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Evaluation of the 3D bone morphology of the glenohumeral joint is necessary for pre-surgical planning. Zero echo time (ZTE) magnetic resonance imaging (MRI) provides excellent bone contrast and can potentially be used in the place of computed tomography. Segmentation of the shoulder anatomy, particularly the humeral head and the acetabulum, is needed for the detailed assessment of each anatomy and for pre-surgical preparation. In this study, we compared the performance of two popular deep learning models based on Google’s DeepLab and U-Net to perform automated segmentation on ZTE MRI of human shoulders. Axial ZTE images of normal shoulders (n = 31) acquired at 3-Tesla were annotated for training with DeepLab and 2D U-Net, and the trained model was validated with testing data (n = 13). While both models showed visually satisfactory results for segmenting the humeral bone, U-Net slightly over-estimated while DeepLab under-estimated the segmented area compared to the ground truth. Testing accuracy quantified by Dice score was significantly higher (p < 0.05) for U-Net (88%) than DeepLab (81%) for the humeral segmentation. We have also implemented the U-Net model onto an MRI console for push-button DL segmentation processing. Although this is an early work with limitations, our approach has the potential to improve shoulder MR evaluation hindered by manual post-processing and may provide clinical benefit for quickly visualizing bones of the glenohumeral joint.

PurposeTo develop a 3D phase modulated UTE adiabatic T1ρ (PM-UTE-AdiabT1ρ ) sequence for whole knee joint mapping on a clinical 3 T scanner.MethodsThis new sequence includes six major features: (1) a magnetization reset module, (2) a train of adiabatic full passage pulses for spin locking, (3) a phase modulation scheme (i.e., RF cycling pair), (4) a fat saturation module, (5) a variable flip angle scheme, and (6) a 3D UTE Cones sequence for data acquisition. A simple exponential fitting was used for T1ρ quantification. Phantom studies were performed to investigate PM-UTE-AdiabT1ρ 's sensitivity to compositional changes and reproducibility as well as its correlation with continuous wave-T1ρ measurement. The PM-UTE-AdiabT1ρ technique was then applied to five ex vivo and five in vivo normal knees to measure T1ρ values of femoral cartilage, meniscus, posterior cruciate ligament, anterior cruciate ligament, patellar tendon, and muscle.ResultsThe phantom study demonstrated PM-UTE-AdiabT1ρ 's high sensitivity to compositional changes, its high reproducibility, and its strong linear correlation with continuous wave-T1ρ measurement. The ex vivo and in vivo knee studies demonstrated average T1ρ values of 105.6 ± 8.4 and 77.9 ± 3.9 ms for the femoral cartilage, 39.2 ± 5.1 and 30.1 ± 2.2 ms for the meniscus, 51.6 ± 5.3 and 29.2 ± 2.4 ms for the posterior cruciate ligament, 79.0 ± 9.3 and 52.0 ± 3.1 ms for the anterior cruciate ligament, 19.8 ± 4.5 and 17.0 ± 1.8 ms for the patellar tendon, and 91.1 ± 8.8 and 57.6 ± 2.8 ms for the muscle, respectively.ConclusionThe 3D PM-UTE-AdiabT1ρ sequence allows volumetric T1ρ assessment for both short and long T2 tissues in the knee joint on a clinical 3 T scanner.

Introduction: The objective of this study was to assess the bi-exponential relaxation times and fractions of the short and long components of the human patellar tendon ex vivo using three-dimensional ultrashort echo time T1ρ (3D UTE-T1ρ) imaging. Materials and Methods: Five cadaveric human knee specimens were scanned using a 3D UTE-T1ρ imaging sequence on a 3T MR scanner. A series of 3D UTE-T1ρ images were acquired and fitted using single-component and bi-component models. Single-component exponential fitting was performed to measure the UTE-T1ρ value of the patellar tendon. Bi-component analysis was performed to measure the short and long UTE-T1ρ values and fractions. Results: The single-component analysis showed a mean single-component UTE-T1ρ value of 8.4 ± 1.7 ms for the five knee patellar tendon samples. Improved fitting was achieved with bi-component analysis, which showed a mean short UTE-T1ρ value of 5.5 ± 0.8 ms with a fraction of 77.6 ± 4.8%, and a mean long UTE-T1ρ value of 27.4 ± 3.8 ms with a fraction of 22.4 ± 4.8%. Conclusion: The 3D UTE-T1ρ sequence can detect the single- and bi-exponential decay in the patellar tendon. Bi-component fitting was superior to single-component fitting.

Evaluation of 3D bone morphology of the glenohumeral joint is necessary for pre-surgical planning. Zero echo time (ZTE) MRI provides excellent bone contrast, and we developed a deep learning model to perform automated segmentation of major bones (i.e., humerus and others) from ZTE to aid evaluation. Axial ZTE images of normal shoulders (n=31) acquired at 3T were annotated for training with a 2D U-Net, and the trained model was validated with testing data (n=10 normal shoulder, n=6 symptomatic). Testing accuracy was around 80 to 90% (Dice score) for either cohort, except for a few failed cases with very low scores.

BackgroundMolecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.MethodsA candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.Findings15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.InterpretationThis first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.FundingUNITAID, Wellcome, MRC, BMGF.

PurposeQuantitative susceptibility mapping (QSM) has surfaced as a promising non-invasive quantitative biomarker that provides information about tissue composition and microenvironment. Recently, ultrashort echo time quantitative susceptibility mapping (UTE-QSM) has been investigated to achieve QSM of short T2 tissues. As the feasibility of UTE-QSM has not been demonstrated in the brain, the goal of this study was to develop a UTE-QSM with an efficient 3D cones trajectory and validate it in the human brain.Materials and methodsAn ultrashort echo time (UTE) cones sequence was implemented in a 3T clinical MRI scanner. Six images were acquired within a single acquisition, including UTE and gradient recalled echo (GRE) images. To achieve QSM, a morphology-enabled dipole inversion (MEDI) algorithm was incorporated, which utilizes both magnitude and phase images. Three fresh cadaveric human brains were scanned using the 3D cones trajectory with eight stretching factors (SFs) ranging from 1.0 to 1.7. In addition, five healthy volunteers were recruited and underwent UTE-QSM to demonstrate the feasibility in vivo. The acquired data were processed with the MEDI-QSM pipeline.ResultsThe susceptibility maps estimated by UTE-QSM showed reliable tissue contrast. In the ex vivo experiment, high correlations were found between the baseline (SF of 1.0) and SFs from 1.1 to 1.7 with Pearson's correlations of 0.9983, 0.9968, 0.9959, 0.9960, 0.9954, 0.9943, and 0.9879, respectively (all p-values < 0.05). In the in vivo experiment, the measured QSM values in cortical gray matter, juxtacortical white matter, corpus callosum, caudate, and putamen were 25.4 ± 4.0, -21.8 ± 3.2, -22.6 ± 10.0, 77.5 ± 18.8, and 53.8 ± 7.1 ppb, consistent with the values reported in the literature.ConclusionUltrashort echo time quantitative susceptibility mapping enables direct estimation of the magnetic susceptibility in the brain with a dramatically reduced total scan time by use of a stretched 3D cones trajectory. This technique provides a new biomarker for susceptibility mapping in the in vivo brain.

ObjectiveTo assess differences in biochemical composition of the deep cartilage layer in subjects with type 2 diabetes mellitus (T2DM) and nondiabetic controls using UTE (ultra-short echo time) T2* mapping and to investigate the association of vascular health and UTE T2* measurements.DesignTen subjects with T2DM matched for age, sex, and body mass index with 10 nondiabetic controls. A 3D UTE sequence with 6 echo times was acquired using 3T magnetic resonance imaging of the knee. For UTE T2* analysis, the deep cartilage layer was segmented and analyzed in 5 compartments (patella, medial, and lateral femur and tibia). The ankle brachial index (ABI) was obtained in all subjects. Linear regression analyses were used to assess associations of T2DM and UTE T2* relaxation times and the associations of ABI measurements and UTE measurements.ResultsCompared with nondiabetic controls, T2DM subjects had significantly lower mean T2*-UTE in the patella (mean difference 4.87 ms; 95% confidence interval [CI] 1.09-8.65; P = 0.015), the lateral tibia (mean difference 2.26 ms; 95% CI 0.06-4.45; P = 0.045), and the lateral femur (mean difference 4.96 ms; 95% CI 0.19-9.73; P = 0.043). Independent of diabetic status, subjects with higher ABI values, indicating better vascular health, had higher T2*-UTE of the patella (coefficient 15.2; 95% CI 3.3-21.4; P = 0.017), the medial tibia (coefficient 9.8; 95% CI 1.0-18.6; P = 0.031), and the lateral femur (coefficient 18.8; 95% CI 3.3-34.3; P = 0.021).ConclusionsT2*-UTE measurements of the deep cartilage layer were consistently lower in subjects with T2DM and in subjects with impaired vascular health, likely indicating increased mineralization of this layer.

Ultrashort echo time (UTE) sequences can image tissues with transverse T 2 /T 2 * relaxations too short to be efficiently observed on routine clinical MRI sequences, such as the vertebral body cartilaginous endplate (CEP). Here, we describe a 3D adiabatic inversion-recovery-prepared fat-saturated ultrashort echo time (3D IR-FS-UTE) sequence to highlight the CEP of vertebral bodies in comparison to the intervertebral disc (IVD) and bone marrow fat (BF) at 3 T. The IR-FS-UTE sequence used a 3D UTE sequence combined with an adiabatic IR preparation pulse centered in the middle of the water and fat peaks, while a fat saturation module was used to suppress the signal from fat. A slab-selective half pulse was used for signal excitation, and a 3D center-out cones trajectory was used for more efficient data sampling. The 3D IR-FS-UTE sequence was applied to an ex vivo human spine sample, as well as the spines of six healthy volunteers and of three patients with back pain. Bright continuous lines representing signal from CEP were found in healthy IVDs. The measured contrast-to-noise ratio was 18.5 ± 4.9 between the CEP and BF, and 20.3 ± 4.15 between the CEP and IVD for the six volunteers. Abnormal IVDs showed CEP discontinuity or irregularity in the sample and patient studies. In conclusion, the proposed 3D IR-FS-UTE sequence is feasible for imaging the vertebral body's CEP in vivo with high contrast.

Abstract Background Although overall health status in the last decades improved, health inequalities due to non-communicable diseases (NCDs) persist between and within European countries. There is a lack of studies giving insights into health inequalities related to NCDs in the European Economic Area (EEA) countries. Therefore, the aim of the present study was to quantify health inequalities in age-standardized disability adjusted life years (DALY) rates for NCDs overall and 12 specific NCDs across 30 EEA countries between 1990 and 2019. Also, this study aimed to determine trends in health inequalities and to identify those NCDs where the inequalities were the highest. Methods DALY rate ratios were calculated to determine and compare inequalities between the 30 EEA countries, by sex, and across time. Annual rate of change was used to determine the differences in DALY rate between 1990 and 2019 for males and females. The Gini Coefficient (GC) was used to measure the DALY rate inequalities across countries, and the Slope Index of Inequality (SII) to estimate the average absolute difference in DALY rate across countries. Results Between 1990 and 2019, there was an overall declining trend in DALY rate, with larger declines among females compared to males. Among EEA countries, in 2019 the highest NCD DALY rate for both sexes were observed for Bulgaria. For the whole period, the highest DALY rate ratios were identified for digestive diseases, diabetes and kidney diseases, substance use disorders, cardiovascular diseases (CVD), and chronic respiratory diseases – representing the highest inequality between countries. In 2019, the highest DALY rate ratio was found between Bulgaria and Iceland for males. GC and SII indicated that the highest inequalities were due to CVD for most of the study period – however, overall levels of inequality were low. Conclusions The inequality in level 1 NCDs DALYs rate is relatively low among all the countries. CVDs, digestive diseases, diabetes and kidney diseases, substance use disorders, and chronic respiratory diseases are the NCDs that exhibit higher levels of inequality across countries in the EEA. This might be mitigated by applying tailored preventive measures and enabling healthcare access.

Abstract Background Pelvic organ prolapse is a bothersome condition affecting many women at advanced age, but also frequently observed in young women with certain risk factors. Various surgical techniques have been developed with the aim of providing effective surgical treatment for apical prolapse. The vaginal bilateral sacrospinous colposuspension surgery (BSC) with ultralight mesh and utilization of the i- stich is a relatively new minimal invasive technique with very promising outcomes. The technique offers apical suspension, in the presence or absence of the uterus. The objective of this study is to evaluate the anatomical and functional outcomes of bilateral sacrospinous colposuspension with ultralight mesh in 30 Patients treated with the vaginal single incision standardized technique. Methods In this retrospective study, 30 patients were treated by BSC for significant vaginal, uterovaginal or cervical prolapse. A simultaneous anterior colporrhaphy, posterior colporrhaphy or both were performed when indicated. Anatomical and functional outcomes were assessed 1 year postoperatively using the Pelvic Organ Prolapse Quantification system (POP-Q) and the standardised Prolapse Quality of Life (P-QOL) questionnair. Results The POP-Q parameters were significantly improved at twelve months after surgery compared to baseline. The total score and all four subdomains of the P-QOL-questionnaire showed positive trends and improvement at twelve months after surgery when compared to preoperative values. All patients were asymptomatic and expressed high satisfaction one year after surgery. No intraoperative adverse events were recorded for all patients. Only minimal postoperative complications were recorded and they all resolved completely with conservative management. Conclusion This study highlights the functional and anatomical outcomes of the minimally invasive vaginal bilateral sacrospinal colposuspension with ultralight mesh for the management of apical prolapse. The one year postoperative results of the proposed procedure reflect excellent outcomes with minimal complications. The data published here are very promising and warrant further investigations and more studies to evaluate the long-term outcomes of BSC in the surgical management of apical defects. Trial registration The study protocol was approved by the Ethics Committee at the University Hospital of Cologne, Germany (Date of registration: 08.02.2022) (Registration number: 21-1494-retro) (retrospectively registered).

Ultra-short echo time (UTE) MRI with post-processing is a promising technique in bone imaging that produces a similar contrast to computed tomography (CT). Here, we propose a 3D slab-selective ultrashort echo time (UTE) sequence together with image post-processing to image bone structures in the lumbar spine. We also explore the intermodality agreement between the UTE and CT images. The lumbar spines of two healthy volunteers were imaged with 3D UTE using five different resolutions to determine the best imaging protocol. Then, four patients with low back pain were imaged with both the 3D UTE sequence and CT to investigate agreement between the imaging methods. Two other patients with low back pain were then imaged with the 3D UTE sequence and clinical conventional T1-weighted and T2-weighted fast spin-echo (FSE) MRI sequences for qualitative comparison. The 3D UTE sequence together with post-processing showed high contrast images of bone and high intermodality agreement with CT images. In conclusion, post-processed slab-selective UTE imaging is a feasible approach for highlighting bone structures in the lumbar spine and demonstrates significant anatomical correlation with CT images.

In regions heavily affected by recurrent typhoons, the need for more resilient electricity infrastructure is pressing. This emphasizes the importance of integrating resilience assessment, including incorporating resilience metrics, into the planning process of power distribution systems against any disruptive events. Although standardized metrics exist for assessing distribution system reliability, the absence of formalized resilience metrics hampers informed investments in critical infrastructure such as microgrid development. In this work, a set of resilience metrics is proposed by reconceptualizing reliability metrics. The metrics were formulated to account for both the type of extreme event and its specific impact on loads with varying levels of criticality. The effectiveness of the proposed metrics is demonstrated through a Philippine microgrid case study. A Monte Carlo framework incorporating an extreme event model, component fragility model, and system response model was used to quantify the resilience improvement before and after stand-alone microgrid operation of the power distribution system. Results show that the proposed metrics can effectively evaluate resilience enhancement and highlight the value of a holistic approach of considering critical loads and types of extreme events to strengthen societal and community resilience, making a compelling case for strategic investments in infrastructure upgrades such as microgrids.

An increasing acceptance of microgrid systems is primarily driven by emission reduction, resilience, reliability, and stability of energy systems. This work proposes a utility-scale grid-connected microgrid generation and network planning for a distribution network based on its available local resources and potential for distributed energy resource (DER) generator installation. Enabling distribution utilities to operate as a microgrid allows their systems to function as stand-alone in worst-case transmission grid scenarios. The main steps include identifying planning objectives, generation planning, and network planning. Results of a case study in Kalinga, Philippines show that the distribution utility can lower the levelized cost of electricity (LCOE) by 0.032 USD/kWh (21.38 %) by adding additional renewable energy capacities into the mix to meet its load demand. Results also show resilience and stability improvements with microgrid operation. Additional requirements for the existing distribution network to operate as a microgrid include additional network switches and line reinforcement upgrades.

PurposeDirect myelin imaging can improve the characterization of myelin-related diseases such as multiple sclerosis. In this study, we explore a novel method to directly image myelin using inversion recovery-prepared hybrid encoding (IR-HE) UTE MRI.MethodsThe IR-HE sequence uses an adiabatic inversion pulse to suppress the long T2 white matter signal, followed by 3D dual-echo HE utilizing both single point imaging and radial frequency encoding, for which the subtraction image between 2 echoes reveals the myelin signal with high contrast. To reduce scan time, it is common to obtain multiple spokes per IR. Here, we invented a novel method to improve the HE, adapted for the multi-spoke IR imaging-termed interleaved HE-for which single point imaging encoding is interleaved between radial frequency encodings near nulling point to allow more efficient IR-signal suppression. To evaluate the proposed approach, a computer simulation, myelin phantom experiment, an ex vivo experiment with a cadaveric multiple sclerosis brain, and an in vivo experiment with 8 healthy volunteers and 13 multiple sclerosis patients were performed.ResultsThe computer simulation showed that IR-interleaved HE allows for improved contrast of myelin signal with reduced imaging artifacts. The myelin phantom experiment showed IR-interleaved HE allows direct imaging of myelin lipid with excellent suppression of water signal. In the ex vivo and in vivo experiments, the proposed method demonstrated highly specific imaging of myelin in white matter of the brain.ConclusionIR-interleaved HE allows for time-efficient, high-contrast direct myelin imaging and can detect demyelinated lesions in multiple sclerosis patients.

Abstract Background Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and PD-L1 thus representing a potential escape mechanism to this combination. Methods We analyzed transcriptomic profile of NSCLC lung adenocarcinoma cohort of TCGA (The Cancer Genome Atlas), stratifying tumors based on EMT (Epithelial mesenchymal Transition) score; in parallel, we investigated the activation of Ido-1 pathway and modulation of immune cytokines productions both in NSCLC cells lines, in peripheral blood mononuclear cells (PBMCs) and in ex-vivo NSCLC spheroids induced by triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor. Results In NSCLC lung adenocarcinoma patient cohort (from TCGA) Ido-1 gene expression was significantly higher in samples classified as mesenchymal according EMT score. Similarly, on a selected panel of NSCLC cell lines higher expression of MEK and Ido-1 related genes was detected in cells with mesenchymal phenotype according EMT score, thus suggesting a potential correlation of co-activation of these two pathways in the context of EMT, with cancer cells sustaining an immune-suppressive microenvironment. While exerting an antitumor activity, the dual blockade of MEK and PD-L1 enhances the secretion of pro-inflammatory cytokines (IFNγ, TNFα, IL-12 and IL-6) and, consequently, the expression of new immune checkpoints such as Ido-1. The triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor demonstrated significant antiproliferative and proapoptotic activity on ex-vivo NSCLC samples; at the same time the triple combination kept increased the levels of pro-inflammatory cytokines produced by both PBMCs and tumor spheroids in order to sustain the immune response and simultaneously decreased the expression of other checkpoint (such as CTLA-4, Ido-1 and TIM-3) thus promoting an immune-reactive and inflamed micro-environment. Conclusions We show that Ido-1 activation is a possible escape mechanism to immune-mediated cell death induced by combination of PD-L1 and MEK inhibitors: also, we show that triple combination of anti-PD-L1, anti-MEK and anti-Ido-1 drugs may overcome this negative feedback and restore anti-tumor immune response in NSCLC patients’ derived three dimensional cultures.