Dynamic Behavior of Polymer Microbubbles During Long Ultrasound Tone-Burst Excitation and Its Application for Sonoreperfusion Therapy.

OBJECTIVE: Ultrasound (US)-targeted microbubble (MB) cavitation (UTMC)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. Because of the potentially longer circulation time and relative ease of storage and reconstitution of polymer-shelled MBs compared with lipid MBs, we investigated the dynamic behavior of polymer microbubbles and their therapeutic potential for sonoreperfusion (SRP) therapy. METHODS: The fate of polymer MBs during a single long tone-burst exposure (1 MHz, 5 ms) at various acoustic pressures and MB concentrations was recorded via high-speed microscopy and passive cavitation detection (PCD). SRP efficacy of the polymer MBs was investigated in an in vitro flow system and compared with that of lipid MBs. DISCUSSION: Microscopy videos indicated that polymer MBs formed gas-filled clusters that continued to oscillate, fragment and form new gas-filled clusters during the single US burst. PCD confirmed continued acoustic activity throughout the 5-ms US excitation. SRP efficacy with polymer MBs increased with pulse duration and acoustic pressure similarly to that with lipid MBs but no significant differences were found between polymer and lipid MBs. CONCLUSION: These data suggest that persistent cavitation activity from polymer MBs during long tone-burst US excitation confers excellent reperfusion efficacy.

Effect of Ultrasound Pulse Length on Sonoreperfusion Therapy.

In recent years, long- and short-pulse ultrasound (US)-targeted microbubble cavitation (UTMC) has been found to increase perfusion in healthy and ischemic skeletal muscle, in pre-clinical animal models of microvascular obstruction and in the myocardium of patients presenting with acute myocardial infarction. There is evidence that the observed microvascular vasodilation is driven by the nitric oxide pathway and purinergic signaling, but the time course of the response and the dependency on US pulse length are not well elucidated. Because our prior data supported that sonoreperfusion efficacy is enhanced by long-pulse US versus short-pulse US, in this study, we sought to compare long-pulse (5000 cycles) and short-pulse (500 × 10 cycles) US at a pressure of 1.5 MPa with an equivalent total number of acoustical cycles, hence constant acoustic energy, and at the same frequency (1 MHz), in a rodent hind limb model with and without microvascular obstruction (MVO). In quantifying perfusion using burst replenishment contrast-enhanced US imaging, we made three findings: (i) Long and short pulses result in different vasodilation kinetics in an intact hind limb model. The long pulse causes an initial spasmic reduction in flow that spontaneously resolved at 4 min, followed by sustained higher flow rates (approximately twofold) compared with baseline, starting 10 min after therapy (p < 0.05). The short pulse caused a short-lived approximately twofold increase in flow rate that peaked at 4 min (p < 0.05), but without the initial spasm. (ii) The sustained increased response with the long pulse is not simply reactive hyperemia. (iii) Both pulses are effective in reperfusion of MVO in our hindlimb model by restoring blood volume, but only the long pulse caused an increase in flow rate after treatment ii, compared with MVO (p < 0.05). Histological analysis of hind limb muscle post-UTMC with either pulse configuration indicates no evidence of tissue damage or hemorrhage. Our findings indicate that the microbubble oscillation induces vasodilation, and therapeutic efficacy for the treatment of MVO can be tuned by varying pulse length; relative to short-pulse US, longer pulses drive greater microbubble cavitation and more rapid microvascular flow rate restoration after MVO, warranting further optimization of the pulse length for sonoreperfusion therapy.

Targeted Anti-Cancer Provascular Therapy Using Ultrasound, Microbubbles, and Nitrite to Increase Radiotherapy Efficacy.

Hypoxia is an important mechanism of resistance to radiation therapy in many human malignancies including prostate cancer. It has been recently shown that ultrasound targeted microbubble cavitation (UTMC) can increase blood perfusion in skeletal muscle by triggering nitric oxide signaling. Interestingly, this effect was amplified with a sodium nitrite coinjection. Since sodium nitrite has been shown to synergize with radiotherapy (RT), we hypothesized that UTMC with a sodium nitrite coinjection could further radiosensitize solid tumors by increasing blood perfusion and thus reduce tumor hypoxia. We evaluated (1) the ability of UTMC with and without nitrite to increase perfusion in muscle (mouse hindlimbs) and human prostate tumors using different pulse lengths and pressure; (2) the efficacy of this approach as a provascular therapy given directly before RT in the human prostate subcutaneous xenografts PC3 tumor model. Using long pulses with various pressures, in muscle, the provascular response following UTMC was strong (6.61 ± 4.41-fold increase in perfusion post-treatment). In tumors, long pulses caused an increase in perfusion (2.42 ± 1.38-fold) at lower mechanical index (MI = 0.25) but not at higher MI (0.375, 0.5, and 0.750) when compared to control (no UTMC). However, when combined with RT, UTMC with long pulses (MI = 0.25) did not improve tumor growth inhibition. With short pulses, in muscle, the provascular response following UTMC (SONOS) + nitrite was strong (13.74 ± 8.60-fold increase in perfusion post-treatment). In tumors, UTMC (SONOS) + nitrite also caused a provascular response (1.94 ± 1.20-fold increase in perfusion post-treatment) that lasted for at least 10 min, but not with nitrite alone. Interestingly, the blunted provascular response observed for long pulses at higher MI without nitrite was reversed with the addition of nitrite. UTMC (SONOS) with and without nitrite caused an increase in perfusion in tumors. The provascular response observed for UTMC (SONOS) + nitrite was confirmed by histology. Finally, there was an improved growth inhibition for the 8 Gy RT dose + nitrite + UTMC group vs 8 Gy RT + nitrite alone. This effect was not significant with mice treated by UTMC + nitrite and receiving doses of 0 or 2 Gy RT. In conclusion, UTMC + nitrite increased blood flow leading to an increased efficacy of higher doses of RT in our tumor model, warranting further study of this strategy.

Mastomys natalensis (Smith, 1834) as a natural host for Schistosoma haematobium (Bilharz, 1852) Weinland, 1858 x Schistosoma bovis Sonsino, 1876 introgressive hybrids.

Cercarial emission of schistosomes is a determinant in the transmission to the definitive host and constitutes a good marker to identify which definitive host is responsible for transmission, mainly in introgressive hybridization situations. Our goal was to test the hypothesis that micro-mammals play a role in Schistosoma haematobium, S. bovis, and/or S. haematobium x S. bovis transmission. Small mammal sampling was conducted in seven semi-lacustrine villages of southern Benin. Among the 62 animals trapped, 50 individuals were investigated for Schistosoma adults and eggs: 37 Rattus rattus, 3 Rattus norvegicus, 9 Mastomys natalensis, and 1 Crocidura olivieri. Schistosoma adults were found in four R. rattus and two M. natalensis, with a local prevalence reaching 80% and 50%, respectively. Two cercarial chronotypes were found from Bulinus globosus experimentally infected with miracidia extracted from naturally infected M. natalensis: a late diurnal and nocturnal chronotype, and an early diurnal, late diurnal, and nocturnal chronotype. The cytochrome C oxidase subunit I mtDNA gene of the collected schistosomes (adults, miracidia, and cercariae) belonged to the S. bovis clade. Eleven internal transcribed spacer rDNA profiles were found; four belonged to S. bovis and seven to S. haematobium x S. bovis. These molecular results together with the observed multi-peak chronotypes add M. natalensis as a new host implicated in S. haematobium x S. bovis transmission. We discuss the origin of the new chronotypes which have become more complex with the appearance of several peaks in a 24-h day. We also discuss how the new populations of offspring may optimize intra-host ecological niche, host spectrum, and transmission time period.

The effect of ultrasound pulse length on microbubble cavitation induced antibody accumulation and distribution in a mouse model of breast cancer.

In solid tumors, the limited diffusion of therapeutic molecules in the perivascular space is a known limitation impacting treatment efficacy. Ultrasound Targeted Microbubble Cavitation (UTMC) has been shown to increase vascular permeability and improve the delivery of therapeutic compounds including small molecules, antibodies (mAb), nanoparticles and even cells, notably across the blood-brain-barrier (BBB). In this study, we hypothesized that UTMC could improve the accumulation and biodistribution of mAb targeting the adenosinergic pathway (i.e. CD73) in mice bearing bilateral subcutaneous 4T1 mammary carcinoma. METHODS: A bolus of fluorescently labeled mAb was given intravenously, followed by a slow infusion of microbubbles. UTMC therapy (1 MHz, 850 kPa) was given under ultrasound image guidance for 5 minutes to the right side tumor only, using three different pulse lengths with identical ultrasound energy (5000cyc "long", 125x40cyc "mid" and 500x10cyc "short"), and leaving the left tumor as a paired control. Longitudinal accumulation at 0 h, 4 h and 24 h was measured using whole-body biofluorescence and confocal microscopy. RESULTS: Our data support an increase in antibody accumulation and extravasation (# extravasated vessels and extravasated signal intensity) at 0 h for all pulses and at 4 h for the mid and short pulses when compared to the control non treated side. However, this difference was not found at 24 h post UTMC, indicative of the transient nature of UTMC. Interestingly, confocal data supported that the highest extravasation range was obtained at 0 h with the long pulse and that the short pulse caused no increase in the extravasation range. Overall, the mid pulse was the only pulse to increase all our metrics (biofluorescence, fraction of extravasated vessels, amount of extravasated Ab, and extravasation range) at 0 h and 4 h time points. CONCLUSIONS: Our results support that UTMC can enhance antibody accumulation in solid tumors at the macroscopic and microscopic levels. This preferential accumulation was evident at early time points (0 h and 4 h) but had started to fade by 24 h, a time dependence that is consistent with the ultrasound blood brain barrier opening literature. Further development and optimization of this theranostic platform, such as repeated UTMC, could help improve antibody based therapies against solid cancer.

[The optimal approach to severe facial trauma following a horse's kick]. / Optimale behandeling van ernstig aangezichtstrauma na trap van paard.

A 15-year-old girl was brought to the emergency department of a hospital by ambulance with extensive facial trauma following a horse's kick. The considerable impact resulted in a combination of injuries to the bone, teeth and soft tissue. Following the transfer from the ambulance, the AE physician immediately consulted an oral and maxillofacial surgeon. Consequently, the patient could be brought to the operating theatre almost straight after stabilisation. There, the oral and maxillofacial surgeon first repositioned her teeth in anatomical position, followed by repositioning and fixation of the mandibular fracture. Next, the teeth in the upper front were stabilised with an acid-etch composite splint and the lip was reconstructed.

Sonoreperfusion therapy for microvascular obstruction: A step toward clinical translation.

Sonoreperfusion therapy is being developed as an intervention for the treatment of microvascular obstruction. We investigated the reperfusion efficacy of two clinical ultrasound systems (a modified Philips EPIQ and a Philips Sonos 7500) in a rat hindlimb microvascular obstruction model. Four ultrasound conditions were tested using 20 min treatments: Sonos single frame, Sonos multi-frame, EPIQ low pressure and EPIQ high pressure. Contrast-enhanced perfusion imaging of the microvasculature was conducted at baseline and after treatment to calculate microvascular blood volume (MBV). EPIQ high pressure treatment resulted in significant recovery of MBV from microvascular obstruction, returning to baseline levels after treatment. EPIQ low pressure and Sonos multi-frame treatment resulted in significantly improved MBV after treatment but below baseline levels. Sonos single-frame and control groups showed no improvement post-treatment. This study demonstrates that the most effective sonoreperfusion therapy occurs at high acoustic pressure coupled with high acoustic intensity. Moreover, a clinically available ultrasound system is readily capable of delivering these effective therapeutic pulses.

Assisted HIV partner services training in three sub-Saharan African countries: facilitators and barriers to sustainable approaches.

INTRODUCTION: Healthcare worker training is essential to successful implementation of assisted partner services (aPS), which aims to improve HIV testing and linkage-to-care outcomes for previously unidentified HIV-positive individuals. Cameroon, Kenya and Mozambique are three African countries that have implemented aPS programmes and are working to bring those programmes to scale. In this paper, we present and compare different aPS training strategies implemented by these three countries, and discuss facilitators and barriers associated with implementation of aPS training in sub-Saharan Africa. DISCUSSION: aPS training programmes in Cameroon, Kenya and Mozambique share the following components: the development of comprehensive and interactive training curricula, recruitment of qualified trainees and trainers with intimate knowledge of the community served, continuous training, and rigorous monitoring and evaluation activities. Cameroon and Kenya were able to engage various stakeholders early on, establishing multilateral coalitions that facilitated attainment of long-term buy-in from the local governments. Ministries of Health and various implementing partners are often included in strategic planning and delivery of training curricula to ensure sustainability of the training programmes. Kenya and Mozambique have integrated aPS training into the national HTS guidelines, which are being rolled out nationwide by the Ministries of Health and implementing partners. Continual revision of training curricula to reflect the country context, as well as ongoing monitoring and evaluation, have also been identified as key facilitators to sustain aPS training programmes. Some of the barriers to scale-up and sustainability of aPS training include limited funding and resources for training and scale-up and shortage of aPS providers to facilitate on-the-job mentorship. CONCLUSIONS: These three programmes demonstrate that aPS training can be implemented and scaled up in sub-Saharan Africa. As countries plan for initial implementation or national scale-up of aPS services, they will need to establish government buy-in, expand funding sources, address the shortage of staff and resources to provide aPS and on-the-job mentorship, and continuously collect data to evaluate and improve aPS training plans. Development of national standards for aPS training, empowered healthcare providers, increased government commitment, and sustained funding for aPS services and training will be crucial for successful aPS implementation.

Time to First-Line ART Failure and Time to Second-Line ART Switch in the IeDEA Pediatric Cohort.

BACKGROUND: Globally, 49% of the estimated 1.8 million children living with HIV are accessing antiretroviral therapy (ART). There are limited data concerning long-term durability of first-line ART regimens and time to transition to second-line. METHODS: Children initiating their first ART regimen between 2 and 14 years of age and enrolled in one of 208 sites in 30 Asia-Pacific and African countries participating in the Pediatric International Epidemiology Databases to Evaluate AIDS consortium were included in this analysis. Outcomes of interest were: first-line ART failure (clinical, immunologic, or virologic), change to second-line, and attrition (death or loss to program ). Cumulative incidence was computed for first-line failure and second-line initiation, with attrition as a competing event. RESULTS: In 27,031 children, median age at ART initiation was 6.7 years. Median baseline CD4% for children ≤5 years of age was 13.2% and CD4 count for those >5 years was 258 cells per microliter. Almost all (94.4%) initiated a nonnucleoside reverse transcriptase inhibitor; 5.3% a protease inhibitor, and 0.3% a triple nucleoside reverse transcriptase inhibitor-based regimen. At 1 year, 7.7% had failed and 14.4% had experienced attrition; by 5 years, the cumulative incidence was 25.9% and 29.4%, respectively. At 1 year after ART failure, 13.7% had transitioned to second-line and 11.2% had experienced attrition; by 5 years, the cumulative incidence was 31.6% and 25.9%, respectively. CONCLUSIONS: High rates of first-line failure and attrition were identified in children within 5 years after ART initiation. Of children meeting failure criteria, only one-third were transitioned to second-line ART within 5 years.

The Role of Nitric Oxide during Sonoreperfusion of Microvascular Obstruction.

Rationale: Microembolization during PCI for acute myocardial infarction can cause microvascular obstruction (MVO). MVO severely limits the success of reperfusion therapies, is associated with additional myonecrosis, and is linked to worse prognosis, including death. We have shown, both in in vitro and in vivo models, that ultrasound (US) and microbubble (MB) therapy (termed "sonoreperfusion" or "SRP") is a theranostic approach that relieves MVO and restores perfusion, but the underlying mechanisms remain to be established. Objective: In this study, we investigated the role of nitric oxide (NO) during SRP. Methods and results: We first demonstrated in plated cells that US-stimulated MB oscillations induced a 6-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation in vitro. We then monitored the kinetics of intramuscular NO and perfusion flow rate responses following 2-min of SRP therapy in the rat hindlimb muscle, with and without blockade of eNOS with LNAME. Following SRP, we found that starting at 6 minutes, intramuscular NO increased significantly over 30 min and was higher than baseline after 13 min. Concomitant contrast enhanced burst reperfusion imaging confirmed that there was a marked increase in perfusion flow rate at 6 and 10 min post SRP compared to baseline (>2.5 fold). The increases in intramuscular NO and perfusion rate were blunted with LNAME. Finally, we tested the hypothesis that NO plays a role in SRP by assessing reperfusion efficacy in a previously described rat hindlimb model of MVO during blockade of eNOS. After US treatment 1, microvascular blood volume was restored to baseline in the MB+US group, but remained low in the LNAME group. Perfusion rates increased in the MB+US group after US treatment 2 but not in the MB+US+LNAME group. Conclusions: These data strongly support that MB oscillations can activate the eNOS pathway leading to increased blood perfusion and that NO plays a significant role in SRP efficacy.

Influence of erythrocyte aggregation on radial migration of platelet-sized spherical particles in shear flow.

Blood platelets when activated are involved in the mechanisms of hemostasis and thrombosis, and their migration toward injured vascular endothelium necessitates interaction with red blood cells (RBCs). Rheology co-factors such as a high hematocrit and a high shear rate are known to promote platelet mass transport toward the vessel wall. Hemodynamic conditions promoting RBC aggregation may also favor platelet migration, particularly in the venous system at low shear rates. The aim of this study was to confirm experimentally the impact of RBC aggregation on platelet-sized micro particle migration in a Couette flow apparatus. Biotin coated micro particles were mixed with saline or blood with different aggregation tendencies, at two shear rates of 2 and 10s-1 and three hematocrits ranging from 20 to 60%. Streptavidin membranes were respectively positioned on the Couette static and rotating cylinders upon which the number of adhered fluorescent particles was quantified. The platelet-sized particle adhesion on both walls was progressively enhanced by increasing the hematocrit (p<0.001), reducing the shear rate (p<0.001), and rising the aggregation of RBCs (p<0.001). Particle count was minimum on the stationary cylinder when suspended in saline at 2s-1 (57±33), and maximum on the rotating cylinder at 60% hematocrit, 2s-1 and the maximum dextran-induced RBC aggregation (2840±152). This fundamental study is confirming recent hypotheses on the role of RBC aggregation on venous thrombosis, and may guide molecular imaging protocols requiring injecting active labeled micro particles in the venous flow system to probe human diseases.

Inertial Cavitation Ultrasound with Microbubbles Improves Reperfusion Efficacy When Combined with Tissue Plasminogen Activator in an In Vitro Model of Microvascular Obstruction.

We have previously reported that long-tone-burst, high-mechanical-index ultrasound (US) and microbubble (MB) therapy can restore perfusion in both in vitro and in vivo models of microvascular obstruction (MVO). Addition of MBs to US has been found to potentiate the efficacy of thrombolytics on large venous thrombi; however, the optimal US parameters for achieving microvascular reperfusion of MVO caused by microthrombi, when combined with tissue plasminogen activator (tPA), are unknown. We sought to elucidate the specific effects of US, with and without tPA, for effective reperfusion of MVO in an in vitro model using both venous and arterial microthrombi. Venous- and arterial-type microthrombi were infused onto a mesh with 40-µm pores to simulate MVO. Pulsed US (1 MHz) was delivered with inertial cavitation (IC) (1.0 MPa, 1000 cycles, 0.33 Hz) and stable cavitation (SC) US (0.23 MPa, 20% duty cycle, 0.33 Hz) regimes while MB suspension (2 × 106 MBs/mL) was infused. The efficacy of sonoreperfusion with these parameters was tested with and without tPA. Sonoreperfusion efficacy was significantly greater for IC + tPA compared with tPA alone, IC, SC and SC + tPA, suggesting lytic synergism between tPA and US for both venous- and arterial-type microthrombi. In contrast to our previous in vitro studies using 1.5 MPa at 5000 US cycles without tPA, the IC regime employed herein used 90% less US energy. These findings suggest an IC regime can be used with tPA synergistically to achieve a high degree of fibrinolysis for both thrombus types.

Sonoreperfusion Therapy Kinetics in Whole Blood Using Ultrasound, Microbubbles and Tissue Plasminogen Activator.

Coronary intervention for myocardial infarction often results in microvascular embolization of thrombus. Sonoreperfusion therapy (SRP) using ultrasound and microbubbles restored perfusion in our in vitro flow model of microvascular obstruction. In this study, we assessed SRP efficacy using whole blood as the perfusate with and without tissue plasminogen activator (tPA). In a phantom vessel bearing a 40-µm-pore mesh to simulate the microvasculature, microthrombi were injected to cause microvascular obstruction and were treated using SRP. Without tPA, the lytic rate increased from 2.6 ± 1.5 mmHg/min with 1000-cycle pulses to 7.3 ± 3.2 mmHg/min with 5000-cycle ultrasound pulses (p < 0.01). The lytic index was similar for tPA-only ([2.0 ± 0.5] × 10-3 mmHg-1 min-1) and 5000 cycles without tPA ([2.3 ± 0.5] × 10-3 mmHg-1 min-1) (p = 0.5) but increased ([3.6 ± 0.8] × 10-3 mmHg-1 min-1) with tPA in conjunction with 5000-cycles ultrasound (p < 0.01). In conclusion, SRP restored microvascular perfusion in whole blood, SRP lytic rate in experiments without tPA increased with ultrasound pulse length and efficacy increased with the addition of tPA.

Effect of Thrombus Composition and Viscosity on Sonoreperfusion Efficacy in a Model of Micro-Vascular Obstruction.

Distal embolization of micro-thrombi during stenting for myocardial infarction causes micro-vascular obstruction (MVO). We have previously shown that sonoreperfusion (SRP), a microbubble (MB)-mediated ultrasound (US) therapy, resolves MVO from venous micro-thrombi in vitro in saline. However, blood is more viscous than saline, and arterial thrombi that embolize during stenting are mechanically distinct from venous clot. Therefore, we tested the hypothesis that MVO created with arterial micro-thrombi are more resistant to SRP therapy compared with venous micro-thrombi, and higher viscosity further increases the US requirement for effective SRP in an in vitro model of MVO. Lipid MBs suspended in plasma with adjusted viscosity (1.1 cP or 4.0 cP) were passed through tubing bearing a mesh with 40-µm pores to simulate a micro-vascular cross-section; upstream pressure reflected thrombus burden. To simulate MVO, the mesh was occluded with either arterial or venous micro-thrombi to increase upstream pressure to 40 mmHg ± 5 mmHg. Therapeutic long-tone-burst US was delivered to the occluded area for 20 min. MB activity was recorded with a passive cavitation detector. MVO caused by arterial micro-thrombi at either blood or plasma viscosity resulted in less effective SRP therapy compared to venous thrombi. Higher viscosity further reduced the effectiveness of SRP therapy. The passive cavitation detector showed a decrease in inertial cavitation when viscosity was increased, while stable cavitation was affected in a more complex manner. Overall, these data suggest that arterial thrombi may require higher acoustic pressure US than venous thrombi to achieve similar SRP efficacy; increased viscosity decreases SRP efficacy; and both inertial and stable cavitation are implicated in observed SRP efficacy.

[Is initial success after Monarc(®) suburethral sling durable at mid-term evaluation?]. / Le succès thérapeutique après bandelette Monarc(®) est-il durable à moyen terme ?

OBJECTIVES: Suburethral sling is the gold standard treatment for stress urinary incontinence (SUI). Short-term cure rates are high, but only few studies are available for longer assessment after transobturator tape procedure. The objectives of this study were to assess mid-term functional outcome for Monarc(®) transobturator tape after initial success, and to identify risk factors for recurrence. MATERIAL AND METHODS: We conducted a single centre retrospective study (2004-2013) on consecutive women with SUI who underwent Monarc(®) transobturator tape procedure and were initially cured at the postoperative medical consultation. Pre- and postoperative data (age, weight, height, body mass index, hormonal status, surgical history, associated organ prolapse [Baden and Walker], associated urinary symptoms, postoperative complications [Clavien-Dindo]) were extracted from the electronic medical record. Subjective cure was defined by a score of zero from the ICIQ-SF questionnaire, no second intervention for recurrent SUI and no need for pads at latest news. Statistical analysis was performed using SAS(®) v9.3 (P<0.05). RESULTS: One hundred and thirty-three consecutive women underwent TOT Monarc(®) procedure, and 125 women were cured in the short-term. Among these women, 103 (82%) were available for mid-term evaluation. Sixty-four women (62%) had pure stress urinary incontinence. The mean follow-up period was 51 months [2-119]. At last follow-up, cure rate was 61%. Seventy-eight percent of women with recurrent urinary incontinence had SUI. Other women had mixed urinary incontinence (3/40), or de novo urgency (6/40). In univariate analysis, we could not identify pejorative prognostic factors for mid-term failure. CONCLUSION: In our experience, mid-term functional outcome after Monarc(®) transobturator tape procedure seems to deteriorate. After 4 years of follow-up, 61% of the women who were initially cured were still free from any leakage. LEVEL OF EVIDENCE: 4.

[Prognostic factors for severe infection after flexible ureteroscopy: Clinical interest of urine culture the day before surgery?]. / Facteurs favorisants les infections sévères après urétéroscopie souple : intérêt de l'ECBU systématique la veille de l'intervention.

OBJECTIVES: The objectives of this study have been to determine prognostic factors for acute pyelonephritis (AP) after flexible ureteroscopy (FU), to assess the frequency of readmission for AP and to study the usefulness of urinalysis the day before surgery. METHODS: Between 2010 and 2013, 266 patients have had at least one ureteroscopy (n=325). All infectious complications and unplanned readmissions within the month after FU were retrospectively evaluated. Several data have been collected: age, sex, BMI, surgical indication (calculis or tumor), number of previous ureteroscopies, number of previous surgeries for calculis, stones number, size and location, bilateral interventions, operating time, preoperative ureteral stenting, postoperative stenting, hospitalization stay, urine culture the day before surgery (j-1) and prescription of antibiotic therapy the week before FU. Correlation between these variables and acute pyelonephritis (AP) the month following the USSR was tested (StatView 4.5, SAS Institute) (P<0.05 significant). RESULTS: We observed 24 postoperative APs (7.4%), 17 prior to hospital discharge and 7 requiring rehospitalization. In univariate analysis, the significant prognostic factors of postoperative AP have been: stone size (>14 mm) (P=0.03); operating time (70 minutes) (P<0.005); positive day - 1 urine culture (P<0.001); antibiotics treatment the week before FU (P<0.001). In multivariate analysis, antibiotics prescription during the week before USSR remained significant (P<0.002; RR 5.8 [1.9-15]). CONCLUSION: Acute pyelonephritis requiring unplanned admission after ureteroscopy is a rare complication (2.4%). Urinalysis one day before ureteroscopy could allow early antibiotic therapy and may reduce 63% of unplanned hospital admissions for acute pyelonephritis. LEVEL OF EVIDENCE: 5.

Low Intensity Ultrasound Mediated Liposomal Doxorubicin Delivery Using Polymer Microbubbles.

Cardiotoxicity is the major dose-limiting factor in the chemotherapeutic use of doxorubicin (Dox). A delivery vehicle that can be triggered to release its payload in the tumoral microvasculature but not in healthy tissue would help improve the therapeutic window of the drug. Delivery strategies combining liposomal encapsulated Dox (LDox), microbubbles (MBs), and ultrasound (US) have been shown to improve therapeutic efficacy of LDox, but much remains to be known about the mechanisms and the US conditions that maximize cytotoxicity using this approach. In this study, we compared different US pulses in terms of drug release and acute toxicity. Drug uptake and proliferation rates using low-intensity US were measured in squamous cell carcinoma cells exposed to LDox conjugated to or coinjected with polymer MBs. The aims of this study were: (1) to compare the effects of low- and high-pressure US on Dox release kinetics; (2) to evaluate whether conjugating the liposome to the MB surface (DoxLPX) is an important factor for drug release and cytotoxicity; and (3) to determine which US parameters most inhibit cell proliferation and whether this inhibition is mediated by drug release or the MB/US interaction with cells. Low-pressure US (170 kPa) at high duty cycle (stable cavitation) released up to ∼ 70% of the encapsulated Dox from the DoxLPX, thus improving Dox bioavailability and cellular uptake and leading to a significant reduction in cell proliferation at 48 h. Flow cytometry showed that US generating stable oscillations of DoxLPX significantly increased cellular Dox uptake at 4 h after US exposure compared to LDox. Drug uptake was correlated with cytotoxicity at 48 h. Our results demonstrate that Dox-containing liposomes conjugated to polymer MBs can be triggered to release ∼ 70% of their payload using noninertial US. Following release, Dox became bioavailable to the cells and induced significantly higher cytotoxicity compared to nonreleased encapsulated drug. Our findings show promise for targeted drug delivery using this theranostic delivery platform at low US intensities.

Unifying Concepts of Statistical and Spectral Quantitative Ultrasound Techniques.

Quantitative ultrasound (QUS) techniques using radiofrequency (RF) backscattered signals have been used for tissue characterization of numerous organ systems. One approach is to use the magnitude and frequency dependence of backscatter echoes to quantify tissue structures. Another approach is to use first-order statistical properties of the echo envelope as a signature of the tissue microstructure. We propose a unification of these QUS concepts. For this purpose, a mixture of homodyned K-distributions is introduced to model the echo envelope, together with an estimation method and a physical interpretation of its parameters based on the echo signal spectrum. In particular, the total, coherent and diffuse signal powers related to the proposed mixture model are expressed explicitly in terms of the structure factor previously studied to describe the backscatter coefficient (BSC). Then, this approach is illustrated in the context of red blood cell (RBC) aggregation. It is experimentally shown that the total, coherent and diffuse signal powers are determined by a structural parameter of the spectral Structure Factor Size and Attenuation Estimator. A two-way repeated measures ANOVA test showed that attenuation (p-value of 0.077) and attenuation compensation (p-value of 0.527) had no significant effect on the diffuse to total power ratio. These results constitute a further step in understanding the physical meaning of first-order statistics of ultrasound images and their relations to QUS techniques. The proposed unifying concepts should be applicable to other biological tissues than blood considering that the structure factor can theoretically model any spatial distribution of scatterers.