosine-1-phosphate receptor modulators, interleukin 12/23 or selective interleukin 23 antagonists, and Janus kinase [JAK] inhibitors) against placebo or another active comparator. Our primary outcomes were induction and maintenance of clinical remission, and our secondary outcome was endoscopic improvement. We performed a network meta-analysis using a frequentist approach and applied Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to appraise certainty of evidence. After excluding JAK inhibitors as potential first-line treatment (in accordance with the United States Food and Drug Administration), low-certainty evidence supports clinically important benefit with infliximab, ozanimod, risankizumab, and guselkumab over adalimumab and mirikizumab for achieving remission with induction therapy in biologically naïve patients with moderate-to-severe UC, with risankizumab and ozanimod being ranked the highest for induction of clinical remission. With the inclusion of JAK inhibitors as first-line therapy, upadacitinib was more efficacious compared with all other medications except ozanimod and risankizumab, with low- to moderate-certainty evidence. In patients with prior biologic exposure, upadacitinib, tofacitinib, and ustekinumab were ranked highest for achieving remission. Using Grading of Recommendations, Assessment, Development and Evaluation to appraise quality of evidence, this updated network meta-analysis will be used to inform comparative efficacy and positioning of advanced therapies for the treatment of biologic-naïve and biologic-exposed patients with moderate-to-severe UC.

No Impact of Concomitant Medications on Efficacy and Safety of Biologics and Small Molecules for Ulcerative Colitis

While participants with inflammatory bowel diseases (IBD) in clinical trials of biologics and small molecule drugs (henceforth, advanced therapies) frequently receive several medications concomitantly, it is unclear how they modify treatment effect. Through an individual patient data pooled analysis of ten clinical trials of advanced therapies for moderate-to-severe ulcerative colitis (UC), we assessed whether concomitant exposure to corticosteroids, immunomodulators, 5-aminosalicylates, proton pump inhibitors (PPIs), histamine receptor antagonists (H2RA), opiates, antidepressants, and antibiotics modified the effect of the intervention on treatment efficacy and safety outcomes, using modified Poisson regression model. Of 6044 patients (4280 receiving intervention, 1764 receiving placebo), several received concomitant corticosteroids (47%), immunomodulators (28%), 5-aminosalicylates (68%), PPIs (14%), H2RAs (2%), opiates (7%), antidepressants (6%), and/or antibiotics (5%). After adjusting for confounders and examining treatment efficacy of intervention vs. placebo, we observed no impact of concomitant exposure to corticosteroids (ratio of relative risk of drug vs. placebo with vs. without concomitant exposure: RRR, 0.81 [95% CI,0.63-1.06], 5-aminosalicylates (RRR, 1.04[0.78-1.39]), PPIs (RRR, 0.87 [0.61-1.22]), H2RAs (RRR, 1.72[0.97-14.29]), opiates (RRR, 0.90[0.54-1.49]), antidepressants (RRR, 1.02[0.57-1.83]), and antibiotics (RRR, 0.72[0.44-1.16]) on likelihood of clinical remission. Concomitant exposure to immunomodulators was associated with lower likelihood of achieving clinical remission (RRR, 0.73[0.55-0.97]), particularly with non-TNF antagonists. In clinical trials of advanced therapies for UC, baseline concomitant exposure to multiple commonly used class of medications does not impact treatment efficacy or safety. These findings directly inform design of regulatory clinical trials with respect to managing concomitant medications at baseline.

693P Proposed NIH core for advanced genetic therapies: spotlight on clinical development of AAV products for neuromuscular disorders

693P Proposed NIH core for advanced genetic therapies: spotlight on clinical development of AAV products for neuromuscular disorders

Bridged Ethylene Polyethylene Oxide Surfaces to Improve Packing Materials for Widepore Size Exclusion Chromatography.

Here, we describe the preparation of bridged ethylene polyethylene oxide (BE-PEO) surface-modified silica packing materials for size exclusion chromatography. BE-PEO surface-modified silica was hydrolyzed and subsequent 1H nuclear magnetic resonance analysis of hydrolysis products confirmed the successful formation of BE-PEO bonded surface. Silica particles exhibiting 3µm diameters and 1000 Å nominal pore diameters were selected as a base material for this work out of the critical need to improve analytical capabilities for the testing of cell and gene therapy drug products. Accelerated high pH aging study revealed significant enhancement in column stability. Multi-angle light scattering noise measurements showed inordinately lower baseline noise. Moreover, we evaluated the chromatographic performance of BE-PEO silica-packed columns through separations of a protein test mixture, DNA ladder, monoclonal antibody-based therapeutics, and adeno-associated viruses. BE-PEO silica columns demonstrated high resolution, high recovery separations that were confirmed to be reproducible and capable of extended column lifetimes and exhibited low ionic and hydrophobic secondary interactions. In summary, BE-PEO silica particles have yielded a new level of performance, improved base stability, and inherently lower baseline noise. These novel widepore particles will facilitate more sensitive size-based detection and characterization of large biologics in the form of advanced gene therapy products.

S1469 Understanding Gastroenterologist Preferences at the Time of Treatment Escalation to First-Line Advanced Therapies in Ulcerative Colitis: A Discrete Choice Experiment in Five European Countries

S1469 Understanding Gastroenterologist Preferences at the Time of Treatment Escalation to First-Line Advanced Therapies in Ulcerative Colitis: A Discrete Choice Experiment in Five European Countries

S1468 Understanding Patient Preferences at the Time of Treatment Escalation to First Line Advanced Therapies in Ulcerative Colitis: A Discrete Choice Experiment in Five European Countries

S1468 Understanding Patient Preferences at the Time of Treatment Escalation to First Line Advanced Therapies in Ulcerative Colitis: A Discrete Choice Experiment in Five European Countries

Placebo rates in Crohn’s disease randomized clinical trials: An individual patient data meta-analysis

Understanding placebo rates is critical for efficient clinical trial design. We assessed placebo rates and associated factors using individual patient data (IPD) from Crohn's disease (CD) trials. We conducted a meta-analysis of phase 2/3 placebo-controlled trials evaluating advanced therapies in moderate-to-severe CD (2010-2021). Deidentified IPD were obtained through Vivli Inc. and Yale University Open Data Access Project. Primary outcomes were clinical response and remission. Pooled placebo rates and 95% confidence intervals (CIs) were estimated using one- and two-stage meta-analytical approaches. Regression analyses identified patient-level factors associated with placebo rates. Using IPD from eight induction (n=1147) and four maintenance (n=524) trials, overall placebo clinical response and remission rates for induction were 27% (95%CI=23-32%) and 10% (95%CI=8-14%) respectively, and 32% (95%CI=23-42%) and 22% (95%CI=14-33%) for maintenance, respectively. Among bio-naïve patients, placebo response and remission rates during induction were 29% (95%CI=24-35%) and 11% (95%CI=8-15%) respectively, and 26% (95% CI=20-33%) and 10% (95% CI=8-14%) for bio-exposed, respectively. During maintenance, bio-naïve response and remission rates were 41% (95%CI=34-48%) and 32% (95%CI=24-40%), respectively, and 29% (95%CI=24-34%) and 16% (95%CI=13-21%) for bio-exposed, respectively. Higher baseline C-reactive protein concentration predicted lower placebo rates, while higher baseline albumin levels and body mass index increased the odds of placebo outcomes. Increased baseline Crohn's Disease Activity Index and 2-item patient-reported outcome scores predicted higher response rates in induction, lower response rates in maintenance, and lower remission rates in induction and maintenance. Patient- and trial-level characteristics influence placebo rates in CD trials. Careful implementation of eligibility criteria, outcome definitions, and patient stratification may reduce placebo rates.

Enumeration and gentle sorting of immune cells on chip, key to next generation advanced therapies in outpatient setting.

A thorough understanding of immune-oncology and molecular medicine has been vital in the development of cell therapeutics. At the basis of this translational research and its future implementation into a medicinal product, lies the availability of pure and viable cell populations. However, a versatile technology able of multi marker detection and isolation of complex cell types with high purity, viability and throughput is lacking. Currently, FACS and magnetic bead isolation are successfully used but suffer to fulfill all requirements. FACS is costly and difficult to upscale due to the limitation of shear stress, especially fragile, cells can handle. Therefore, magnetic bead isolation is often used as it is gentler but it lacks the multiparametric aspect to isolate more complex cellular profiles. We have developed a gentle sorting mechanism based on a jet flow created by micro vapor bubbles, enabling a closed microfluidic cell isolation platform capable of multiparametric sorting with high viability, purity and throughput.In previous work, we demonstrated high purity and recovery of rare cells and the multiparametric detection capability. Here we demonstrate that this tool can achieve a pure population of CD4+ CD14- cells with high viability without compromising the recovery. These characteristics complete the list of requirements for the phenotyping and isolation of therapeutic cells. On top of the viability also the growth and activation potential of sorted cells is unhampered by comparison to the benchmark gentle magnetic isolation, mostly deployed in the context of cell therapy manufacturing. Our technology allows for the development of a compact system which sets it apart from other efforts intended to create automated cell therapeutic solutions.

Venous thromboembolism during pregnancy and postpartum period: an updated review.

Venous thromboembolism (VTE) is a leading cause of maternal mortality. The risk of VTE in pregnant and postpartum women is ~ five times higher compared with non-pregnant women. There is a physiological tendency to a hypercoagulable state, from conception to the postpartum period. Several non-obstetric risk factors independently increase the risk of VTE. Since most signs and symptoms of VTE might mimic those of a normal pregnancy, a high index of suspicion is warranted to establish the diagnosis. D-dimer, ultrasonography and computed tomography pulmonary angiography are the primary tools for VTE diagnosis. Management mainly revolves around systemic anticoagulation with heparin. Advanced therapy options exist, but these can be considered for selected high-risk cases.