Patient-specific Optimization Research Articles

Quantified assessment of deep brain stimulation on Parkinson\u2019s patients with task fNIRS measurements and functional connectivity analysis: a pilot study

BackgroundDeep brain stimulation (DBS) has proved effective for Parkinson’s disease (PD), but the identification of stimulation parameters relies on doctors’ subjective judgment on patient behavior.MethodsFive PD patients performed 10-meter walking tasks under different brain stimulation frequencies. During walking tests, a wearable functional near-infrared spectroscopy (fNIRS) system was used to measure the concentration change of oxygenated hemoglobin (△HbO2) in prefrontal cortex, parietal lobe and occipital lobe. Brain functional connectivity and global efficiency were calculated to quantify the brain activities.ResultsWe discovered that both the global and regional brain efficiency of all patients varied with stimulation parameters, and the DBS pattern enabling the highest brain efficiency was optimal for each patient, in accordance with the clinical assessments and DBS treatment decision made by the doctors.ConclusionsTask fNIRS assessments and brain functional connectivity analysis promise a quantified and objective solution for patient-specific optimization of DBS treatment.Trial registrationName: Accurate treatment under the multidisciplinary cooperative diagnosis and treatment model of Parkinson’s disease. Registration number is ChiCTR1900022715. Date of registration is April 23, 2019.

Abstract 222: Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics

Abstract Introduction: Standard-of-care neoadjuvant therapeutic regimens are based on clinical trials designed to identify treatment protocols at the population level, which cannot capture the unique characteristics of individual patients. Moreover, it is impossible for clinical trials to experimentally evaluate all the possible treatment combinations and dosing strategies. Mechanism-based, mathematical modeling can potentially address this critical barrier to achieving truly personalized treatment. In this contribution, we present preliminary results using a fluid dynamics model personalized with a patient's imaging data to optimize a drug injection protocol in breast cancer. Methods: Nine breast cancer patients are included in this study. MRI data are acquired, processed, and used to estimate hemodynamics and imported to our drug delivery model. By varying the dosing schedule, the model predicts varying dynamics of drug distribution throughout the breast. We define an objective function, MSTD, balancing the treatment efficacy and toxicity, and use it to optimize the injection protocol for each patient. The injection schedules tested include: (a) single injection on day 1 of each 3-week cycle; double injections of half the total dose each at (b) day 1 and 2, (c) day 1 and 3, (d) day 1 and 5, and (e) day 1 and 8 within each 3-week cycle. The doses tested vary from 0 to 100 μg/ml of maximal plasma concentration. Improvement ratio of the optimal protocol to a standard protocol, 10 μg/ml via schedule (a), is measured. Results: The optimal protocol and improvement are reported for each patient in Table 1. Conclusion: Our modeling system can efficiently solve the personalization of drug injection protocol as an optimal control problem. Different patients have different optimal treatment protocols, each of which is predicted to outperform the standard protocol. Table 1.Optimal injection protocol for individual patientsPatientOptimal scheduleOptimal dose (μg/ml)Improvement ratio1(e)8.891.492(e)6.071.823(e)5.882.124(e)7.362.415(e)5.193.266(e)5.203.377(e)5.703.598(e)4.103.079(e)4.593.49NCI U01CA142565, U01CA174706, R01CA218700, R01CA172801, U24CA226110, P30CA014599. CPRIT RR160005. Citation Format: Chengyue Wu, David A. Hormuth, Federico Pineda, Gregory S. Karczmar, Thomas E. Yankeelov. Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics [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 222.

Radiobiological risks following dentomaxillofacial imaging: should we be concerned?

Objectives:This review aimed to present studies that prospectively investigated biological effects in patients following diagnostic dentomaxillofacial radiology (DMFR).Methods:Literature was systematically searched to retrieve all studies assessing radiobiological effects of using X-ray imaging in the dentomaxillofacial area, with reference to radiobiological outcomes for other imaging modalities and fields.Results:There is a lot of variability in the reported radiobiological assessment methods and radiation dose measures, making comparisons of radiobiological studies challenging. Most radiological DMFR studies are focusing on genotoxicity and cytotoxicity, data for 2D dentomaxillofacial radiographs, albeit with some methodological weakness biasing the results. For CBCT, available evidence is limited and few studies include comparative data on both adults and children.ConclusionsIn the future, one will have to strive towards patient-specific measures by considering age, gender and other individual radiation sensitivity-related factors. Ultimately, future radioprotection strategies should build further on the concept of personalized medicine, with patient-specific optimization of the imaging protocol, based on radiobiological variables.

"All-In-One" Genetic Tool Assessing Endometrial Receptivity for Personalized Screening of Female Sex Steroid Hormones.

Endometrium is the uterine lining that undergoes hundreds of cycles of proliferation, differentiation, and desquamation throughout a woman's reproductive life. Recently, much attention is paid to the appropriate endometrial functioning, as decreased endometrial receptivity is stated to be one of the concerns heavily influencing successes of embryo implantation rates and the efficacy of in vitro fertilization (IVF) treatment. In order to acquire and maintain the desired endometrial receptivity during IVF cycles, luteal phase support by various progestagens or other hormonal combinations is generally recommended. However, today, the selection of the specific hormonal therapy during IVF seems to be empirical, mainly due to a lack of appropriate tools for personalized approach. Here, we designed the genetic tool for patient-specific optimization of hormonal supplementation schemes required for the maintenance of endometrial receptivity during luteal phase. We optimized and characterized in vitro endometrial stromal cell (ESC) decidualization model as the adequate physiological reflection of endometrial sensitivity to steroid hormones. Based on the whole transcriptome RNA sequencing and the corresponding bioinformatics, we proposed that activation of the decidual prolactin (PRL) promoter containing ancient transposons MER20 and MER39 may reflect functioning of the core decidual regulatory network. Furthermore, we cloned the sequence of decidual PRL promoter containing MER20 and part of MER39 into the expression vector to estimate the effectiveness of ESC decidual response and verified sensitivity of the designed system. We additionally confirmed specificity of the generated tool using human diploid fibroblasts and adipose-derived human mesenchymal stem cells. Finally, we demonstrated the possibility to apply our tool for personalized hormone screening by comparing the effects of natural progesterone and three synthetic analogs (medroxyprogesterone 17-acetate, 17α-hydroxyprogesterone caproate, dydrogesterone) on decidualization of six ESC lines obtained from patients planning to undergo the IVF procedure. To sum up, we developed the “all-in-one” genetic tool based on the MER20/MER39 expression cassette that provides the ability to predict the most appropriate hormonal cocktail for endometrial receptivity maintenance specifically and safely for the patient, and thus to define the personal treatment strategy prior to the IVF procedure.

Immunosuppression trends in solid organ transplantation: The future of individualization, monitoring, and management.

Immunosuppression regimens used in solid organ transplant have evolved significantly over the past 70years in the United States. Early immunosuppression and targets for allograft success were measured by incidence and severity of allograft rejection and 1-year patient survival. The limited number of agents, infancy of human leukocyte antigen (HLA) matching techniques and lack of understanding of immunoreactivity limited the early development of effective regimens. The 1980s and 1990s saw incredible advancements in these areas, with acute rejection rates halving in a short span of time. However, the constant struggle to achieve the optimal balance between under- and overimmunosuppression is weaved throughout the history of transplant immunosuppression. The aim of this paper is to discuss the different eras of immunosuppression and highlight the important milestones that were achieved while also discussing this in the context of rational agent selection and regimen design. This discussion sets the stage for how we can achieve optimal long-term outcomes during the next era of immunosuppression, which will move from universal protocols to patient-specific optimization.

Inter-individual differences in the response to an exercise training intervention in patients with metabolic syndrome

Abstract Background Regular physical exercise and standardized exercise training (ET) programmes positively affect a number of metabolic and cardiovascular risk factors. Yet, response to ET varies between patients and between individual risk parameters. We investigated inter-individual responses regarding blood pressure, heart rate, lipids and glucose metabolism, as well as physical fitness to a 16-weeks supervised exercise training protocol in patients with metabolic syndrome (MetS). Methods 29 MetS patients (20M/9F, age 52–70 y, BMI 24.9–38.2 kg/m2) exercised for 16 weeks in a supervised setting with varying volume and intensity. At baseline and at completion of the programme, blood pressure, heart rate, plasma lipids, glucose and insulin levels, as well as physical fitness were assessed, as were quantitative and morphological leukocyte parameters, cytokines and 86 metabolically relevant plasma proteins. Associations between individual risk parameters, leukocyte profile and plasma proteins were explored by recursive partitioning and network analysis. T-distributed stochastic neighbor embedding and hierarchical clustering were used for clustering based on cardiometabolic target parameters at 16 weeks. Results In the whole cohort, VO2peak increased and plasma counts of total leukocytes, neutrophils, monocytes (classical and intermediate), NK cells and effector and regulatory CD4+ lymphocytes, as well as circulating endothelial microvesicles were reduced at the end of the ET programme versus baseline. Plasma levels of carboxylesterase 1 decreased and soluble interleukin-7 receptor increased. Based on patient's cardio-metabolic parameters, three clusters were identified: cluster 1 had lower values of triglycerides, total and LDL cholesterol, cluster 2 had higher levels of triglycerides and cluster 3 had a greater heart rate recovery and lower insulin levels, but higher total and LDL cholesterol levels at follow-up. In cluster 1, absolute and relative NK cell counts were decreased and no morphological activation was observed. In cluster 2, reduced relative counts of NK-T cells were decreased, but their size was increased. In cluster 3, size of most effector leukocyte subtypes (CD8+, CD4+ Teff, NK-T, neutrophils) was increased at follow-up versus baseline. Network analysis suggested four distinct networks of (1) triglycerides, (2) VO2peak, (3) diastolic BP and (4) a cluster containing total and LDL cholesterol, insulin and HR recovery, each associated with partly distinct sets of plasma proteins and leukocyte parameters. Conclusion Despite improved physical fitness in all patients participating in the 16 weeks ET programme, inter-individual differences regarding cardio-metabolic target parameters and leukocyte activation was evident. Identification of specific leukocyte responses and of plasma protein “fingerprints” might help to optimize patient-specific prevention programmes, integrating medication and lifestyle optimization. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DZHK, DSHF

In silico patient-specific optimization of correction strategies for thoracic adolescent idiopathic scoliosis

BackgroundWith modelling and simulation (or in silico) techniques, patient-specific optimization algorithms represent promising tools to support the surgical decision-making process, particularly in 3D correction of adolescent idiopathic scoliosis, where the best intraoperative instrumentation strategy and the correction goals are debated. Methods1080 biomechanical intraoperative simulations of a representative pediatric thoracic curve were run according to a full-factorial design approach. Widely accepted instrumentation configurations (5 screw patterns, 4 upper and 3 lower instrumented vertebrae, 6 rod curvatures and 3 rod stiffnesses) were analyzed, assuming concave rod rotation and en bloc derotation as main correction maneuvers. Results in terms of 3D correction and mobility were rated using an objective function for thoracic scoliosis also including surgeon-dependent correction objectives. An extensive sensitivity analysis on correction objectives was performed. FindingsMultiple optimal strategies were identified, depending on the selected correction objective. They provided significantly better coronal (67% vs. 55%) correction, using comparable instrumented levels (9.9 ± 1.6 vs. 10.7 ± 2.1), screw patterns and significantly higher implant density (1.6 ± 0.3 vs. 1.4 ± 0.2 screws/vertebra) compared to worst ones. Optimal strategies typically included the neutral and the last touching vertebrae in the construct and high stiffness (CoCr, 6 mm) differentially/highly contoured rods. InterpretationThe computerized algorithm determined the best instrumentation parameters to achieve optimal correction for the considered thoracic case. Multiple clinically equivalent strategies may be used, as supported by the variety of considered correction objectives. The current approach could be translated to any scoliotic curves, including surgeon preferences in terms of instrumentation parameters, intraoperative correction maneuvers and correction objectives.

Automatic quality measurement of aortic contrast-enhanced CT angiographies for patient-specific dose optimization

PurposeIodine-containing contrast agent (CA) used in contrast-enhanced CT angiography (CTA) can pose a health risk for patients. A system that adjusts the frequently used standard CA dose for individual patients based on their clinical parameters can be useful. As basis the quality of the image contrast in CTA volumes has to be determined, especially to recognize excessive contrast induced by CA overdosing. However, a manual assessment with a ROI-based image contrast classification is a time-consuming step in everyday clinical practice.MethodsWe propose a method to automate the contrast measurement of aortic CTA volumes. The proposed algorithm is based on the mean HU values in selected ROIs that were automatically positioned in the CTA volume. First, an automatic localization algorithm determines the CTA image slices for certain ROIs followed by the localization of these ROIs. A rule-based classification using the mean HU values in the ROIs categorizes images with insufficient, optimal and excessive contrast.ResultsIn 95.89% (70 out of 73 CTAs obtained with the ulrich medical CT motion contrast media injector) the algorithm chose the same image contrast class as the radiological expert. The critical case of missing an overdose did not occur with a positive predicative value of 100%.ConclusionThe resulting system works well within our range of considered scan protocols detecting enhanced areas in CTA volumes. Our work automized an assessment for classifying CA-induced image contrast which reduces the time needed for medical practitioners to perform such an assessment manually.

3D PRINTED HEART VALVES: CHALLENGES AND OPPORTUNITIES

3D printing holds the promise of constructing precision replacement heart valves with patient-specific customization and optimization. Can functional heart valves be 3D printed? Five heart valves were designed in CAD and fabricated using a Polyjet Stratasys J750 printer with elastomeric resin: 2

Integration of mathematical model predictions into routine workflows to support clinical decision making in haematology

BackgroundIndividualization and patient-specific optimization of treatment is a major goal of modern health care. One way to achieve this goal is the application of high-resolution diagnostics together with the application of targeted therapies. However, the rising number of different treatment modalities also induces new challenges: Whereas randomized clinical trials focus on proving average treatment effects in specific groups of patients, direct conclusions at the individual patient level are problematic. Thus, the identification of the best patient-specific treatment options remains an open question. Systems medicine, specifically mechanistic mathematical models, can substantially support individual treatment optimization. In addition to providing a better general understanding of disease mechanisms and treatment effects, these models allow for an identification of patient-specific parameterizations and, therefore, provide individualized predictions for the effect of different treatment modalities.ResultsIn the following we describe a software framework that facilitates the integration of mathematical models and computer simulations into routine clinical processes to support decision-making. This is achieved by combining standard data management and data exploration tools, with the generation and visualization of mathematical model predictions for treatment options at an individual patient level.ConclusionsBy integrating model results in an audit trail compatible manner into established clinical workflows, our framework has the potential to foster the use of systems-medical approaches in clinical practice. We illustrate the framework application by two use cases from the field of haematological oncology.

Dynamic atrioventricular delay programming improves ventricular electrical synchronization as evaluated by 3D vectorcardiography

BackgroundOptimal timing of the atrioventricular delay in cardiac resynchronization therapy (CRT) can improve synchrony in patients suffering from heart failure. The purpose of this study was to evaluate the impact of SyncAV™ on electrical synchrony as measured by vectorcardiography (VCG) derived QRS metrics during bi-ventricular (BiV) pacing. MethodsPatients implanted with a cardiac resynchronization therapy (CRT) device and quadripolar left ventricular (LV) lead underwent 12‑lead ECG recordings. VCG metrics, including QRS duration (QRSd) and area, were derived from the ECG by a blinded observer during: intrinsic conduction, BiV with nominal atrioventricular delays (BiV Nominal), and BiV with SyncAV programmed to the optimal offset achieving maximal synchronization (BiV + SyncAV Opt). ResultsOne hundred patients (71% male, 40% ischemic, 65% LBBB, 32 ± 9% ejection fraction) completed VCG assessment. QRSd during intrinsic conduction (166 ± 25 ms) was narrowed successively by BiV Nominal (137 ± 23 ms, p < .05 vs. intrinsic) and BiV + SyncAV Opt (122 ± 22 ms, p < .05 vs. BiV Nominal). Likewise, 3D QRS area during intrinsic conduction (90 ± 42 mV ∗ ms) was reduced by BiV Nominal (65 ± 39 mV ∗ ms, p < .05 vs. intrinsic) and further by BiV + SyncAV Opt (53 ± 30 mV ∗ ms, p = .06 vs. BiV Nominal). ConclusionWith VCG-based, patient-specific optimization of the programmable offset, SyncAV reduced electrical dyssynchrony beyond conventional CRT.

Extracorporeal life support bridge for pulmonary hypertension: A high-volume single-center experience.

Application of extracorporeal life support (ECLS) for advanced pulmonary hypertension (PH) is evolving and may be deployed as a bridge to transplantation (BTT) or in one of several non-BTT uses, such as bridge to recovery (BTR) to the chronic PH clinical state in the setting of an acute PH trigger, bridge through non-transplant surgery (BTNTS), or bridge post-transplantation (BPT). We conducted a retrospective analysis of all adult patients with World Symposium on Pulmonary Hypertension Group 1, 3, 4, or 5 PH who received ECLS at Columbia University Medical Center/New York Presbyterian Hospital between January 1, 2010 and August 18, 2018. We describe patient characteristics, outcomes, and our approach to medical and surgical management of these patients. There were 98 patients with significant PH in the cohort (54 female; median age, 48 years [interquartile range, 32-58]). Of these, 44 (45%) patients with PH received ECLS as non-BTT with intent to recover back to their baseline functional state, optimize therapy, or support through a definitive surgery, including 19 BTR, 17 BTNTS, and 8 BPT, and 54 (55%) patients received ECLS as BTT. In the overall cohort, 67 (68.4%) patients received venoarterial ECLS and 31 (31.6%) received venovenous (VV) ECLS. Out of 83 patients, 52 (63%) were liberated from invasive mechanical ventilation, and 85.2% of BTT patients with PH ambulated while on ECLS. Management of PH medications was individualized, often requiring titration with use of inhaled pulmonary vasodilators increased after cannulation in non-BTT. Overall 30-day survival was 73.5%, survival to ECLS decannulation was 66.3%, and survival to hospital discharge was 54.1%. All 8 BPT patients (100%) survived to hospital discharge, 64.7% of BTNTS patients survived to hospital discharge, and 32 (59.3%) BTT patients survived to lung transplantation. Early-era use of VV-ECLS for BTT had worse survival to discharge than those initially configured with venoarterial ECLS, impacting the overall survival and leading to limited use of VV-ECLS in the current era for BPT, BTNTS, and select BTR cases. ECLS instituted by a specialized, multidisciplinary team has a role in the management of advanced PH as BTT or as non-BTT (including BTR, BTNTS, and BPT). Careful selection of ECLS cannulation configurations, patient-specific optimization of PH medical therapies, and avoidance of endotracheal intubation may be effective strategies in managing these complex patients.

Radiation dosimetry considerations for skeletal survey imaging of multiple myeloma

PurposeThis paper aims to review the dosimetry and utility of currently implemented imaging modalities for assessment of multiple myeloma and consider the role of tin filtration computed tomography (CT) as a potential replacement to current standard practice. MethodsRadiation output of tin CT was measured experimentally and used for software-based dose calculation. Resultant effective dose was then compared to calculated planar radiography doses and published doses of other imaging modalities. ResultsBased on example patient parameters used for modalities and 14 projection planar radiography site protocols, doses are comparable between planar radiography and tin filtration CT (approximately 0.9 and 1.0 mSv respectively). Both studies carried a reduced radiation burden compared to Expected Pathologically Increased Contrast-CT (EPIC-CT), FDG-PET and MIBI SPECT/CT (5.7, 11.1–20.0 and 13.0 mSv respectively). ConclusionTin filtered CT provided visualisation of multiple myeloma at doses comparable to planar radiography and where available may be a suitable alternative, following due consideration of patient specific justification and optimisation in line with best practice.

Towards automated patient-specific optimization of deep brain stimulation for movement disorders.

In this paper we present a simulation framework for automated optimization of deep brain stimulation (DBS) parameters based on the hand kinematics signal as the feedback signal, in patients with essential tremor. We used Gaussian Process regression (GPR) models to develop patient-specific models for predicting the effect of DBS on the hand kinematics using the clinical data that was recorded during DBS programming. In this framework, we characterized the performance of a Bayesian Optimization method to identify the optimal DBS parameters that maximized the clinical efficacy. Our results demonstrate the feasibility of using black-box optimization methods for automated identification of optimal DBS parameters in clinical settings.

C.05 Direct visualization of the human zona incerta region using ultra-high field imaging: implications for stereotactic neurosurgery

Background: The zona incerta (ZI) is a small structure in the deep brain first identified by Auguste Forel for which robust in vivo visualization has remained elusive. The increased inherent signal from ultra-high field (7-Tesla or greater; 7T) magnetic resonance imaging (MRI) presents an opportunity to see structures not previously visible. In this study, we investigated the possibility of using quantitative T1 mapping at 7T to visualize the ZI region. Methods: We recruited healthy participants (N=32) and patients being considered for deep brain stimulation therapy as part of a prospective imaging study at 7T. Computational methods were used to process and fuse images to produce a high-resolution group average from which ZI anatomy could be delineated. Results: We pooled 7T data using image fusion methods and found that the contrast from quantitative T1 mapping was strikingly similar to classic histological staining, permitting facile identification of the ZI and nearby structures in reference to conventional stereotactic atlases. Conclusions: Using computational neuroimaging techniques, we demonstrate for the first time that the ZI is visible in vivo. Furthermore, we determined that this nuclear region can be decoupled from surrounding fibre pathways. This work paves the way for more accurate patient-specific optimization of deep brain targets for neuromodulation.

Medical and Surgical Management of ECLS as Bridge to Recovery and Transplantation for Pulmonary Hypertension: A Large Single Center Experience

Purpose Despite advanced targeted medical therapy, patients with pulmonary hypertension (PH) can experience gradual or sudden progression of their symptoms due to an acute insult. Application of extracorporeal life support (ECLS) for advanced PH is evolving. We examined our single-center experience using ECLS as bridge to recovery (BTR), non-transplant surgery (BTNTS), or lung transplantation (BTT) in patients with PH. Methods We conducted a retrospective analysis of all adult patients with non-WHO group 2 PH who received ECLS at New York Presbyterian - Columbia University Medical Center between 2010 and 2018. We describe clinical characteristics and our specialized approach to medical and surgical management in this cohort. Results There were 98 PH patients in the cohort (54 female; median age 48 years (IQR 32-58)). Thirty-six (36.7%) patients received ECLS with intent to BTR (including 10 BTNTS) and 62 (63.3%) to BTT, including 8 who received ECLS during or immediately after lung transplantation. In the overall cohort, 58 (59.1%) patients received VA-ECLS, including upper body Sport Model (n=13), and upper body Central Sport Model (n=7). Nine (9.2%) patents received VVA-ECLS. Thirty-two (32.7%) patients received VV-ECLS including 4 via a congenital pulmonary-systemic shunt for “VA” physiology. Serum lactate, creatinine, brain natriuretic peptide, and arterial blood gas measures improved after ECLS cannulation. Sixty-eight (70%) patients were liberated from invasive mechanical ventilation while receiving ECLS. Management of PH medications followed an intentional strategy of de-escalation for BTT and ramp down and then ramp up for non-surgical BTR. PH medications including intravenous and inhaled prostanoids, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors were used most often in BTR patients and in WHO group 1 PH BTT patients. Survival to decannulation in this cohort was 85.7%; 30-day survival was 71.4%. Conclusion ECLS instituted by a specialized, multidisciplinary PH/ECLS team has a growing role in the management of advanced non-WHO group 2 PH as BTR, BTNTS, or to BTT. Careful selection of cannulation configurations, patient-specific optimization of PH medical therapies, and avoidance of endotracheal intubation may be an effective strategy in managing these complex patients.

Dynamic programming of atrioventricular delay improves electrical synchrony in a multicenter cardiac resynchronization therapy study

Patient-specific programming of cardiac resynchronization therapy (CRT) is often neglected, despite significant nonresponse rates. The device-based SyncAV CRT algorithm dynamically adjusts atrioventricular delays to the intrinsic AV interval, reduced by a programmable offset, to accommodate each patient's changing needs. The purpose of this study was to evaluate the acute effect of biventricular (BiV) pacing enhanced by SyncAV on electrical synchrony in a broad patient population. Patients with existing CRT implants were prospectively evaluated at 5 international centers. Blinded 12-lead electrocardiographic QRS duration (QRSd) measurements were used to compare intrinsic conduction with nominal BiV pacing, BiV + SyncAV (default 50 ms offset), and BiV + SyncAV (optimized, patient-specific offset). BiV configurations were tested twice using the latest activating and earliest activating left ventricular (LV) electrodes as cathodes. Ninety patients (mean age 67.1 ± 9.5 years; 67 (74%) men; 55 (63%) with left bundle branch block; 37 (43%) with ischemic cardiomyopathy; LV ejection fraction 32% ± 9%) with intact atrioventricular conduction (PR interval 195 ± 45 ms) were enrolled. With BiV pacing from the latest activating LV electrode, the intrinsic QRSd of 155 ± 29 ms was reduced by 9% ± 20% to 138 ± 27 ms using traditional BiV pacing and by 13% ± 14% to 133 ± 25 ms using BiV + SyncAV (50 ms offset). The maximal QRSd reduction by 20% ± 10% to 123 ± 22 ms was achieved by BiV + SyncAV with an optimized offset. Similar QRSd reductions were observed with BiV pacing from the earliest activating LV electrode across all settings. Of all baseline characteristics, intrinsic QRSd was the only significant predictor of QRSd reduction magnitude. SyncAV improved acute electrical synchrony beyond conventional CRT, particularly with patient-specific optimization. The degree of synchrony restored was contingent on intrinsic QRSd, but not limited by other baseline characteristics or by the LV pacing electrode used.

Deep Brain Stimulation for Obsessive Compulsive Disorder: Evolution of Surgical Stimulation Target Parallels Changing Model of Dysfunctional Brain Circuits.

Obsessive compulsive disorder (OCD) is a common, disabling psychiatric disease characterized by persistent, intrusive thoughts and ritualistic, repetitive behaviors. Deep brain stimulation (DBS) is thought to alleviate OCD symptoms by modulating underlying disturbances in normal cortico-striato-thalamo-cortical (CSTC) circuitry. Stimulation of the ventral portion of the anterior limb of the internal capsule (ALIC) and underlying ventral striatum (“ventral capsule/ventral striatum” or “VC/VS” target) received U.S. FDA approval in 2009 for patients with severe, treatment-refractory OCD. Over the decades, DBS surgical outcome studies have led to an evolution in the electrical stimulation target. In parallel, advancements in neuroimaging techniques have allowed investigators to better visualize and define CSTC circuits underlying the pathophysiology of OCD. A critical analysis of these new data suggests that the therapeutic mechanism of DBS for OCD likely involves neuromodulation of a widespread cortical/subcortical network, accessible by targeting fiber bundles in the ventral ALIC that connect broad network regions. Future studies will include advances in structural and functional imaging, analysis of physiological recordings, and utilization of next-generation DBS devices. These tools will enable patient-specific optimization of DBS therapy, which will hopefully further improve outcomes.

Patient-specific optimization of mechanical ventilation for patients with acute respiratory distress syndrome using quasi-static pulmonary P-V data.

Quasi-static, pulmonary pressure-volume (P-V) curves were combined with a respiratory system model to analyze tidal pressure cycles, simulating mechanical ventilation of patients with acute respiratory distress syndrome (ARDS). Two important quantities including 1) tidal recruited volume and 2) tidal hyperinflated volume were analytically computed by integrating the distribution of alveolar elements over the affected pop-open pressure range. We analytically predicted the tidal recruited volume of four canine subjects and compared our results with similar experimental measurements on canine models for the validation. We then applied our mathematical model to the P-V data of ARDS populations in four stages of Early ARDS, Deep Knee, Advanced ARDS and Baby Lung to quantify the tidal recruited volume and tidal hyperinflated volume as an indicator of ventilator-induced lung injury (VILI). These quantitative predictions based on patient-specific P-V data suggest that the optimum parameters of mechanical ventilation including PEEP and Tidal Pressure (Volume) are largely varying among ARDS population and are primarily influenced by the degree in the severity of ARDS.

Instrumented Ankle–Foot Orthosis: Toward a Clinical Assessment Tool for Patient-Specific Optimization of Orthotic Ankle Stiffness

In this paper, we detail the design and operation of the instrumented ankle–foot orthosis ( i AFO), a clinical assessment tool that can be used to quantify the functional consequences of selectively modifying orthotic ankle joint stiffness, particularly for individuals with locomotor deficits such as foot drop. We discuss the sensing capabilities of the system, which include ankle joint kinematics and kinetics, electromyography, and orthosis interface pressures. We further describe the mechanical design of the device, which allows for user-defined manipulation of orthotic stiffness through an interchangeable extension spring mechanism. Finally, we demonstrate a validation of the i AFO's capabilities by presenting results both of benchtop testing and of a preliminary human-subject study. Future work will include in-depth signal analyses of gait parameters and algorithmic development for patient-specific orthosis optimization.