Indirect Surrogate Research Articles

Factors influencing high cardiovascular risk in subpopulation of young adults

Abstract Introduction The cardiovascular risk factors determine the development of early atheriosclerotic lesions, and the susceptibility to their proartheriosclerotic action is programmed by external factors and also those present during fetal development. The occurrence of atherosclerotic risk factors depends on an age. In population of children and young adults it seems reasonable to assess the classical risk factors for atherosclerosis in the connection with such additional given as family history being an indirect surrogate of genetic factors, and a low birth weight. Aim of the study was to categorize the study group into two groups - those who exhibit a low-risk and those who exhibit a high-risk of cardiovascular disease, and to determine the factors characteristic for each risk group. Materials and Methods The study was done on 512 volunteers, students in the following Faculties: Health Care Faculty: Nursing Course (178 / 34,7%), Physiotherapy Course (109 / 21,3%), Obstetrics Course (49 / 9,5%), Faculty of Medicine (176 / 34,3%). The questionnaire on cardiovascular risk factors was constructed. According to the results of its assessment the following groups were divided: the group of high risk (10% of investigated with the highest awarding of points) and the group of low risk (10% of investigated with the lowest awarding of points). Results Significant quantitative and qualitative differences were found between the low-risk and high-risk groups. Groups of the high and low risk did not differ in respect of sexes investigated and in respect of the direction of studies. One ascertained essential differences in variable qualitative and quantitative between the group of the low and high risk. Family history of diabetes, arterial hypertension, cardiovascular diseases, lipid disturbances, stroke were indeed greater in the group of high risk. The low birth weight was significantly lower in the group of high risk (p=0,02). The current and chronic stress status grading according to the punctual scale (0-10) was significantly higher in the group of high risk as compared to the low risk group (p=0,01, p=0,03, respectively). The systolic pressure was significantly higher in the high risk group in comparison to the low risk subjects (p=0,01). Conclusions High cardiovascular risk in subgroup of young adults results from high smoking status, low physical activity, diet and family history of cardiovascular disorders. The numerous cardiovascular risk factors that occur in some students are associated with low birth weight and a positive family medical history. The above observations show the influence of genetic and fetal factors on the development of atherosclerosis. Young adults with high cardiovascular risk are characterized by higher subjective stress level. Quantitative differences in high risk Medical family history

Optimized Design of Micro-Joint Motors Using MPSO With Embedded ELM Indirect Surrogate

Optimized Design of Micro-Joint Motors Using MPSO With Embedded ELM Indirect Surrogate

Bendamustine Lymphodepletion (LD) Prior to Idecabtagene Vicleucel (Ide-cel) Is Associated with Inferior Outcomes in Relapsed Refractory Multiple Myeloma (RRMM)

Background Chimeric antigen receptor therapy (CART) has revolutionized the management of RRMM. LD prior to CART cells modulates the immune environment creating optimal conditions for T cell expansion and subsequent efficacy. Fludarabine/cyclophosphamide (FLU/CY) is an effective LD regimen, and its use has been adopted widely prior to CART cells for all indications. Since the safety of FLU/CY is not established in patients with substantial renal impairment and given recent nationwide fludarabine shortage, alternative lymphodepletion strategies have been explored. Bendamustine (BENDA) has been shown to be a safe alternative with equivalent efficacy and reduced toxicity in non-Hodgkin's lymphoma (NHL). While its use has been extrapolated to RRMM, efficacy and long-term outcomes have not been examined. Methods We retrieved and analyzed data on sequential patients (pts) with RRMM treated with commercial Ide-cel at a single institution from its approval in 3/2021 until 5/2023. We captured baseline patient, disease and treatment characteristics. We used IgG (with monoclonal component deducted) and uninvolved FLC as indirect surrogate of CAR-T expansion and on target, off tumor killing of non-malignant plasma cells. We assessed cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) based on the American Society for Transplantation and Cellular Therapy criteria and disease responses using the International Myeloma Working Group response criteria. We graded hematologic toxicity using the Common Terminology Criteria for Adverse Events version 5.0. We compared efficacy between the cohorts using overall response rate (ORR) and progression-free survival (PFS), since overall survival is expected to be affected by choice of subsequent, often experimental therapies. Results We identified 28 pts with RRMM who met the inclusion criteria. Nine pts received alternative LD with BENDA (2 pts - renal dysfunction with creatinine clearance <30ml/min; 7 - fludarabine shortage) and 19 received FLU/CY as LD. Baseline characteristics are summarized in Table. Prior autologous stem cell transplant (ASCT) and prior B cell maturation antigen (BCMA) targeting therapy were more frequent in the FLU/CY cohort. Median absolute lymphocyte count (measured in 10^3/ cmm) prior to LD chemotherapy was similar in both cohorts (0.85 in BENDA vs 0.80 in FLU/CY). Median duration of absolute neutrophil count <1,000/μL was shorter in the BENDA cohort. The incidence of any grade CRS (56% vs. 90%, p=0.06) and tocilizumab use (56% vs. 84%, p=0.16) was lower with BENDA compared to FLU/CY. In the absence of ide-cel expansion data, we used nadir polyclonal IgG and uninvolved free light chain (uFLC) in the initial 90 days post CART cell infusion as surrogate of non-malignant plasma burden and therefore ide-cel expansion. We noted lower median uFLC and median IgG with FLU/CY vs. BENDA. The overall response rate was lower with BENDA (22%) vs. FLU/CY (79%, p=0.01). With median follow up of 4.8 mo., all pts in the BENDA cohort progressed with median PFS of 1.6 months vs 7.8 months for FLU/CY (p<0.001, Figure). The median OS for both cohorts is not yet reached. Conclusion: BENDA LD prior to ide-cel infusion results in suboptimal lymphodepletion and subsequent inferior outcomes including low rate of objective responses and decreased progression free survival. The inferior efficacy of BENDA as LD likely results from inferior ide-cel expansion and persistence resulting in less frequent and severe CRS and cytopenias and less suppression of unaffected immunoglobulins. Future efforts to study alternative lymphodepletion approaches is essential given inability to use fludarabine in patients with severe renal dysfunction and periods of critical drug shortages. While there is a need to develop alternatives for LD prior to ide-cel, BENDA is an inadequate substitute of FLU/CY.

Relation between Road-Salt Application and Increasing Radium Concentrations in a Low-pH Aquifer, Southern New Jersey

The Kirkwood–Cohansey aquifer in southern New Jersey is an important source of drinking-water supplies, but the availability of the resource is limited in some areas by high concentrations of radium, a potential carcinogen at elevated concentrations. Radium (226Ra plus 228Ra) concentrations from a network of 25 drinking-water wells showed a statistically significant increase over a decadal time scale (p < 0.05), with a median increase of 0.35 picocuries per liter. Increases in Ra are correlated with road-salt application rates, and we hypothesize that the correlation is causal. Geochemical processes associated with road-salt applications that can mobilize Ra into solution include competition by excess sodium for sorption sites and formation of chloride complexes (RaCl+ and RaCl2). The largest increases in Ra were in groundwater with low pH (≤5), which is an indirect surrogate for low cation-sorption capacity. Correlations with other potential anthropogenic causes for the increase in Ra were not observed, further suggesting a road-salt effect. Given the significant increase in Ra concentrations in this drinking-water source, the known carcinogenic risks from Ra, the direct link to road-salt application, and the likelihood for continued increases, additional monitoring is necessary in areas with similar hydrogeologic and geochemical settings.

Abstract 1667: A pilot study correlating baseline plasma levels of adenosine 2A receptor (A2aR) with acute phase reactants in advanced non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors

Abstract Background: Acute-phase reactants, such as C-reactive protein (CRP) and IL-6, can modulate immune suppression within the tumor microenvironment (TME) and thus potentially result in inferior outcomes to immune checkpoint inhibitors (ICIs). Immunosuppression within the TME is also be mediated by tumoral adenosine production, via hypoxia-induced exonuclease activity of CD39 and CD73 and adenosine 2a receptor (A2aR) signaling. We sought to evaluate whether plasma levels of A2aR correlate with the acute phase reactants (CRP and IL-6) in advanced NSCLC patients treated with ICIs. Methods: Between December 2016 and April 2019, we enrolled 18 patients with advanced NSCLC treated with single-agent ICIs or in combination with chemotherapy. We isolated plasma samples from patients before ICI initiation and again after each treatment. Plasma concentrations of A2aR and IL-6 were measured using ELISA. The baseline level of CRP was obtained from peripheral blood at ICI initiation (± 3 days). Previous studies correlating CRP and cancer outcomes defined a C-reactive protein (CRP) cutoff of 10 mg/L to define normal (CRP-N) and high CRP (CRP-H) levels. We assessed the relationship between CRP, IL-6, and A2aR plasma levels. Statistical analyses were performed using the Mann-Whitney test and linear regression analysis. Results: At the initiation of ICI, the median age of the cohort was 63. Two patients had stage III disease and 16 patients had stage IV disease. Four had squamous cell carcinoma, and 14 had non-squamous cell carcinoma. Six patients were treated with concomitant chemotherapy (pembrolizumab with carboplatin and pemetrexed). Patients received a median of 4 ICI cycles (range: 1-8 cycles) in our study. In the cohort, the median baseline levels of CRP, IL-6, and A2aR were 16.9 mg/L, 5.1 pg/mL, and 3.6 ng/mL, respectively. A positive correlation was present between baseline CRP levels and IL-6 plasma levels (R=0.76; p=0.003). Seven patients were CRP-N, and 11 patients were CRP-H. CRP-H patients had a greater median baseline level of A2aR (6.0 ng/mL vs. 1.3 ng/mL; p=0.01). Likewise, patients with baseline IL-6 levels greater than 5 pg/mL had a higher median baseline level of A2aR (6.0 ng/mL vs. 1.3 ng/mL; p=0.02). Conclusions: In a small, heterogeneous cohort of advanced NSCLC patients treated with ICIs, we demonstrate that elevated baseline levels of acute-phase reactants (CRP and IL-6) potentially act as an indirect surrogate for high plasma A2aR levels. Validation from larger studies is required to understand the biomarker implications of these findings in determining outcomes to ICIs. J.D.M. and A.R.N contributed equally to this work. Citation Format: Justin D. McCallen, Abdul R. Naqash, Mona A. Marie, Nitika Sharma, Mahvish Muzaffar, Paul R. Walker, Li Yang. A pilot study correlating baseline plasma levels of adenosine 2A receptor (A2aR) with acute phase reactants in advanced non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1667.

Implementation of a Resource-Efficient Indirect Handshake Stewardship Model at an Academic Medical Center

Background: Handshake antibiotic stewardship is an effective but resource-intensive strategy for reducing antimicrobial utilization. At larger hospitals, widespread implementation of direct handshake rounds may be constrained by available resources. To optimize resource utilization and mirror handshake antimicrobial stewardship, we designed an indirect feedback model utilizing existing team pharmacy infrastructure. Methods: The antibiotic stewardship program (ASP) utilized the plan-do-study-act (PDSA) improvement methodology to implement an antibiotic stewardship intervention centered on antimicrobial utilization feedback and patient-level recommendations to optimize antimicrobial utilization. The intervention included team-based antimicrobial utilization dashboard development, biweekly antimicrobial utilization data feedback of total antimicrobial utilization and select drug-specific antimicrobial utilization, and twice weekly individualized review by ASP staff of all patients admitted to the 5 hospitalist teams on antimicrobials with recommendations (discontinuation, optimization, etc) relayed electronically to team-based pharmacists. Pharmacists were to communicate recommendations as an indirect surrogate for handshake antibiotic stewardship. As reviewer duties expanded to include a rotation of multiple reviewers, a standard operating procedure was created. A closed-loop communication model was developed to ensure pharmacist feedback receipt and to allow intervention acceptance tracking. During implementation optimization, a team pharmacist-champion was identified and addressed communication lapses. An outcome measure of days of therapy per 1,000 patient days present (DOT/1,000 PD) and balance measure of in-hospital mortality were chosen. Implementation began April 5, 2019, and data were collected through October 31, 2019. Preintervention comparison data spanned December 2017 to April 2019. Results: Overall, 1,119 cases were reviewed by the ASP, of whom 255 (22.8%) received feedback. In total, 236 of 362 recommendations (65.2%) were implemented (Fig. 1). Antimicrobial discontinuation was the most frequent (147 of 362, 40.6%), and most consistently implemented (111 of 147, 75.3%), recommendation. The DOT/1,000 PD before the intervention compared to the same metric after intervention remained unchanged (741.1 vs 725.4; P = .60) as did crude in-hospital mortality (1.8% vs 1.7%; P = .76). Several contributing factors were identified: communication lapses (eg, emails not received by 2 pharmacists), intervention timing (mismatch of recommendation and rounding window), and individual culture (some pharmacists with reduced buy-in selectively relayed recommendations). Conclusion: Although resource efficient, this model of indirect handshake did not significantly impact total antimicrobial utilization. Through serial PDSA cycles, implementation barriers were identified that can be addressed to improve the feedback process. Communication, expectation management, and interpersonal relationship development emerged as critical issues contributing to poor recommendation adherence. Future PDSA cycles will focus on streamlining processes to improve communication among stakeholders.Funding: NoneDisclosures: None

Appropriate heart rate during exercise in Fontan patients.

To evaluate heart rate against workload and oxygen consumption during exercise in Fontan patients. Fontan patients (n = 27) and healthy controls (n = 25) underwent cardiopulmonary exercise testing with linear increase of load. Heart rate and oxygen uptake were measured during tests. Heart rate recovery was recorded for 10 minutes. Heart rate at midpoint (140 ± 14 versus 153 ± 11, p < 0.001) and at maximal effort (171 ± 14 versus 191 ± 10 beats per minute, p < 0.001) of test was lower for patients than controls. Heart rate recovery was similar between groups. Heart rate in relation to workload was higher for patients than controls both at midpoint and maximal effort. Heart rate in relation to oxygen uptake was similar between groups throughout test. Oxygen pulse, an indirect surrogate measure of stroke volume, was reduced at maximal effort in patients compared to controls (6.6 ± 1.1 versus 7.5 ± 1.4 ml·beat-1·m-2, p < 0.05) and increased significantly less from midpoint to maximal effort for patients than controls (p < 0.05). Heart rate is increased in relation to workload in Fontan patients compared with controls. At higher loads, Fontan patients seem to have reduced heart rate and smaller increase in oxygen pulse, which may be explained by inability to further increase stroke volume and cardiac output. Reduced ability to increase or maintain stroke volume at higher heart rates may be an important limiting factor for maximal cardiac output, oxygen uptake, and physical performance.

Loop Gain in High Tonnage Truck Vehicles' Drivers Exposed to Chronic Intermittent High Altitude at the First, Third, and Fifth Day of Nocturnal Sleep

Introduction: The aim of this paper was to measure the loop gain (LG) in central apneas (CA), in workers workers exposed to chronic intermittently high altitude during the first, third and fifth night shift. To asses if the loop gain is attenuated as an indirect surrogate of acclimatization. Material and Methods: This is a secondary crosssectional and descriptive study applied to high tonnage trucks's drivers that work in an open-pit mine located at 4300 m.a.s.l. The drivers alternate ten working days at mine site with ten resting days at home. We used a type III device. The acquisition was taken during the first, third and fifth night while workers were sleeping at mine site. We measured the respiratory cycle and the LG. Inclusion criteria: a) At least ≥3 consecutive CA separated by an interapnea recovery breaths, b) CA Index≥5 and c) More than 50% of events were CA. In order to be included in the analysis, workers must fulfil requirements a, b and c in the first night. We used non-parametric tests for the comparison of continuous values between groups. Results: Seventeen workers, age 41.6±9.7 and all were male. BMI 27.2±1.9 kg/m2, Epworth Sleepiness Scale 4.8±3.5, and living home altitude 1426±1498 m.a.s.l. The values for the first, third and fifth nights were: AHI 33.4±16.8, 21.6±16.3 and 27.9±16.9 (p=0.012), CAI 20.4±13.5, 9.5±9.8, 14.2±14.9 (p=0.022), MediaO2Sat 83.6±2.1, 84.9±2.1, 83.8±3.5 (p=0.019) and LG 1.95±1.88, 2.10±1.20, 3.35±4.23 (p=0.028). Conclusions: Workers had high respiratory index with clear predominance of central events, and profound desaturation. The LG value was over 1 and documented ventilatory instability. This variable showed absence of attenueation of LG and CA Index which could be suggestive that acclimatization was not reached. Funding Statement: Study sponsored by Compania Minera Antamina. Declaration of Interests: All the authors declare no conflict of interest. Ethics Approval Statement: Drivers signed an informed consent. The Comite de Etica de Investigacion from the Universidad Catolica de Santa Maria approved and authorized the study. The study was carried out according to the Declaration of Helsinski.

Multimodality Monitoring in Neurocritical Care: Decision-Making Utilizing Direct And Indirect Surrogate Markers.

Substantial progress has been made to create innovative technology that can monitor the different physiological characteristics that precede the onset of secondary brain injury, with the ultimate goal of intervening prior to the onset of irreversible neurological damage. One of the goals of neurocritical care is to recognize and preemptively manage secondary neurological injury by analyzing physiologic markers of ischemia and brain injury prior to the development of irreversible damage. This is helpful in a multitude of neurological conditions, whereby secondary neurological injury could present including but not limited to traumatic intracranial hemorrhage and, specifically, subarachnoid hemorrhage, which has the potential of progressing to delayed cerebral ischemia and monitoring postneurosurgical interventions. In this study, we examine the utilization of direct and indirect surrogate physiologic markers of ongoing neurologic injury, including intracranial pressure, cerebral blood flow, and brain metabolism.

Serial Measurements of Splanchnic Vein Diameters in Rats Using High-Frequency Ultrasound.

The purpose of this study was to investigate serial ultrasound imaging in rats as a fully non-invasive method to (1) quantify the diameters of splanchnic veins in real time as an indirect surrogate for the capacitance function of those veins, and (2) assess the effects of drugs on venous dimensions. A 21 MHz probe was used on anesthetized male Sprague–Dawley rats to collect images containing the portal vein (PV), superior mesenteric vein (SMV), abdominal inferior vena cava (IVC), and splenic vein (SpV; used as a landmark in timed studies) and the abdominal aorta (AA). Stable landmarks were established that allowed reproducible quantification of cross-sectional diameters within an animal. The average diameters of vessels measured every 5 min over 45 min remained within 0.75 ± 0.15% (PV), 0.2 ± 0.09% (SMV), 0.5 ± 0.12% (IVC), and 0.38 ± 0.06% (AA) of baseline (PV: 2.0 ± 0.12 mm; SMV: 1.7 ± 0.04 mm; IVC: 3.2 ± 0.1 mm; AA: 2.3 ± 0.14 mm). The maximal effects of the vasodilator sodium nitroprusside (SNP; 2 mg/kg, i.v. bolus) on venous diameters were determined 5 min post SNP bolus; the diameters of all noted veins were significantly increased by SNP, while mean arterial pressure (MAP) decreased 29 ± 4 mmHg. By contrast, administration of the venoconstrictor sarafotoxin (S6c; 5 ng/kg, i.v. bolus) significantly decreased PV and SpV, but not IVC, SMV, or AA, diameters 5 min post S6c bolus; MAP increased by 6 ± 2 mmHg. In order to determine if resting splanchnic vein diameters were stable over much longer periods of time, vessel diameters were measured every 2 weeks for 8 weeks. Measurements were found to be highly reproducible within animals over this time period. Finally, to evaluate the utility of vein imaging in a chronic condition, images were acquired from 4-week deoxycorticosterone acetate salt (DOCA-salt) hypertensive and normotensive (SHAM) control rats. All vessel diameters increased from baseline while MAP increased (67 ± 4 mmHg) in DOCA-salt rats compared to SHAM at 4 weeks after pellet implantation. Vessel diameters remained unchanged in SHAM animals. Together, these results support serial ultrasound imaging as a non-invasive, reliable technique able to measure acute and chronic changes in the diameter of splanchnic veins in intact rats.

Objective pain assessment after ureteral reimplantation: Comparison of open versus robotic approach

While open ureteral reimplantation is the gold standard of surgical intervention for vesicoureteral reflux (VUR), minimally invasive approaches offer the potential benefits of decreased postoperative pain, improved cosmesis, and shorter hospital stay and convalescence. Studies comparing open and minimally invasive surgery with respect to postoperative pain in children have been inconclusive. We sought to compare postoperative pain in children undergoing open versus robotic ureteral reimplantation by using age-appropriate, validated pain assessment scales. A prospective cohort of all patients enrolled in an Institutional Review Board-approved VUR surgery registry between July 2010 and February 2013 was analyzed. Patients who underwent endoscopic treatment or who received caudal or epidural anesthesia were excluded. Age-appropriate, validated pain scales ranging from 0 to 10 were utilized for pain assessment. Pain scores and narcotic doses administered on the first postoperative day were analyzed. Of the 34 subjects included, 11 underwent open intravesical reimplantation, while 23 patients underwent robotic extravesical reimplantation. Table 1 displays patient characteristics and results of pain assessment. Robotic surgery was associated with lower narcotic requirement compared to open surgery (P < 0.05). The difference in pain scores between the two cohorts approached, but did not reach, statistical significance (P = 0.12). However, the percentage of patients with mild or no pain (57% robotic, 27% open) versus severe pain (9% robotic, 45% open) was notably different between the two cohorts. Previous studies addressing the effect of surgical modality on pediatric postoperative pain are limited by their reliance on narcotic administration as an indirect surrogate for measuring pain. In the present study, postoperative pain was assessed with narcotic requirements and consistently collected validated pain scores, which more accurately reflect a patient's perceived pain. Although there was no significant difference in subjective pain scores between patients undergoing open versus robotic reimplantation, the percentage of patients with mild or no pain (57% robotic, 27% open) versus severe pain (9% robotic, 45% open) was notably different between the two cohorts. This study was limited by a lack of randomization as well as small sample size, which did not allow for age sub-group analysis or small differences to be statistically significant. In the present study, robotic ureteral reimplantation was associated with lower narcotic requirement compared to open surgery, and lower intensity of postoperative pain according to a direct pain assessment tool. Larger sample sizes are necessary to strengthen statistical comparisons.

Relationships between annual plant productivity, nitrogen deposition and fire size in low-elevation California desert scrub

Although precipitation is correlated with fire size in desert ecosystems and is typically used as an indirect surrogate for fine fuel load, a direct link between fine fuel biomass and fire size has not been established. In addition, nitrogen (N) deposition can affect fire risk through its fertilisation effect on fine fuel production. In this study, we examine the relationships between fire size and precipitation, N deposition and biomass with emphasis on identifying biomass and N deposition thresholds associated with fire spreading across the landscape. We used a 28-year fire record of 582 burns from low-elevation desert scrub to evaluate the relationship of precipitation, N deposition and biomass with the distribution of fire sizes using quantile regression. We found that models using annual biomass have similar predictive ability to those using precipitation and N deposition at the lower to intermediate portions of the fire size distribution. No distinct biomass threshold was found, although within the 99th percentile of the distribution fire size increased with greater than 125 g m–2 of winter fine fuel production. The study did not produce an N deposition threshold, but did validate the value of 125 g m–2 of fine fuel for spread of fires.

Calibration of an acoustic pipe sensor through bedload traps in a glacierized basin

Quantifying sediment transport in small mountain basins is of great relevance to assess the morphological and ecological dynamics of the entire channel network and to predict flood hazards. In high-elevation, glacierized basins, seasonal variability in sediment transport is dramatic, but despite the relevance of such basins in many regions worldwide, very few investigations have tried to quantify it. Since direct methods to assess bedload transport are time consuming and practically challenging at high flows, indirect surrogate methods, allowing continuous measurements over time, are highly desirable. Yet, these methods require calibration to provide reliable estimations. The present research is focused on the calibration of an acoustic pipe sensor in the recently established (Spring 2011) monitoring station in the Saldur basin, a high-elevation glacierized watershed in the Eastern Italian Alps. The acoustic pipe signal (which is amplified through 6 channels having different gains) was calibrated against samples collected over 26 sampling periods using “Bunte” bedload traps along a cross-section 12m upstream of the pipe. Samples were collected from June to August 2011 during daily discharge fluctuations (ranging from 1.40 to 3.63m3s−1) due to snow- and glacier-melt, featuring very different bedload rates (up to 0.14kgs−1m−1). In order to calibrate the pipe sensor signal, the average number of impulses was plotted against the corresponding unit bedload rates for the associated bedload sampling periods. As expected, the signal from the two most sensitive channels of the acoustic sensor resulted dampened even at low discharges, and thus could not be used for calibration and bedload assessment. Instead, power laws (R2 from 0.76 to 0.92) relating the number of impulses per minute to unit bedload rate were obtained using channels having intermediate and low sensitivities, with higher correlations associated with the less sensitive channels.

SU‐E‐QI‐15: Single Point Dosimetry by Means of Cerenkov Radiation Energy Transfer (CRET)

Purpose:Cerenkov light is generated when a charged particles with energy greater then 250 keV, moves faster than the speed of light in a given medium. Both x‐ray photons and electrons produce optical Cerenkov photons during the static megavoltage linear accelerator (LINAC) operational mode. Recently, Cerenkov radiation gained considerable interest as possible candidate as a new imaging modality. Optical signals generated by Cerenkov radiation may act as a surrogate for the absorbed superficial radiation dose. We demonstrated a novel single point dosimetry method for megavoltage photon and electron therapy utilizing down conversion of Cerenkov photons.Methods:The custom build signal characterization system was used: a sample holder (probe) with adjacent light tight compartments was connected via fiber‐optic cables to a photon counting photomultiplier tube (PMT). One compartment contains a medium only while the other contains medium and red‐shifting nano‐particles (Q‐dots, nanoclusters). By taking the difference between the two signals (Cerenkov photons and CRET photons) we obtain a measure of the down‐converted light, which we expect to be proportional to dose as measured with an adjacent ion chamber. Experimental results are compared to Monte Carlo simulations performed using the GEANT4 code.Results:The signal correlation between CR signal, CRET readings and dose produced by LINAC at a single point were investigated. The experimental results were compared with simulations. The dose linearity, signal to noise ratio and dose rate dependence were tested with custom build CRET based probe.Conclusion:Performance characteristics of the proposed single point CRET based probe were evaluated. The direct use of the induced Cerenkov emission and CRET in an irradiated single point volume as an indirect surrogate for the imparted dose was investigated. We conclude that CRET is a promising optical based dosimetry method that offers advantages over those already proposed.

Capturing the His‐Purkinje System is Not Possible from Conventional Right Ventricular Apical and Nonapical Pacing Sites

Direct His bundle capture may negate ventricular electrical dyssynchrony induced by right ventricular (RV) apical pacing. We sought to evaluate if direct His bundle pacing is possible with conventional pacemaker lead implantation at various sites in the RV. Consecutive patients underwent RV pacing using standard implantable active fixation pacing leads in a random order in the RV outflow tract, middle RV, and RV apex at stimulation threshold and at increasing voltages of 2.5, 5, 7.5, and 10 volts (V). At each location, QRS width and morphology on 12-lead electrocardiograph (ECG) were compared in sinus and paced rhythm at the different voltages. Twelve patients underwent a total of 2,160 paced QRS measurements. Progressive increases in stimulation voltage did not change QRS morphology or duration regardless of site of pacing (RV outflow tract, middle RV, and RV apex) in any of the 12 ECG leads. In addition, apart from the stimulation threshold between the RV outflow tract and RV apex, there was no statistically significant difference in QRS duration between the three pacing sites. In patients with a baseline normal QRS duration, none of the three conventional RV pacing sites were able to produce QRS narrowing and capture the His-Purkinje system. Furthermore, based on paced QRS duration as an indirect surrogate of electrical LV dyssynchrony, there was no clear advantage of one pacing site over another.

Quantitative PET/CT Measures of Myocardial Flow Reserve and Atherosclerosis for Cardiac Risk Assessment and Predicting Adverse Patient Outcomes

Conventional scintigraphic myocardial perfusion imaging with SPECT/CT or with PET/CT has evolved as an important clinical tool for the diagnostic assessment of flow-limiting epicardial lesions and risk stratification of patients with suspected CAD. By determining the relative distribution of radiotracer-uptake in the left-ventricular (LV) myocardium during stress, the presence of flow-limiting CAD lesions can be identified. While this approach successfully identifies epicardial coronary artery lesions, the presence of subclinical and non-obstructive CAD may go undetected. In this direction, the concurrent ability of PET/CT to assess absolute myocardial blood flow (MBF) in ml/g/min, rather that relative regional distribution of radiotracer-uptake, and myocardial flow reserve (MFR), expands the scope of conventional myocardial perfusion imaging from the identification of more advanced and flow-limiting epicardial lesions to (1) subclinical CAD, (2) an improved characterization of the extent and severity of CAD burden, and (3) the discovery of "balanced" reduction in myocardial blood flow as a consequence of 3 vessel CAD. Concurrent to the PET data, the CT component of the hybrid PET/CT allows the assessment of coronary artery calcification as an indirect surrogate for CAD burden, without contrast, or with contrast angiography to directly denote coronary stenosis and/or plaque morphology with CT. Hybrid PET/CT system, therefore, has the potential to not only identify and characterize flow-limiting epicardial lesions but also subclinical stages of functional and/or structural stages of CAD. Whether the application of PET/CT for an optimal assessment of coronary pathology, its downstream effects on myocardial perfusion, and coronary circulatory function will in effect lead to changes in clinical decision-making process, investiture in preventive health care, and improved long-term outcome, awaits scientific verification.

Verifying 4D gated radiotherapy using time-integrated electronic portal imaging: a phantom and clinical study

BackgroundRespiration-gated radiotherapy (RGRT) can decrease treatment toxicity by allowing for smaller treatment volumes for mobile tumors. RGRT is commonly performed using external surrogates of tumor motion. We describe the use of time-integrated electronic portal imaging (TI-EPI) to verify the position of internal structures during RGRT deliveryMethodsTI-EPI portals were generated by continuously collecting exit dose data (aSi500 EPID, Portal vision, Varian Medical Systems) when a respiratory motion phantom was irradiated during expiration, inspiration and free breathing phases. RGRT was delivered using the Varian RPM system, and grey value profile plots over a fixed trajectory were used to study object positions. Time-related positional information was derived by subtracting grey values from TI-EPI portals sharing the pixel matrix. TI-EPI portals were also collected in 2 patients undergoing RPM-triggered RGRT for a lung and hepatic tumor (with fiducial markers), and corresponding planning 4-dimensional CT (4DCT) scans were analyzed for motion amplitude.ResultsIntegral grey values of phantom TI-EPI portals correlated well with mean object position in all respiratory phases. Cranio-caudal motion of internal structures ranged from 17.5–20.0 mm on planning 4DCT scans. TI-EPI of bronchial images reproduced with a mean value of 5.3 mm (1 SD 3.0 mm) located cranial to planned position. Mean hepatic fiducial markers reproduced with 3.2 mm (SD 2.2 mm) caudal to planned position. After bony alignment to exclude set-up errors, mean displacement in the two structures was 2.8 mm and 1.4 mm, respectively, and corresponding reproducibility in anatomy improved to 1.6 mm (1 SD).ConclusionTI-EPI appears to be a promising method for verifying delivery of RGRT. The RPM system was a good indirect surrogate of internal anatomy, but use of TI-EPI allowed for a direct link between anatomy and breathing patterns.

Inflammatory Bowel Disease Is Not a Risk Factor for Cardiovascular Disease Mortality: Results from a Systematic Review and Meta-Analysis

Inflammation in general, and C-reactive protein (CRP) in particular, are closely associated with atherosclerosis. Similarly, the risk of cardiovascular (CV) disease is increased in several systemic inflammatory diseases. The purpose of this study was to examine whether inflammatory bowel disease (IBD) increases CV mortality, an indirect surrogate for CV disease incidence. A systematic review of studies on CV mortality rates in patients with IBD published between 1965 and 2006 was performed. Studies were included for analysis if they reported data on CV-disease-specific standardized mortality ratios (SMRs) for Crohn's disease (CD) and/or ulcerative colitis (UC). A meta-analysis of SMRs from included studies was performed. The review ultimately included 11 studies. Overall there were 4,532 patients with CD and 9,533 patients with UC. SMR point estimates ranged from 0.7 to 1.5 for patients with CD and 0.6-1.1 for patients with UC. There was not a statistically significant increase in CV SMR for either CD or UC in any study. However, two studies demonstrated a statistically significant decrease in CV SMR for UC. Finally, the meta-SMR for CD was 1.0 (95% CI 0.8-1.1) and the meta-SMR for UC was 0.9 (95% CI 0.8-1.0). IBD is not associated with increased CV mortality. Although CV mortality is a suboptimal surrogate for CV disease incidence, this finding provides indirect evidence against an association between IBD and CV disease.

High Throughput Screening Identified a Substituted Imidazole as a Novel RANK Pathway-Selective Osteoclastogenesis Inhibitor

Receptor activator of nuclear factor-kappaB (NF-kappaB) (RANK) plays a key role in the differentiation, activation, and survival of osteoclasts. Upon activation of RANK with RANK ligand (RANKL), osteoclast precursor cells differentiate into tartrate-resistant acid phosphatase (TRAP)-positive, multinucleated osteoclasts. To identify compounds that block osteoclastogenesis, a cell-based assay was developed using RAW264.7 cells stably transfected with a TRAP promoter-dependent reporter gene as a surrogate readout for differentiation. Described herein is the strategy for high throughput screening and subsequent secondary biological assays for hit triage, which resulted in the identification of compound 1, a 4-nitroimidazole derivative, that specifically inhibited RANKL-induced TRAP gene and protein expression. Compound 1 did not affect the tumor necrosis factor-alpha- or lipopolysaccharide-induced TRAP-luciferase response, suggesting selective inhibition of the RANKL-induced pathway. Reverse transcription polymerase chain reaction analysis confirmed the inhibition of expression of osteoclast marker genes, such as TRAP, cathepsin K, and carbonic anhydrase type II. Compound 1 did not inhibit the RANKL-induced activation of a NF-kappaB reporter gene, or p38 kinase activity, suggesting a mechanism of action downstream of NF-kappaB. Together, these results suggest that we have identified a RANK pathway-specific inhibitor able to block the RANKL-induced osteoclast differentiation process. The hit identification strategy described here can be applied to other cell-based assays using an indirect surrogate readout to improve success rates.

Evaluation of Drug-Induced QT Interval Prolongation

Assessment of proarrhythmic toxicity of newly developed drugs attracts significant attention from drug developers and regulatory agencies. Although no guidelines exist for such assessment, the present experience allows several key suggestions to be made and an appropriate technology to be proposed. Several different in vitro and in vitro preclinical models exist that, in many instances, correctly predict the clinical outcome. However, the correspondence between different preclinical models is not absolute. None of the available models has been demonstrated to be more predictive and/or superior to others. Generally, compounds that do not generate any adverse preclinical signal are less likely to lead to cardiac toxicity in humans. Nevertheless, differences in likelihood offer no guarantee compared with entities with a preclinical signal. Thus, the preclinical investigations lead to probabilistic answers with the possibility of both false positive and false negative findings. Clinical assessment of drug-induced QT interval prolongation is crucially dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. An integral part of this is a precise heart rate correction of QT interval, which has been shown to require the assessment of QT/RR relationship in each study individual. The numbers of electrocardiograms required for such an assessment are larger than usually obtained in pharmacokinetic studies. Thus, cardiac safety considerations need to be an integral part of early phase I/II studies. Once proarrhythmic safety has been established in phase I/II studies, large phase III studies and postmarketing surveillance can be limited to less strict designs. The incidence of torsade de pointes tachycardia varies from 1 to 5% with clearly proarrhythmic drugs (e.g. quinidine) to 1 in hundreds of thousands with drugs that are still considered unsafe (e.g. terfenadine, cisapride). Thus, not recording any torsade de pointes tachycardia during large phase III studies offers no guarantee, and the clinical premarketing evaluation has to rely on the assessment of QT interval changes. However, since QT interval prolongation is only an indirect surrogate of predisposition to the induction of torsade de pointes tachycardia, any conclusion that a drug is safe should be reserved until postmarketing surveillance data are reviewed. The area of drug-related cardiac proarrhythmic toxicity is fast evolving. The academic perspective includes identification of markers more focused compared with simple QT interval measurement, as well as identification of individuals with an increased risk of torsade de pointes. The regulatory perspective includes careful adaptation of new research findings.