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OBJECTIVES: In the United States, people with serious illness often experience gaps and discontinuity in care. Gaps are frequently exacerbated by limited mobility, need for social support, and challenges managing multiple comorbidities. The Advanced Illness Care (AIC) Program provides nurse practitioner-led, home-based care for people with serious or complex chronic illnesses that specifically targets palliative care needs and coordinates with patients' primary care and specialty health care providers. We sought to investigate the effect of the AIC Program on hospital encounters [hospitalizations and emergency department (ED) visits], hospice conversion, and mortality. DESIGN: Retrospective nearest-neighbor matching. SETTING AND PARTICIPANTS: Patients in AIC who had ≥1 inpatient stay within the 60 days prior to AIC enrollment to fee-for-service Medicare controls at 9 hospitals within one health system. METHODS: We matched on demographic characteristics and comorbidities, with exact matches for diagnosis-related group and home health enrollment. Outcomes were hospital encounters (30- and 90-day ED visits and hospitalizations), hospice conversion, and 30- and 90-day mortality. RESULTS: We included 110 patients enrolled in the AIC Program matched to 371 controls. AIC enrollees were mean age 77.0, 40.9% male, and 79.1% white. Compared with controls, AIC enrollees had a higher likelihood of ED visits at 30 [15.1 percentage points, confidence interval (CI) 4.9, 25.3; P = .004] and 90 days (27.8 percentage points, CI 16.0, 39.6; P < .001); decreased likelihood of hospitalization at 30 days (11.4 percentage points, CI -17.7, -5.0; P < .001); and a higher likelihood of converting to hospice (22.4 percentage points, CI 11.4, 33.3; P < .001). CONCLUSIONS: The AIC Program provides care and coordination that the home-based serious illness population may not otherwise receive. IMPLICATIONS: By identifying and addressing care needs and gaps in care early, patients may avoid unnecessary hospitalizations and receive timely hospice services as they approach the end of life.

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OBJECTIVE: To describe the collaboration between Youth Justice New South Wales (YJNSW) and Justice Health and Forensic Mental Health Network (JHFMHN) during the early COVID-19 Response (CR) across the six Youth Justice centres in NSW, and the reduced incidence of self-harm noted over this period. METHODS: Narrative article with analysis of self-harm incident data during the initial CR period of March to May 2020, compared to the same period in 2019. RESULTS: During the initial CR period (March to May 2020), there was a highly significant, four-fold reduction in self-harming incidents recorded by both YJNSW and JHFMHN compared with the equivalent time period in 2019 (p < .00001). CONCLUSION: The greater than four-fold reduction in self-harm by young people during the early CR may relate to the 'interagency response', with an increase in positive interactions between staff, and between staff and young people. The reduction in self-harm and improvements in mental health will be further explored through standardised interviews with the young people and staff.

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OBJECTIVES: To compare rates of 30- and 90-day hospital readmissions and observation or emergency department (ED) returns of older adults using the University of Pittsburgh Medical Center (UPMC) Health Plan Home Transitions (HT) with those of Medicare fee-for-service (FFS) controls without HT. DESIGN: Retrospective cohort study. SETTING: Analysis of home health and hospital records from 8 UPMC hospitals in Allegheny County, Pennsylvania, from July 1, 2015, to April 30, 2017. PARTICIPANTS: HT program participants (n=1,900) and controls (n=1,300). INTERVENTION: HT is a care transitions program aimed at preventing readmission that identifies older adults at risk of readmission using a robust inclusion algorithm; deploys a multidisciplinary care team, including a nurse practitioner (NP), a social worker (SW), or both; and provides a multimodal service including personalized care planning, education, treatment, monitoring, and communication facilitation. MEASUREMENT: We used multivariable logistic regression to determine the effects of HT on the odds of hospital readmission and observation or ED return, controlling for index admission participant characteristics and home health process measures. RESULTS: The adjusted odds of 30-day readmission was 0.31 (95% confidence interval (CI) = 0.11-0.87, P = .03) and of 90-day readmission was 0.47 (95% CI=CI = 0.26-0.85, P = .01), for participants at medium risk of readmission in HT who received a team visit. The adjusted odds of 30-day readmission was 0.29 (95% CI = 0.10-0.83, P = .02) for participants at high risk of readmission in HT who received a team visit. The adjusted odds of 30-day observation or ED return was 1.90 (95% CI = 1.28-2.82, P = .001) for participants at medium risk of readmission in HT who received a team visit. CONCLUSION: The HT program may be associated with lower odds of 30- and 90-day hospital readmission and counterbalancing higher odds of observation or ED return. J Am Geriatr Soc 67:156-163, 2019.

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Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting ß-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.

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Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates ß-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of ß-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).

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Potent and selective inhibitors of tankyrases have recently been characterized to bind to an induced pocket. Here we report the identification of a novel potent and selective tankyrase inhibitor that binds to both the nicotinamide pocket and the induced pocket. The crystal structure of human TNKS1 in complex with this "dual-binder" provides a molecular basis for their strong and specific interactions and suggests clues for the further development of tankyrase inhibitors.

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Aberrant activation of the Wnt pathway has been implicated in the development and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt signaling via Axin stabilization in APC mutant colon cancer cell lines. We employed structure-based design to identify a series of 2-aminopyridine oxazolidinones as potent and selective TNKS inhibitors. These compounds exhibited good enzyme and cell potency as well as selectivity over other PARP isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones complexed to TNKS reveal an induced-pocket binding mode that does not involve interactions with the nicotinamide binding pocket. Oral dosing of lead compounds 3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a three day DLD-1 mouse tumor PD model.

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BACKGROUND: Obesity is a parallel problem in canine and human populations. We describe health perceptions and levels of companion animal attachment in a cohort of dog owners. METHODS: As part of a larger trial examining the impact of veterinary counseling on activity levels of dog owners and their pets, owners presenting to a veterinary referral center were asked to self-report perceived levels of health and attachment to their dog (Lexington Attachment to Pets Scale). Owner body mass index and the body conditioning score of the companion dog were also recorded. RESULTS: Heavier pet owners reported a greater sense of attachment to their dogs. Heavier owners also reported lower perceived health and less social support. CONCLUSIONS: Increasing body mass index is associated with higher pet attachment, lower perceived health, and less social support. This information can impact wellness counseling for overweight pet owners and canine companions.

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Screening of the Amgen compound library led to the identification of 2-phenylamino-6-cyano-1H-benzimidazole 1a as a potent CK1 gamma inhibitor with excellent kinase selectivity and unprecedented CK1 isoform selectivity. Further structure-based optimization of this series resulted in the discovery of 1h which possessed good enzymatic and cellular potency, excellent CK1 isoform and kinase selectivity, and acceptable pharmacokinetic properties.

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BACKGROUND: Residency education requires large numbers of skilled teaching faculty. Potential faculty can often be identified during residency training. AIMS: Employ a 4-week immersive faculty development mini-fellowship to enhance the teaching skills of selected PGY-3 residents and study outcomes over 5 years. METHODS: PGY-3 residents were competitively selected and completed the 4-week curriculum to increase skills in precepting, small group teaching, large group teaching, learner feedback/assessment, academic career development, and research. RESULTS: Fifteen residents completed the mini-fellowship over the 5-year study period. The curriculum was rated highly by the residents with mean ratings of curriculum components ranging from 4.5 to 4.9 on a 5-point scale. Eight residents (53%) were selected for faculty positions compared to a usual selection rate of 11%. Compared to new faculty without mini-fellowship completion, program directors rated the residents completing the mini-fellowship as better prepared to perform learner feedback (4.1 vs. 3.0, p ≤ 0.01) and to understand the conduct of research (3.6 vs. 2.5 p ≤ 0.01). CONCLUSIONS: This study demonstrates short-term success at growing faculty with enhanced teaching skills during residency. While long-term retention in academic medicine cannot be predicted, this program represents one method to mitigate shortages of qualified junior residency faculty.

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BACKGROUND: Foot friction blisters in military personnel lessen a soldier's mobility, concentration, and critical decision-making skills. OBJECTIVE: To determine the prevalence of and factors associated with friction blisters during deployment in all military personnel who nonurgently presented to the 28th Combat Support Hospital. METHODS: A cross-sectional survey was performed at the 28th Combat Support Hospital. Statistical tests used included descriptive statistics, chi-square tests, and logistic regression for nominal data. RESULTS: The response rate was 97% with 872 surveys completed. Blister prevalence was 33% (95% confidence interval [CI] = 30.0-36.4). Eleven percent of these sought treatment (p < 0.001). Factors increasing the risk of developing blisters include female sex (prevalence ratio [PR] = 1.55, 95% CI = 1.27-1.91), wearing boots not broken in (PR = 1.52, CI = 1.26-1.85), longer than 6 months in theater (PR = 1.33, CI = 1.09-1.63), and history of prior blisters (PR = 2.08, CI = 1.69-2.56). CONCLUSIONS: The prevalence of foot friction blisters was 33% during a 12-month block of Operation Iraqi Freedom I. Of these, 11% required medical care. The group most likely to develop blisters is women, ages 26 to 34, who are unable to break in their boots and have a past history of blisters.

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Aberrant activation of the Wnt pathway is believed to drive the development and growth of some cancers. The central role of CK1γ in Wnt signal transduction makes it an attractive target for the treatment of Wnt-pathway dependent cancers. We describe a structure-based approach that led to the discovery of a series of pyridyl pyrrolopyridinones as potent and selective CK1γ inhibitors. These compounds exhibited good enzyme and cell potency, as well as selectivity against other CK1 isoforms. A single oral dose of compound 13 resulted in significant inhibition of LRP6 phosphorylation in a mouse tumor PD model.

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The elderly military beneficiary is a valued, high-risk, high-cost, and complex individual with unique medical needs. Attention to common geriatric syndromes (such as incontinence) and quality end-of-life care is critical in this population. Care of older adults is part of every adult medical and surgical specialty and represents a significant portion of the care rendered by the Military Health System (MHS)--a system that is currently oriented to warrior care and the care of young adults and families. Unique additional knowledge and expertise to care for the age-related geriatric syndromes is required by all providers. Maintaining quality of care for this older vulnerable population also requires unique measurement metrics and is facilitated by use of validated practice tools. This article will review validated practice tools that can assist military physicians and facilities in prospective and retrospective quality improvement (QI) initiatives to improve the therapeutic and palliative care of our older beneficiaries.

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Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-to-mesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 mICROM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40-59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (chi2 = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with "triple-negative" breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).

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BACKGROUND: Medical schools require time for end-of-life topic. However, there is very little medical literature that directly addresses how medical students and residents are to behave, manage emotion, and confront their own grieving process when patients die. OBJECTIVE: The purpose of this study was to understand how preclinical medical students describe feelings toward the death of a hypothetical patient in order to affect curricular change at our institution. DESIGN: Qualitative methods using narrative analysis of student papers to identify patterns, core constructs, and themes related to student's projected feelings on patient death. SETTING/SUBJECTS: Federal medical school with volunteer medical students from the class of 2005. RESULTS: Two thirds of the students (108/162) volunteered to participate. Five significant themes emerged including: (1) affective responses (guilt, fear, blame, impotence), (2) personal experience with death, (3) survivorship and professionalism, (4) the meaning of death, and (5) the affects of religion and spirituality. Many feared facing families and responding to grief. An active belief in an afterlife was mentioned as a coping strategy by 40% of the students. CONCLUSIONS: End-of-life curriculum is more than teaching about the clinical care of the patient and support of family. These medical students overwhelmingly identified the need for coping strategies when confronting the dying patient. Teaching students these coping strategies should be an integral part of an end-of-life curriculum. Writing exercises cannot only help students recognize and reflect upon their emotions and feelings, but also allow educators a window into curricular elements that need to be added to death and dying education.

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INTRODUCTION: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-beta) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-beta1 on breast cancer cells in the presence or absence of overexpressed HER-2. METHODS: Cell proliferation assays were used to determine the effect of TGF-beta on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-beta1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-beta signaling pathway was assessed using TGF-beta1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. RESULTS: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-beta1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-beta in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-beta induced pro-invasive and pro-metastatic gene signature. CONCLUSION: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-beta. In contrast, HER-2 and TGF-beta signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model.

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Genomic expression profiling has greatly improved our ability to subclassify human breast cancers according to shared molecular characteristics and clinical behavior. The logical next question is whether this technology will be similarly useful for identifying the dominant signaling pathways that drive tumor initiation and progression within each breast cancer subtype. A major challenge will be to integrate data generated from the experimental manipulation of model systems with expression profiles obtained from primary tumors. We highlight some recent progress and discuss several obstacles in the use of expression profiling to identify pathway signatures in human breast cancer.

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