Individual Axis Research Articles

Construction of the working surfaces of the tillage screw body from the compartments of the developable helicoid

Improvement of the screw working bodies for surface tillage is important for increasing the efficiency and quality of agricultural work. The purpose of the work was to calculate the design of the screw a working body for the surface cultivation of the soil from the compartment of the developable helicoid, which would perform the technological process with minimal resistance to plunging in the soil. The surface theory, analytical, and differential geometry were used to design the working body. It is shown in the paper that through a given spiral line, which is the cutting edge of the surface (blade), it is possible to draw developable helicoids with different inclinations of rectilinear generators. Designing the surface for the best plunging into the soil is important. It is established that the proposed working body is an alternative to the existing disc-type tools. It has been proven that for a long time, spherical discs for surface cultivation of the soil were fixed on a common shaft, which was installed on the unit with a certain angle between its axis and the direction of movement of the unit, which contributed to the plunging of the discs in the soil. It is confirmed that the disc-type tillage implements were improved, but this complicated the design of the unit since each disc received an individual axis of rotation. Studies have shown that this made it possible to additionally set the roll angle, that is, the deviation of the plane of the disc blade from the vertical direction, which improved the plunging of the disc in the soil and ensured more effective turning and mixing of plant residues. The proposed screw working body combines the simplicity of the design of the common shaft and the presence of the angle of attack and roll, which confirms its effectiveness in comparison with existing analogs. The necessary calculations were made, and the surfaces of the right and left courses were constructed with the designation of the necessary structural parameters. The application of the obtained results can simplify the design of the soil processing unit

A single-institution experience with 177Lu RPT workflow improvements and qualifying the SPECT/CT imaging for dosimetry.

Implementing any radiopharmaceutical therapy (RPT) program requires a comprehensive review of system readiness, appropriate workflows, and training to ensure safe and efficient treatment delivery. A quantitative assessment of the dose delivered to targets and organs at risk (OAR) using RPT is possible by correlating the absorbed doses with the delivered radioactivity. Integrating dosimetry into an established RPT program demands a thorough analysis of the necessary components and system fine-tuning. This study aims to report an optimized workflow for molecular radiation therapy using 177Lu with a primary focus on integrating patient-specific dosimetry into an established radiopharmaceutical program in a radiation oncology setting. We comprehensively reviewed using the Plan-Do-Check-Act (PDCA) cycle, including efficacy and accuracy of delivery and all aspects of radiation safety of the RPT program. The GE Discovery SPECT/CT 670DR™ system was calibrated per MIM protocol for dose calculation on MIM SurePlan™ MRT software. Jaszcak Phantom with 15-20 mCi of 177Lu DOTATATE with 2.5 µM EDTA solution was used, with the main energy window defined as 208 keV ±10% (187.6 to 229.2 keV); the upper scatter energy window was set to 240 keV ±5% (228 to 252 keV), while the lower scatter energy window was 177.8 keV ±5% (168.9 to 186.7 keV). Volumetric quality control tests and adjustments were performed to ensure the correct alignment of the table, NM, and CT gantry on SPECT/CT. A comprehensive end-to-end (E2E) test was performed to ensure workflow, functionality, and quantitative dose accuracy. Workflow improvements and checklists are presented after systematically analyzing over 400 administrations of 177Lu-based RPT. Injected activity to each sphere in the NEMA Phantom scan was quantified, and the MIM Sureplan MRT reconstruction images calculated activities within ±12% of the injected activity. Image alignment tests on the SPECT/CT showed a discrepancy of more than the maximum tolerance of 2.2 mm on any individual axis. As a result of servicing the machine and updating the VQC and COR corrections, the hybrid imaging system was adjusted to achieve an accuracy of <1 mm in all directions. Workflows and checklists, after analysis of system readiness and adequate training for staff and patients, are presented. Hardware and software components for patient-specific dosimetry are presented with a focus on hybrid image registration and correcting any errors that affect dosimetric quantification calculation. Moreover, this manuscript briefly overviews the necessary quality assurance requirements for converting diagnostic images into dosimetry measurement tools and integrating dosimetry for RPT based on 177Lu.

Lens injury as acomplication of intravitreal medication injection

Intravitreal medication injections are an efficient and low-risk delivery technique for treating various retinal diseases. Rare serious complications include increased intraocular pressure, vitreous hemorrhage, retinal tears and detachment, intraocular inflammation and endophthalmitis. In the case series presented here, we report iatrogenic lens injuries caused by inadequate performance of intravitreal injections. Amulticenter data collection of patients treated with intravitreal injections with visible iatrogenic lens defects from 2016 to 2023 was retrospectively performed. Lens trauma after intravitreal injections was identified in six cases (69.3±6.5 years). While five cases were observed after anti-VEGF therapy, we identified lens injury after dexamethasone implantation in one patient. Iatrogenic lens injury during intravitreal injection is preventable with the correct injection technique. Knowledge of individual axis length and lens status also helps to avoid this complication.

Individual axis control for industrial robots by posture-variant dynamic compensation and feedback control using the FDTD method

Industrial robots experience posture-dependent inertial variation and interference forces between joints, which in turn generates undesired vibrations due to the inherent elasticity of the reduction gears, making it difficult to control each axis independently. Conventionally, dynamic compensation is used to compensate the robot dynamics and decouple each axis, while state feedback control based on a two-inertia model is used for dealing with the vibrations caused by the elasticity of the reduction gears. However, the control design for this approach usually assumes a fixed moment of inertia, so its performance is compromised when large and fast changes in the robot posture occurs. In this paper, a posture-variant approach that takes into account the posture-dependent inertial variation in real time is proposed to achieve exact dynamic compensation and independent control of each axis regardless of the robot posture. The state equations of the posture-variant two-inertia system model for each robot axis are discretized using the finite-difference time-domain (FDTD) method and adapted on both the dynamic compensation and feedback control parts, allowing to easily redesign the whole control system considering the inertial variation at each control cycle. The effectiveness of the method is confirmed by experimental verification on a 6-axis industrial robot.

Uncertainty in the association between socio-demographic characteristics and mental health.

Questionnaires are among the most basic and widespread tools to assess the mental health of a population in epidemiological and public health studies. Their most obvious advantage (firsthand self-report) is also the source of their main problems: the raw data requires interpretation, and are a snapshot of the specific sample's status at a given time. Efforts to deal with both issues created a bi-dimensional space defined by two orthogonal axes, in which most of the quantitative mental health research can be located. Methods aimed to assure that mental health diagnoses are solidly grounded on existing raw data are part of the individual validity axis. Tools allowing the generalization of the results across the entire population compose the collective validity axis. This paper raises a different question. Since one goal of mental health assessments is to obtain results that can be generalized to some extent, an important question is how robust is a questionnaire result when applied to a different population or to the same population at a different time. In this case, there is deep uncertainty, without any a priori probabilistic information. The main claim of this paper is that this task requires the development of a new robustness to deep uncertainty axis, defining a three-dimensional research space. We demonstrate the analysis of deep uncertainty using the concept of robustness in info-gap decision theory. Based on data from questionnaires collected before and during the Covid-19 pandemic, we first locate a mental health assessment in the space defined by the individual validity axis and the collective validity axis. Then we develop a model of info-gap robustness to uncertainty in mental health assessment, showing how the robustness to deep uncertainty axis interacts with the other two axes, highlighting the contributions and the limitations of this approach. The ability to measure robustness to deep uncertainty in the mental health realm is important particularly in troubled and changing times. In this paper, we provide the basic methodological building blocks of the suggested approach using the outbreak of Covid-19 as a recent example.

Intensity-Modulated Radiotherapy (IMRT) for the Treatment of Cushing's Disease

Aim to investigate the efficacy and toxicity of IMRT in treating Cushing's Disease (CD). A total of 78 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). Endocrine recurrence was considered when patients who have reached hormonal remission showed no suppression of 1 mg DST and relapse of clinical features. The outcome of endocrine remission, tumor control and complications were retrieved from medical record. At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95% CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 23.1%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P = 0.044) was significant favorable factors for endocrine remission. But no prognostic factors for endocrine remission were found in the multivariate analysis. IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Intensity-modulated radiotherapy for cushing's disease: single-center experience in 70 patients.

Intensity-modulated radiotherapy (IMRT) is a modern precision radiotherapy technique for the treatment of the pituitary adenoma. Aim to investigate the efficacy and toxicity of IMRT in treating Cushing's Disease (CD). 70 of 115 patients with CD treated with IMRT at our institute from April 2012 to August 2021 were included in the study. The radiation doses were usually 45-50 Gy in 25 fractions. After IMRT, endocrine evaluations were performed every 6 months and magnetic resonance imaging (MRI) annually. Endocrine remission was defined as suppression of 1 mg dexamethasone test (DST) or normal 24-hour urinary free cortisol level (24hUFC). The outcome of endocrine remission, endocrine recurrence, tumor control and complications were retrieved from medical record. At a median follow-up time of 36.8 months, the endocrine remission rate at 1, 2, 3 and 5 years were 28.5%, 50.2%, 62.5% and 74.0%, respectively. The median time to remission was 24 months (95%CI: 14.0-34.0). Endocrine recurrence was found in 5 patients (13.5%) till the last follow-up. The recurrence-free rate at 1, 2, 3 and 5 years after endocrine remission was 98.2%, 93.9%, 88.7% and 88.7%, respectively. The tumor control rate was 98%. The overall incidence of new onset hypopituitarism was 22.9%, with hypothyroidism serving as the most common individual axis deficiency. Univariate analysis indicated that only higher Ki-67 index (P=0.044) was significant favorable factors for endocrine remission. IMRT was a highly effective second-line therapy with low side effect profile for CD patients. Endocrine remission, tumor control and recurrence rates were comparable to previous reports on FRT and SRS.

Abstract P2-11-05: Effects of Intrinsic Subtypes and 21-gene Assay on the Early and Late Recurrence Risks in Patients with Early Stage HER2+ Breast Cancer: An Analysis of the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) Trial

Abstract Background: We previously demonstrated that intrinsic subtypes were associated with prognosis for early recurrence risk in patients (pts) with early-stage HER2-positive (HER2+) BC treated with trastuzumab (H) in the N9831 trial. Here, we evaluated the prognostic value of Intrinsic subtypes and 21-gene assay and the risk of early and late recurrence in the N9831 trial. Methods: NanoString custom code set, which included PAM50 and housekeeping genes, was used to quantify mRNA and generated intrinsic subtypes and risk of recurrence (ROR) score from the N9831 trial in Arms A and C: Arm A chemotherapy alone and arm C concurrent H. Quantitative RT-PCR of 21 genes, calculation of the axis, including estrogen axis (ER, PGR, BCL2, SCUBE2), HER2 axis (GRB7, HER2), proliferation axis (Ki67, STK15, Survivin, CCNB1, MYBL2), invasion axis (MMP11, CTSL2), and recurrence score (RS) risk group assignment (RS group 1 and 2: RS &amp;lt; 31 and RS group 3: RS ≥ 31) were performed using Oncotype DX assay. Cox regression models for RFS were used for analysis. Early recurrence was defined as a recurrence that occurred at ≤ 5 years, and late recurrence was defined as recurrence at &amp;gt; 5 years. Results: A total of 783 patients (Arm A 409 and Arm C 374) were included in this analysis. Using multivariate Cox regression analysis to evaluate the risk of early recurrence in patients who received chemotherapy alone in arm A, both invasion genes (MMP11 HR 1.23, 95%CI 1.05-1.44, p 0.01 and CTSL2 HR 1.36, 95%CI 1.1-1.69, p 0.005) and invasion axis (HR 1.64, 95%CI 1.26-2.13, p &amp;lt; 0.001) were associated with a higher rate of early recurrence. CD68 was associated with improved outcomes (HR 0.56, 95%CI 0.38-0.83, p 0.004). For the risk of early recurrence in patients treated with trastuzumab in arm C, ER (HR 0.85, 95%CI 0.74-0.97, p 0.02), PR (HR 0.78, 95%CI 0.64-0.94, p 0.008), and estrogen axis (HR 0.7, 95%CI 0.57-0.87, p 0.001) were associated with improved outcomes. Invasion axis (HR 1.61, 95%CI 1.08-2.41, p 0.02), Oncotype Dx risk group (3 vs. 1 and 2, HR 8.89, 95%CI 1.27-1124, p 0.02), and basal subtype (HR 2.77, 95%CI 1.1-5.95, p 0.03) were also significantly associated with worse outcomes. For risk of late recurrence, in arm A, ER (HR 1.22, 95%CI 1.04-1.44, p 0.02), PR (1.26, 95%CI 1.05-1.5, p 0.01), and estrogen axis (1.39, 95%CI 1.09-1.77, p 0.008) were associated with worse outcomes. Oncotype Dx risk group (3 vs. 1 and 2, HR 0.4, 95%CI 0.16-0.98, p 0.05) was associated with improved outcomes. However, neither individual gene, axis, nor intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Conclusions: For risks of early recurrence, the invasion genes/axis were associated with increased risks of recurrence in patients with early-stage HER2+ BC regardless of trastuzumab treatment. Among patients treated with trastuzumab, ER genes/axis, Oncotype Dx risk group, and intrinsic subtype were prognostic for risks of recurrence in the first five years. For risks of late recurrence, ER genes/axis and Oncotype Dx risk group were prognostic but only in patients treated with chemotherapy alone. The ER genes/axis were associated with less recurrence in the first five years but worse after five years, reflecting a higher risk of late recurrence in ER/PR+ HER2+ BC patients treated with chemotherapy alone. However, none of the individual gene, axis, or intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Therefore, future studies are needed to identify biomarkers for the risk of late recurrence in HER2+ BC patients treated with adjuvant trastuzumab. Support: BCRF-19-161; U10CA180821, U10CA180882, Genentech. https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT00005970 Citation Format: Saranya Chumsri, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Keith L. Knutson, Antonio C. Wolff, Edith A. Perez, E. A. Thompson. Effects of Intrinsic Subtypes and 21-gene Assay on the Early and Late Recurrence Risks in Patients with Early Stage HER2+ Breast Cancer: An Analysis of the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-05.

Iterative learning contouring control: Theory and application to biaxial systems

This paper is concerned with the iterative learning control (ILC) for the contouring control of multi-axis motion system. A novel ILC algorithm, which is called iterative learning contouring control (ILCC), is proposed and verified with biaxial motion systems. In motion control, conventional ILC requires that the number of control objectives is the same as the number of command inputs, which is called square property. This allows for the formulation of transfer function or matrix inversion. The unique feature of contouring control is its non-square property. For contouring control, conventional ILC circumvents the non-square property by adopting the configuration of cross-coupled control (CCC). In other words, the estimated contour error is decomposed into components of individual axis for compensation by ILC and thus the contour error is reduced indirectly. The proposed ILCC can deal with the non-square property and can directly reduce the contour error by adopting the equivalent contour error as the control objective of the ILC. The equivalent contour error represents an accurate contour error model and hence better contouring accuracy can be achieved. The ILCC algorithm is implemented on two platforms, an XY table and a commercial CNC machine tool. Experiments on the contouring control of a circular path with different speeds and a B-spline path are conducted. It is found that the contour error can be reduced about 88% after several learning iterations. The experimental results confirm the effectiveness of the proposed method and show the excellent contouring performance.

Quad-Mag board for CubeSat applications

Abstract. The design, characteristics, and performance of a CubeSat magnetometer board (Quad-Mag) equipped with four PNI RM3100 magnetometers is presented. The low size, weight, power, and cost of the RM3100 enables the inclusion of four sensors on a single board, allowing a potential factor of 2 reduction in the noise floor established for an individual sensor via oversampling with multiple sensors. The instrument experimentally achieved a noise floor of 5.34 nT (individual axis), averaging across each axis of the four magnetometers, at a 65 Hz sampling rate. This approaches the theoretically established limit for the system of 4.37 nT at 40 Hz. A single onboard Texas Instrument MSP430 microcontroller handles synchronization of the magnetometers and facilitates data collection through a simple UART-based command interface to a host system. The Quad-Mag system has a mass of 59.05 g and total power consumption of 23 mW while sampling and 14 mW while idle. The Quad-Mag enables nearly 1 nT magnetic field measurements at 1 Hz using commercial off-the-shelf sensors for space applications under optimal conditions.

Individualised left anterior oblique projection for lead implantation into interventricular septum

ObjectiveWe sought to investigate whether it is possible to obtain individualised left anterior oblique (LAO) by preprocedural electrocardiographic parameters and, if so, whether these parameters can help to improve the...

Abstract 3956: MYC inhibition overcomes IMiD resistance in heterogeneous multiple myeloma populations

Abstract Introduction: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable, with patients enduring multiple relapses and development of drug resistance. Immunomodulatory drugs (IMiDs) are critical anti-MM agents. IMiDs act by inducing CRBN-dependent proteasomal degradation of the transcription factors IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). Although CRBN aberrations occur, whether they are a functional mechanism of resistance in patients remains unclear. Based on the importance of CRBN in IMiD response, we hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD-resistant MM cells. Methods: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative IKZF1, IKZF3, IRF4 and MYC protein levels in MM cells following ex vivo pomalidomide (Pom) treatment. We established this assay using IMiD-sensitive parental and dose-escalated Pom resistant MM1S and H929 cell lines before utilizing it in patient samples (isolated mononuclear cells). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used mass cytometry to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. Results: Our hypothesis was supported in MM cell lines, as sensitive parental lines showed a significant decrease in all Ikaros axis protein levels following Pom treatment, while resistant lines showed no IMiD-induced decrease in any Ikaros axis protein. However, when assessed in CD38+CD138+ cells from patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating Pom resistant MM cells with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. Conclusions: Our findings did not support our initial hypothesis, as IMiD-induced IKZF1 and IKZF3 degradation remains intact in IMiD resistant MM cells from patient samples. However, our data support a mechanism where the Ikaros axis no longer drives MYC expression in IMiD-resistant MM. Therefore, we propose that the critical mediator of IMiD resistance is conversion to a cell state where MYC expression is Ikaros axis independent. This suggests targeting MYC directly or via the as yet uncharacterized mechanism controlling MYC may be an effective strategy to eradicate IMiD resistant MM. Citation Format: Lorraine N. Davis, Zachary J. Walker, Denis Ohlstrom, Brett M. Stevens, Peter A. Forsberg, Tomer M. Mark, Craig T. Jordan, Daniel W. Sherbenou. MYC inhibition overcomes IMiD resistance in heterogeneous multiple myeloma populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3956.

Angular-Momentum-Based Sizing of Control Moment Gyro Cluster for an Agile Spacecraft

The sizing of a control moment gyro (CMG) cluster is covered sparsely in literature, but it is of considerable interest to a practicing engineer. In this paper, the sizing of a cluster of four control moment gyros is investigated based on the mission angular momentum requirement of a typical agile spacecraft. The CMG skew angle and individual CMG angular momentum are determined as part of the sizing. The work focuses on the sizing of a minimally redundant cluster of four CMGs in a pyramid and roof-type arrangement considering their external angular momentum surfaces. Two approaches are discussed: the first considers maximum angular momentum about individual axis separately, and the second considers the momentum requirement about two axes simultaneously. The internal momentum surfaces of the CMG clusters are analyzed. Gimbal angle desaturation and the fuel consumed for it by the roof-type and pyramid configurations are also examined. Both the four CMG clusters are able to meet the maximum nonspherical angular momentum demanded by a typical mission about each axes. However, using method 1, the cluster is able to generate only 88% of the two-axis mission demand. The clusters meet the mission demand completely with method 2 using 20% more angular momentum per CMG and an increase in skew angle by compared to method 1. The 20% increase in momentum increases power consumption by 11%. For a typical gimbal angle desaturation, the roof-type cluster uses 8.5% more fuel than the pyramid arrangement. However, the former has only one major internal singular surface in contrast with seven for the latter. This makes the roof-type arrangement very desirable to keep the singularity avoidance algorithm simple and amenable with the CMGs operating within the momentum capability, and achieve the required spacecraft agility.

Linkage strategy and vulnerabilities in the barriers to HIV/AIDS treatment for men who have sex with men.

This study aims to analyze the linkage to HIV/AIDS treatment among Men who have Sex with Men (MSM) of the project "A Hora é Agora" in Curitiba, Paraná, Brazil. The concept of vulnerability with its three axes, namely, the individual, social, and programmatic, was the theoretical framework. The barriers from testing up to the onset of the treatment were mapped through linkage registration and minutes from supervisory meetings. In the individual axis, the data revealed that the MSM struggled to address the HIV diagnosis, besides psychological problems that could cause the delay in starting treatment. Considering the social axis, stigma/discrimination was identified in the service at the Basic Health Care Network and within the families, delaying the disclosure of serology. Lastly, in the programmatic axis, the MSM found barriers in accessing the health services due to requests to repeat the HIV test, changing doctors due to poor service, and difficulties in conducting further tests, which adversely reflected on health care. In order to overcome these barriers, it is recommended not only a macro-structural work within this group, but also an investment in the micropolitics, which will enable a real change of attitude, continued care, and a stance related to approaches of care and the defense of life.

309 MYC Inhibition Overcomes IMiD Resistance in Heterogeneous Multiple Myeloma Populations

OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.

Vectorial analysis of the electrocardiogram from conventional limb leads in healthy adult Nepalese females

Introduction: ECG interpretation plays a vital role in the initial evaluation of patients presenting with cardiac complaints. Assessment of degree of cardiac vector is one of the important parameters to be studied in ECG. Methods: A prospective cross-sectional study was carried out among 84 female subjects, aged 18- 40 years of age, including students and staff of Gandaki Medical College Teaching hospital and Research Center, Pokhara, Nepal over a period of one month from 1st Oct to 1st Nov 2021. A Standard ECG machine was used and the ECG was recorded using the conventional limb leads. The individual mean electrical axis of the heart was plotted using the net voltage of QRS complex of Lead-I and Lead-III. The possible correlation between cardiac vector and physical measurements like height weight BSA and BMI were analyzed. The data were analyzed in SPSS version 27. Results: The normal mean electrical axis of the healthy female subjects was observed as 61.7±23.51°. There was a significant positive correlation of cardiac vector with height (p&lt; 0.05), whereas a negative correlation was observed with weight and BMI (p&lt; 0.01). However, there was no significant correlation with BSA. In our study, we observed the maximum left axis cardiac vector as -2° and right axis as 98° among 84 female subjects. Conclusion: Documentation of cardiac vector was made using standard bipolar limb leads in normal healthy female subjects. BMI is involved in the deviation of cardiac vector with a negative correlation. This observation could make it quite attractive for use in clinical practice.

Kinematic alignment in total knee arthroplasty.

The objective of kinematic alignment in total knee arthroplasty is to implant the prosthesis according to the individual joint line, leg axis and ligament tension. Knee osteoarthritis with failure of nonsurgical treatment according to current guidelines. Severe deformity or instability requiring aconstrained knee prosthesis. Necessity of intramedullary stems. Medial parapatellar approach to the knee. Resection of the cruciate ligaments, the meniscus and the osteophytes. Femur-first technique with distal resection of the femur, the intramedullary guide is only used for the extension/flexion positioning of the femoral component. The positioning in varus-valgus is orientated according to the native joint line after correction of chondral wear. The distal resection should be equal to the thickness of the prosthesis considering the chondral wear (up to 2 mm) and the thickness of the saw blade (1 mm). The rotation of the femoral component is set according to the posterior condylar axis under consideration of chondral wear. The amount of resected dorsal bone should correspond to the thickness of the dorsal condyles of the prosthesis. The alignment of the tibia is parallel to the individual joint line. This enables reconstruction of the individual physiological slope, rotation and the varus-valgus axis. Extension and flexion gap are controlled. Asymmetries between the lateral and medial joint space are corrected through avarus or valgus recut of the tibia as long as the surgical planning has not been achieved. The hip-knee angle is controlled; however, the aim in kinematic alignment is to reconstruct the individual axes and ligament tensions and not astraight leg axis. Persisting asymmetries in ligament tension are adjusted by classical soft tissue balancing techniques. Differences between the extension and flexion spaces are corrected by adapting the tibial slope. Release of the ligaments is usually not necessary; sometimes astripping of the dorsal capsule is performed. After the trial implantation, the original prosthesis is implanted. Functional rehabilitation with weight bearing as tolerated. Randomized studies showed abetter function in the Knee Society Score and abetter range of motion with kinematically aligned prostheses compared to mechanical alignment. Available meta-analyses also showed better results for kinematically aligned knees. The first mid-term results of this new technique with afollow-up of 10years show asurvival rate of 97.5% of the prosthesis.

Digital twins, artificial intelligence, and machine learning technology to identify a real personalized motion axis of the tibiotalar joint for robotics in total ankle arthroplasty.

Axial alignment of the talar implant in total ankle arthroplasty remains a major issue, since the real axis of motion of each patient is impossible to determine with usual techniques. Further knowledge regarding individual axis of motion of the ankle is therefore needed. Therefore, digital twins, artificial intelligence, and machine learning technology were used to identify a real personalized motion axis of the tibiotalar joint. Three-dimensional (3D) models of distal extremities were generated using computed tomography data of normal patients. Digital twins were used to reproduce the mobility of the ankles, and the real ankle of the patients was matched to the digital twin with machine learning technology. The results showed that a personalized axis can be obtained for each patient. When the origin of the axis is the centre of mass of the talus, this axis can be represented in a geodesic system. The mean value of the axis is a line passing in first approximation through the centre of the sphere (with a variation of 3mm from the centre of the mass of the talus) and through a point with the coordinates 91.6° west and 7.4° north (range 84° to 98° west; - 2° to 12° north). This study improves the understanding of the axis of the ankle, as well as its relationship to the possibility to use the geodesic system for robotic in ankle arthroplasty. The consideration of a personalized axis of the ankle might be helpful for better understanding of ankle surgery and particularly total ankle arthroplasty.

Establishing a New Patient-Specific Implantation Technique for Total Ankle Replacement: An In Vitro Study.

Revision rates after total ankle replacements (TARs) are higher compared with other total joint replacements. The present study aimed to establish a new patient-specific implantation (PSI) technique for TAR. A total of 10 complete Caucasian cadaver legs had whole leg computed tomography scans. The individual geometrical ankle joint axis was determined, and based on this axis, the position of the prosthesis was planned. We assessed prosthesis placement, guiding block position, and preoperative and postoperative ankle rotational axes. The guiding block position interobserver reliability was 0.37 mm 0.45 (mean ± SD) for the tibial guiding block. The value for the first talar guiding block was 1.72 ± 1.3 mm and for the second talar guiding block, 0.61 ± 0.39 mm. The tibial slope as well as the frontal angles of the anatomical tibial axis compared to the tibial and talar articular surfaces showed no statistically relevant differences with numbers available. The deviation of the assessed preoperative joint axis to the postoperative joint axis was 14.6° ± 7.8. The present study describes the results of an establishing process of a new PSI technique for TAR. The reliability of guiding block positioning and, thereby, prosthesis placement is sufficient. Biomechanical study.

Chronic stress and Alzheimer's disease: the interplay between the hypothalamic-pituitary-adrenal axis, genetics and microglia.

Chronic psychosocial stress is increasingly being recognised as a risk factor for sporadic Alzheimer's disease (AD). The hypothalamic-pituitary-adrenal axis (HPA axis) is the major stress response pathway in the body and tightly regulates the production of cortisol, a glucocorticoid hormone. Dysregulation of the HPA axis and increased levels of cortisol are commonly found in AD patients and make a major contribution to the disease process. The underlying mechanisms remain poorly understood. In addition, within the general population there are interindividual differences in sensitivities to glucocorticoid and stress responses, which are thought to be due to a combination of genetic and environmental factors. These differences could ultimately impact an individuals' risk of AD. The purpose of this review is first to summarise the literature describing environmental and genetic factors that can impact an individual's HPA axis reactivity and function and ultimately AD risk. Secondly, we propose a mechanism by which genetic factors that influence HPA axis reactivity may also impact inflammation, a key driver of neurodegeneration. We hypothesize that these factors can mediate glucocorticoid priming of the immune cells of the brain, microglia, to become pro-inflammatory and promote a neurotoxic environment resulting in neurodegeneration. Understanding the underlying molecular mechanisms and identifying these genetic factors has implications for evaluating stress-related risk/progression to neurodegeneration, informing the success of interventions based on stress management and potential risks associated with the common use of glucocorticoids.