Prodrugs and prodrug-activated systems in gene therapy.

The inclusion of genes that control cell fate (so-called suicide, or kill-switch, genes) into gene therapy vectors is based on a compelling rationale for the safe and selective elimination of aberrant transfected cells. Prodrug-activated systems were developed in the 1980s and 1990s and rely on the enzymatic conversion of non-active prodrugs to active metabolites that lead to cell death. Although considerable effort and ingenuity has gone into vector design for gene therapy, less attention has been directed at the efficacy or associated adverse effects of the prodrug systems employed. In this review, we discuss prodrug systems employed in clinical trials and consider their role in the field of gene therapy. We highlight potential drawbacks associated with the use of specific prodrugs, such as systemic toxicity of the activated compound, the paucity of data on biodistribution of prodrugs, bystander effects, and destruction of genetically modified cells, and how these can inform future advances in cell therapies.

[Paraprotein-related kidney disease. Experience in 22 cases]. / Nefropatías secundarias a paraproteína: perfil clínico a partir de hallazgos histológicos.

BACKGROUND: One of the devastating consequences of monoclonal gammopathies is the development of end-stage kidney disease, which can be prevented with an early diagnosis. Renal involvement can be secondary to saturation of paraproteins with intratubular precipitation or the glomerular deposition of paraproteins with secondary inflammation and destruction. These conditions can also be associated with monoclonal gammopathies that do not meet hematological treatment criteria, called monoclonal gammopathies of renal significance (MGRS). AIM: To report a retrospective analysis of patients who underwent a renal biopsy and whose final diagnosis was a form of monoclonal gammopathy. MATERIAL AND METHODS: We reviewed the clinical and laboratory features and response to treatment of 22 patients aged 63 ± 12 years (55% women) with a pathological diagnosis of a nephropathy associated with paraproteinemia. RESULTS: The most common hematological diagnosis was amyloidosis in 50% of patients, followed by cast nephropathy. The predominant clinical presentations were proteinuria (without nephrotic syndrome) and nephritic syndrome. Classic criteria such as erythrocyte sedimentation rate > 100 mm/h and protein-albumin gap were unusual. Serum light chain quantification was the test with the best yield to detect paraproteins. CONCLUSIONS: In this group of patients, light chains tend to affect the kidney more commonly than heavy chains. The prognosis of multiple myeloma is much worse than MGRS.

[Hypophosphatemia induced by carboxymaltose iron and imatinib. Report of two cases]. / Hipofosfatemia inducida por drogas: fierro carboximaltosa e imatinib. Casos clínicos.

Hypophosphatemia is a relatively frequent and a potentially serious adverse drug effect. Clinically it is characterized by bone pain and muscle weakness. There are several mechanisms by which a drug can induce hypophosphatemia and they can be classified according to whether or not they are mediated by an excess of Fibroblast Growth Factor 23 (FGF23). We report two patients with the condition: (i) A 49-year-old woman with Chronic Myeloid Leukemia (CML) and gastric sleeve surgery at 46 years of age. After receiving intravenous carboxymaltose iron in one occasion due to refractory anemia, she developed symptomatic hypophosphatemia. Urinary phosphate losses associated with high FGF23 levels were confirmed. Plasma phosphate returned to normal values 90 days after the iron administration. (ii) A 40-year-old man with a history of CML in whom imatinib was started. He developed symptomatic hypophosphatemia due to non FGF23-mediated hyperphosphaturia. As treatment with imatinib could not be interrupted, hypophosphatemia and its symptoms resolved with oral phosphate intake. These cases illustrate the importance of recognizing and treating drug-induced hypophosphatemia in a timely manner, and thus avoid the morbidity associated with this entity.

[Cytarabine and hematopoietic cell transplantation for mantle cell lymphoma. Analysis of 20 patients]. / Resultados de pacientes con linfoma del manto: impacto de terapias basadas en citarabina y trasplante hematopoyético.

BACKGROUND: Mantle cell lymphoma (MCL) has high relapse and mortality rates. There is a survival benefit when treatment is intensified with cytarabine (AraC), hematopoietic cell transplantation (HCT) and maintenance with rituximab. AIM: To assess the outcomes of patients with MCL treated in a university hospital. MATERIAL AND METHODS: Review of an oncology center database and medical records identifying patients with MCL treated between 2006 and 2017. Death dates were obtained from the death certificate database of the National Identification Service. We analyzed the response rate, overall survival (OS) and progression-free survival (PFS). As a secondary objective, the survival impact of AraC, HCT and maintenance with rituximab, was also analyzed. RESULTS: Information on 20 patients aged 62 ± 11 years, followed for a median of 45 months was retrieved. Eighty-five percent were diagnosed at an advanced stage. The most used first-line regime was R-CHOP in 11 patients, followed by R-HyperCVAD in five. Only 47% achieved complete response. 4-year PFS and OS were of 30 and 77% respectively. Mantle Cell Lymphoma International Prognostic Index (MIPI) significantly predicted PFS and OS. Maintenance with rituximab or HCT was associated with better PFS (48 vs 21 months, p < 0.01). The exposure to AraC or HCT, in refractory or relapsed disease, was associated with an increase in PFS from 9 to 28 months (p = 0,02) and 4-year OS from 40 to 100% (p = 0.05). OS increased even more, from 25 to 100% in those with high-risk MIPI (p = 0.04). CONCLUSIONS: The incorporation of AraC, HCT and maintenance with rituximab in the therapeutic backbone of MCL, especially for high-risk cases, was associated with improved survival.

[Response to ABVD chemotherapeutic protocol in patients with early stage Hodgkin’s lymphoma]. / Excelente respuesta a tratamiento con ABVD en pacientes con linfoma de Hodgkin localizado.

BACKGROUND: Recent trials show that > 90% of patients with early stage Hodgkin`s Lymphoma (ESHL) can be cured, especially when using the ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapeutic (CT) protocol. The use of radiotherapy (RT) is variable and can be selected according to the presence of specific risk factors, including PET-CT, as recently reported. AIM: To report the experience in the treatment of ESHL. MATERIAL AND METHODS: Retrospective and descriptive analysis of patients with ESHL treated at the Red de Salud UC-Christus between 2011-2015. RESULTS: Twenty-two patients were treated. In 73%, the tumor was of nodular sclerosis histologic type. Most patients (95%) were in stage II, and 78% had a favorable prognosis according to the Deutsche Hodgkin Studiengruppe (GHSG) criteria. All patients were stratified using PET-CT and treated using the ABVD CT protocol, for 4-6 cycles. Only 5 patients received RT. There was no change of conduct after interim-PET-CT results. Ninety one percent of patients achieved complete response and there were two cases of refractory disease. Both cases underwent hematopoietic stem cell transplantation. After 17 months of median follow-up, 91% of patients are relapse-free, and only one patient died (5%). CONCLUSIONS: ABVD offers excellent results for ESHL patients. The benefit of PET-CT should be evaluated with prospective protocols, aiming to select patients needing RT or to reduce the number of CT cycles.

A Red-Light-Activated Ruthenium-Caged NAMPT Inhibitor Remains Phototoxic in Hypoxic Cancer Cells.

We describe two water-soluble ruthenium complexes, [1]Cl2 and [2]Cl2 , that photodissociate to release a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with a low dose (21 J cm-2 ) of red light in an oxygen-independent manner. Using a specific NAMPT activity assay, up to an 18-fold increase in inhibition potency was measured upon red-light activation of [2]Cl2 , while [1]Cl2 was thermally unstable. For the first time, the dark and red-light-induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1 % O2 ). In skin (A431) and lung (A549) cancer cells, a 3- to 4-fold increase in cytotoxicity was found upon red-light irradiation for [2]Cl2 , whether the cells were cultured and irradiated with 1 % or 21 % O2 . These results demonstrate the potential of photoactivated chemotherapy for hypoxic cancer cells, in which classical photodynamic therapy, which relies on oxygen activation, is poorly efficient.

[Vitamin D and parathyroid hormone levels and bone mineral density in patients undergoing hematopoietic cell transplantation]. / Salud ósea en pacientes sometidos a trasplante de precursores hematopoyéticos: un nuevo problema a considerar.

BACKGROUND: Patients undergoing hematopoietic cell transplantation (HCT) are at increased risk of developing osteoporosis. AIM: To determine the frequency and severity of Vitamin D deficiency, secondary hyperparathyroidism and low bone mass in patients undergoing HCT. PATIENTS AND METHODS: Analysis of the database of patients undergoing HCT in our institution in the 2010-2015 period. We searched for patients with measurements of 25-OH vitamin D (25OHD), parathyroid hormone (PTH) and bone densitometry by double beam X ray absorptiometry (DXA) prior and up to one year after HCT. RESULTS: Ninety patients were included, 53 were evaluated prior to HCT and 37 after HCT. They represent 73% of all patients undergoing HCT in the period. Median 25OHD was 12 ng/ml (range 4-41.4). Ninety seven percent of patients had levels considered insufficient and 85% compatible with deficiency. Median PTH was 60.5 pg/ml (range 21-186). Forty five percent of patients had secondary hyperparathyroidism. DXA was performed in 65 patients (prior to HCT in 54 and after HCT in 11). Of these, 11% had had a low bone mineral density. CONCLUSIONS: Patients undergoing HCT have a high risk of vitamin D deficiency, secondary hyperparathyroidism and low bone mineral density.

Admission of hematopoietic cell transplantation patients to the intensive care unit at the Pontificia Universidad Católica de Chile Hospital.

Patients undergoing hematopoietic cell transplantation (HCT) can have complications that require management in the intensive care unit (ICU). We conducted a retrospective study of patients undergoing HCT between 2007 and 2011 with admission to the ICU. We analyzed 97 patients, with an average age of 37 (range, 15 to 68). The main indications for HCT were hematologic malignancies (84%, n = 82). Ninety percent (n = 87) received myeloablative conditioning. Thirty-one percent were admitted (autologous transplant recipients 15%, allogeneic transplant recipients 34%, and umbilical cord blood [UCB] transplant recipients 48%) with an average length of stay of 19 days (range, 1 to 73 days). The average time between transplantation and transfer was 15 days. The main causes of admission were acute respiratory failure (63%) and septic shock (20%). ICU mortality was 20% for autologous transplantations and 64% for allogeneic transplantations (adult donor and UCB combined). On average, patients died 108 days after the transplantation (range, 4 to 320 days). One-year overall survival, comparing patients entering the ICU with those never admitted, was 16% versus 82% (P < .0001) for allogeneic transplantations (adult donor and UCB combined) and 80% versus 89% (P = not significant) for autologous transplantations. Acute graft-versus-host disease was significantly associated with death in ICU after UCB HCT. ICU support is satisfactory in about one half of patients admitted, characterized by a short and medium term prognosis not as unfavorable as has been previously reported.

[Results of acute myeloid leukemia treatment. Analysis of 63 patients between 2010-2014]. / Resultados en el tratamiento de pacientes con leucemia mieloide aguda no promielocítica en el Hospital Clínico de la Pontificia Universidad Católica entre los años 2010-2014.

BACKGROUND: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, emphasizing its high recurrence rate despite hematopoietic cell transplantation (HCT). AIM: To report the results of AML treatment at the Catholic University of Chile Clinical Hospital. PATIENTS AND METHODS: Review of medical records of patients with AML. RESULTS: 63 patients, median age 55.4 years (range:16-89), treated between 2010 and 2014. Admission laboratory values showed (median values): leukocytes 45.989/mm³, hemoglobin 9.1 g/dl, platelets 75.548/mm³, peripheral blood blasts 38% and bone marrow blasts 74%. According to cytogenetic risk classification we observed the following groups: favorable 8% (n = 5), intermediate 51% (n = 32), unfavorable 13% (n = 8) and unknown 28% (n = 17). Seventy five percent of patients received induction chemotherapy and 25% palliative care. Median survival of treated and palliative care patients was 27.3 and 1 month respectively. Induction chemotherapy (IC) mortality (ICM) was 4.2%. Seventy percent (n = 33) of patients who received IC had complete response (CR) with a 3-year relapse free survival (RFS) of 25% and overall survival (OS) of 31%. Multivariate analysis demonstrated that achievement of CR, cytogenetic risk group and receiving consolidation chemotherapy were significantly associated with better RFS and OS. CONCLUSIONS: AML treatment with standard chemotherapy in our center achieves similar results to what has been described in international series regarding induction rates and ICM, however RFS and OS are still very low, especially in intermediate and high cytogenetic risk groups.

Systemic embolization due to non-bacterial thrombotic endocarditis: An autopsy case report and mini review of the literature.

Nonbacterial thrombotic endocarditis is a rare, non-infectious complication associated with hypercoagulable states, such as malignancies and autoimmune diseases. Due to the difficulty distinguishing marantic endocarditis from infective endocarditis, the diagnosis is often delayed or even a postmortem finding. We present the case of a 70-year-old Caucasian female with marantic endocarditis secondary to metastatic duodenal adenocarcinoma. The patient presented with a short history of memory deficits, personality disturbances, and left homonymous hemianopia. Diffusion-weighted magnetic resonance imaging showed multi-territorial bihemispheric cerebral infarctions. Transthoracic echocardiography revealed native mitral valve endocarditis, and serial blood cultures remained negative. Despite antibiotic therapy, the patient's condition continuously deteriorated, and she died within 3 weeks after her initial presentation. Postmortem examination showed a non-bacterial thrombotic endocarditis. Early clinical suspicion and prompt diagnosis are of decisive importance for the survival of the patients.

Integration of T-cell clonality screening using TRBC-1 in lymphoma suspect samples by flow cytometry.

BACKGROUND: The diagnosis of T-cell non-Hodgkin lymphomas (NHL) is challenging. The development of a monoclonal antibody specific for T-cell receptor ß constant region 1 (TRBC1) provides an alternative to discriminate clonal T cells. The aim of this study was to evaluate the diagnostic potential of an anti-TRBC1 mAb for the identification of T-NHL. METHODS: We performed a cross-sectional diagnostic analytic study of samples tested for lymphoma. All samples sent for lymphoma screening were first evaluated using the standard Euroflow LST, to which a second additional custom-designed T-cell clonality assessment tube was added CD45/TRBC1/CD2/CD7/CD4/TCRγδ/CD3. Flow cytometry reports were compared with morphological and molecular tests. RESULTS: Fifty-nine patient samples were evaluated. Within the T-cell population, cut-off percentages in the CD4+ cells were from 29.4 to 54.6% and from 23.9 to 52.1% in CD8+ cells. Cut-off ratios in CD4+ T cells were from 0.33 to 1.1, and in CD8+ cells between 0.22 and 1.0. Using predefined normal cut-off values, 18 of 59 (30.5%) samples showed a restricted expression of TRBC1. A final diagnosis of a T-NHL was confirmed clinically and/or by histopathological studies in 15 of the 18 cases (83.3%). There were no cases of T-NHL by morphology/IHC with normal TRBC1 expression. Non-neoplastic patient samples behaved between predefined TRBC1 cut-off values. CONCLUSIONS: Expression of TRBC1 provides a robust method for T-cell clonality assessment, with very high sensitivity and good correlation with complementary methods. TRBC1 can be integrated into routine lymphoma screening strategies via flow cytometry.

Association of part-time clinical work with well-being and mental health in General Internal Medicine: A survey among Swiss hospitalists.

INTRODUCTION: Burnout and low job satisfaction are increasing among the General Internal Medicine (GIM) workforce. Whether part-time compared to full-time clinical employment is associated with better wellbeing, job satisfaction and health among hospitalists remains unclear. MATERIALS AND METHODS: We conducted an anonymized cross-sectional survey among board-certified general internists (i.e. hospitalists) from GIM departments in 14 Swiss hospitals. Part-time clinical work was defined as employment of <100% as a clinician. The primary outcome was well-being, as measured by the extended Physician Well-Being Index (ePWBI), an ePWBI ≥3 indicating poor wellbeing. Secondary outcomes included depressive symptoms, mental and physical health, and job satisfaction. We compared outcomes in part-time and full time workers using propensity score-adjusted multivariate regression models. RESULTS: Of 199 hospitalists invited, 137 (69%) responded to the survey, and 124 were eligible for analysis (57 full-time and 67 part-time clinicians). Full-time clinicians were more likely to have poor wellbeing compared to part-time clinicians (ePWBI ≥3 54% vs. 31%, p = 0.012). Part-time compared to full-time clinical work was associated with a lower risk of poor well-being in adjusted analyses (odds ratio 0.20, 95% confidence interval 0.07-0.59, p = 0.004). Compared to full-time clinicians, there were fewer depressive symptoms (3% vs. 18%, p = 0.006), and mental health was better (mean SF-8 Mental Component Summary score 47.2 vs. 43.2, p = 0.028) in part-time clinicians, without significant differences in physical health and job satisfaction. CONCLUSIONS: Full-time clinical hospitalists in GIM have a high risk of poor well-being. Part-time compared to full-time clinical work is associated with better well-being and mental health, and fewer depressive symptoms.

A New Methodological Approach to the Characterization of Optimal Charging Rates at the Hydrogen Plasma Smelting Reduction Process Part 1: Method.

The development of a carbon lean steel production process following the concept of direct carbon avoidance is one of the most challenging tasks the iron and steel industry must tackle in just a few decades. The necessary drastic reduction of 80% of the process's inherent emissions by 2050 is only possible if a new process concept that uses hydrogen as the primary reductant is developed. The Hydrogen Plasma Smelting Reduction (HPSR) of ultra-fine iron ores is one of those promising concepts. The principle was already proven at a lab scale. The erection of a bench-scale facility followed this, and further scaled-ups are already planned for the upcoming years. For this scale-up, a better understanding of the fundamentals of the process is needed. In particular, knowledge of the kinetics of the process is essential for future economically feasible operations. This investigation shows the principles for evaluating and comparing the process kinetics under varying test setups by defining a representative kinetic parameter. Aside from the fundamentals for this definition, the conducted trials for the first evaluation are shown and explained. Several differences in the reduction behavior of the material at varying parameters of the process have already be shown. However, this investigation focuses on the description and definition of the method. An overall series of trials for detailed investigations will be conducted as a follow-up.

A New Methodological Approach on the Characterization of Optimal Charging Rates at the Hydrogen Plasma Smelting Reduction Process Part 2: Results.

To meet the target for anthropogenic greenhouse gas (GHG) reduction, the European steel industry is obliged to reduce its emissions. A possible pathway to reach this requirement is through developments of new technologies for a GHG-free steel production. One of these processes is the hydrogen plasma smelting reduction (HPSR) developed since 1992 at the Chair of Ferrous Metallurgy at the Montanuniversitaet Leoben in Austria. Based on the already available publication of the methodology in this work, potential process parameters were investigated that influence the reduction kinetics during continuous charging to improve the process further. Preliminary tests with different charging rates and plasma gas compositions were carried out to investigate the impacts on the individual steps of the reduction process. In the main experiments, the obtained parameters were used to determine the effect of the pre-reduction degree on the kinetics and the hydrogen conversion. Finally, the preliminary and main trials were statistically evaluated using the program MODDE® 13 Pro to identify the significant influences on reduction time, oxygen removal rate, and hydrogen conversion. High hydrogen utilization degrees could be achieved with high iron ore feeding rates and low hydrogen concentrations in the plasma gas composition. The subsequent low reduction degree and thus a high proportion of oxide melt leads to a high oxygen removal rate in the post-reduction phase and, consequently, short process times. Calculations of the reduction constant showed an average value of 1.13 × 10-5 kg oxygen/m2 s Pa, which is seven times higher than the value given in literature.

Elimination of hospital-acquired central line-associated bloodstream infection on a mixed-service pediatric unit.

INTRODUCTION: Hospital-acquired central line-associated bloodstream infections (CLABSI) are "never events" in U.S. healthcare. National efforts to improve CLABSI rates are ongoing. Efforts are important for all patients with a central venous catheter (CVC) and critical to children with intestinal failure (IF) who depend on long-term, daily use of a CVC and undergo extended hospitalizations. We describe outcomes of a multidisciplinary CLABSI elimination effort on a 24-bed medical-surgical unit caring for children with IF. METHODS: Unit CLABSI events from 1/9/2012 to 4/16/2020 were evaluated with multiple improvement interventions. We leveraged prospectively maintained clinical registries and National Healthcare Safety Network (NHSN) reporting data to extract patient and unit demographics, ethanol lock utilization, and unit CVC days. Interventions were developed utilizing expert consensus and CDC guidelines with active frontline staff engagement. Descriptive statistics and tests of non-parametric data were employed for analysis. RESULTS: Ninety-five patients with IF and 862 non-IF patients experienced a total of 1,629 admissions with 20,372 CVC days. Twelve hospital-acquired CLABSI events occurred during the study period, including 7 following NHSN definition change on 1/1/2015 (0.56 per 1,000 CVC days). After the last unit CLABSI on 12/5/2016, there were 7,117 CVC days through study conclusion. CONCLUSIONS: Described interventions with an enhanced culture of collaborative care profoundly improved hospital-acquired CLABSI occurrence. Success in a specific population translated to all other unit patients with a CVC. Findings suggest elimination is not the result of a single new product or practice, but also includes support and empowerment of those caring for the patient and their CVC.

Metallated phthalocyanines and their hydrophilic derivatives for multi-targeted oncological photodynamic therapy.

BACKGROUND AND AIM: A photosensitizer (PS) delivery and comprehensive tumor targeting platform was developed that is centered on the photosensitization of key pharmacological targets in solid tumors (cancer cells, tumor vascular endothelium, and cellular and non-cellular components of the tumor microenvironment) before photodynamic therapy (PDT). Interstitially targeted liposomes (ITLs) encapsulating zinc phthalocyanine (ZnPC) and aluminum phthalocyanine (AlPC) were formulated for passive targeting of the tumor microenvironment. In previous work it was established that the PEGylated ITLs were taken up by cultured cholangiocarcinoma cells. The aim of this study was to verify previous results in cancer cells and to determine whether the ITLs can also be used to photosensitize cells in the tumor microenvironment and vasculature. Following positive results, rudimentary in vitro and in vivo experiments were performed with ZnPC-ITLs and AlPC-ITLs as well as their water-soluble tetrasulfonated derivatives (ZnPCS4 and AlPCS4) to assemble a research dossier and bring this platform closer to clinical transition. METHODS: Flow cytometry and confocal microscopy were employed to determine ITL uptake and PS distribution in cholangiocarcinoma (SK-ChA-1) cells, endothelial cells (HUVECs), fibroblasts (NIH-3T3), and macrophages (RAW 264.7). Uptake of ITLs by endothelial cells was verified under flow conditions in a flow chamber. Dark toxicity and PDT efficacy were determined by cell viability assays, while the mode of cell death and cell cycle arrest were assayed by flow cytometry. In vivo systemic toxicity was assessed in zebrafish and chicken embryos, whereas skin phototoxicity was determined in BALB/c nude mice. A PDT efficacy pilot was conducted in BALB/c nude mice bearing human triple-negative breast cancer (MDA-MB-231) xenografts. RESULTS: The key findings were that (1) photodynamically active PSs (i.e., all except ZnPCS4) were able to effectively photosensitize cancer cells and non-cancerous cells; (2) following PDT, photodynamically active PSs were highly toxic-to-potent as per anti-cancer compound classification; (3) the photodynamically active PSs did not elicit notable systemic toxicity in zebrafish and chicken embryos; (4) ITL-delivered ZnPC and ZnPCS4 were associated with skin phototoxicity, while the aluminum-containing PSs did not exert detectable skin phototoxicity; and (5) ITL-delivered ZnPC and AlPC were equally effective in their tumor-killing capacity in human tumor breast cancer xenografts and superior to other non-phthalocyanine PSs when appraised on a per mole administered dose basis. CONCLUSIONS: AlPC(S4) are the safest and most effective PSs to integrate into the comprehensive tumor targeting and PS delivery platform. Pending further in vivo validation, these third-generation PSs may be used for multi-compartmental tumor photosensitization.

Road to Acquisition: Preparing a MEMS Microphone Array for Measurement of Fuselage Surface Pressure Fluctuations.

Preparing and pre-testing experimental setups for flight tests is a lengthy but necessary task. One part of this preparation is comparing newly available measurement technology with proven setups. In our case, we wanted to compare acoustic Micro-Electro-Mechanical Systems (MEMS) to large and proven surface-mounted condenser microphones. The task started with the comparison of spectra in low-speed wind tunnel environments. After successful completion, the challenge was increased to similar comparisons in a transonic wind tunnel. The final goal of performing in-flight measurements on the outside fuselage of a twin-engine turboprop aircraft was eventually achieved using a slim array of 45 MEMS microphones with additional large microphones installed on the same carrier to drawn on for comparison. Finally, the array arrangement of MEMS microphones allowed for a complex study of fuselage surface pressure fluctuations in the wavenumber domain. The study indicates that MEMS microphones are an inexpensive alternative to conventional microphones with increased potential for spatially high-resolved measurements even at challenging experimental conditions during flight tests.

Maternal and perinatal outcomes of a venous thromboembolism high-risk cohort using a multidisciplinary treatment approach.

OBJECTIVE: To evaluate the maternal and perinatal outcomes in a cohort of pregnant women at high risk of venous thromboembolism (VTE). METHODS: Women at high risk of VTE were evaluated in a multidisciplinary program using a complete diagnostic workup, and specific prophylactic or therapeutic treatment. RESULTS: Women were considered at high risk of VTE in 57% (85/148) because of prior (75) or current (10) thromboembolism, and in 27% (40/148) of the cases due to adverse obstetric history. Thrombophilia was diagnosed in 57% of the cases (85/148), either in patients with previous thromboembolism (48%, 41/85) or without a history of thrombosis (70%, 44/63). The most common thrombophilia was antiphospholipid syndrome in 34% (29/85) of the cases. Under respective prophylactic or therapeutic treatment, there were no VTE during pregnancy (0%, 0/148), whereas four events occurred during the puerperium (3%, 4/148). An adverse obstetric outcome was present in 5% (7/148) of all pregnancies, with four early spontaneous abortions (3%, 4/148) and three late miscarriages (2%, 3/148). CONCLUSION: Pregnant women at high risk of VTE can be effectively managed using a risk-adapted treatment. Our results support prospective enrollment and a multidisciplinary assessment of VTE in high-risk pregnant women.