Stromal Rigidity Stress Accelerates Pancreatic Intraepithelial Neoplasia Progression and Chromosomal Instability via Nuclear Protein Tyrosine Kinase 2 Localization.

Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-µm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)-overexpressing cancer cells and derived subclusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas-Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the KPC mice. Reduction of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.

Influence of PhoPQ and PmrAB two component system alternations on colistin resistance from non-mcr colistin resistant clinical E. Coli strains.

BACKGROUND: The current understanding of acquired chromosomal colistin resistance mechanisms in Enterobacterales primarily involves the disruption of the upstream PmrAB and PhoPQ two-component system (TCS) control caused by mutations in the regulatory genes. Interestingly, previous studies have yielded conflicting results regarding the interaction of regulatory genes related to colistin resistance in Escherichia coli, specifically those surrounding PhoPQ and PmrAB TCS. RESULTS: In our study, we focused on two clinical non-mcr colistin-resistant strains of E. coli, TSAREC02 and TSAREC03, to gain a better understanding of their resistance mechanisms. Upon analysis, we discovered that TSAREC02 had a deletion (Δ27-45) in MgrB, as well as substitutions (G206R, Y222H) in PmrB. On the other hand, TSAREC03 exhibited a long deletion (Δ84-224) in PhoP, along with substitutions (M1I, L14P, P178S, T235N) in PmrB. We employed recombinant DNA techniques to explore the interaction between the PhoPQ and PmrAB two-component systems (TCSs) and examine the impact of the mutated phoPQ and pmrB genes on the minimum inhibitory concentrations (MICs) of colistin. We observed significant changes in the expression of the pmrD gene, which encodes a connector protein regulated by the PhoPQ TCS, in the TSAREC02 wild-type (WT)-mgrB replacement mutant and the TSAREC03 WT-phoP replacement mutant, compared to their respective parental strains. However, the expressions of pmrB/pmrA, which reflect PmrAB TCS activity, and the colistin MICs remained unchanged. In contrast, the colistin MICs and pmrB/pmrA expression levels were significantly reduced in the pmrB deletion mutants from both TSAREC02 and TSAREC03, compared to their parental strains. Moreover, we were able to restore colistin resistance and the expressions of pmrB/pmrA by transforming a plasmid containing the parental mutated pmrB back into the TSAREC02 and TSAREC03 mutants, respectively. CONCLUSION: While additional data from clinical E. coli isolates are necessary to validate whether our findings could be broadly applied to the E. coli population, our study illuminates distinct regulatory pathway interactions involving colistin resistance in E. coli compared to other species of Enterobacterales. The added information provided by our study contribute to a deeper understanding of the complex pathway interactions within Enterobacterales.

Support for a hypothetical sugar-sweetened beverage tax in Taiwan.

Sugar-sweetened beverages (SSBs) are drinks that contain added sugar or sweeteners and provide calories with no additional nutrients, and some countries have imposed additional taxes on the SSBs to reduce consumption, which is considered an SSB tax policy. This study used a cross-sectional online survey to examine the patterns of public support for an SSB tax in Taiwan. The sample included 1617 adults aged ≥ 20 years, who answered the survey questionnaire between May 2020 and April 2021. The respondents were recruited using convenience sampling, but sampling weights were applied to represent the Taiwanese population. Generalized ordered logit models with sampling weights were used to examine the correlates of public support for an SSB tax. Results showed that ~60% of the respondents supported the SSB tax and 47% perceived the tax to be effective. The respondents who were aware of the perceived health risks of SSBs or those who believed that one should be partly responsible for the health impact of SSBs were more likely to show support for the SSB tax. In adjusted regression models, both one's perceived risk and perceived responsibility of SSBs were positively associated with the perceived effectiveness of the SSB tax after sociodemographic characteristics were controlled. These research findings show evidence that there is public support for implementing an SSB tax to reduce SSB consumption in Taiwan.

Placental mesenchymal stem cells boost M2 alveolar over M1 bone marrow macrophages via IL-1ß in Klebsiella-mediated acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a lethal complication of severe bacterial pneumonia due to the inability to dampen overexuberant immune responses without compromising pathogen clearance. Both of these processes involve tissue-resident and bone marrow (BM)-recruited macrophage (MΦ) populations which can be polarised to have divergent functions. Surprisingly, despite the known immunomodulatory properties of mesenchymal stem cells (MSCs), simultaneous interactions with tissue-resident and recruited BMMΦ populations are largely unexplored. OBJECTIVES: We assessed the therapeutic use of human placental MSCs (PMSCs) in severe bacterial pneumonia with elucidation of the roles of resident alveolar MΦs (AMΦs) and BMMΦs. METHODS: We developed a lethal, murine pneumonia model using intratracheal infection of a clinically relevant Klebsiella pneumoniae (KP) strain with subsequent intravenous human PMSC treatment. Pulmonary AMΦ and recruited BMMΦ analyses, histological evaluation, bacterial clearance and mice survival were assessed. To elucidate the role of resident AMΦs in improving outcome, we performed AMΦ depletion in the KP-pneumonia model with intratracheal clodronate pretreatment. MEASUREMENTS AND MAIN RESULTS: Human PMSC treatment decreased tissue injury and improved survival of severe KP-pneumonia mice by decreasing the presence and function of recruited M1 BMMΦ while preserving M2 AMΦs and enhancing their antibacterial functions. Interestingly, PMSC therapy failed to rescue AMΦ-depleted mice with KP pneumonia, and PMSC-secreted IL-1ß was identified as critical in increasing AMΦ antibacterial activities to significantly improve pathogen clearance-especially bacteraemia-and survival. CONCLUSIONS: Human PMSC treatment preferentially rescued resident M2 AMΦs over recruited M1 BMMΦs with overall M2 polarisation to improve KP-related ARDS survival.

The psychometric properties of the Physical Resilience Instrument for Older Adults (PRIFOR): a Rasch analysis.

BACKGROUND: Prior psychometric evidence of the Physical Resilience Instrument for Older Adults (PRIFOR) showed good criterion-related validity, concurrent validity, known-group validity, predictive validity, and internal consistency. However, it is unclear whether older patients with different treatment diagnoses interpret the PRIFOR similarly. AIMS: This study aimed to test the psychometric properties of the PRIFOR scores among different treatment diagnoses of older patients. METHODS: We recruited 413 hospitalized older patients with a medical diagnosis and 207 with a surgical diagnosis in a 1343-bed tertiary-care medical center in Taiwan. Data analyses included Rasch models, Principal Components Analysis (PCA), and Pearson correlations. RESULTS: The Rasch analyses showed that all PRIFOR items were embedded within their belonged constructs, reflecting good construct validity and unidimensionality. Person and item separation reliability support the internal consistency of the studied samples and PRIFOR items. However, six PRIFOR items were found to have meaningful differential item functioning (DIF) problems among treatment diagnoses. CONCLUSIONS: The PRIFOR is a solid measurement and can be used for monitoring the status of older adults' physical resilience. However, because six items were found to have meaningful DIF among treatment diagnosis groups, future studies should consider designing specific items for different patient populations to assess their needs in physical resilience.

[Management of Patients With Kennedy Terminal Ulcer: Challenges and Best Practices].

Whether receiving acute, long-term, or home care, patients at the end of life may experience skin failure due to hemodynamic changes and insufficient perfusion of skin tissue. Skin failure begins as superficial ulcers that can quickly become full-thickness lesions, which are referred to as Kennedy terminal ulcers. Skin lesions commonly occur in the final 6 weeks of life and can occur even in the presence of a comprehensive care plan. The pathogenesis of Kennedy terminal ulcers is often misunderstood and these ulcers are commonly misdiagnosed as pressure injuries. This confusion may lead to aggressive care with subpar clinical outcomes that cause further psychological and emotional distress to patients and family members. Patients at the end of life must be provided care focused on their comfort rather than wound healing. To provide the highest quality of care to patients, four end-of-life strategies should be used, including: taking account of the preferences of patients and families, protecting the skin, describing the wound, and preserving a high quality of care. The terms, pathophysiological and clinical manifestations, and nursing treatments related to skin failure at the end of life described in the literature are introduced in this paper. Furthermore, monitoring indicators of nursing quality are provided.

Optimal saturation recovery time for minimizing the underestimation of arterial input function in quantitative cardiac perfusion MRI.

PURPOSE: The purpose of this study was to determine an optimal saturation-recovery time (TS) for minimizing the underestimation of arterial input function (AIF) in quantitative cardiac perfusion MRI without multiple gadolinium injections per subject. METHODS: We scanned 18 subjects (mean age = 59 ± 14 years, 9/9 males/females) to acquire resting perfusion data and 1 additional subject (age = 38 years, male) to obtain stress-rest perfusion data using a 5-fold accelerated pulse sequence with radial k-space sampling and applied k-space weighted image contrast (KWIC) filters on the same k-space data to retrospectively reconstruct five AIF images with effective TS ranging from 10 to 21.2 ms (2.8 ms steps). Undersampled images were reconstructed using a compressed sensing framework with temporal-total-variation and temporal-principal-component as 2 orthogonal sparsifying transforms. The image processing steps included, same motion correction across five different AIF images, signal normalization by the proton-density-weighted-image, signal-to-T1 conversion using a Bloch equation, T1 -to-gadolinium-concentration conversion assuming fast water exchange, T2 * correction to the AIF, and gadolinium-concentration to myocardial blood flow (MBF) conversion based on a Fermi model. RESULTS: Among five TS values, the shortest TS (10 ms) produced significantly (P < 0.05) higher peak AIF and lower resting MBF (13.73 mM, 0.73 mL g-1 min-1 ) than 12.8 ms (11.24 mM, 0.89 mL g-1 min-1 ), 15.6 ms (9.56 mM, 1.05 mL g-1 min-1 ), 18.4 ms (8.55 mM, 1.17 mL g-1 min-1 ), and 21.2 ms (7.95 mM, 1.27 mL g-1 min-1 ). Similarly, shorter TS reduced underestimation of AIF (or overestimation of MBF) for both during stress and at rest, but this effect was canceled in myocardial-perfusion-reserve (MPR). CONCLUSION: This study demonstrates that TS of 10 ms reduces the underestimation of AIF and, hence, the overestimation of MBF compared with longer TS values (12.8-21.2 ms).

A theoretical framework for retrospective T2∗ correction to the arterial input function in quantitative myocardial perfusion MRI.

PURPOSE: To develop and evaluate a flexible, Bloch-equation based framework for retrospective T2∗ correction to the arterial input function (AIF) obtained with quantitative cardiac perfusion pulse sequences. METHODS: Our framework initially calculates the gadolinium concentration [Gd] based on T1 measurements alone. Next, T2∗ is estimated from this initial calculation of [Gd] while assuming fast water exchange and using the literature native T2 and static magnetic field variation (ΔB0 ) values. Finally, the [Gd] is recalculated after performing T2∗ correction to the Bloch equation signal model. Using this approach, we performed T2∗ correction to historical phantom and in vivo, dual-imaging perfusion data sets from 3 different patient groups obtained using different pulse sequences and imaging parameters. Images were processed to quantify both the AIF and resting myocardial blood flow (MBF). We also performed a sensitivity analysis of our T2∗ correction to ±20% variations in native T2 and ΔB0 . RESULTS: Compared with the ground truth [Gd] of phantom, the normalized root-means-square-error (NRMSE) in measured [Gd] was 5.1%, 1.3%, and 0.6% for uncorrected, our corrected, and Kellman's corrected, respectively. For in vivo data, both the peak AIF (7.0 ± 3.0 mM vs. 8.6 ± 7.1 mM, 7.2 ± 0.9 mM vs. 8.6 ± 1.7 mM, 7.7 ± 1.8 mM vs. 10.3 ± 5.1 mM, P < .001) and resting MBF (1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.3 ± 0.1 mL/g/min vs. 1.1 ± 0.1 mL/g/min, 1.2 ± 0.1 mL/g/min vs. 0.9 ± 0.1 mL/g/min, P < .001) values were significantly different between uncorrected and corrected for all 3 patient groups. Both the peak AIF and resting MBF values varied by <5% over the said variations in native T2 and ΔB0 . CONCLUSION: Our theoretical framework enables retrospective T2∗ correction to the AIF obtained with dual-imaging, cardiac perfusion pulse sequences.

Reliable segmentation of 2D cardiac magnetic resonance perfusion image sequences using time as the 3rd dimension.

OBJECTIVES: Cardiac magnetic resonance (CMR) first-pass perfusion is an established noninvasive diagnostic imaging modality for detecting myocardial ischemia. A CMR perfusion sequence provides a time series of 2D images for dynamic contrast enhancement of the heart. Accurate myocardial segmentation of the perfusion images is essential for quantitative analysis and it can facilitate automated pixel-wise myocardial perfusion quantification. METHODS: In this study, we compared different deep learning methodologies for CMR perfusion image segmentation. We evaluated the performance of several image segmentation methods using convolutional neural networks, such as the U-Net in 2D and 3D (2D plus time) implementations, with and without additional motion correction image processing step. We also present a modified U-Net architecture with a novel type of temporal pooling layer which results in improved performance. RESULTS: The best DICE scores were 0.86 and 0.90 for LV myocardium and LV cavity, while the best Hausdorff distances were 2.3 and 2.1 pixels for LV myocardium and LV cavity using 5-fold cross-validation. The methods were corroborated in a second independent test set of 20 patients with similar performance (best DICE scores 0.84 for LV myocardium). CONCLUSIONS: Our results showed that the LV myocardial segmentation of CMR perfusion images is best performed using a combination of motion correction and 3D convolutional networks which significantly outperformed all tested 2D approaches. Reliable frame-by-frame segmentation will facilitate new and improved quantification methods for CMR perfusion imaging. KEY POINTS: • Reliable segmentation of the myocardium offers the potential to perform pixel level perfusion assessment. • A deep learning approach in combination with motion correction, 3D (2D + time) methods, and a deep temporal connection module produced reliable segmentation results.

Cardiovascular magnetic resonance predictors of heart failure in hypertrophic cardiomyopathy: the role of myocardial replacement fibrosis and the microcirculation.

INTRODUCTION: Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study. METHODS: Serial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV. RESULTS: A total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6-2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16-1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14-1.82, p = 0.002) age (HR 1.37, 95% CI 1.06-1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively). DISCUSSION: The annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR is low. Myocardial fibrosis and LVESVI are strongly predictive of future HF, however CMR visual assessment of myocardial perfusion was not.

Staged surgery for advanced cardiac intimal sarcoma involving the right atrium and the inferior vena cava.

Intimal sarcomas simultaneously involving the right atrium and the inferior vena cava (IVC) are rare. We report an advanced cardiac intimal sarcoma in the right atrium of a 19-year-old man that was complicated by tumor-related IVC thrombosis. We initially performed partial tumor resection and vena cava thrombectomy to resolve the circulatory obstruction, because complete resection was difficult due to the invading malignancy and an unclear margin. The patient received adjuvant chemo- and radiotherapy along with anticoagulant therapy. After 3 months, the border of the residual sarcoma was clear, and the patient underwent a secondary complete sarcoma excision (including that of the right atrium) and a suprahepatic vena cava reconstruction. At the 2-year follow-up, there was no tumor recurrence. We conclude that aggressive treatment and a staged complete resection can lead to improved outcomes for advanced cardiac intimal sarcoma with poor prognosis.

Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction.

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. CONCLUSION: We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03193294.

2D Material-Enabled Nanomechanical Bolometer.

We here describe a novel type of long-wavelength radiation detector that measures illumination intensity at room temperature through mechanical transduction. Compared to semiconductor-based bolometers, our nanomechanical detector exhibits low measurement noise and is inherently transparent and flexible. The presented solid-state device is based on a 2D-material film that acts as radiation absorber and detector of mechanical strain at the substrate-absorber interface. Optimization of the 2D material properties and realization of a novel edge-on device geometry combines unprecedented detectivity of 3.34 × 108 cm Hz1/2 W-1 with micrometer-scale spatial resolution. The observed combination of superior performance with the facile and scalable fabrication using only liquid processes shows the potential of the presented detector for future ubiquitous and wearable electronics.

A Novel Deletion Mutation in pmrB Contributes to Concurrent Colistin Resistance in Carbapenem-Resistant Escherichia coli Sequence Type 405 of Clinical Origin.

We report the first clinical Escherichia coli strain EC3000 with concomitant chromosomal colistin and carbapenem resistance. A novel in-frame deletion, Δ6-11 (RPISLR), in pmrB that contributes to colistin resistance was verified using recombinant DNA techniques. Although being less fit than the wild-type (WT) strain or EC3000 revertant (chromosomal replacement of WT pmrB in EC3000), a portion of serially passaged EC3000 strains preserving colistin resistance without selective pressure raises the concern for further spread.

[Differences in Patient Safety Reporting Attitudes and Knowledge Among Different Hospital Levels].

BACKGROUND: Establishing a positive reporting culture, which helps medical and healthcare workers learn from errors and reduce the risks of future adverse events, is essential to fostering a culture of patient safety. PURPOSE: The objectives of this study were to investigate the differences among the three levels of hospitals in terms of the knowledge and attitudes of hospital staff regarding the patient safety reporting system and to identify the potential factors affecting these differences. METHODS: This cross-sectional study was carried out in six hospitals, including two academic medical centers, two regional hospitals, and two district hospitals. The subjects were physicians, nurses, medical technicians, and administrative staffs. Data were collected using a patient safety reporting questionnaire. RESULTS: Three hundred and forty-eight participants were recruited, with 348 valid questionnaires returned (response rate: 100%). The average score for knowledge of patient safety reporting was 12.76 (total possible score: 14). Age, work position, and work experience were significantly associated with knowledge of patient safety reporting (p < .01). The patient safety reporting attitudes questionnaire comprised 21 items, each of which was scored using a five-point Likert scale. The mean score for each item was 3.92 ± 0.50. Gender, age, work position, work experience, and job discipline were significantly associated with attitude toward reporting (p < .01). The level of hospital was found to significantly impact attitudes toward patient safety reporting (p = .01), with participants working at medical centers scoring the highest. In addition, participants who were older and in more-senior positions scored higher and more positively for both knowledge and attitudes. CONCLUSIONS: The key factors to successfully fostering a strong patient safety reporting culture are staff security, a reliable reporting system, and a user-friendly interface. Improving attitudes toward reporting requires more resources and time than improving knowledge of reporting, which may be improved using education and promotion. Regional hospitals may invest more resources to enhance positive attitudes toward reporting and increase the willingness of staff to report.

Widowhood and health in late life: does health change before or after widowhood in older Taiwanese men and women?

This study investigated (a) whether significant health changes occur before imminent widowhood and (b) the effects of widowhood on the physical and psychological health of men and women ≥ 50 years old. Generalized estimating equations were used to examine a matched-pair sample of the Taiwanese Elderly. We found that for men, the major effect of widowhood was on psychological health, but that for women, the major effect was on physical health. Psychological health was significantly worse for widowed than for non-widowed women, but not for men. The difference in psychological health between widowed and non-widowed women, however, changed before widowhood.

NLRP7 Is Involved in the Differentiation of the Decidual Macrophages.

Macrophage polarization, regulated appropriately, may play important roles in successful pregnancy. In the face of the vital roles of decidua macrophages in pregnancy, it is insufficient to recognize the trigger of macrophage differentiation and polarization. We aimed to explore the link between the NLRP7 gene and macrophage polarization in human deciduas. Here, we enrolled the endometrial tissues from eight pregnant women in the first trimester. We found that NLRP7 was abundant in endometrial tissues and that NLRP7 was expressed in decidual macrophages of the first-trimester pregnancy. NLRP7 was predominately expressed in the decidual M2 macrophages, as compared with the M1 macrophages. Furthermore, our results suggest that NLRP7 is associated with decidual macrophage differentiation. NLRP7 over-expression suppresses the expression of M1 markers and enhances the expression of the M2 markers. Considering that NLRP7 relates to decidualization and macrophage differentiation, we propose that NLRP7 is a primate-specific multitasking gene to maintain endometrial hemostasis and reproductive success. This finding may pave the way for therapies of pathological pregnancies.

Fully quantitative pixel-wise analysis of cardiovascular magnetic resonance perfusion improves discrimination of dark rim artifact from perfusion defects associated with epicardial coronary stenosis.

BACKGROUND: Dark rim artifacts in first-pass cardiovascular magnetic resonance (CMR) perfusion images can mimic perfusion defects and affect diagnostic accuracy for coronary artery disease (CAD). We evaluated whether quantitative myocardial blood flow (MBF) can differentiate dark rim artifacts from true perfusion defects in CMR perfusion. METHODS: Regadenoson perfusion CMR was performed at 1.5 T in 76 patients. Significant CAD was defined by quantitative invasive coronary angiography (QCA) ≥ 50% diameter stenosis. Non-significant CAD (NonCAD) was defined as stenosis by QCA < 50% diameter stenosis or computed tomographic coronary angiography (CTA) < 30% in all major epicardial arteries. Dark rim artifacts had study specific and guideline-based definitions for comparison purposes. MBF was quantified at the pixel-level and sector-level. RESULTS: In a NonCAD subgroup with dark rim artifacts, stress MBF was lower in the subendocardial than midmyocardial and epicardial layers (2.17 ± 0.61 vs. 3.06 ± 0.75 vs. 3.24 ± 0.80 mL/min/g, both p < 0.001) and was also 30% lower than in remote regions (2.17 ± 0.61 vs. 2.83 ± 0.67 mL/min/g, p < 0.001). However, subendocardial stress MBF in dark rim artifacts was 37-56% higher than in true perfusion defects (2.17 ± 0.61 vs. 0.95 ± 0.43 mL/min/g, p < 0.001). Absolute stress MBF differentiated CAD from NonCAD with an accuracy ranging from 86 to 89% (all p < 0.001) using pixel-level analyses. Similar results were seen at a sector level. CONCLUSION: Quantitative stress MBF is lower in dark rim artifacts than remote myocardium but significantly higher than in true perfusion defects. If confirmed in larger series, this approach may aid the interpretation of clinical stress perfusion exams. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00027170 ; first posted 11/28/2001; updated 11/27/2017.

Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomized controlled cross-over trial.

AIMS: To determine the clinical impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a) > 500 mg/L on the primary end point of quantitative myocardial perfusion, as well as secondary end points including atheroma burden, exercise capacity, symptoms, and quality of life. METHODS: We conducted a single-blinded randomized controlled trial in 20 patients with refractory angina and raised lipoprotein(a) > 500 mg/L, with 3 months of blinded weekly lipoprotein apheresis or sham, followed by crossover. The primary endpoint was change in quantitative myocardial perfusion reserve (MPR) assessed by cardiovascular magnetic resonance. Secondary endpoints included measures of atheroma burden, exercise capacity, symptoms and quality of life. RESULTS: The primary endpoint, namely MPR, increased following apheresis (0.47; 95% CI 0.31-0.63) compared with sham (-0.16; 95% CI - 0.33-0.02) yielding a net treatment increase of 0.63 (95% CI 0.37-0.89; P < 0.001 between groups). Improvements with apheresis compared with sham also occurred in atherosclerotic burden as assessed by total carotid wall volume (P < 0.001), exercise capacity by the 6 min walk test (P = 0.001), 4 of 5 domains of the Seattle angina questionnaire (all P < 0.02) and quality of life physical component summary by the short form 36 survey (P = 0.001). CONCLUSION: Lipoprotein apheresis may represent an effective novel treatment for patients with refractory angina and raised lipoprotein(a) improving myocardial perfusion, atheroma burden, exercise capacity and symptoms.

Roles of ramR and tet(A) Mutations in Conferring Tigecycline Resistance in Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates.

Tigecycline is regarded as a last-resort treatment for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, but increasing numbers of tigecycline-resistant K. pneumoniae isolates have been reported. The tigecycline resistance mechanisms in CRKP are undetermined. This study aimed to elucidate the mechanisms underlying tigecycline resistance in 16 tigecycline- and carbapenem-resistant K. pneumoniae (TCRKP) isolates. Mutations in tigecycline resistance determinant genes [ramR, acrR, oqxR, tet(A), tet(L), tet(X), tet(M), rpsJ] were assessed by PCR amplicon sequencing, and mutations in ramR and tet(A) exhibited high prevalences individually (81%) and in combination (63%). Eight functional ramR mutation profiles reducing tigecycline sensitivity were verified by plasmid complementation of wild-type and mutant ramR Using a site-specific mutant, the most frequent RamR mutation, A19V (60%), had no significant effect on tigecycline susceptibility or the upregulation of ramA and acrA Two tet(A) variants with double frameshift mutations, type 1 and type 2, were identified; type 2 tet(A) is novel. A parent strain transformed with a plasmid carrying type 1 or type 2 tet(A) increased the tigecycline MIC by 8-fold or 4-fold, respectively. Synergistic effects were observed in strains harboring no ramR gene and a mutated tet(A), with an 8-fold increase in the tigecycline MIC compared with that in strains harboring only mutated tet(A) being seen. Overall, mutations in the ramR and tet(A) efflux genes constituted the major tigecycline resistance mechanisms among the studied TCRKP isolates. The identification of strains exhibiting the combination of a ramR deficiency and widespread mutated tet(A) is concerning due to the possible dissemination of increased tigecycline resistance in K. pneumoniae.