High-frequency oscillatory ventilation in pediatric acute hypoxemic respiratory failure: disease-specific morbidity survival analysis.

BackgroundMultiple ventilatory strategies for acute hypoxemic respiratory failure (AHRF) in children have been advocated, including high-frequency oscillatory ventilation (HFOV). Despite the frequent deployment of HFOV, randomized controlled trials remain elusive and currently there are no pediatric trials looking at its use. Our longitudinal study analyzed the predictive clinical outcome of HFOV in pediatric AHRF given disease-specific morbidity.MethodsA retrospective 8-year review on pediatric intensive care unit admissions with AHRF ventilated by HFOV was performed. Primary outcomes included survival, morbidity, length of stay (LOS), and factors associated with survival or mortality.ResultsA total of 102 patients underwent HFOV with a 66 % overall survival rate. Survivors had a greater LOS than nonsurvivors (p = 0.001). Mortality odds ratio (OR) for patients without bronchiolitis was 8.19 (CI = 1.02, 65.43), and without pneumonia it was 3.07 (CI = 1.12, 8.39). A lower oxygenation index (OI) after HFOV commencement and at subsequent time points analyzed predicted survival. After 24 h, mortality was associated with an OI > 35 [OR = 31.11 (CI = 3.25, 297.98)]. Sepsis-related mortality was associated with a higher baseline FiO(2) (0.88 vs. 0.65), higher OI (42 vs. 22), and augmented metabolic acidosis (pH of 7.25 vs. 7.32) evaluated 4 h on HFOV (p < 0.05).ConclusionHigh-frequency oscillatory ventilation may be safely utilized. It has a 66 % overall survival rate in pediatric AHRF of various etiologies. Patients with morbidity limited to the respiratory system and optimized oxygenation indices are most likely to survive on HFOV

Active Living after Cancer: adaptation and Evaluation of a Community-Based Physical activity Program For Minority and Medically Underserved Breast Cancer Survivors

BACKGROUND: An expanding body of research documents the benefits of physical activity for cancer survivors\u27 physical functioning and quality of life, but few successful models provide community-based physical activity programs to cancer survivors. This report presents an evaluation of Active Living After Cancer, an evidence-based physical activity program for breast cancer survivors, adapted for community delivery to minority and medically underserved survivors. METHODS: Survivors were recruited from health care and community settings. The program consisted of 12 weekly group sessions providing training in cognitive and behavioral skills for behavior change, brief physical activity, and cancer survivorship-related content. At the baseline and follow-up, participants completed assessments of their physical activity, quality of life, and physical functioning (6-minute walk and 30-second sit-to-stand test). At follow-up, they also completed questionnaires to measure program content mastery and satisfaction. RESULTS: The outcome analysis included 127 participants. Physical activity and quality of life (mental and physical) improved from the baseline to follow-up (all P \u3c .01). Physical functioning improved, with increases in sit-to-stand repetitions (mean, 12.5 at the baseline vs 14.9 at the follow-up; P \u3c .01) and 6-minute walk distances (mean, 428 m at the baseline vs 470 m at the follow-up; P \u3c .01). CONCLUSIONS: The results highlight the effectiveness of an evidence-based program adapted for community-based delivery to minority and medically underserved breast cancer survivors. The program could be delivered to improve outcomes in diverse survivor populations. LAY SUMMARY: Physical activity in breast cancer survivors is related to better quality of life and longer cancer-free survival. However, there are few community-based programs to help breast cancer survivors to become more physically active. The Active Living After Cancer program was adapted from an evidence-based program and delivered in community-based settings to minority and medically underserved breast cancer survivors. It consisted of 12 weekly group sessions in which participants learned skills to increase their physical activity. The program participants increased their physical activity and improved their mental and physical well-being and physical functioning

Cytoplasmic VDR expression as an independent risk factor for ovarian cancer

The vitamin D receptor (VDR), primarily known as a crucial mediator of calcium homeostasis and metabolism, has been shown to play a significant role in various cancer entities. Previous studies have focused on vitamin D and its receptor in gynecological cancers, noting that the receptor is upregulated in epithelial ovarian cancer (EOC). The aim of this study is to analyze the prognostic impact of VDR and its functional significance in ovarian cancer. Through immunohistochemistry, VDR staining was examined in 156 ovarian cancer samples. Evaluation of VDR staining was conducted in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score, and the scores were classified into high- and low-level expressions. Expression levels were correlated with clinical and pathological parameters as well as with overall survival to assess for prognostic impact. Differences in cytoplasmic VDR expression were identified between the histological subtypes (p = 0.001). Serous, clear cell, and endometrioid subtypes showed the highest staining, while the mucinous subtype showed the lowest. Cytoplasmic VDR correlated with higher FIGO stage (p = 0.013; Cc = 0.203), positive lymph node status (p = 0.023; Cc = 0.236), high-grade serous histology (p = 0.000; Cc = 0.298) and grading from the distinct histological subtypes (p = 0.006; Cc = - 0.225). Nuclear VDR did not correlate with clinicopathological data. High cytoplasmic expression of VDR was associated with impaired overall survival (HR 2.218, 32.5~months vs. median not reached; p < 0.001) and was confirmed as a statistically independent prognostic factor in the Cox regression multivariate analysis. Additional knowledge of VDR as a biomarker and its interactions within the mitogen-activated protein kinase (MAPK) signaling pathway could potentially improve the prognosis of therapeutic approaches for specific subgroups in EOC

Protection against Bronchiolitis Obliterans Syndrome Is Associated with Allograft CCR7+CD45RA− T Regulatory Cells

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, yet markers for early detection and intervention are currently lacking. Given the role of regulatory T cells (Treg) in modulation of immunity, we hypothesized that frequencies of Treg in bronchoalveolar lavage fluid (BALF) after lung transplantation would predict subsequent development of BOS. Seventy BALF specimens obtained from 47 lung transplant recipients were analyzed for Treg lymphocyte subsets by flow cytometry, in parallel with ELISA measurements of chemokines. Allograft biopsy tissue was stained for chemokines of interest. Treg were essentially all CD45RA−, and total Treg frequency did not correlate to BOS outcome. The majority of Treg were CCR4+ and CD103− and neither of these subsets correlated to risk for BOS. In contrast, higher percentages of CCR7+ Treg correlated to reduced risk of BOS. Additionally, the CCR7 ligand CCL21 correlated with CCR7+ Treg frequency and inversely with BOS. Higher frequencies of CCR7+ CD3+CD4+CD25hiFoxp3+CD45RA− lymphocytes in lung allografts is associated with protection against subsequent development of BOS, suggesting that this subset of putative Treg may down-modulate alloimmunity. CCL21 may be pivotal for the recruitment of this distinct subset to the lung allograft and thereby decrease the risk for chronic rejection

Platelet-activating factor acetylhydrolase expression in BRCA1 mutant ovarian cancer as a protective factor and potential negative regulator of the Wnt signaling pathway

Aberrantly activated Wnt/β-catenin signaling pathway, as well as platelet-activating factor (PAF), contribute to cancer progression and metastasis of many cancer entities. Nonetheless, the role of the degradation enzyme named platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer etiology is still unclear. This study investigated the functional impact of platelet-activating factor acetylhydrolase on BRCA1 mutant ovarian cancer biology and its crosstalk with the Wnt signaling pathway. PAF-AH, pGSK3β, and β-catenin expressions were analyzed in 156 ovarian cancer specimens by immunohistochemistry. PAF-AH expression was investigated in ovarian cancer tissue, serum of BRCA1-mutated patients, and in vitro in four ovarian cancer cell lines. Functional assays were performed after PLA2G7 silencing. The association of PAF-AH and β-catenin was examined by immunocytochemistry. In an established ovarian carcinoma collective, we identified PAF-AH as an independent positive prognostic factor for overall survival (median 59.9 vs. 27.4 months; p = 0.016). PAF-AH correlated strongly with the Wnt signaling proteins pGSK3β (Y216; nuclear: cc = 0.494, p < 0.001; cytoplasmic: cc = 0.488, p < 0.001) and β-catenin (nuclear: cc = 0.267, p = 0.001; cytoplasmic: cc = 0.291, p < 0.001). In particular, high levels of PAF-AH were found in tumor tissue and in the serum of BRCA1 mutation carriers. By in vitro expression analysis, a relevant gene and protein expression of PLA2G7/PAF-AH was detected exclusively in the BRCA1-negative ovarian cancer cell line UWB1.289 (p < 0.05). Functional assays showed enhanced viability, proliferation, and motility of UWB1.289 cells when PLA2G7/PAF-AH was downregulated, which underlines its protective character. Interestingly, by siRNA knockdown of PLA2G7/PAF-AH, the immunocytochemistry staining pattern of β-catenin changed from a predominantly membranous expression to a nuclear one, suggesting a negative regulatory role of PAF-AH on the Wnt/β-catenin pathway. Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact, which seems particularly relevant in BRCA1 mutant ovarian cancer. For the first time, we show that its protective character may be mediated by a negative regulation of the Wnt/β-catenin pathway. Further studies need to specify this effect. Potential use of PAF-AH as a biomarker for predicting the disease risk of BRCA1 mutation carriers and for the prognosis of patients with BRCA1-negative ovarian cancer should be explored

Twice‐weekly ixazomib in combination with lenalidomide‐dexamethasone in patients with newly diagnosed multiple myeloma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/1/bjh15394.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144661/2/bjh15394_am.pd

Circulating Markers Reflect Both Anti- and Pro-Atherogenic Drug Effects in ApoE-Deficient Mice

Background: Current drug therapy of atherosclerosis is focused on treatment of major risk factors, e.g. hypercholesterolemia while in the future direct disease modification might provide additional benefits. However, development of medicines targeting vascular wall disease is complicated by the lack of reliable biomarkers. In this study, we took a novel approach to identify circulating biomarkers indicative of drug efficacy by reducing the complexity of the in vivo system to the level where neither disease progression nor drug treatment was associated with the changes in plasma cholesterol.Results: ApoE-/- mice were treated with an ACE inhibitor ramipril and HMG-CoA reductase inhibitor simvastatin. Ramipril significantly reduced the size of atherosclerotic plaques in brachiocephalic arteries, however simvastatin paradoxically stimulated atherogenesis. Both effects occurred without changes in plasma cholesterol. Blood and vascular samples were obtained from the same animals. In the whole blood RNA samples, expression of MMP9, CD14 and IL-1RN reflected pro and anti-atherogenic drug effects. In the plasma, several proteins, e.g. IL-1β, IL-18 and MMP9 followed similar trends while protein readout was less sensitive than RNA analysis.Conclusion: In this study, we have identified inflammation-related whole blood RNA and plasma protein markers reflecting anti-atherogenic effects of ramipril and pro-atherogenic effects of simwastatin in a mouse model of atherosclerosis. This opens an opportunity for early, non-invasive detection of direct drug effects on atherosclerotic plaques in complex in vivo systems

Clinical outcomes of ED patients with bandemia

BackgroundAlthough an elevated white blood cell count is a widely utilized measure for evidence of infection and an important criterion for evaluation of systemic inflammatory response syndrome, its component band count occupies a more contested position within clinical emergency medicine. Recent studies indicate that bandemia is highly predictive of a serious infection, suggesting that clinicians who do not appreciate the value of band counts may delay diagnosis or overlook severe infections.ObjectivesWhereas previous studies focused on determining the quantitative value of the band count (ie, determining sensitivity, threshold for bandemia, etc.), this study directs attention to patient-centered outcomes, hypothesizing that the degree of bandemia predisposes patients to subsequent negative clinical outcomes associated with underappreciated severe infections.MethodsThis retrospective study of electronic medical records includes patients who initially presented to the emergency department (ED) with bandemia and were subsequently discharged from the ED. These patients were screened for repeat ED visits within 7 days and death within 30 days.ResultsIn patients with severe bandemia who were discharged from the ED, there was a 20.9% revisit rate at 7 days and a 4.9% mortality rate at 30 days, placing severely bandemic patients at 5 times significantly greater mortality compared to nonbandemic patients (P = .032).ConclusionOur review of patient outcomes suggests that the degree of bandemia, especially in the setting of concurrent tachycardia or fever, is associated with greater likelihood of negative clinical outcomes

A biomechanical characterisation of acellular porcine super flexor tendons for use in anterior cruciate ligament replacement: Investigation into the effects of fat reduction and bioburden reduction bioprocesses

The decellularisation of xenogenic and allogeneic biological grafts offers a promising solution to replacement of the anterior cruciate ligament (ACL). The purpose of this investigation was to determine the biomechanical effects of additional fat reduction and bioburden reduction steps in the decellularisation of porcine super flexor tendon (pSFT). Study 1 investigated the use of acetone or chloroform-methanol as a fat reduction agent. The most effective of these was then carried forward into Study 2, which investigated the use of antibiotics or peracetic acid (PAA) as a bioburden reduction agent. Stress relaxation data was analysed using a Maxwell-Wiechert viscoelastic model and, in addition to classical material properties, the tangent modulus of the toe-region was determined from strength testing data. In both studies, the majority of decellularised groups demonstrated no statistical differences for material properties such as tensile strength and Young's modulus compared to native controls. Different trends were observed for many of the viscoelastic parameters, but also for the tangent modulus in the toe-region indicating a change in performance at low strains. The most severe deviations from the profile of the native tangent modulus were found to occur in Study 2 when PAA was used for bioburden reduction. Classic material properties (E, UTS etc.) are often used to compare the characteristics of native and decellularised tissues, however they may not highlight changes occurring in the tissues at low strains. In this study, this represented the physiological strains encountered by substitute acellular ACL grafts. Acetone was chosen as the fat reduction step whereas, antibiotics was preferable over PAA as a bioburden reduction step