Ranking hospitals based on preventable hospital death rates:a systematic review with implications for both direct measurement and indirect measurement through standardized mortality rates

Objectives There is interest in monitoring avoidable or preventable deaths measured directly or indirectly through standardized mortality rates (SMRs). We reviewed studies that use implicit case note reviews to estimate the range of preventable death rates observed, the measurement characteristics of those estimates, and the measurement procedures used to generate them. We comment on the implications for monitoring SMRs and illustrate a way to calculate the number of reviews needed to establish a reliable estimate of preventability of one death or the hospital preventable death rate. Design Systematic review of the literature supplemented by re-analysis of authors previously published and un-published data and measurement design calculations. Data source Searches in PubMed, MEDLINE (OvidSP) and Web of Knowledge in June 2012, updated December 2017. Eligibility criteria Studies of hospital-wide admissions from general and acute medical wards where preventable deaths rates are provided or can be estimate and which can provide inter- observer variations. Results Twenty-four studies were included from 1983-2017. Recent larger studies suggest consistently low rates of preventable deaths (3.0-6.5% since 2012). Reliability of a single review for distinguishing between individual cases with regard to the preventability of death had a Kappa rate of 0.27-0.50 for deaths and 0.24-0.76 for adverse events. A Kappa of 0.35 would require an average of 8-17 reviews of a single case to be precise enough to have confidence about high stakes decisions to change care procedures or impose sanctions within a hospital as a result. No study estimated the variation in preventable deaths across hospitals, although we were able to re-analyse one study to obtain an estimate. Based on this estimate, 200-300 total case-note reviews per hospital could be required to reliably distinguish between hospitals. The studies display considerable heterogeneity: 13/24 studies defined preventable with a threshold of ≥4 in a six-category Likert scale; 11/24 involved a two-stage screening process with nurses at the first stage and physicians at the second. Fifteen studies provided expert clinical review support for reviewer disagreements, advice, or quality control. A ‘generalist/internist’ was the modal physician specialty for reviewers and they received 1-3 days of generic tools orientation and case-note review practice. Methods did not consider the influence of human or environmental factors. Conclusions The literature provides limited information about the measurement characteristics of preventable deaths that suggests substantial numbers of reviews may be needed to create reliable estimates of preventable deaths at the individual or hospital level. Any operational program would require population specific estimates of reliability. Preventable death rates are low, which is likely to make it difficult to use SMRs based on all deaths to validly profile hospitals. The literature provides little information to guide improvements in the measurement procedures. Systematic review registration The systematic review was conceived prior to PROSPERO, and so has not been registered

The G-protein-coupled estrogen receptor agonist G-1 suppresses proliferation of ovarian cancer cells by blocking tubulin polymerization.

The G-protein-coupled estrogen receptor 1 (GPER) has recently been reported to mediate the non-genomic action of estrogen in different types of cells and tissues. G-1 (1-[4-(6-bromobenzo[1,3] dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone) was developed as a potent and selective agonist for GPER. G-1 has been shown to induce the expression of genes and activate pathways that facilitate cancer cell proliferation by activating GPER. Here we demonstrate that G-1 has an anticancer potential with a mechanism similar to vinca alkaloids, the commonly used chemotherapy drugs. We found that G-1 blocks tubulin polymerization and thereby interrupts microtubule assembly in ovarian cancer cells leading to the arrest of cell cycle in the prophase of mitosis and the suppression of ovarian cancer cell proliferation. G-1 treatment also induces apoptosis of ovarian cancer cells. The ability of G-1 to target microtubules to suppress ovarian cancer cell proliferation makes it a promising candidate drug for treatment of ovarian cancer

Transforming growth factor alpha (TGFα) regulates granulosa cell tumor (GCT) cell proliferation and migration through activation of multiple pathways.

Granulosa cell tumors (GCTs) are the most common ovarian estrogen producing tumors, leading to symptoms of excessive estrogen such as endometrial hyperplasia and endometrial adenocarcinoma. These tumors have malignant potential and often recur. The etiology of GCT is unknown. TGFα is a potent mitogen for many different cells. However, its function in GCT initiation, progression and metastasis has not been determined. The present study aims to determine whether TGFα plays a role in the growth of GCT cells. KGN cells, which are derived from an invasive GCT and have many features of normal granulosa cells, were used as the cellular model. Immunohistochemistry, Western blot and RT-PCR results showed that the ErbB family of receptors is expressed in human GCT tissues and GCT cell lines. RT-PCR results also indicated that TGFα and EGF are expressed in the human granulosa cells and the GCT cell lines, suggesting that TGFα might regulate GCT cell function in an autocrine/paracrine manner. TGFα stimulated KGN cell DNA synthesis, cell proliferation, cell viability, cell cycle progression, and cell migration. TGFα rapidly activated EGFR/PI3K/Akt and mTOR pathways, as indicated by rapid phosphorylation of Akt, TSC2, Rictor, mTOR, P70S6K and S6 proteins following TGFα treatment. TGFα also rapidly activated the EGFR/MEK/ERK pathway, and P38 MAPK pathways, as indicated by the rapid phosphorylation of EGFR, MEK, ERK1/2, P38, and CREB after TGFα treatment. Whereas TGFα triggered a transient activation of Akt, it induced a sustained activation of ERK1/2 in KGN cells. Long-term treatment of KGN cells with TGFα resulted in a significant increase in cyclin D2 and a decrease in p27/Kip1, two critical regulators of granulosa cell proliferation and granulosa cell tumorigenesis. In conclusion, TGFα, via multiple signaling pathways, regulates KGN cell proliferation and migration and may play an important role in the growth and metastasis of GCTs

Quantifying full phenological event distributions reveals simultaneous advances, temporal stability and delays in spring and autumn migration timing in long-distance migratory birds

Acknowledgements We thank all Fair Isle Bird Observatory staff and volunteers for help with data collection and acknowledge the foresight of George Waterston and Ken Williamson in instigating the observatory and census methodology. We thank all current and previous directors of Fair Isle Bird Observatory Trust for their contributions, particularly Dave Okill and Mike Wood for their stalwart support for the long-term data collection and for the current analyses. Dawn Balmer and Ian Newton provided helpful guidance on manuscript drafts. We thank Ally Phillimore and two anonymous referees for helpful comments. This study would have been impossible without the Fair Isle community's invaluable support and patience over many decades, which is very gratefully acknowledged. WTSM and JMR designed and undertook analyses, wrote the paper and contributed to data collection and compilation, MB contributed to analysis and editing, all other authors oversaw and undertook data collection and compilation and contributed to editing.Peer reviewedPostprin

Yes-associated protein 1 is required for proliferation and function of bovine granulosa cells in vitro

Yes-associated protein 1 (YAP1) is a major component of the Hippo signaling pathway. Although the exact extracellular signals that control the Hippo pathway are currently unknown, increasing evidence supports a critical role for the Hippo pathway in embryonic development, regulation of organ size, and carcinogenesis. Granulosa cells (GCs) within the ovarian follicle proliferate and produce steroids and growth factors, which facilitate the growth of follicle and maturation of the oocyte.We hypothesize that YAP1 plays a role in proliferation and estrogen secretion of GCs. In the current study, we examined the expression of the Hippo signaling pathway in bovine ovaries and determined whether it was important for GC proliferation and estrogen production. Mammalian STE20-like protein kinase 1 (MST1) and large tumor suppressor kinase 2 (LATS2) were identified as prominent upstream components of the Hippo pathway expressed in granulosa and theca cells of the follicle and large and small cells of the corpus luteum. Immunohistochemistry revealed that YAP1 was localized to the nucleus of growing follicles. In vitro, nuclear localization of the downstream Hippo signaling effector proteins YAP1 and transcriptional co-activator with PDZbinding motif (TAZ) was inversely correlated with GC density, with greater nuclear localization under conditions of low cell density. Treatment with verteporfin and siRNA targeting YAP1 or TAZ revealed a critical role for these transcriptional co-activators in GC proliferation. Furthermore, knockdown of YAP1 in GCs inhibited follicle-stimulating hormone (FSH)-induced estradiol biosynthesis. The data indicate that Hippo pathway transcription co-activators YAP1/TAZ play an important role in GC proliferation and estradiol synthesis, two processes necessary for maintaining normal follicle development

Arbitrary real-time three-dimensional corporal object sensing and reconstruction scheme

A real-time three-dimensional (3D) object sensing and reconstruction scheme is presented that can be applied on any arbitrary corporeal shape. Operation is demonstrated on several calibrated objects. The system uses curvature sensors based upon in-line fiber Bragg gratings encapsulated in a low-temperature curing synthetic silicone. New methods to quantitatively evaluate the performance of a 3D object-sensing scheme are developed and appraised. It is shown that the sensing scheme yields a volumetric error of 1% to 9%, depending on the object

DALC: Distributed Automatic LSTM Customization for Fine-Grained Traffic Speed Prediction

Over the past decade, several approaches have been introduced for short-term traffic prediction. However, providing fine-grained traffic prediction for large-scale transportation networks where numerous detectors are geographically deployed to collect traffic data is still an open issue. To address this issue, in this paper, we formulate the problem of customizing an LSTM model for a single detector into a finite Markov decision process and then introduce an Automatic LSTM Customization (ALC) algorithm to automatically customize an LSTM model for a single detector such that the corresponding prediction accuracy can be as satisfactory as possible and the time consumption can be as low as possible. Based on the ALC algorithm, we introduce a distributed approach called Distributed Automatic LSTM Customization (DALC) to customize an LSTM model for every detector in large-scale transportation networks. Our experiment demonstrates that the DALC provides higher prediction accuracy than several approaches provided by Apache Spark MLlib.Comment: 12 pages, 5 figures, the 34th International Conference on Advanced Information Networking and Applications (AINA 2020), Springe

Factorization of Operators Through Orlicz Spaces

[EN] We study factorization of operators between quasi-Banach spaces. We prove the equivalence between certain vector norm inequalities and the factorization of operators through Orlicz spaces. As a consequence, we obtain the Maurey-Rosenthal factorization of operators into L-p-spaces. We give several applications. In particular, we prove a variant of Maurey's Extension Theorem.The research of the first author was supported by the National Science Centre (NCN), Poland, Grant No. 2011/01/B/ST1/06243. The research of the second author was supported by Ministerio de Economia y Competitividad, Spain, under project #MTM2012-36740-C02-02Mastylo, M.; Sánchez Pérez, EA. (2017). Factorization of Operators Through Orlicz Spaces. Bulletin of the Malaysian Mathematical Sciences Society. 40(4):1653-1675. https://doi.org/10.1007/s40840-015-0158-5S16531675404Calderón, A.P.: Intermediate spaces and interpolation, the complex method. Stud. Math. 24, 113–190 (1964)Davis, W.J., Garling, D.J.H., Tomczak-Jaegermann, N.: The complex convexity of quasi-normed linear spaces. J. Funct. Anal. 55, 110–150 (1984)Defant, A.: Variants of the Maurey–Rosenthal theorem for quasi Köthe function spaces. Positivity 5, 153–175 (2001)Defant, A., Mastyło, M., Michels, C.: Orlicz norm estimates for eigenvalues of matrices. Isr. J. Math. 132, 45–59 (2002)Defant, A., Sánchez Pérez, E.A.: Maurey–Rosenthal factorization of positive operators and convexity. J. Math. Anal. Appl. 297, 771–790 (2004)Defant, A., Sánchez Pérez, E.A.: Domination of operators on function spaces. Math. Proc. Camb. Phil. Soc. 146, 57–66 (2009)Diestel, J.: Sequences and Series in Banach Spaces. Springer, Berlin (1984)Diestel, J., Jarchow, H., Tonge, A.: Absolutely Summing Operators. Cambridge University Press, Cambridge (1995)Dilworth, S.J.: Special Banach lattices and their applications. In: Handbook of the Geometry of Banach Spaces, vol. 1. Elsevier, Amsterdam (2001)Figiel, T., Pisier, G.: Séries alétoires dans les espaces uniformément convexes ou uniformément lisses. Comptes Rendus de l’Académie des Sciences, Paris, Série A 279, 611–614 (1974)Kalton, N.J., Montgomery-Smith, S.J.: Set-functions and factorization. Arch. Math. (Basel) 61(2), 183–200 (1993)Kamińska, A., Mastyło, M.: Abstract duality Sawyer formula and its applications. Monatsh. Math. 151(3), 223–245 (2007)Kantorovich, L.V., Akilov, G.P.: Functional Analysis, 2nd edn. Pergamon Press, Oxford (1982)Lindenstrauss, J., Tzafriri, L.: Classical Banach Spaces II. Springer, Berlin (1979)Lozanovskii, G.Ya.: On some Banach lattices IV, Sibirsk. Mat. Z. 14, 140–155 (1973) (in Russian); English transl.: Siberian. Math. J. 14, 97–108 (1973)Lozanovskii, G.Ya.:Transformations of ideal Banach spaces by means of concave functions. In: Qualitative and Approximate Methods for the Investigation of Operator Equations, Yaroslavl, vol. 3, pp. 122–147 (1978) (Russian)Mastyło, M., Szwedek, R.: Interpolative constructions and factorization of operators. J. Math. Anal. Appl. 401, 198–208 (2013)Nikišin, E.M.: Resonance theorems and superlinear operators. Usp. Mat. Nauk 25, 129–191 (1970) (Russian)Okada, S., Ricker, W.J., Sánchez Pérez, E.A.: Optimal Domain and Integral Extension of Operators acting in Function Spaces. Operator Theory: Adv. Appl., vol. 180. Birkhäuser, Basel (2008)Pisier, G.: Factorization of linear operators and geometry of Banach spaces. CBMS Regional Conference Series in Mathematics, vol. 60. Published for the Conference Board of the Mathematical Sciences, Washington, DC (1986)Reisner, S.: On two theorems of Lozanovskii concerning intermediate Banach lattices, geometric aspects of functional analysis (1986/87). Lecture Notes in Math., vol. 1317, pp. 67–83. Springer, Berlin (1988)Wojtaszczyk, P.: Banach Spaces for Analysts. Cambridge University Press, Cambridge (1991

The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression

The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer