Relationship between Tibial conformation, cage size and advancement achieved in TTA procedure

Previous studies have suggested that there is a theoretical discrepancy between the cage size and the resultant tibial tuberosity advancement, with the cage size consistently providing less tibial tuberosity advancement than predicted. The purpose of this study was to test and quantify this in clinical cases. The hypothesis was that the advancement of the tibial tuberosity as measured by the widening of the proximal tibia at the tibial tuberosity level after a standard TTA, will be less than the cage sized used, with no particular cage size providing a relative smaller or higher under-advancement, and that the conformation of the proximal tibia will have an influence on the amount of advancement achieved

Evaluation of copanlisib in combination with eribulin in triple-negative breast cancer patient-derived xenograft models

UNLABELLED: The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were examined by reverse phase protein array, immunohistochemistry (IHC) and 18F-fluorodeoxyglucose PET (18F-FDG PET). Compared with each drug alone, the combination of eribulin and copanlisib led to enhanced tumor growth inhibition, which was observed in both eribulin-sensitive and -resistant TNBC PDX models, regardless of PI3K pathway alterations or PTEN status. Copanlisib reduced PI3K signaling and enhanced eribulin-induced mitotic arrest. The combination enhanced induction of apoptosis compared with each drug alone. Interestingly, eribulin upregulated PI3K pathway signaling in PDX tumors, as demonstrated by increased tracer uptake by 18F-FDG PET scan and AKT phosphorylation by IHC. These changes were inhibited by the addition of copanlisib. These data support further clinical development for the combination of copanlisib and eribulin and led to a phase I/II trial of copanlisib and eribulin in patients with metastatic TNBC. SIGNIFICANCE: In this research, we demonstrated that the pan-PI3K inhibitor copanlisib enhanced the cytotoxicity of eribulin in a panel of TNBC PDX models. The improved tumor growth inhibition was irrespective of PI3K pathway alteration and was corroborated by the enhanced mitotic arrest and apoptotic induction observed in PDX tumors after combination therapy compared with each drug alone. These data provide the preclinical rationale for the clinical testing in TNBC

Indiana Medical Resident’s Knowledge of Surrogate Decision Making Laws

Introduction During the care of incapacitated patients, physicians, and medical residents discuss treatment options and gain consent to treat through healthcare surrogates. The purpose of this study is to ascertain medical residents’ knowledge of healthcare consent laws, application during clinical practice, and appraise the education residents received regarding surrogate decision making laws. Methods Beginning in February of 2018, 35 of 113 medical residents working with patients within Indiana completed a survey. The survey explored medical residents’ knowledge of health care surrogate consent laws utilized in Indiana hospitals and Veterans Affairs (VA) hospitals via clinical vignettes. Results Only 22.9% of medical residents knew the default state law in Indiana did not have a hierarchy for settling disputes among surrogates. Medical residents correctly identified which family members could participate in medical decisions 86% of the time. Under the Veterans Affairs surrogate law, medical residents correctly identified appropriate family members or friends 50% of the time and incorrectly acknowledged the chief decision makers during a dispute 30% of the time. All medical residents report only having little or some knowledge of surrogate decision making laws with only 43% having remembered receiving surrogate decision making training during their residency. Conclusions These findings demonstrate that medical residents lack understanding of surrogate decision making laws. In order to ensure medical decisions are made by the appropriate surrogates and patient autonomy is upheld, an educational intervention is required to train medical residents about surrogate decision making laws and how they are used in clinical practice

Functional Neuronal Circuits Promote Disease Progression in Cancer

The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues. We also demonstrate pharmacologic silencing of tumoral electrical activity. Tumors implanted in transgenic animals lacking nociceptor neurons show reduced electrical activity. These data suggest that intratumoral nerves remain functional at the tumor bed. Immunohistochemical staining demonstrates the presence of the neuropeptide, Substance P (SP), within the tumor space. We show that tumor cells express the SP receptor, NK1R, and that ligand/receptor engagement promotes cellular proliferation and migration. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression

Adaptive capacity in social–ecological systems: a framework for addressing bark beetle disturbances in natural resource management

The ability of natural resource agencies to act before, during, and after outbreaks of conifer bark beetles (Coleoptera: Curculionidae) is important to ensure the continued provision of ecosystem services. Adaptive capacity refers to the capability of an agent or system to adapt to change, regardless of whether it is examined as an independent social or ecological entity, or as a coupled social–ecological system. Understanding the components of a disturbance and the associated effects to ecosystem services, social systems, and natural resource management increases the ability to adapt to change and ensure continued resilience. This paper presents a definition and conceptual framework of adaptive capacity relevant to bark beetle disturbances that was developed through an interdisciplinary workshop held in 2016. The intent is to assist natural resource managers and policy-makers in identifying important adaptation characteristics to effectively address bark beetle disturbances. The current state of knowledge regarding institutional, social, and environmental factors that influence adaptive capacity are identified. The mountain pine beetle (Dendroctonus ponderosae) in the western USA is used as a specific example to discuss several factors that influence adaptive capacity for increasing resilience. We hope that our proposed framework serves as a model for future collaborations among both social and physical scientists and land managers to better address landscape-level disturbances that are being exacerbated by climate change

How do parents manage irritability, challenging behavior, non-compliance and anxiety in children with Autism Spectrum Disorders? A meta-synthesis

Although there is increasing research interest in the parenting of children with ASD, at present, little is known about everyday strategies used to manage problem behaviour. We conducted a meta-synthesis to explore what strategies parents use to manage irritability, non-compliance, challenging behaviour and anxiety in their children with ASD. Approaches included: (1) accommodating the child; (2) modifying the environment; (3) providing structure, routine and occupation; (4) supervision and monitoring; (5) managing non-compliance with everyday tasks; (6) responding to problem behaviour; (7) managing distress; (8) maintaining safety and (9) analysing and planning. Results suggest complex parenting demands in children with ASD and problem behaviour. Findings will inform the development of a new measure to quantify parenting strategies relevant to ASD