Optimized Atlas-Based Auto-Segmentation of Bony Structures from Whole-Body Computed Tomography.

PURPOSE: To develop and test a method for fully automated segmentation of bony structures from whole-body computed tomography (CT) and evaluate its performance compared with manual segmentation. METHODS AND MATERIALS: We developed a workflow for automatic whole-body bone segmentation using atlas-based segmentation (ABS) method with a postprocessing module (ABSPP) in MIM MAESTRO software. Fifty-two CT scans comprised the training set to build the atlas library, and 29 CT scans comprised the test set. To validate the workflow, we compared Dice similarity coefficient (DSC), mean distance to agreement, and relative volume errors between ABSPP and ABS with no postprocessing (ABSNPP) with manual segmentation as the reference (gold standard). RESULTS: The ABSPP method resulted in significantly improved segmentation accuracy (DSC range, 0.85-0.98) compared with the ABSNPP method (DSC range, 0.55-0.87; P < .001). Mean distance to agreement results also indicated high agreement between ABSPP and manual reference delineations (range, 0.11-1.56 mm), which was significantly improved compared with ABSNPP (range, 1.00-2.34 mm) for the majority of tested bony structures. Relative volume errors were also significantly lower for ABSPP compared with ABSNPP for most bony structures. CONCLUSIONS: We developed a fully automated MIM workflow for bony structure segmentation from whole-body CT, which exhibited high accuracy compared with manual delineation. The integrated postprocessing module significantly improved workflow performance.

Management and clinical outcomes of patients with homozygous familial hypercholesteremia in Saudi Arabia.

We report the incidence, patient characteristic with clinical outcomes in patients with homozygous familial hypercholesterolemia (HoFH) in Saudi Arabia. This is a retrospective and prospective, single center study which included 37 patients 14 years and older enrolled and followed up between 2018-2021 for three years. 46% were females, 78% were offspring of consanguineous marriage. LDLR mutation was in 78% and LDL-C/LDLRAP in 3% of patients. Mean LDL-C at the first presentation was 14.2±3.7 mmol/L, average Dutch lipid score was 20.9±6.24. LDL apheresis was performed on 70% of patients. Most patients were on ezetimibe (92%), high-dose statins ( 84%) and  PCSK9 inhibitors (32%). 48.6% had aortic stenosis, out of which 30% had severe aortic stenosis. Ten underwent aortic valve surgery (5 mechanical valve, 3 Ross procedure, 1 aortic valve repair, 1 bioprosthetic valve) and one had transcatheter aortic valve implantation (TAVI). Coronary artery bypass surgery (CABG) was performed on 32% and percutaneous intervention (PCI) on 11% of patients. HoFH patients have complex diseases with high morbidity and mortality, and benefit from a highly specialized multidisciplinary clinic to address their clinical needs. Although there are several therapeutic agents on the horizon, early diagnosis, and treatment of HoFH remain critical to optimize patient outcomes.

Improved Prognosis of Treatment Failure in Cervical Cancer with Nontumor PET/CT Radiomics.

Radiomics has been applied to predict recurrence in several disease sites, but current approaches are typically restricted to analyzing tumor features, neglecting nontumor information in the rest of the body. The purpose of this work was to develop and validate a model incorporating nontumor radiomics, including whole-body features, to predict treatment outcomes in patients with previously untreated locoregionally advanced cervical cancer. Methods: We analyzed 127 cervical cancer patients treated definitively with chemoradiotherapy and intracavitary brachytherapy. All patients underwent pretreatment whole-body 18F-FDG PET/CT. To quantify effects due to the tumor itself, the gross tumor volume (GTV) was directly contoured on the PET/CT image. Meanwhile, to quantify effects arising from the rest of the body, the planning target volume (PTV) was deformably registered from each planning CT to the PET/CT scan, and a semiautomated approach combining seed-growing and manual contour review generated whole-body muscle, bone, and fat segmentations on each PET/CT image. A total of 965 radiomic features were extracted for GTV, PTV, muscle, bone, and fat. Ninety-five patients were used to train a Cox model of disease recurrence including both radiomic and clinical features (age, stage, tumor grade, histology, and baseline complete blood cell counts), using bagging and split-sample-validation for feature reduction and model selection. To further avoid overfitting, the resulting models were tested for generalization on the remaining 32 patients, by calculating a risk score based on Cox regression and evaluating the c-index (c-index > 0.5 indicates predictive power). Results: Optimal performance was seen in a Cox model including 1 clinical biomarker (whether or not a tumor was stage III-IVA), 2 GTV radiomic biomarkers (PET gray-level size-zone matrix small area low gray level emphasis and zone entropy), 1 PTV radiomic biomarker (major axis length), and 1 whole-body radiomic biomarker (CT bone root mean square). In particular, stratification into high- and low-risk groups, based on the linear risk score from this Cox model, resulted in a hazard ratio of 0.019 (95% CI, 0.004, 0.082), an improvement over stratification based on clinical stage alone, which had a hazard ratio of 0.36 (95% CI, 0.16, 0.83). Conclusion: Incorporating nontumor radiomic biomarkers can improve the performance of prognostic models compared with using only clinical and tumor radiomic biomarkers. Future work should look to further test these models in larger, multiinstitutional cohorts.

Delayed post-hypoxic leukoencephalopathy following alcohol consumption and cardiopulmonary arrest.

Delayed post hypoxic leukoencephalopathy (DPHL) is a rare consequence of hypoxic brain injury that occurs several days to weeks following an initial hypoxic insult. Most of the previously published cases occur in the setting of drug overdoses or carbon monoxide poisoning, where the incidence of DPHL is as high as 3%. Our case depicts a patient with delayed hypoxic brain injury following cardiac arrest with cardiopulmonary resuscitation. Initial neuroimaging was normal, and a repeat MRI scan six days later revealed DWI changes consistent with DPHL. Our patient remained comatose throughout his clinical course until his eventual death nine days after the initial incident. The autopsy confirmed hypoxic-ischemic brain injury with co-existent Wernicke's encephalopathy, a known consequence of alcohol use disorder. This case outlines the clinical course of DPHL accompanied by the unique neuroimaging features that distinguish it from conventional hypoxic-ischemic brain injury.

Transcatheter mitral valve-in-valve implantation for failed bioprosthesis.

OBJECTIVE: This study is a report of clinical and echocardiographic outcomes of experience with transapical mitral valve-in-valve (VIV) replacement. METHODS: Eleven patients with a mean age of 63.7±13.0 years who underwent transapical mitral VIV implantation for a failed bioprosthesis at a single institution were enrolled. All of the patients were considered high-risk for surgical intervention, with a Society of Thoracic Surgery predicted risk of mortality of 14.2±17.6%, and a mean European System for Cardiac Operative Risk Evaluation (EuroSCORE II) of 10.5±6.1%. RESULTS: Transapical mitral VIV implantation was successful in all of the patients. Edwards, Sapien XT and Sapien 3 valves (Edwards Lifesciences Corp., Irvine, CA, USA) were used in 8 (73%), 2 (18%), and 1 (9%) patients, respectively. Size 26 valves were used in 6 (55%) patients while size 29 valves were used in 5 (45%) patients. All of the patients (11, 100%) had no or only trace mitral regurgitation at the end of the procedure. The mean length of hospital stay was 19±8.0 days. The survival was 100% at 14 days, and 90% at 30 days and at 4 years. One patient died as a result of multiorgan failure on day 16 of intensive care unit stay. The mean mitral valve gradient across the percutaneous valve was 2.26±1.047 mmHg, and the mean valve area was 2.20±0.14 cm2. Through the 4 years follow up, the New York Heart Association class of the 10 patients remaining improved to class II with no readmission for heart failure. All of the patients were on coumadin with a target international normalized ratio of 2-3. CONCLUSION: In high-risk patients, transapical mitral VIV implantation can be performed with a high success rate and considerable improvement in clinical status.

Isolated Reoperative Tricuspid Valve Surgery: Outcomes and Risk Assessment.

OBJECTIVE: To describe patient characteristics and post-operative outcomes, including early and late mortality, defined by death within 30 days and after 30 days post-surgery, respectively, as well as 20-year survival after isolated reoperative tricuspid surgery. METHODS: We retrospectively analyzed 169 patients who underwent isolated reoperative tricuspid valve surgery at our institution (between 1997 and 2000) and describe post-surgical outcomes including intraoperative, early and late mortality. All patients included completed 21 years of follow-up. RESULTS: The majority of our patients were females 147 (87%) with the mean age of 45.9 ± 12.9 years. The mean body mass index (BMI, kg/m2) was 27.4 ± 6.0. Previous cardiac surgeries included tricuspid valve surgeries in 169 (100%) patients, with bioprosthetic valves, mechanical valves, annual rings and tricuspid repair surgeries utilized in 37 (21.9%), 21 (12.4%), 38 (22.4%) and 73 (43.2%) patients, respectively. The indication for previous tricuspid surgery was rheumatic heart disease in 154 (91.5%) patients.The most common cause of reoperative valvular surgery was tricuspid regurgitation (TR) in 139 (82.2%), with 66% of patients having severe TR. Other reasons for reoperative surgery included tricuspid stenosis 22 (13%) and dehiscence 8 (4.7%). For the redo surgery, 125 (74%) patients underwent Tricuspid Valve Replacement (TVR), 90 (53%) of whom received bioprosthetic valves while 35 (21%) received mechanical valves. Forty-four patients (26%) underwent Tricuspid Valve Repair. Mortality within 30 days of surgery was 11.3% (20 patients) and 11.4% after 30 days, with 20 years survival being about 80%. CONCLUSIONS: Based on our experience, reoperation for failed isolated tricuspid valve replacement or repair was associated with reasonable mortality and good survival rate over long period of time.

Knowledge-Based Planning for Intact Cervical Cancer.

Cervical cancer radiotherapy is often complicated by significant variability in the quality and consistency of treatment plans. Knowledge-based planning (KBP), which utilizes prior patient data to correlated achievable optimal dosimetry with patient-specific anatomy, has demonstrated promise as a quality control tool for controlling this variability, with consequences for patient outcomes, as well as for the reliability of data from multi-institutional clinical trials. In this article we highlight the application of KBP-based quality control to cervical cancer radiotherapy. We discuss the potential impact of KBP on multi-institutional clinical trials to standardize cervical cancer treatment planning across diverse clinics, and discuss challenges and progress in the implementation of KBP for brachytherapy treatment planning. Additionally, we briefly discuss secondary applications of KBP for cervical cancer. The emerging picture from these studies indicates several exciting opportunities for increasing the utilization of KBP in day-to-day cervical cancer radiotherapy.

A knowledge-based organ dose prediction tool for brachytherapy treatment planning of patients with cervical cancer.

PURPOSE: The purpose of this study is to explore knowledge-based organ-at-risk dose estimation for intracavitary brachytherapy planning for cervical cancer. Using established external-beam knowledge-based dose-volume histogram (DVH) estimation methods, we sought to predict bladder, rectum, and sigmoid D2cc for tandem and ovoid treatments. METHODS AND MATERIALS: A total of 136 patients with loco-regionally advanced cervical cancer treated with 456 (356:100 training:validation ratio) CT-based tandem and ovoid brachytherapy fractions were analyzed. Single fraction prescription doses were 5.5-8 Gy with dose criteria for the high-risk clinical target volume, bladder, rectum, and sigmoid. DVH estimations were obtained by subdividing training set organs-at-risk into high-risk clinical target volume boundary distance subvolumes and computing cohort-averaged differential DVHs. Full DVH estimation was then performed on the training and validation sets. Model performance was quantified by ΔD2cc = D2cc(actual)-D2cc(predicted) (mean and standard deviation). ΔD2cc between training and validation sets were compared with a Student's t test (p < 0.01 significant). Categorical variables (physician, fraction-number, total fractions, and case complexity) that might explain model variance were examined using an analysis of variance test (Bonferroni-corrected p < 0.01 threshold). RESULTS: Training set deviations were bladder ΔD2cc = -0.04 ± 0.61 Gy, rectum ΔD2cc = 0.02 ± 0.57 Gy, and sigmoid ΔD2cc = -0.05 ± 0.52 Gy. Model predictions on validation set did not statistically differ: bladder ΔD2cc = -0.02 ± 0.46 Gy (p = 0.80), rectum ΔD2cc = -0.007 ± 0.47 Gy (p = 0.53), and sigmoid ΔD2cc = -0.07 ± 0.47 Gy (p = 0.70). The only significant categorical variable was the attending physician for bladder and rectum ΔD2cc. CONCLUSION: A simple boundary distance-driven knowledge-based DVH estimation exhibited promising results in predicting critical brachytherapy dose metrics. Future work will examine the utility of these predictions for quality control and automated brachytherapy planning.

Outcomes of Routine Coronary Angiography in Asymptomatic Patients With End-Stage Renal Disease Prior to Kidney Transplantation.

We report the prevalence of coronary artery disease (CAD) in asymptomatic patients with end-stage kidney disease (ESKD) on hemodialysis and explore the best revascularization strategies prior to kidney transplantation. This is a retrospective single-center study, which included all patients who were candidates for kidney transplantation and underwent coronary angiography between 2003 and 2018. All included patients underwent coronary angiography without noninvasive testing and were asymptomatic cardiac-wise. Out of the 368 patients with ESRD, 45% had coronary vessel disease, 17% had 3-vessel disease, 11% had 2-vessel disease, 5.2% had significant left main artery narrowing, and 17% had single-vessel disease. Patients with 3-vessel disease had the worst survival rate at 5 and 10 years. The patients with significant 3-vessel disease or left main artery involvement underwent revascularization; 19% underwent coronary artery bypass grafting, 5% had stenting of the coronary arteries, and 4.7% were on maximal medical therapy. The patients who underwent stenting had a better survival than those on medical therapy, but the difference was not significant (P = .445). Our findings reflect a high prevalence of CAD in patients with ESKD. There is a need for further studies to evaluate benefits of cardiovascular screening in this patient population.

Disruption of microbial communication yields a two-dimensional percolation transition.

Bacteria communicate with each other to coordinate macroscale behaviors including pathogenesis, biofilm formation, and antibiotic production. Empirical evidence suggests that bacteria are capable of communicating at length scales far exceeding the size of individual cells. Several mechanisms of signal interference have been observed in nature, and how interference influences macroscale activity within microbial populations is unclear. Here we examined the exchange of quorum sensing signals to coordinate microbial activity over long distances in the presence of a variable amount of interference through a neighboring signal-degrading strain. As the level of interference increased, communication over large distances was disrupted and at a critical amount of interference, large-scale communication was suppressed. We explored this transition in experiments and reaction-diffusion models, and confirmed that this transition is a two-dimensional percolation transition. These results demonstrate the utility of applying physical models to emergence in complex biological networks to probe robustness and universal quantitative features.

Nanoparticle Enhanced Eutectic Reaction during Diffusion Brazing of Aluminium to Magnesium.

Diffusion brazing has gained much popularity as a technique capable of joining dissimilar lightweight metal alloys and has the potential for a wide range of applications in aerospace and transportation industries, where microstructural changes that will determine the mechanical and chemical properties of the final joint must be controlled. This study explores the effect of Al2O3 nanoparticles on the mechanical and microstructural properties of diffusion brazed magnesium (AZ31) and aluminium (Al-1100) joints. The results showed that the addition of Al2O3 nanoparticle to the electrodeposited Cu coating increased the volume of eutectic liquid formed at the interface which caused a change to the bonding mechanism and accelerated the bonding process. When the Cu/Al2O3 nanocomposite coatings were used as the interlayer, a maximum bond strength of 46 MPa was achieved after 2 min bonding time while samples bonded using pure-Cu interlayers achieved maximum strength after 10 min bonding time. Chemical analysis of the bond region confirmed that when short bonding times are used, the intermetallic compounds formed at the interface are limited to the compounds consumed in the eutectic reaction.

Association of BCL-2 with oxidative stress and total antioxidant status in pediatric acute lymphoblastic leukemia.

B-Cell Lymphoma protein-2 (BCL-2) is one of the most studied proteins with substantial regulatory potential for both apoptosis and autophagy. BCL-2 confer chemoresistance through influencing cancer pathophysiology. Serum level of lactate dehydrogenase (LDH) predicts increased anaerobic glycolysis and is associated with metabolic modulation in cancer cells. In the present research, the interplay of BCL-2, total oxidative status (TOS) and LDH was investigated in patients with acute lymphoblastic leukemia (ALL). The studied parameters, BCL-2 protein (p less than 0.001), TOS (p less than 0.001) and LDH (p less than 0.001) were significantly elevated in the ALL group compared to the normal group (N-group). However, the total antioxidant status (TAS) was reduced significantly (p less than 0.01) in ALL patients. In the ALL group, the TOS had significant negative correlation with TAS (p less than 0.01). Furthermore, non-significant positive correlations were found between BCL-2 and LDH, BCL-2 and TAS and LDH and TAS (each with; p>0.05). However, a negative non-significant correlation was observed between BCL-2 and TOS and LDH and TOS (each with; p>0.05).

Mapping quorum sensing onto neural networks to understand collective decision making in heterogeneous microbial communities.

Microbial communities frequently communicate via quorum sensing (QS), where cells produce, secrete, and respond to a threshold level of an autoinducer (AI) molecule, thereby modulating gene expression. However, the biology of QS remains incompletely understood in heterogeneous communities, where variant bacterial strains possess distinct QS systems that produce chemically unique AIs. AI molecules bind to 'cognate' receptors, but also to 'non-cognate' receptors found in other strains, resulting in inter-strain crosstalk. Understanding these interactions is a prerequisite for deciphering the consequences of crosstalk in real ecosystems, where multiple AIs are regularly present in the same environment. As a step towards this goal, we map crosstalk in a heterogeneous community of variant QS strains onto an artificial neural network model. This formulation allows us to systematically analyze how crosstalk regulates the community's capacity for flexible decision making, as quantified by the Boltzmann entropy of all QS gene expression states of the system. In a mean-field limit of complete cross-inhibition between variant strains, the model is exactly solvable, allowing for an analytical formula for the number of variants that maximize capacity as a function of signal kinetics and activation parameters. An analysis of previous experimental results on the Staphylococcus aureus two-component Agr system indicates that the observed combination of variant numbers, gene expression rates and threshold concentrations lies near this critical regime of parameter space where capacity peaks. The results are suggestive of a potential evolutionary driving force for diversification in certain QS systems.

Is foliar spray of proline sufficient for mitigation of salt stress in Brassica juncea cultivars?

The effects of foliar application of proline (20 mM) on growth, physio-biochemical, and yield parameters were assessed in two Brassica juncea (L.) Czern & Coss cultivars, namely, Varuna and RH-30, at different levels (2.8, 4.2, or 5.6 dsm(-1)) of NaCl in soil. At 29 days after sowing (DAS), plants were sprayed with either 20 mM proline or water in the presence or absence of NaCl stress. The NaCl negatively affected parameters related to growth, photosynthesis, and yield in both varieties but more in RH-30 than in Varuna. Exogenous application of proline counteracted the effects of salt stress in Varuna only, by increasing the antioxidative capacity of the plants. Moreover, proline was not effective in alleviating the detrimental effects of higher salt concentrations on the studied parameters. Proline application to unstressed plants increased growth, photosynthesis, and yield parameters in both varieties; however, the effects were more prominent in Varuna than in RH-30.

Spatial dispersal of bacterial colonies induces a dynamical transition from local to global quorum sensing.

Bacteria communicate using external chemical signals called autoinducers (AI) in a process known as quorum sensing (QS). QS efficiency is reduced by both limitations of AI diffusion and potential interference from neighboring strains. There is thus a need for predictive theories of how spatial community structure shapes information processing in complex microbial ecosystems. As a step in this direction, we apply a reaction-diffusion model to study autoinducer signaling dynamics in a single-species community as a function of the spatial distribution of colonies in the system. We predict a dynamical transition between a local quorum sensing (LQS) regime, with the AI signaling dynamics primarily controlled by the local population densities of individual colonies, and a global quorum sensing (GQS) regime, with the dynamics being dependent on collective intercolony diffusive interactions. The crossover between LQS to GQS is intimately connected to a trade-off between the signaling network's latency, or speed of activation, and its throughput, or the total spatial range over which all the components of the system communicate.

Effect of acetaminophen on sulfamethazine acetylation in male volunteers.

The effect of acetaminophen on sulfamethazine N-acetylation by human N-acetyltrasferase-2 (NAT2) was studied in 19 (n=19) healthy male volunteers in two different phases. In the first phase of the study the volunteers were given an oral dose of sulfamethazine 500 mg alone and blood and urine samples were collected. After the 10-day washout period the same selected volunteers were again administered sulfamethazine 500 mg along with 1000 mg acetaminophen. The acetylation of sulfamethazine by human NAT2 in both phases with and without acetaminophen was determined by HPLC to establish their respective phenotypes. In conclusion obtained statistics of present study revealed that acetaminophen significantly (P<0.0001) decreased sulfamethazine acetylation in plasma of both slow and fast acetylator male volunteers. A highly significant (P<0.0001) decrease in plasma-free and total sulfamethazine concentration was also observed when acetaminophen was co-administered. Urine acetylation status in both phases of the study was found not to be in complete concordance with that of plasma. Acetaminophen significantly (P<0.0001) increased the acetyl, free and total sulfamethazine concentration in urine of both slow and fast acetylators. Urine acetylation analysis has not been found to be a suitable approach for phenotypic studies.

Arginine-phosphate salt bridges between histones and DNA: intermolecular actuators that control nucleosome architecture.

Structural bioinformatics and van der Waals density functional theory are combined to investigate the mechanochemical impact of a major class of histone-DNA interactions, namely, the formation of salt bridges between arginine residues in histones and phosphate groups on the DNA backbone. Principal component analysis reveals that the configurational fluctuations of the sugar-phosphate backbone display sequence-specific directionality and variability, and clustering of nucleosome crystal structures identifies two major salt-bridge configurations: a monodentate form in which the arginine end-group guanidinium only forms one hydrogen bond with the phosphate, and a bidentate form in which it forms two. Density functional theory calculations highlight that the combination of sequence, denticity, and salt-bridge positioning enables the histones to apply a tunable mechanochemical stress to the DNA via precise and specific activation of backbone deformations. The results suggest that selection for specific placements of van der Waals contacts, with high-precision control of the spatial distribution of intermolecular forces, may serve as an underlying evolutionary design principle for the structure and function of nucleosomes, a conjecture that is corroborated by previous experimental studies.

5-Methylation of cytosine in CG:CG base-pair steps: a physicochemical mechanism for the epigenetic control of DNA nanomechanics.

van der Waals density functional theory is integrated with analysis of a non-redundant set of protein-DNA crystal structures from the Nucleic Acid Database to study the stacking energetics of CG:CG base-pair steps, specifically the role of cytosine 5-methylation. Principal component analysis of the steps reveals the dominant collective motions to correspond to a tensile "opening" mode and two shear "sliding" and "tearing" modes in the orthogonal plane. The stacking interactions of the methyl groups globally inhibit CG:CG step overtwisting while simultaneously softening the modes locally via potential energy modulations that create metastable states. Additionally, the indirect effects of the methyl groups on possible base-pair steps neighboring CG:CG are observed to be of comparable importance to their direct effects on CG:CG. The results have implications for the epigenetic control of DNA mechanics.

Effect of remote ischemic preconditioning on serum troponin T level following elective percutaneous coronary intervention.

BACKGROUND: Elective percutaneous coronary intervention (PCI) is associated with myocardial necrosis, as evidenced by troponin release, in approximately one-third of cases. This is known to be linked with subsequent cardiovascular events. This study assessed the ability of remote ischemic preconditioning (RIPC) to attenuate cardiac troponin T (cTnT) release after elective PCI. OBJECTIVE: Evaluation of effect of RIPC on myocardial markers following elective PCI. METHODS: One hundred and forty nine consecutive patients undergoing elective PCI with undetectable preprocedural cTnT were recruited. Subjects were randomized to receive RIPC (induced by three 5-min inflations of a blood pressure cuff to 200 mm Hg around the upper arm, followed by 5-min intervals of reperfusion) or control (cuff deflated) immediately before arrival in the cardiac catheterization room. The primary outcome was cTnT level at approximately 16 hr after PCI. Secondary outcomes included occurrence of postprocedural myocardial infarction (MI), CKMB levels at 16 hr after PCI and assessment of the inflammatory response as measured by C-reactive protein (CRP) levels. RESULTS: The mean cTnT at 16 hr after PCI was lower in the RIPC group compared with the control group. (0.020 vs. 0.047 ng/ml; P = 0.047) Occurrence of postprocedural MI, CKMB and CRP levels did not differ in both groups (P = 0.097, 0.537, and 0.481 respectively). CONCLUSION: The use of RIPC immediately prior to PCI attenuates procedure-related cTnT release and does not affect occurrence of post procedural MI, CKMB, or CRP levels.