Patient-specific Target Research Articles

Glycated Hemoglobin A1c Time in Range and Dementia in Older Adults With Diabetes

Individuals with diabetes commonly experience Alzheimer disease and related dementias (ADRD). Factors such as hypoglycemia, hyperglycemia, and glycemic variability have been associated with increased risk of ADRD. Traditional glycemic measures, such as mean glycated hemoglobin A1c (HbA1c), may not identify the dynamic and complex pathophysiologic factors in the association between diabetes and ADRD. The HbA1c time in range (TIR) is a previously developed measure of glycemic control that expresses HbA1c stability over time within specific ranges. This measure may inform the current understanding of the association between glucose levels over time and ADRD incidence. To examine the association between HbA1c TIR and incidence of ADRD in older veterans with diabetes. The study sample for this cohort study was obtained from administrative and health care utilization data from the Veterans Health Administration and Medicare from January 1, 2004, to December 31, 2018. Veterans 65 years or older with diabetes were assessed. Participants were required to have at least 4 HbA1c tests during the 3-year baseline period, which could start between January 1, 2005, and December 31, 2014. Data analysis was conducted between July and December 2023. Hemoglobin A1c TIR was calculated as the percentage of days during baseline in which HbA1c was in individualized target ranges based on clinical characteristics and life expectancy, with higher HbA1c TIR viewed as more favorable. The association between HbA1c TIR and ADRD incidence was estimated. Additional models considered ADRD incidence in participants who were above or below HbA1c target ranges most of the time. The study included 374 021 veterans with diabetes (mean [SD] age, 73.2 [5.8] years; 369 059 [99%] male). During follow-up of up to 10 years, 41 424 (11%) developed ADRD. Adjusted Cox proportional hazards regression models showed that lower HbA1c TIR was associated with increased risk of incident ADRD (HbA1c TIR of 0 to <20% compared with ≥80%: hazard ratio, 1.19; 95% CI, 1.16-1.23). Furthermore, the direction of out-of-range HbA1c levels was associated with incident ADRD. Having greater time below range (≥60%, compared with ≥60% TIR) was associated with significantly increased risk (hazard ratio, 1.23; 95% CI, 1.19-1.27). Findings remained significant after excluding individuals with baseline use of medications associated with hypoglycemia risk (ie, insulin and sulfonylureas) or with hypoglycemia events. In this study of older adults with diabetes, increased HbA1c stability within patient-specific target ranges was associated with a lower risk of ADRD. Lower HbA1c TIR may identify patients at increased risk of ADRD.

Integrating muscle fiber orientation from visible human data into radiotherapy target volumes.

Objective.A major challenge in treatment of tumors near skeletal muscle is defining the target volume for suspected tumor invasion into the muscle. This study develops a framework that generates radiation target volumes with muscle fiber orientation directly integrated into their definition. The framework is applied to nineteen sacral tumor patients with suspected infiltration into surrounding muscles.Approach.To compensate for the poor soft-tissue contrast of CT images, muscle fiber orientation is derived from cryo-images of two cadavers from the human visible project (VHP). The approach consists of (a) detecting image gradients in the cadaver images representative of muscle fibers, (b) mapping this information onto the patient image, and (c) embedding the muscle fiber orientation into an expansion method to generate patient-specific clinical target volumes (CTV). The validation tested the consistency of image gradient orientation across VHP subjects for the piriformis, gluteus maximus, paraspinal, gluteus medius, and gluteus minimus muscles. The model robustness was analyzed by comparing CTVs generated using different VHP subjects. The difference in shape between the new CTVs and standard CTV was analyzed for clinical impact.Main results.Good agreement was found between the image gradient orientation across VHP subjects, as the voxel-wise median cosine similarity was at least 0.86 (for the gluteus minimus) and up to 0.98 for the piriformis. The volume and surface similarity between the CTVs generating from different VHP subjects was on average at least 0.95 and 5.13 mm for the Dice Similarity Coefficient and the Hausdorff 95% Percentile Index, showing excellent robustness. Finally, compared to the standard CTV with different margins in muscle and non-muscle tissue, the new CTV margins are reduced in muscle tissue depending on the chosen clinical margins.Significance.This study implements a method to integrate muscle fiber orientation into the target volume without the need for additional imaging.

Multimodal MRI segmentation of key structures for microvascular decompression via knowledge-driven mutual distillation and topological constraints.

Microvascular decompression (MVD) is a widely used neurosurgical intervention for the treatment of cranial nerves compression. Segmentation of MVD-related structures, including the brainstem, nerves, arteries, and veins, is critical for preoperative planning and intraoperative decision-making. Automatically segmenting structures related to MVD is still challenging for current methods due to the limited information from a single modality and the complex topology of vessels and nerves. Considering that it is hard to distinguish MVD-related structures, especially for nerve and vessels with similar topology, we design a multimodal segmentation network with a shared encoder-dual decoder structure and propose a clinical knowledge-driven distillation scheme, allowing reliable knowledge transferred from each decoder to the other. Besides, we introduce a class-wise contrastive module to learn the discriminative representations by maximizing the distance among classes across modalities. Then, a projected topological loss based on persistent homology is proposed to constrain topological continuity. We evaluate the performance of our method on in-house dataset consisting of 100 paired HR-T2WI and 3D TOF-MRA volumes. Experiments indicate that our model outperforms the SOTA in DSC by 1.9% for artery, 3.3% for vein and 0.5% for nerve. Visualization results show our method attains improved continuity and less breakage, which is also consistent with intraoperative images. Our method can comprehensively extract the distinct features from multimodal data to segment the MVD-related key structures and preserve the topological continuity, allowing surgeons precisely perceiving the patient-specific target anatomy and substantially reducing the workload of surgeons in the preoperative planning stage. Our resources will be publicly available at https://github.com/JaronTu/Multimodal_MVD_Seg .

Clinical Implementation and Initial Validation of Respiratory-Gated Stereotactic Body Radiotherapy for Thoracoabdominal Tumors Under Abdominal Compression Using an Anzai Laser-Based Gating Device With Visual Guidance on an Elekta Linear Accelerator.

We have clinically implemented gated stereotactic body radiotherapy under abdominal compression using an Anzai laser-based gating device with visual guidance in combination with an Elekta linear accelerator. To ensure accuracy, we configured the gating window for each patient by correlating the respiratory curve from the laser sensor and the tumor positions from the 4D computed tomography (CT) images reconstructed with the aid of the respiratory curve. This allowed us to define a patient-specific gating window to keep the tumor displacement below 5 mm from the end-expiration, assuming the reproducibility of the tumor trajectories and the laser-based body surface measurements. Results are summarized as follows: 1) A patient-specific gating window internal target volume (ITV) with a prespecified maximum tumor displacement relative to the end-expiration was obtained by acquiring a 4D CT consisting of 20 phase CT sets and a respiratory curve from the Anzai system. 2) Respiratory hysteresis was managed by setting two different thresholds on the respiratory curve based on the predetermined maximum tumor displacement relative to end-expiration. 3) Abdominal compression increased gating window width, thereby presumably leading to faster gated-beam delivery. 4) Gamma index pass rates in sliding-window gated intensity-modulated radiotherapy (IMRT) were superior to those in gated volumetric modulated arc therapy (VMAT). 5) Intrafraction gated cone-beam computed tomography (CBCT) demonstrated that the tumor appeared to remain within the gating window ITV during the stereotactic gated sliding-window IMRT. In conclusion, we have successfully implemented gated stereotactic body radiotherapy at our clinic and achieved a favorable clinical validation result. More cases need to be evaluated to increase the validity.

Feasibility and constraints of Bragg peak FLASH proton therapy treatment planning.

FLASH proton therapy (FLASH-PT) requires ultra-high dose rate (≥40 Gy/s) protons to be delivered in a short timescale whilst conforming to a patient-specific target. This study investigates the feasibility and constraints of Bragg peak FLASH-PT treatment planning, and compares the in silico results produced to plans for intensity modulated proton therapy (IMPT). Bragg peak FLASH-PT and IMPT treatment plans were generated for bone (n=3), brain (n=3), and lung (n=4) targets using the MIROpt research treatment planning system and the Conformal FLASH library developed by Applications SA from the open-source version of UCLouvain. FLASH-PT beams were simulated using monoenergetic spot-scanned protons traversing through a conformal energy modulator, a range shifter, and an aperture. A dose rate constraint of ≥ 40 Gy/s was included in each FLASH-PT plan optimisation. Space limitations in the FLASH-PT adapted beam nozzle imposed a maximum target width constraint, excluding 4 cases from the study. FLASH-PT plans did not satisfy the imposed target dose constraints (D95% ≥ 95% and D2%≤ 105%) but achieved clinically acceptable doses to organs at risk (OARs). IMPT plans adhered to all target and OAR dose constraints. FLASH-PT plans showed a reduction in both target homogeneity (p < 0.001) and dose conformity (non-significant) compared to IMPT. Without accounting for a sparing effect, IMPT plans were superior in target coverage, dose conformity, target homogeneity, and OAR sparing compared to FLASH-PT. Further research is warranted in treatment planning optimisation and beam delivery for clinical implementation of Bragg peak FLASH-PT.

True Confessions of Neutral Mechanical Disciple-How I Learned to Love a Patient-Specific Target.

Classical neutral mechanical alignment in total knee arthroplasty (TKA) has been a standard paradigm, while more recently, other alignment schemas, such as kinematic, individualized, and functional, have been explored. This study aimed to investigate the effect of three-dimensional (3D) computed tomography (CT)-based surgical robotics inputs on a classically trained surgeon's TKA component positions and alignment targets over time. Data from 1,394 consecutive robotically-assisted TKAs by a single surgeon from 2016 to 2020 were analyzed. Metrics collected included pre-balance planned implant component positions, final planned implant component positions after soft tissue balancing, and constitutional alignment from CT scans. Joint line obliquity was plotted against the arithmetic hip-knee angle (aHKA) using coronal plane alignment of the knee (CPAK). Three categories of alignment strategy were defined: true mechanical alignment (tMA), adjusted mechanical alignment (aMA), and no mechanical alignment (noMA). A shift to overall varus component positioning was observed over the years. Joint line obliquity according to CPAK showed a wider spread in later years, and the distribution of tibial and femoral coronal alignment angles expanded over time. The study revealed a change in alignment targets and final positioning of components away from neutral biomechanical axes in a large volume of TKAs by a single, classically trained surgeon over five years of using a robotic arm-assisted TKA system with CT-based planning. The most dominant factor for this change was the use of 3D CT planning, allowing the surgeon to assess patient-specific anatomy and plan accordingly. Outcome data is needed to determine if this change in behavior and surgical technique was beneficial. In summary, using a CT scan-based robotically assisted technique led to a gradual and complete shift from tMA to predominantly a non-mechanically aligned philosophy in TKA.

Deep brain stimulation for refractory major depressive disorder: a comprehensive review.

Deep brain stimulation (DBS) has emerged as a promising treatment for select patients with refractory major depressive disorder (MDD). The clinical effectiveness of DBS for MDD has been demonstrated in meta-analyses, open-label studies, and a few controlled studies. However, randomized controlled trials have yielded mixed outcomes, highlighting challenges that must be addressed prior to widespread adoption of DBS for MDD. These challenges include tracking MDD symptoms objectively to evaluate the clinical effectiveness of DBS with sensitivity and specificity, identifying the patient population that is most likely to benefit from DBS, selecting the optimal patient-specific surgical target and stimulation parameters, and understanding the mechanisms underpinning the therapeutic benefits of DBS in the context of MDD pathophysiology. In this review, we provide an overview of the latest clinical evidence of MDD DBS effectiveness and the recent technological advancements that could transform our understanding of MDD pathophysiology, improve the clinical outcomes for MDD DBS, and establish a path forward to develop more effective neuromodulation therapies to alleviate depressive symptoms.

Cine MRI-based analysis of intrafractional motion in radiation treatment planning of head and neck cancer patients

Purpose/Objective(s)To investigate intrafraction motion of (HN) target volumes and to determine patient-specific planning target volume (PTV) margins. Materials/MethodsMR-cine imaging was performed for radiation treatment planning in HN cancer patients treated with definitive EBRT (n = 62) or SBRT (n = 4) on a 1.5 T MRI between 2017–2019. Dynamic MRI scans (sagittal orientation, 2 × 82 × 7 mm3 resolution), ranging from 3–5 min and 900–1500 images, were acquired. The position of the maximum tumor displacement along each direction in the anterior/posterior (A/P) and superior/inferior (S/I) position was recorded and analyzed to determine average PTV margins. ResultsPrimary tumor sites (n = 66) were oropharynx (n = 39), larynx (n = 24) and hypopharynx (n = 3). PTV margins for A/P/S/I positions were 4.1/4.4/5.0/6.2 mm and 4.9/4.3/6.7/7.7 mm for oropharyngeal and laryngeal/hypopharyngeal cancers when accounting for all motion. V100 for PTV was calculated and compared to the original plans. The mean drop in PTV coverage was in most cases under 5%. For a subset of patients with 3 mm plans available, V100 for PTV had more substantial decreases in coverage averaging 8.2% - and 14.3% for oropharyngeal and laryngeal/hypopharynx plans, respectively. ConclusionThe use of MR-cine in treatment planning allows for quantification of tumor motion during swallow and resting periods and should be accounted for during treatment planning. With motion considered, the derived margins may exceed the commonly used 3–5 mm PTV margins. Quantification and analysis of tumor and patient-specific PTV margins is a step towards real-time MRI guidance adaptive radiotherapy.

Association of hemoglobin A1c stability with mortality and diabetes complications in older adults with diabetes

IntroductionHemoglobin A1c (A1c) treatment goals in older adults should be individualized to balance risks and benefits. It is unclear if A1c stability over time within unique target ranges also affects...

Patient-Specific Safe Zones for Acetabular Component Positioning in Total Hip Arthroplasty: Mathematically Accounting for Spinopelvic Biomechanics

BackgroundDespite a growing understanding of spinopelvic biomechanics in total hip arthroplasty (THA), there is no validated approach for executing patient-specific acetabular component positioning. The purpose of this study was to (1) validate quantitative, patient-specific acetabular “safe zone” component positioning from spinopelvic parameters and (2) characterize differences between quantitative patient-specific acetabular targets and qualitative hip-spine classification targets. MethodsFrom 2,457 consecutive primary THA patients, 22 (0.88%) underwent revision for instability. Spinopelvic parameters were measured prior to index THA. Acetabular position was measured following index and revision arthroplasty. Using a mathematical proof, we developed an open-source tool translating a surgeon-selected, preoperative standing acetabular target to a patient-specific safe zone intraoperative acetabular target. Difference between the patient-specific safe zone and the actual component position was compared before and after revision. Hip-spine classification targets were compared to patient-specific safe zone targets. ResultsOf the 22 who underwent revision, none dislocated at follow-up (4.6 [range, 1 to 6.9]). Patient-specific safe zone targets differed from prerevision acetabular component position by 9.1 ± 4.2° inclination/13.3 ± 6.7° version; after revision, the mean difference was 3.2 ± 3.0° inclination/5.3 ± 2.7° version. Differences between patient-specific safe zones and the median and extremes of recommended hip-spine classification targets were 2.2 ± 1.9° inclination/5.6 ± 3.7° version and 3.0 ± 2.3° inclination/7.9 ± 3.5° version, respectively. ConclusionA mathematically derived, patient-specific approach accommodating spinopelvic biomechanics for acetabular component positioning was validated by approximating revised, now-stable hips within 5° version and 3° inclination. These patient-specific safe zones augment the hip-spine classification with prescriptive quantitative targets for nuanced preoperative planning.

Inverse kinematic alignment accommodates native coronal knee alignment better in comparison to adjusted mechanical alignment and restricted kinematic alignment.

The purpose was to determine the proportion of native non-arthritic knees that fit within the target zones of adjusted mechanical alignment (aMA), restricted kinematic alignment (rKA), and inverse kinematic alignment (iKA), and to estimate adjustments in native coronal alignment to bring outlier knees within the respective target zones. The hypothesis was that the target zone of iKA, compared to the target zones of aMA and rKA, accommodates a higher proportion of native non-arthritic knees. The study used measurements obtained from a computed tomography (CT) scan database (SOMA, Stryker) of 972 healthy knees (Caucasian, 586; Asian, 386). Hip knee ankle (HKA) angle, medial proximal tibial angle (MPTA) and lateral distal femoral angle (LDFA) were used to estimate the proportions of knees within the patient-specific alignment target zones; and to estimate theoretical adjustments of MPTA, LDFA and soft tissue balance (HKA) to bring outlier knees within target zones. Theoretical adjustments to bring outlier knees within the alignment target zones of aMA, rKA and iKA were calculated by subtracting the native coronal alignment angles (MPTAnative, LDFAnative and HKAnative) from angles on the nearest target zone border (MPTAtarget, LDFAtarget and HKAtarget). Patients were aged 59.8 ± 15.8years with a BMI of 25.0 ± 4.4kg/m2. The HKA angles were between 168° and 186°, MPTA between 78° and 98° and LDFA between 79° and 93°. Of the 972 knees, 81 (8%) were in the aMA target zone, 530 (55%) were in the rKA target zone, and 721 (74%) were in the iKA target zone. Adjustments of MPTA, LDFA and HKA angle to bring outlier knees within the target zones, were, respectively, 90, 91 and 28% for aMA, 45, 28 and 25% for rKA, and 25, 23 and 7% for iKA. There is considerable variability in native knee coronal alignment that corresponds to different proportions of the restricted patient-specific alignment target zones for TKA. Although extension of the MPTA and LDFA target zones with rKA accommodate native knee alignment better than aMA, up to 25% would require adjustment of native HKA angle. By also extending the HKA angle target zone into varus, iKA accommodates a greater proportion (93%) of native limb alignment. IV.

Performance evaluation of online motion synchronizing systems for patient-specific respiratory movements with helical tomotherapy

Background and purpose. The introduction of online motion synchronizing system on helical tomotherapy paves way for robust motion tracking. A recent upgrade launches modifications on both hardware and software of the kV tracking system. An evaluation on the kV subsystems, prior (Version1) and post upgrade (Version2), was performed to compare tracking accuracy by means of fiducial tracking error and resulted root-mean-square (RMS). Impacts influenced by various patient-specific breathing pattern regularities and target movements were also investigated to refine motion tracking error estimations upon future selection of possible candidates. Materials and methods. Respiratory patterns from twenty-five lung cases were imported individually into a commercial dynamic platform model. Situating a phantom implanted with gold fiducial markers on the platform, superior-inferior (SI) movements of corresponding targets were simulated. Each case was delivered via an identical treatment plan in Version1 and was repeated in Version2. Motion tracking accuracy, by means of discrepancies between subsystem predicted model and raw data motion recorded in patient CT simulation, was analyzed statistically. Wilcoxon signed ranked test was employed to evaluate the difference in tracking error range between the two versions. Statistical model was fitted to inspect the dependence of internal target movement towards fiducial tracking errors. Results. A small difference of ±1 mm was exhibited in 99% of fiducial tracking errors for all cases experimented under both versions. RMS errors were all below 0.5 mm. Version2 demonstrated a greater extremity in fiducial tracking error (p = 0.04). A positive correlation was depicted between internal target amplitudes and 95% interval of fiducial tracking errors (p < 0.02). Overall, irregular respiratory patterns tended to have greater fiducial tracking errors. Conclusions. The excellent tracking performance in both kV subsystem versions offers motion compensations benefits, yet Version1 outperformed Version2 in fiducial tracking accuracy. It is noticeable that greater magnitude in internal target movement and irregular breathing patterns yield greater tracking error.

CT-Guided Adaptive Radiotherapy (CT-ART) Improves Target Coverage in Hypofractionated Radiation Therapy for Bladder Cancer

<h3>Purpose/Objective(s)</h3> We assess the feasibility and dosimetric characteristics of CT-guided daily adaptive radiotherapy (CT-ART) for patients with muscle-invasive bladder cancer (MIBC). Compared to the scheduled treatment, we hypothesized that CT-ART would allow us to optimize target coverage and dose to organs at risk (OARs) by accounting for inter-fraction motion of the bladder and OARs. <h3>Materials/Methods</h3> Four patients with cT2a-T4aN0M0 MIBC treated with hypofractionated RT or chemoRT at 2.75 Gy/Fx (55Gy/20) with empty bladder using CT-ART were retrospectively reviewed. There were 42 total fractions delivered with CT-ART. For each Fx, cone beam CT (CBCT) scans were acquired with artificial-intelligent segmented target and OARs. Contours were manually edited and a patient-specific internal target volume (ITV) was applied for bladder filling during the adaptive process. An adaptive plan (P_A) was then created and optimized based on these volumes. Adaptive plan metrics for target/OARs were then compared to the initial plan (P_I) for each Fx. The PTV_5500 V₁₀₀ (%), V₉₅ (%), D_97% (Gy), and D_95% (Gy); rectum D_47Gy (cc); and non-sigmoid bowel OARs were compared between the P_I and P_A plans using paired samples t-test (Table). <h3>Results</h3> CT-ART improved PTV coverage, with mean per Fx improvement of 12.4% and 28.3% for V₉₅ and V₁₀₀ and 0.4 Gy/Fx for both D _97% and D_95% (<i>p</i><0.01 for all). The P_I plan did not meet PTV V₁₀₀ ≥95% in 39 of 42 Fxs (92.9%) vs. 4 of 42 Fx (9.5%) with the P_A plans. P_A plans did not result in increased dose to OARs (Table). Median CT-ART treatment duration improved over time [median 33 min (range 30-47) for the last patient treated]. <h3>Conclusion</h3> CT-based online adaptive radiation therapy was feasible and significantly improved PTV coverage without a corresponding increase in dose to OARs. This study demonstrates the potential value of CT-ART for MIBC. This approach will be tested in an upcoming phase II trial.

The role of the atrium in the development of the Takotsubo Syndrome – investigation of a patient-specific atrial stem cell model

Abstract Background and aims The Takotsubo syndrome (TTS) is characterised by an acute left ventricular dysfunction without exhibiting signs of stenosis. TTS affects mainly the left ventricle, however, its pathophysiology comprises transient impairments in left atrium functions with a prevalence of atrial fibrillation (AF) of around 18% correlating with higher ventricular heart rhythm disorders. In this study, we aimed to prove the hypothesis that molecular and cellular arrhythmic events contribute to the development of TTS under catecholamine stress and to test if the currently clinically used β-blockers (Metoprolol) or the PDE4 activator MR-L2 are suitable for Takotsubo cardiomyopathy in vitro. Methods and results We generated induced pluripotent stem cell-derived atrial cardiomyocytes (TTS-iPSC-aCMs) from TTS patients, confirmed atrial marker expression (MLC2a, PItX2, NR2F2), and treated them with catecholamines (Iso) to mimic TTS-phenotype. Using a cytosolic Förster resonance energy transfer (FRET) based cAMP sensor, we tested the activity of phosphodiesterases (PDEs) in TTS-iPSC-aCMs and observed that after β-AR stimulation, the strong effects of the PDE4 family in the cytosol of atrial control cells were significantly decreased in aCMs of the TTS patients. This effect was rescued after application of PDE4 activator MR-L2 and is in line with the previously described downregulation of PDE4 in human atrial myocardium of AF patients. In functional studies, Iso-induced increase in systolic Ca2+ transient amplitude was more pronounced in TTS iPSC-aCM compared to controls. These effects were rescued by both, the clinically approved β-blocker Metoprolol and by MR-L2. To analyse arrhythmic events in atrial TTS CMs, we performed confocal microscope Ca2+ measurements and demonstrated that the diastolic sarcoplasmic reticulum Ca2+ leak was increased in iPSC aCMs of TTS patients compared to control under basal conditions and after Iso-treatment. In addition, TTS patients displayed faster Ca2+ kinetics compared to control cells, already under basal conditions. These results were underlined on a molecular level by increased phospholamban phosphorylation in TTS iPSC-aCM. Subsequent treatment with Metoprolol rescued the Ca2+ kinetic parameters and the increased calcium sparks in all cell lines. Conclusion In conclusion, we were able to draw a comprehensive picture on the role of the atrium in the development of arrhythmias in TTS. We found TTS-patient-specific differences with reduced PDE4 activity, elevated arrhythmic events and enhanced reactions to catecholamines, which could be rescued by the clinically approved drug Metoprolol and partly by the PDE4 activator MR-L2. Therefore, Metoprolol has proven to be an effective treatment option for TTS and preliminary data of MR-L2 demonstrate promising effects as a new patient-specific therapeutic target for TTS under catecholamine-stress. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German centre for cardiovascular research

Abstract P2106: Arrhythmia As Cause For The Development Of The Takotsubo Syndrome In A Patient-specific Atrial Stem Cell Model

Background and Aims: The Takotsubo syndrome (TTS) is characterised by an acute left ventricular dysfunction without exhibiting signs of stenosis. TTS affects mainly the left ventricle, however, its pathophysiology comprises transient impairments in left atrium functions with a prevalence of atrial fibrillation (AF) of around 18% correlating with higher ventricular heart rhythm disorders. In this study, we aimed to prove the hypothesis that molecular and cellular arrhythmic events contribute to the development of TTS under catecholamine stress and to test if the currently clinically used β-blockers (Metoprolol) are suitable for Takotsubo cardiomyopathy in vitro. Methods and Results: We generated induced pluripotent stem cell-derived atrial cardiomyocytes (TTS-iPSC- a CMs) from TTS patients, confirmed atrial marker expression (MLC2a, PItX2, NR2F2), and treated the cells with catecholamines to mimic TTS-phenotype. Using a cytosolic Förster resonance energy transfer (FRET) based cAMP sensor, we tested the activity of phosphodiesterases (PDEs) in TTS-iPSC-aCMs, which are besides β-ARs main players involved in cAMP signaling in CMs. We observed that after β-AR stimulation, the strong effects of the PDE4 family in the cytosol of atrial controls were significantly decreased in aCMs of the TTS patients. This effect was completely rescued after application of PDE4 activator MR-L2 and is in line with the previously described downregulation of PDE4 in human atrial myocardium of AF patients. In functional studies, isoprenaline-induced increase in systolic Ca 2+ transient amplitude was more pronounced in TTS iPSC-aCM compared to controls. These effects were rescued by both, the clinically approved β-blocker Metoprolol as well as the PDE4 activator MR-L2. To analyse arrhythmic events in atrial TTS CMs, we performed confocal Ca 2+ measurements and demonstrated that the diastolic sarcoplasmic reticulum Ca 2+ leak was increased in iPSC aCMs of TTS patients compared to control under basal conditions and after Iso-treatment. In addition, TTS patients displayed faster Ca 2+ kinetics compared to control cells, already under basal conditions. These results were underlined on a molecular level by increased phospholamban phosphorylation in TTS iPSC-aCM .Subsequent treatment with the beta-blocker Metoprolol rescued the Ca 2+ kinetic parameters in all cell lines. Conclusion: In conclusion, we were able to draw a comprehensive picture on the role of the arrhythmia in the development of TTS. We found TTS-specific differences with reduced PDE4 activity, elevated arrhythmic events and enhanced reactions to catecholamines, which could be rescued by the clinically approved drug Metoprolol and partly by the PDE4 activator MR-L2. Therefore, Metoprolol as well as MR-L2 demonstrate promising effects as patient-specific therapeutic target for TTS.

SALUS—a non-inferiority trial to compare self-tonometry in glaucoma patients with regular inpatient intraocular pressure controls: study design and set-up

PurposeThe SALUS study aims to improve the healthcare situation for glaucoma patients in Germany. In order to detect diurnal intraocular pressure (IOP) fluctuations, inpatient monitoring of IOP in an eye hospital for a minimum of 24 h is the current standard. SALUS assesses the benefits of a new form of outpatient care, where IOP can be measured by the patients themselves at home using a self-tonometer. This approach should promote the patient’s health competence and empowerment within the healthcare system while reducing treatment costs.MethodsThe SALUS study is a randomized controlled, open non-inferiority trial, alongside an economic analysis, determining whether outpatient monitoring of IOP with self-tonometry is at least as effective as current standard care and would reduce treatment costs. Participants (n = 1980) will be recruited by local ophthalmologists in the area of Westphalia-Lippe, Germany, and randomized to receive 7-day outpatient or 24-h inpatient monitoring. Participants in both study arms will also receive 24-h blood pressure monitoring. Furthermore, patient data from both study groups will be collected in an electronic case file (ECF), accessible to practitioners, hospitals, and the study participants. The primary endpoint is the percentage of patients with IOP peaks, defined as levels 30% above the patient-specific target pressure. Data will also be collected during initial and final examinations, and at 3, 6, and 9 months after the initial examination.ResultsThe study implementation and trial management are represented below.ConclusionSALUS is a pioneering prospective clinical trial focused on the care of glaucoma patients in Germany. If SALUS is successful, it could improve the healthcare situation and health literacy of the patients through the introduction of various telemedical components. Furthermore, the approach would almost certainly reduce the treatment costs of glaucoma care.Trial registrationClinicalTrials.gov ID: NCT04698876, registration date: 11/25/2020.DRKS-ID: DRKS00023676, registration date: 11/26/2020.

New energy sources and technologies for atrial fibrillation catheter ablation.

Ablation has become a cornerstone for the management of symptomatic atrial fibrillation (AF) in patients where anti-arrhythmic drugs fail. Electrical isolation of the pulmonary veins (PVs) is the basic step for every procedure but is still hampered by tools and energy sources that do not lead to durability of isolation. Novel therapies include high power short duration radiofrequency ablation in combination with optimal cooling of the electrode-tissue interface by irrigation or new electrode material to allow for optimal safe energy transfer. Novel tools include competitive balloon catheters using cryoenergy, laser, or radiofrequency current, or linear array ablation with ultralow temperature cryoablation to enhance durability of lesions. A novel energy source is rapidly evolving in the form of pulsed electrical field ablation resulting in irreversible electroporation of cardiac tissue, potentially without collateral side effects. Beyond PV isolation, ablation targets are still under study as standardized addition of lesion lines shows limited benefits. Mapping of the activation pattern during AF to guide patient-specific target ablation has been developing over the last decade, with mixed results by different platforms. The field of ablation for AF is evolving more rapidly than ever which will hopeful result in better long-term outcomes.

Implications of the uncertainty of postoperative functional parameters for the preoperative planning of total hip arthroplasty.

The functional parameters pelvic tilt (PT) and hip joint force (HJF) are required to calculate patient-specific target zones based on the range of motion (ROM) and implant loading for preoperative planning of total hip arthroplasty (THA). Both functional parameters may change after THA. The preoperative prediction of the postoperative PT and HJF is associated with a specific amount of uncertainty. The prediction uncertainty has to be considered in the preoperative planning process to avoid a suboptimal implantation. So far, very little attention has been paid to the necessary reduction of patient-specific target zones by the prediction uncertainties of postoperative functional parameters. Prediction models for the postoperative PT in standing position and for the HJF during one-leg stance as a surrogate for the peak force phase during level walking were used to quantify the reduction of the ROM- and load-based target zones of 196 Japanese THA patients. The prediction uncertainty was about 14° for the postoperative standing PT and ranged from 17% body weight to 37% body weight for the components of the HJF. On average, the prosthetic ROM-based target zone had to be significantly reduced by 43% and the load-based target zone by 39%. This led to a median reduction of the combined prosthetic ROM- and load-based target zone of 96%. The study sharpens the awareness for the substantial reduction of ROM- and load-based target zones by prediction uncertainties of the postoperative PT and HJF and highlights the importance of further research to improve prediction models for both functional parameters.

Conversion of the Sagittal Functional Safe Zone to the Coronal Plane Using a Mathematical Algorithm: The Reason for Failure of the Lewinnek Safe Zone.

Ante-inclination (AI) of the cup is a key component of the combined sagittal index (CSI) for predicting joint stability after total hip arthroplasty (THA). We aimed to (1) validate a mathematical algorithm relating AI to radiographic anteversion (RA), radiographic inclination (RI), and pelvic tilt (PT); (2) convert the AI criterion of the CSI into the coronal functional safe zone (CFSZ) and explore the influences of standing-to-sitting pelvic motion (PM) and pelvic incidence (PI) on the CFSZ; and (3) attempt to locate a universal cup orientation that always fulfills the AI criterion of the CSI for all patients. In the first phase, a phantom pelvis was designed to simulate a range of PT values, and an acetabular cup was implanted with different RA, RI, and PT settings using a robot-assisted technique and scanned using the EOS imaging system. The second phase involved patient radiographs. We enrolled 100 patients who underwent robot-assisted THA from April 2019 to December 2019, and EOS images before THA and at the 12-month follow-up were recorded. The AI was measured on a lateral radiograph; this angle was used as the reference and compared with the calculated AI to assess the accuracy of the algorithm. Linear regression was conducted to explore the relationship between the size of the CFSZ and the values of PM and PI. We calculated the intersection of the CFSZs of the patients to find a universal cup orientation (RA and RI) for the CSI. The algorithm was accurate according to both the phantom study and patient radiographs using PT at the time of follow-up, with mean absolute errors (MAEs) of 1.5° (width of 95% confidence interval [CI], 2.2°) and 2.8° (width of 95% CI, 3.0°), respectively. However, the preoperatively predicted AI had an MAE of 9.0° (width of 95% CI, 10.5°). In patient subgroups with lower PM or PI, the sizes of the CFSZ and of its intersection with the Lewinnek safe zone were significantly smaller (p < 0.017). No universal cup orientation existed to fulfill the CSI criteria for all patients or for any of the PM or PI subgroups. The target orientation for the cup in THA should be individualized. Our validated algorithm may serve as a quantitative tool for the patient-specific optimization of cup AI on the basis of the functional safe zone. The Lewinnek safe zone fails because it cannot predict the functional orientation of the cup. The concept of a universal safe zone of cup orientation should be abandoned and replaced by a patient-specific surgical target.

Methods for Assessing Circadian Rhythms and Cell Cycle in Intestinal Enteroids.

Endogenous circadian clocks play a key role in regulating a vast array of biological processes from cell cycle to metabolism, and disruption of circadian rhythms exacerbates a range of human ailments including cardiovascular, metabolic, and gastrointestinal diseases. Determining the state of a patient's circadian rhythms and clock-controlled signaling pathways has important implications for precision and personalized medicine, from improving the diagnosis of circadian-related disorders to optimizing the timing of drug delivery. Patient-derived 3-dimensional enteroids or in vitro "mini gut" is an attractive model uncovering human- and patient-specific circadian target genes that may be critical for personalized medicine. Here, we introduce several procedures to assess circadian rhythms and cell cycle dynamics in enteroids through time course sample collection methods and assay techniques including immunofluorescence, live cell confocal microscopy, and bioluminescence. These methods can be applied to evaluate the state of circadian rhythms and circadian clock-gated cell division cycles using mouse and human intestinal enteroids.