PROMIS Global Health: Feasibility in home health.

PURPOSE: This feasibility study assessed if the Patient-Reported Outcomes Measurement Information System (PROMIS®) 10-item Global Health Survey (PROMIS-10) could be a reliable and valid patient-reported outcome measure (PROM) for a population of cognitively intact home health (HH) patients. METHODS: The Centers for Medicare and Medicaid Services (CMS) along with their measurement contractor, Abt Associates, held a field test (2016-2017) to test the feasibility of the PROMIS-10 in in the Outcome and Assessment Information Set (OASIS). Home Health clinician data collectors (registered nurses and physical therapists) were trained to complete the PROMIS-10 along with procedures to facilitate patient self-administration of PROMIS-10. These clinicians provided feedback about their experiences at a focus group at the end of data collection. RESULTS: 213 HH patients comprised the field test sample, 150 of whom completed PROMIS-10 surveys. Clinicians reported they found the PROMIS-10 relevant and acceptable for their HH patients, and noted the surveys provided insight into patients' views of their health. The PROMIS-10 measured the full range of patient-reported health and was sensitive to change between admission and discharge. CONCLUSIONS: The study confirmed that the PROMIS-10 can be implemented in the HH setting, opening the door for consideration for implementing the PROMIS-10 in post-acute care (PAC) settings. This study is a first step toward establishing an assessment that captures the patient's voice and could be reported by the CMS PAC quality reporting programs.

Intermittent hypoxia exacerbates increased blood pressure in rats with chronic kidney disease.

Kidney injury and sleep apnea (SA) are independent risk factors for hypertension. Exposing rats to intermittent hypoxia (IH) to simulate SA increases blood pressure whereas adenine feeding causes persistent kidney damage to model chronic kidney disease (CKD). We hypothesized that exposing CKD rats to IH would exacerbate the development of hypertension and renal failure. Male Sprague-Dawley rats were fed a 0.2% adenine diet or control diet (Control) until blood urea nitrogen was >120 mg/dl in adenine-fed rats (14 ± 4 days, mean ± SE). After 2 wk of recovery on normal chow, rats were exposed to IH (20 exposures/h of 5% O2-5% CO2 7 h/day) or control conditions (Air) for 6 wk. Mean arterial pressure (MAP) was monitored with telemeters, and plasma and urine samples were collected weekly to calculate creatinine clearance as an index of glomerular filtration rate (GFR). Prior to IH, adenine-fed rats had higher blood pressure than rats on control diet. IH treatment increased MAP in both groups, and after 6 wk, MAP levels in the CKD/IH rats were greater than those in the CKD/Air and Control/IH rats. MAP levels in the Control/Air rats were lower than those in the other three groups. Kidney histology revealed crystalline deposits, tubule dilation, and interstitial fibrosis in both CKD groups. IH caused no additional kidney damage. Plasma creatinine was similarly increased in both CKD groups throughout whereas IH alone increased plasma creatinine. IH increases blood pressure further in CKD rats without augmenting declines in GFR but appears to impair GFR in healthy rats. We speculate that treating SA might decrease hypertension development in CKD patients and protect renal function in SA patients.

NFAT regulation of cystathionine γ-lyase expression in endothelial cells is impaired in rats exposed to intermittent hypoxia.

Sleep apnea is a risk factor for cardiovascular disease, and intermittent hypoxia (IH, 20 episodes/h of 5% O2-5% CO2 for 7 h/day) to mimic sleep apnea increases blood pressure and impairs hydrogen sulfide (H2S)-induced vasodilation in rats. The enzyme that produces H2S, cystathionine γ-lyase (CSE), is decreased in rat mesenteric artery endothelial cells (EC) following in vivo IH exposure. In silico analysis identified putative nuclear factor of activated T cell (NFAT) binding sites in the CSE promoter. Therefore, we hypothesized that IH exposure reduces Ca2+ concentration ([Ca2+]) activation of calcineurin/NFAT to lower CSE expression and impair vasodilation. In cultured rat aortic EC, inhibiting calcineurin with cyclosporine A reduced CSE mRNA, CSE protein, and luciferase activity driven by a full-length but not a truncated CSE promoter. In male rats exposed to sham or IH conditions for 2 wk, [Ca2+] in EC in small mesenteric arteries from IH rats was lower than in EC from sham rat arteries (Δfura 2 ratio of fluorescence at 340 to 380 nm from Ca2+ free: IH = 0.05 ± 0.02, sham = 0.17 ± 0.03, P < 0.05), and fewer EC were NFATc3 nuclear positive in IH rat arteries than in sham rat arteries (IH = 13 ± 3, sham = 59 ± 11%, P < 0.05). H2S production was also lower in mesenteric tissue from IH rats vs. sham rats. Endothelium-dependent vasodilation to acetylcholine (ACh) was lower in mesenteric arteries from IH rats than in arteries from sham rats, and inhibiting CSE with ß-cyanoalanine diminished ACh-induced vasodilation in arteries from sham but not IH rats but did not affect dilation to the H2S donor NaHS. Thus, IH lowers EC [Ca2+], NFAT activity, CSE expression and activity, and H2S production while inhibiting NFAT activation lowers CSE expression. The observations that IH exposure decreases NFATc3 activation and CSE-dependent vasodilation support a role for NFAT in regulating endothelial H2S production.NEW & NOTEWORTHY This study identifies the calcium-regulated transcription factor nuclear factor of activated T cells as a novel regulator of cystathionine γ-lyase (CSE). This pathway is basally active in mesenteric artery endothelial cells, but, after exposure to intermittent hypoxia to mimic sleep apnea, nuclear factor of activated T cells c3 nuclear translocation and CSE expression are decreased, concomitant with decreased CSE-dependent vasodilation.

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics.

3-heterocyclyl quinolone inhibitors of the HCV NS5B polymerase.

The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.

Discovery and optimization of thieno[2,3-d]pyrimidines as B-Raf inhibitors.

The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described.

Home Health Care Nursing Visit Intensity and Heart Failure Patient Outcomes.

This study is a secondary analysis of data for 107 home health care heart failure patients. The authors investigate the impact of patient characteristics and nursing visit intensity on change in activities of daily living (ADL) status and instrumental activities of daily living (IADL) status and improvement/stabilization of dyspnea. Prior hospital stay (ß = .38, p = .001) and nursing visit intensity (ß = -.39, p = .001) predict improvement in ADL status. The model for change in IADL status is not significant. Patients with more than two comorbidities (OR = 6.5, p = .04) and patients who received higher nursing visit intensity (OR = 7.0, p = .04) are more likely to have improved/stabilized dyspnea at home care discharge.

Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity.

TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.

Effect of intramolecular Paternò-Büchi reaction on the thermodynamics and kinetics of nearly degenerate [3,3]-sigmatropic shift in fluxional polycycles.

In reactions with weak dienophiles, cyclooctatetraene (COT) often yields 2:1 adducts possessing the fluxional bicyclo[5.1.0]octadiene moiety. They undergo fast, nearly degenerate Cope rearrangement with an activation barrier similar to that of the parent dihydrobullvalene. Irradiation to excite the carbonyl moiety induces an intramolecular Paterno-Buchi cyclization yielding endo-oxetanes and significantly changing the Cope-averaged NMR spectra. In this paper we examine the effect of skeletal distortion caused by intramolecular [2 + 2]-photoaddition on thermodynamics and the activation barrier of the [3,3]-sigmatropic tautomerism. Our finding is that such a distortion lifts the energetic degeneracy of the two valence tautomers, while not affecting the activation barrier.

Evolution of Cereblon-Mediated Protein Degradation as a Therapeutic Modality.

Many cellular processes and pathways are mediated by the regulation of protein-protein complexes. For example, E3 ubiquitin ligases recruit substrate proteins and transfer a ubiquitin tag to target those proteins for destruction by the proteasome. It has now been shown that this cellular process for protein destruction can be redirected by small molecules in both laboratory and clinical settings. This presents a new paradigm in drug discovery, enabling the rapid removal of target proteins linked to disease. In this Innovations review, we will describe the work done on cereblon as a case study on the different strategies available for targeted protein degradation.

Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy.

Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.

Synthetic Lethal Strategy Identifies a Potent and Selective TTK and CLK1/2 Inhibitor for Treatment of Triple-Negative Breast Cancer with a Compromised G1-S Checkpoint.

Historically, phenotypic-based drug discovery has yielded a high percentage of novel drugs while uncovering new tumor biology. CC-671 was discovered using a phenotypic screen for compounds that preferentially induced apoptosis in triple-negative breast cancer cell lines while sparing luminal breast cancer cell lines. Detailed in vitro kinase profiling shows CC-671 potently and selectively inhibits two kinases-TTK and CLK2. Cellular mechanism of action studies demonstrate that CC-671 potently inhibits the phosphorylation of KNL1 and SRp75, direct TTK and CLK2 substrates, respectively. Furthermore, CC-671 causes mitotic acceleration and modification of pre-mRNA splicing leading to apoptosis, consistent with cellular TTK and CLK inhibition. Correlative analysis of genomic and potency data against a large panel of breast cancer cell lines identifies breast cancer cells with a dysfunctional G1-S checkpoint as more sensitive to CC-671, suggesting synthetic lethality between G1-S checkpoint and TTK/CLK2 inhibition. Furthermore, significant in vivo CC-671 efficacy was demonstrated in two cell line-derived and one patient tumor-derived xenograft models of triple-negative breast cancer (TNBC) following weekly dosing. These findings are the first to demonstrate the unique inhibitory combination activity of a dual TTK/CLK2 inhibitor that preferably kills TNBC cells and shows synthetic lethality with a compromised G1-S checkpoint in breast cancer cell lines. On the basis of these data, CC-671 was moved forward for clinical development as a potent and selective TTK/CLK2 inhibitor in a subset of patients with TNBC. Mol Cancer Ther; 17(8); 1727-38. ©2018 AACR.

The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen.

Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.

Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115.

We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.

Discovery of mammalian target of rapamycin (mTOR) kinase inhibitor CC-223.

We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.

Proposing advancement criteria for efficient DMPK triage of new chemical entities.

With the goal of refining our discovery DMPK workflow, we conducted a retrospective analysis on internal Celgene compounds by calculating the physicochemical properties and gathering data from several assays including solubility, rat and human liver S9 stability, Caco-2 permeability, and rat intravenous (iv.) and oral pharmacokinetics. Our analysis identified plasma clearance to be most statistically relevant for prediction of oral exposure. In rat, compounds with rat S9 stability of ≥70% at 60 min and a plasma clearance of ≤43 ml/min/kg had the greatest chance of achieving oral exposures above 3 µM.h. Compounds with the dual advantage of plasma clearance ≤43 ml/min/kg and Caco-2 permeability ≥8 × 10(-6) cm/s or efflux ratio ≤8 were highly likely to achieve those oral exposures. Implementation of these criteria leads to a significant increase in efficiency, good pharmacokinetic properties, cost savings and a reduction in the use of animals.

"Don't get weak in your compassion": bereaved next of kin's suggestions for improving end-of-life care in Veterans Affairs Medical Centers.

OBJECTIVES: To analyze bereaved next of kin's suggestions for improving end-of-life (EOL) care in Veterans Affairs (VA) Medical Centers (VAMCs). DESIGN: Qualitative. SETTING: This study was part of a larger study testing the effectiveness of a multimodal intervention strategy to improve processes of EOL care in six southeast U.S. VAMCs (Best Practices for End-of-Life Care for Our Nation's Veterans-BEACON Trial). PARTICIPANTS: Bereaved next of kin (n = 78) of veterans who died between 2005 and 2010. MEASUREMENTS: Data addressing praise, criticism, and recommendations for enhancing EOL care were abstracted from semistructured interviews of next of kin and aggregated into a code labeled "Suggestions." Content analysis proceeded iteratively through data review, comparison, and negotiation of emergent themes and integration of all coauthors' insights and interpretations into the evolving interpretive scheme. RESULTS: Next of kin provided examples that resonated with their conceptions of quality EOL care. They also described distressing situations and perceptions of deficits in care. Major themes derived were compassionate care, good communication, support for family visits and privacy, and the need for death preparation and postdeath guidance. The fifth theme, unique to this study, was the salience of the relationship between the veterans and their families and the VA and the expectations this engendered in terms of dignity and honor. CONCLUSION: Interventions that support staff's ability to convey compassion, communicate information to families and other staff, listen to patients and families, prepare families for the individual's death, and provide consistent, coordinated information regarding after-death activities may optimize EOL hospital care for veterans.

Predictors of functional capacity changes in a US population of Medicare home health care (HHC) patients with heart failure (HF).

PURPOSE: Functional capacity is widely recognized as a key factor in maintaining the ability of older people to live independently and safely at home. Promoting functional capacity is an important priority particularly in HHC. The purpose of the study was to examine predictors of functional capacity change among HHC patients with HF. MATERIALS AND METHODS: Clinical and administrative data from 2005 from the Medicare Chronic Conditions Warehouse were linked at the population level for HHC patients with a primary diagnosis of HF. The primary outcome was change in functional capacity score from HHC admission to HHC discharge. RESULTS: Over the course of the episode (M=44 days), most (70%) patients improved, 15.6% stayed the same, and 14.4% declined in activities of daily living (ADL) scores. The mean change score was modest (mean=-0.74, SD=1.11) with a median change of -0.58. Multivariate analyses (R(2)=0.23) showed that the largest influence was the admission ADL score followed by receiving any physical therapy (PT), admission ability to manage oral medications, cognitive functioning, rehabilitation prognosis, and urinary incontinence. DISCUSSION: There is a modest rate of improvement from admission to discharge that likely represents the progressive nature of HF and/or the short time frames over which HHC is provided. Providers may want to use the predictive factors to identify patients most at risk for functional decline.

Rehospitalization in a national population of home health care patients with heart failure.

OBJECTIVE: Patients with heart failure (HF) have high rates of rehospitalization. Home health care (HHC) patients with HF are not well studied in this regard. The objectives of this study were to determine patient, HHC agency, and geographic (i.e., area variation) factors related to 30-day rehospitalization in a national population of HHC patients with HF, and to describe the extent to which rehospitalizations were potentially avoidable. DATA SOURCES: Chronic Condition Warehouse data from the Centers for Medicare & Medicaid Services. STUDY DESIGN: Retrospective cohort design. DATA EXTRACTION: The 2005 national population of HHC patients was matched with hospital and HHC claims, the Provider of Service file, and the Area Resource File. PRINCIPAL FINDINGS: The 30-day rehospitalization rate was 26 percent with 42 percent of patients having cardiac-related diagnoses for the rehospitalization. Factors with the strongest association with rehospitalization were consistent between the multilevel model and Cox proportional hazard models: number of prior hospital stays, higher HHC visit intensity category, and dyspnea severity at HHC admission. Substantial numbers of rehospitalizations were judged to be potentially avoidable. CONCLUSIONS: The persistently high rates of rehospitalization have been difficult to address. There are health care-specific actions and policy implications that are worth examining to improve rehospitalization rates.