Multiaxial pressure-strain analysis of regional myocardial work in the setting of graded coronary stenoses and dobutamine stress.

We present a detailed analysis of regional myocardial blood flow and work to better understand the effects of coronary stenoses and low-dose dobutamine stress. Our analysis is based on a unique open-chest model in anesthetized canines that features invasive hemodynamic monitoring, microsphere-based blood flow analysis, and an extensive three-dimensional (3-D) sonomicrometer array that provides multiaxial deformational assessments in the ischemic, border, and remote vascular territories. We use this model to construct regional pressure-strain loops for each territory and quantify the loop subcomponent areas that reflect myocardial work contributing to the ejection of blood and wasted work that does not. We demonstrate that reductions in coronary blood flow markedly alter the shapes and temporal relationships of pressure-strain loops, as well as the magnitudes of their total and subcomponent areas. Specifically, we show that moderate stenoses in the mid-left anterior descending coronary artery decrease regional midventricle myocardial work indices and substantially increase indices of wasted work. In the midventricle, these effects are most pronounced along the radial and longitudinal axes, with more modest effects along the circumferential axis. We further demonstrate that low-dose dobutamine can help to restore or even improve function, but often at the cost of increased wasted work. This detailed, multiaxial analysis provides unique insight into the physiology and mechanics of the heart in the presence of ischemia and low-dose dobutamine, with potential implications in many areas, including the detection and characterization of ischemic heart disease and the use of inotropic support for low cardiac output.NEW & NOTEWORTHY Our unique experimental model assesses cardiac pressure-strain relationships along multiple axes in multiple regions. We demonstrate that moderate coronary stenoses decrease regional myocardial work and increase wasted work and that low-dose dobutamine can help to restore myocardial function, but often with further increases in wasted work. Our findings highlight the significant directional variation of cardiac mechanics and demonstrate potential advantages of pressure-strain analyses over traditional, purely deformational measures, especially in characterizing physiological changes related to dobutamine.

Self-reported symptoms in patients with acromegaly: a 6-month follow-up in a single neurosurgical center.

Acromegaly is characterized by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), accompanied by a compromise in the perception of wellness. The Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) is relevant to assessing signs and symptoms but is mainly used to evaluate the efficacy of a pharmacological intervention. To explore the perioperative variation in symptom severity, the divergence between subgroups stratified according to clinical outcomes or treatment modalities, and the interaction between symptom scores and clinical indices, we prospectively recruited 106 patients with acromegaly from 2016 to 2018. Oral glucose tolerance and GH tests were performed, and PASQ was administered before treatment and 6 months postoperatively. Patients were divided into active (n = 49) and remission (n = 57) groups according to postoperative GH and IGF-1 levels. PASQ scores and GH and IGF-1 levels decreased significantly postoperatively in both groups. A significantly higher preoperative headache score and greater extent of decrease in arthralgia were seen in the active and remission groups, respectively. No significant variation in PASQ scores was found between patients receiving surgery alone and those receiving preoperative somatostatin analogs. Preoperative fasting GH (GH0) levels were positively correlated with preoperative excessive perspiration. Further regression analyses validated the variation in GH0 as a noteworthy determinant of the extent of change in soft-tissue swelling, excessive perspiration, fatigue, and total PASQ scores. Patient-reported symptoms were substantially alleviated after surgery, independent of endocrine remission or use of preoperative somatostatin. A GH level decrease was a notable coefficient for PASQ scores.

Abnormal left atrial body stiffness is predicted by appendage size: impact of appendage occlusion on left atrial mechanics assessed by pressure-volume analysis.

Atrial cardiomyopathy has been recognized as having important consequences for cardiac performance and clinical outcomes. The pathophysiological role of the left atrial (LA) appendage and the effect of percutaneous left atrial appendage occlusion (LAAO) upon LA mechanics is incompletely understood. We evaluated if changes in LA stiffness due to endocardial LAAO can be detected by LA pressure-volume (PV) analysis and whether stiffness parameters are associated with baseline characteristics. Patients undergoing percutaneous endocardial LAAO (n = 25) were studied using a novel PV analysis using near-simultaneous three-dimensional LA volume measurements by transesophageal echocardiography (TEE) and direct invasive LA pressure measurements. LA stiffness (dP/dV, change in pressure with change in volume) was calculated before and after LAAO. Overall LA stiffness significantly increased after LAAO compared with baseline (median, 0.41-0.64 mmHg/mL; P ≪ 0.001). LA body stiffness after LAAO correlated with baseline LA appendage size by indexed maximum depth (Spearman's rank correlation coefficient Rs = 0.61; P < 0.01). LA stiffness change showed an even stronger correlation with baseline LA appendage size by indexed maximum depth (Rs = 0.70; P < 0.001). We found that overall LA stiffness increases after endocardial LAAO. Baseline LA appendage size correlates with the magnitude of increase and LA body stiffness. These findings document alteration of LA mechanics after endocardial LAAO and suggest that the LA appendage modulates overall LA compliance.NEW & NOTEWORTHY Our study documents a correlation of LA appendage remodeling with the degree of chronically abnormal LA body stiffness. In addition, we found that LA appendage size was the baseline parameter that best correlated with the magnitude of a further increase in overall LA stiffness after appendage occlusion. These findings offer insights about the LA appendage and LA mechanics that are relevant to patients at risk for adverse atrial remodeling, especially candidates for LA appendage occlusion.

Ramucirumab plus triplet chemotherapy as an alternative salvage treatment for patients with metastatic colorectal cancer.

BACKGROUND: Ramucirumab is indicated for salvage treatment after failure of first-line treatment for metastatic colorectal cancer (mCRC). However, the application of ramucirumab at later-line treatment in real-world practice has not received much discussion. METHODS: In this retrospective study, we enrolled 70 patients with mCRC who received ramucirumab plus chemotherapy at National Taiwan University Hospital between 2018 and 2019. RESULTS: Compared with those who received third- or later-line ramucirumab treatment, patients who received second-line ramucirumab treatment had significantly longer median time to treatment discontinuation (mTTD; 6.7 vs 3.6 months, P = .004) and median overall survival (mOS; not reached vs 7.6 months, P = .009). Multivariate analyses revealed that second-line ramucirumab and triplet chemotherapy backbone were the only independent predictive factors for long mTTD and mOS. Patients who received ramucirumab with triplet chemotherapy had a significantly longer mOS than did patients who received ramucirumab with doublet chemotherapy (not reached vs 5.6 months, P = .002). Among those receiving second-line ramucirumab treatment, combination with triplet chemotherapy led to a longer mTTD than did combination with doublet chemotherapy, but the difference was non-significant (not reached vs 4.4 months, P = .108). By contrast, in patients receiving fourth- or later-line ramucirumab, combination with triplet chemotherapy led to significantly longer mTTD than did combination with doublet chemotherapy (8.0 vs 2.9 months, P = .032). CONCLUSION: Ramucirumab plus triplet chemotherapy may be an alternative regimen in patients with mCRC, particularly as a later-line treatment modality.

Electric Control of Fermi Arc Spin Transport in Individual Topological Semimetal Nanowires.

The exotic topological surface states of Dirac or Weyl semimetals, namely Fermi arcs, are predicted to be spin polarized, while their spin polarization nature is still not revealed by transport measurements. Here, we report the spin-polarized transport in a Dirac semimetal Cd_{3}As_{2} nanowire employing the ferromagnetic electrodes for spin detection. The spin-up and spin-down states can be changed by reversing the current polarity, showing the spin-momentum locking property. Moreover, the nonlocal measurements show a high fidelity of the spin signals, indicating the topological protection nature of the spin transport. As tuning the Fermi level away from the Dirac point by gate voltages, the spin signals gradually decrease and finally are turned off, which is consistent with the fact that the Fermi arc surface state has the maximum ratio near the Dirac point and disappears above the Lifshitz transition point. Our results should be valuable for revealing the transport properties of the spin-polarized Fermi arc surface states in topological semimetals.

Identification of apoptosis-associated protein factors distinctly expressed in cigarette smoke condensate-exposed airway bronchial epithelial cells.

Smoking is associated with an increased risk of respiratory diseases, including lung cancer and asthma. However, the mechanisms or diagnostic markers for smoking-related diseases remain largely unknown. Here we investigated the role of cigarette smoke condensate (CSC) in the regulation of human bronchial epithelial cell (BEAS-2B) behavior. We found that exposure to CSC significantly inhibited BEAS-2B cell viability, impaired cell morphology, induced cell apoptosis, triggered oxidative damage, and promoted inflammatory response, which suggests a deleterious effect of CSC on bronchial epithelial cells. In addition, CSC markedly altered the expression of apoptosis-associated protein factors, including p21, soluble tumor necrosis factor receptor 1, and Fas ligand. In sum, our study identified a panel of novel protein factors that may mediate the actions of CSC on bronchial epithelial cells and have a predictive value for the development and progression of smoking-related diseases, thus providing insights into the development of potential diagnostic and therapeutic strategies against these diseases.

Regional myocardial strain analysis via 2D speckle tracking echocardiography: validation with sonomicrometry and correlation with regional blood flow in the presence of graded coronary stenoses and dobutamine stress.

BACKGROUND: Quantitative regional strain analysis by speckle tracking echocardiography (STE) may be particularly useful in the assessment of myocardial ischemia and viability, although reliable measurement of regional strain remains challenging, especially in the circumferential and radial directions. We present an acute canine model that integrates a complex sonomicrometer array with microsphere blood flow measurements to evaluate regional myocardial strain and flow in the setting of graded coronary stenoses and dobutamine stress. We apply this unique model to rigorously evaluate a commercial 2D STE software package and explore fundamental regional myocardial flow-function relationships. METHODS: Sonomicrometers (16 crystals) were implanted in epicardial and endocardial pairs across the anterior myocardium of anesthetized open chest dogs (n = 7) to form three adjacent cubes representing the ischemic, border, and remote regions, as defined by their relative locations to a hydraulic occluder on the mid-left anterior descending coronary artery (LAD). Additional cardiac (n = 3) and extra-cardiac (n = 3) reference crystals were placed to define the cardiac axes and aid image registration. 2D short axis echocardiograms, sonometric data, and microsphere blood flow data were acquired at baseline and in the presence of mild and moderate LAD stenoses, both before and during low-dose dobutamine stress (5 µg/kg/min). Regional end-systolic 2D STE radial and circumferential strains were calculated with commercial software (EchoInsight) and compared to those determined by sonomicrometry and to microsphere blood flow measurements. Post-systolic indices (PSIs) were also calculated for radial and circumferential strains. RESULTS: Low-dose dobutamine augmented both strain and flow in the presence of mild and moderate stenoses. Regional 2D STE strains correlated moderately with strains assessed by sonomicrometry (Rradial = 0.56, p < 0.0001; Rcirc = 0.55, p < 0.0001) and with regional flow quantities (Rradial = 0.61, Rcirc = 0.63). Overall, correspondence between 2D STE and sonomicrometry was better in the circumferential direction (Bias ± 1.96 SD: - 1.0 ± 8.2% strain, p = 0.06) than the radial direction (5.7 ± 18.3%, p < 0.0001). Mean PSI values were greatest in low flow conditions and normalized with low-dose dobutamine. CONCLUSIONS: 2D STE identifies changes in regional end-systolic circumferential and radial strain produced by mild and moderate coronary stenoses and low-dose dobutamine stress. Regional 2D STE end-systolic strain measurements correlate modestly with regional sonomicrometer strain and microsphere flow measurements.

Observation of an Odd-Integer Quantum Hall Effect from Topological Surface States in Cd_{3}As_{2}.

The quantum Hall effect (QHE) in a 3D Dirac semimetal thin film is attributed to either the quantum confinement induced bulk subbands or the Weyl orbits that connect the opposite surfaces via bulk Weyl nodes. However, it is still unknown whether the QHE based on the Weyl orbit can survive as the bulk Weyl nodes are gapped. Moreover, there are closed Fermi loops rather than open Fermi arcs on the Dirac semimetal surface, which can also host the QHE. Here we report the QHE in the 3D Dirac semimetal Cd_{3}As_{2} nanoplate by tuning the gate voltage under a fixed 30 T magnetic field. The quantized Hall plateaus at odd filling factors are observed as a magnetic field along the [001] crystal direction, indicating a Berry's phase π from the topological surface states. Furthermore, even filling factors are observed when the magnetic field is along the [112] direction, indicating the C_{4} rotational symmetry breaking and a topological phase transition. The results shed light on the understanding of QHE in 3D Cd_{3}As_{2}.

Differentiating spontaneous echo contrast, sludge, and thrombus in the left atrial appendage: Can ultrasound enhancing agents help?

The accurate identification of thrombus in the left atrial appendage with transesophageal echocardiogram (TEE) in patients with atrial fibrillation (AF) before cardioversion is essential. Most of these patients have some grade of spontaneous echo contrast (SEC). Severe SEC is often called "sludge," and its prognosis and treatment are still controversial. Current guidelines suggest the use of ultrasound enhancing agents (UEAs) when significant SEC is present. However, little is known about the utility of the UEAs in the differentiation between sludge and less severe SEC.

Higher Volume Surgeons Have Lower Medicare Payments, Readmissions, and Mortality After THA.

BACKGROUND: The advent of value-based care, in which surgeons and hospitals accept more responsibility for clinical and financial results, has increased the focus on surgeon- and hospital-specific outcomes. However, methods to identify high-quality, low-cost surgeons are not well developed. QUESTIONS/PURPOSES: (1) Is there an association between surgeon THA volume and 90-day Centers for Medicare & Medicaid Services (CMS) Part A payments, readmissions, or mortality? (2) What proportion of THAs in the United States is performed by low- and high-volume surgeons? METHODS: We performed a retrospective analysis of the CMS Limited Data Set on all primary elective THAs performed in the United States (except Maryland) between January 2013 and June 2016 on patients insured by Medicare. This represented 409,844 THAs totaling more than USD 7.7 billion in direct CMS expenditures. Surgeons were divided into five groups based on annualized volume of CMS elective THAs over the study period. Using linear and logistic regression, we calculated and compared 90-day CMS Part A payments, readmissions, and mortality among the groups. For each episode, demographic information (age, sex, and race), geographic location, and Elixhauser comorbidities were calculated to control for major confounding factors in the regression. RESULTS: When compared with the highest volume group, each lower volume group had increased payments, increased readmission rates, and increased mortality rates in a stepwise fashion when controlling for patient-specific variables including Elixhauser comorbidity index, demographic information, region, and background trend. The lowest volume group resulted in 27.2% more CMS payments per case (p < 0.001; 95% confidence interval [CI], 26.6%-27.8%), had an increased readmission odds ratio (OR) of 1.8 (p < 0.001; 95% CI, 1.7-1.9), and an increased mortality OR of 4.7 (p < 0.001; 95% CI, 4.0-5.5) when compared with the highest volume group. There was also variation within volume groups: some lower volume surgeons had lower payments, readmissions, and mortality than some higher volume surgeons despite the general trend. In terms of CMS volume, surgeons who were at least moderate volume (11+ annual cases) performed 78% of THAs and represented 26% of operating surgeons. The low- and lowest volume surgeons (10 or fewer annual cases) performed only 22% of THAs in the United States while representing 74% of unique operating surgeons. CONCLUSIONS: There is a strong association between a surgeon's Medicare volume and lower CMS payments, readmissions, and mortality. Furthermore, the majority of Medicare THAs in the United States are performed by surgeons who perform > 10 CMS operations annually. Compared with previous work, these results suggest a trend toward higher volume surgeons in the Medicare population. The results also suggest a benefit to the shift toward higher volume surgeons in reducing payments, readmissions, and mortality for elective THA in the United States. However, given that payments, readmission, and mortality of surgeons varied widely, it is important to note that available individual CMS data can be used to directly evaluate each individual surgeon based on their actual results well as through association with volume. LEVEL OF EVIDENCE: Level III, therapeutic study.

2018 John Charnley Award: Analysis of US Hip Replacement Bundled Payments: Physician-initiated Episodes Outperform Hospital-initiated Episodes.

BACKGROUND: The Centers for Medicare & Medicaid Services (CMS) launched the Bundled Payment for Care Improvement (BPCI) initiative in 2013 to create incentives to improve outcomes and reduce costs in various clinical settings, including total hip arthroplasty (THA). This study seeks to quantify BPCI initiative outcomes for THA and to determine the optimal party (for example, hospital versus physician group practice [PGP]) to manage the program. QUESTIONS/PURPOSES: (1) Is BPCI associated with lower 90-day payments, readmissions, or mortality for elective THA? (2) Is there a difference in 90-day payments, readmissions, or mortality between episodes initiated by PGPs and episodes initiated by hospitals for elective THA? (3) Is BPCI associated with reduced total Elixhauser comorbidity index or age for elective THA? METHODS: We performed a retrospective analysis on the CMS Limited Data Set on all Medicare primary elective THAs without a major comorbidity performed in the United States (except Maryland) between January 2013 and March 2016, totaling more than USD 7.1 billion in expenditures. Episodes were grouped into hospital-run BPCI (n = 42,922), PGP-run BPCI (n = 44,662), and THA performed outside of BPCI (n = 284,002). All Medicare Part A payments were calculated over a 90-day period after surgery and adjusted for inflation and regional variation. For each episode, age, sex, race, geographic location, background trend, and Elixhauser comorbidities were determined to control for major confounding variables. Total payments, readmissions, and mortality were compared among the groups with logistic regression. RESULTS: When controlling for demographics, background trend, geographic variation, and total Elixhauser comorbidities in elective Diagnosis-Related Group 470 THA episodes, BPCI was associated with a 4.44% (95% confidence interval [CI], -4.58% to -4.30%; p < 0.001) payment decrease for all participants (USD 1244 decrease from a baseline of USD 18,802); additionally, odds ratios (ORs) for 90-day mortality and readmissions were unchanged. PGP groups showed a 4.81% decrease in payments (95% CI, -5.01% to -4.61%; p < 0.001) after enrolling in BPCI (USD 1335 decrease from a baseline of USD 17,841). Hospital groups showed a 4.04% decrease in payments (95% CI, -4.24% to 3.84%; p < 0.01) after enrolling in BPCI (USD 1138 decrease from a baseline of USD 19,799). The decrease in payments of PGP-run episodes was greater compared with hospital-run episodes. ORs for 90-day mortality and readmission remained unchanged after BPCI for PGP- and hospital-run BPCI programs. Patient age and mean Elixhauser comorbidity index did not change after BPCI for PGP-run, hospital-run, or overall BPCI episodes. CONCLUSIONS: Even when controlling for decreasing costs in traditional fee-for-service care, BPCI is associated with payment reduction with no change in adverse events, and this is not because of the selection of younger patients or those with fewer comorbidities. Furthermore, physician group practices were associated with greater payment reduction than hospital programs with no difference in readmission or mortality from baseline for either. Physicians may be a more logical group than hospitals to manage payment reduction in future healthcare reform. LEVEL OF EVIDENCE: Level II, economic and decision analysis.

Fano Interference between Bulk and Surface States of a Dirac Semimetal Cd_{3}As_{2} Nanowire.

Dirac semimetals possess Fermi-arc surface states, which will be a set of discrete surface subbands in a nanowire due to the quantum confinement effect. Here, we report a tunable Fano effect induced by the interference between the discrete surface states and continuous bulk states of a Dirac semimetal Cd_{3}As_{2} nanowire. The discrete surface bands lead to a zero bias peak in conductance as the Femi level is tuned to across the surface subbands. The Fano resonance results in an asymmetric line shape in the differential conductance dI/dV spectrum. Furthermore, the Fano interference would introduce an additional phase into the Weyl orbits and lead to a modification of the oscillation frequency. The results are valuable for further understanding the exotic quantum transport properties of topological semimetals.

Endocrine Disruption Activity of 30-day Dietary Exposure to Decabromodiphenyl Ethane in Balb/C Mouse.

OBJECTIVE: This study aimed to evaluate the hepatotoxicity, metabolic disturbance activity and endocrine disrupting activity of mice treated by Decabromodiphenyl ethane (DBDPE). METHODS: In this study, Balb/C mice were treated orally by gavage with various doses of DBDPE. After 30 days of treatment, mice were sacrificed; blood, livers and thyroid glands were obtained, and hepatic microsomes were isolated. Biochemical parameters including 8 clinical chemistry parameters, blood glucose and hormone levels including insulin and thyroid hormone were assayed. The effects of DBDPE on hepatic cytochrome P450 (CYP) levels and activities and uridinediphosphate-glucuronosyltransferase (UDPGT) activities were investigated. Liver and thyroid glands were observed. RESULTS: There were no obvious signs of toxicity and no significant treatment effect on body weight, or liver-to-body weight ratios between treatment groups. The levels of ALT and AST of higher dose treatment groups were markedly increased. Blood glucose levels of treatment groups were higher than those of control group. There was also an induction in TSH, T3, and fT3. UDPGT, PROD, and EROD activities were found to have been increased significantly in the high dose group. Histopathologic liver changes were characterized by hepatocyte hypertrophy and cytoplasmic vacuolization. Our findings suggest that DBDPE can cause a certain degree of mouse liver damage and insufficiency. CONCLUSION: DBDPE has the activity of endocrine disruptors in Bal/C mice, which may induce drug-metabolizing enzymes including CYPs and UDPGT, and interfere with thyroid hormone levels mediated by AhR and CAR signaling pathways. Endocrine disrupting activity of DBDPE could also affect the glucose metabolism homeostasis.

Inhibitory mechanisms of decoy receptor 3 in cecal ligation and puncture-induced sepsis.

Despite its high mortality, specific and effective drugs for sepsis are lacking. Decoy receptor 3 (DcR3) is a potential biomarker for the progression of inflammatory diseases. The recombinant human DcR3-Fc chimera protein (DcR3.Fc) suppresses inflammatory responses in mice with sepsis, which is critical for improving survival. The Fc region can exert detrimental effects on the patient, and endogenous peptides are highly conducive to clinical application. However, the mechanisms underlying the effects of DcR3 on sepsis are unknown. Herein, we aimed to demonstrate that DcR3 may be beneficial in treating sepsis and investigated its mechanism of action. Recombinant DcR3 was obtained in vitro. Postoperative DcR3 treatment was performed in mouse models of lipopolysaccharide- and cecal ligation and puncture (CLP)-induced sepsis, and their underlying molecular mechanisms were explored. DcR3 inhibited sustained excessive inflammation in vitro, increased the survival rate, reduced the proinflammatory cytokine levels, changed the circulating immune cell composition, regulated the gut microbiota, and induced short-chain fatty acid synthesis in vivo. Thus, DcR3 protects against CLP-induced sepsis by inhibiting the inflammatory response and apoptosis. Our study provides valuable insights into the molecular mechanisms associated with the protective effects of DcR3 against sepsis, paving the way for future clinical studies. IMPORTANCE: Sepsis affects millions of hospitalized patients worldwide each year, but there are no sepsis-specific drugs, which makes sepsis therapies urgently needed. Suppression of excessive inflammatory responses is important for improving the survival of patients with sepsis. Our results demonstrate that DcR3 ameliorates sepsis in mice by attenuating systematic inflammation and modulating gut microbiota, and unveil the molecular mechanism underlying its anti-inflammatory effect.

Integrated Microbiome and Metabolome Analysis Reveals Hypothalamic-Comorbidities Related Signatures in Craniopharyngioma.

Craniopharyngioma (CP) is an intracranial tumor with high mortality and morbidity. Though biologically benign, CP will damage the hypothalamus, inducing comorbidities such as obesity, metabolic syndrome, and cognitive impairments. The roles of gut microbiome and serum metabolome in CP-associated hypothalamic comorbidities are aimed to be explored. Patients with CP are characterized by increased Shannon diversity, Eubacterium, Clostridium, and Roseburia, alongside decreased Alistipes and Bacteroides. CP-enriched taxa are positively correlated with dyslipidemia and cognitive decline, while CP-depleted taxa are negatively associated with fatty liver. Subsequent serum metabolomics identified notably up-regulated purine metabolism, and integrative analysis indicated an association between altered microbiota and elevated hypoxanthine. Phenotypic study and multi-omics analysis in the Rax-CreERT2::BrafV600E/+::PtenFlox/+ mouse model validated potential involvement of increased Clostridium and dysregulated purine metabolism in hypothalamic comorbidities. To further consolidate this, intervention experiments are performed and it is found that hypoxanthine co-variated with the severity of hypothalamic comorbidities and abundance of Clostridium, and induced dysregulated purine metabolism along with redox imbalance in target organs (liver and brain cortex). Overall, the study demonstrated the potential of increased Clostridium and up-regulated purine metabolism as signatures of CP-associated hypothalamic-comorbidities, and unveiled that elevated Clostridium, dysregulated purine metabolism, and redox imbalance may mediate the development and progression of CP-associated hypothalamic-comorbidities.

Assessment of left ventricular 2D flow pathlines during early diastole using spatial modulation of magnetization with polarity alternating velocity encoding: a study in normal volunteers and canine animals with myocardial infarction.

A high-temporal resolution 2D flow pathline analysis method to study early diastolic filling is presented. Filling patterns in normal volunteers (n = 8) and canine animals [baseline (n = 1) and infarcted (n = 6)] are studied. Data are acquired using spatial modulation of magnetization with polarity alternating velocity encoding, which permits simultaneous quantification of 1D blood velocities (using phase contrast encoding) and myocardial strain (using spatial modulation of magnetization tagging and harmonic phase analysis) at high-temporal resolution of 14 ms within a single breath hold. Virtual emitter particles, released from the mitral valve plane every time frame during rapid filling, are tracked to depict the 2D pathlines on the imaged plane. The pathline regional distribution is compared with myocardial longitudinal strains and to regional pressure gradients. Quantitative analysis of net kinetic energy of pathlines is finally performed. Our results demonstrate a linear correlation (r(2) = 0.85) between pathline spatial distribution and myocardial strain. Peak net kinetic energy of 0.06 ± 0.01 mJ in normal volunteers, 0.043 mJ in baseline dog, 0.143 ± 0.03 mJ in infarcted dogs with nominal flow dysfunction, and 0.016 ± 0.007 mJ in infarcted dogs with severe flow dysfunction is observed. In conclusion, 2D pathline analysis provides a direct regional assessment of early diastolic filling patterns and is sensitive to abnormalities in early diastolic filling.

Single wall carbon nanotube induced inflammation in cruor-fibrinolysis system.

OBJECTIVE: To study single wall carbon nanotubes (SWCNT) and its role in inducing inflammatory cytokines in the cruor-fibrinolysis system of rat. METHODS: Twenty one Wistar rats were divided into four groups: 1) control; 2) low-dose SWCNT (0.15 mg/kg BW); 3) medium-dose SWCNT (0.75 mg/kg BW); 4) high-dose SWCNT (1.5 mg/kg BW). Intratracheal instillation of SWCNT suspensions was administered to rats once per day for 21 days. In order to assess the exposure effect of SWCNT to the rats, activity of Inflammatory cytokine was measured and markers of cruor-fibrinolysis system were studied via ELSIA. Also, change in clotting time was recorded and histopathology was studied. RESULTS: IL-6 and IL-8 concentrations of rats exposed to SWCNT were significantly higher than those in controls (P<0.05). The activity of inflammatory cytokines and histopathological change indicated that oxidative damage occurred. Change in clotting time in rats exposed to SWCNT decreased compared with controls. Meanwhile, t-PA (tissue-tupe plassminogen activator) and AT-III (antithrombin-III) levels in rats exposed to particulates increased or decreased significantly compared with controls (P<0.05). A similar trend was observed for D-dimer (D2D) levels, indicating that SWCNT can impact the cruor-fibrinolysis system of rat. CONCLUSION: The results from our study suggest that an increased procoagulant activity and reduced fibrinolytic activity in rats exposed to SWCNT can cause pulmonary oxidative stress and inflammation, due to the release of pro-thrombotic and inflammatory cytokines into the blood circulation of rat.

Gut microbiota in brain tumors: An emerging crucial player.

In recent decades, various roles of the gut microbiota in physiological and pathological conditions have been uncovered. Among the many interacting pathways between the host and gut flora, the gut-brain axis has drawn increasing attention and is generally considered a promising way to understand and treat brain tumors, one of the most lethal neoplasms. In this narrative review, we aimed to unveil and dissect the sophisticated mechanisms by which the gut-brain axis exerts its influence on brain tumors. Furthermore, we summarized the latest research regarding the gastrointestinal microbial landscape and the effect of gut-brain axis malfunction on different brain tumors. Finally, we outlined the ongoing developing approaches of microbial manipulation and their corresponding research related to neuro-malignancies. Collectively, we recapitulated the advances in gut microbial alterations along with their potential interactive mechanisms in brain tumors and encouraged increased efforts in this area.

Assessment of quality of life in patients with craniopharyngioma and identification of risk factors for compromised overall wellness.

Objective: Quality of Life (QoL) has been a multifactorial concerning issue in oncology. We aimed to inspect the pre-operative QoL among patients with craniopharyngioma and to explore the potential correlations between parameters of QoL and clinical indices. Subjects and methods: We enrolled a total of 109 patients with craniopharyngioma. We utilized Short Form 36 (SF-36), Symptom Check List-90, Generalized Anxiety Disorder Questionnaire scale (GAD7), Patient Health Questionnaire Depression (PHQ9) and Pittsburgh Sleep Quality Index to prospectively evaluated their QoL. Parameters of QoL along with clinical indices were compared among sub-groups divided according to Puget classification. Correlation analyses and regression analyses were performed to detect influential determinants to self-reported wellness. Results: Patients presented impaired QoL compared with general population (p < 0.001), as assessed by SF-36. Correlation analyses indicated the detrimental influence resulting from central diabetes insipidus (CDI). Multivariate linear regression unveiled the adverse effect of CDI on Mental Component Summary (coefficient = -13.869, p= 0.007), GAD7 total score (coefficient = 2.072, p = 0.049) as well as PHQ9 total score (coefficient = 3.721, p = 0.001). Multivariate logistic regression verified CDI as a risk factor of developing depressive symptoms (OR = 6.160, p = 0.001). Conclusion: QoL of patients with craniopharyngioma was remarkably compromised before operation. CDI exerted detrimental influences on patients' QoL and it might serve as a marker for early identification of patients at risk of depression.

Anti-PD-1/Her2 Bispecific Antibody IBI315 Enhances the Treatment Effect of Her2-Positive Gastric Cancer through Gasdermin B-Cleavage Induced Pyroptosis.

The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation of immune checkpoints plays an essential role. Herein, a recombinant fully human IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed  and its antitumor efficacy as well as the underlying mechanism is investigated. IBI315 crosslinks the physical interaction between Her2-positive tumor cells and PD-1-positive T cells, resulting in significantly enhanced antitumor effects compared to each parent antibody or their combination, both in vitro and in vivo mouse tumor models reconstituted with human immune cells using patient-derived xenografts and organoids. Moreover, IBI315 treatment also induces the recruitment and activation of immune cells in tumors. Mechanistically, IBI315 triggers gasdermin B (GSDMB)-mediated pyroptosis in tumor cells, leading to the activation and recruiments of T cells. The activated T cells secret IFNγ, enhancing GSDMB expression and establishing a positive feedback loop of T cell activation and tumor cell killing. Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.