Enhanced recovery after surgery (ERAS) for vascular surgery: an evidence map and scoping review.

BACKGROUND: Enhanced recovery after surgery (ERAS) interventions aim to improve patient outcomes. Vascular surgery patients have unique requirements and it is unclear which ERAS interventions are supported by an evidence base. METHODS: We conducted a scoping review to identify ERAS randomized controlled trials (RCTs) published in the biomedical or nursing literature. We assessed interventions for applicability to vascular surgery and differentiated interventions given at preadmission, preoperative, intraoperative, and postoperative surgery stages. We documented the research in an evidence map. RESULTS: We identified 76 relevant RCTs. Interventions were mostly administered in preoperative (23 RCTs; 30%) or intraoperative surgery stages (35 RCTs; 46%). The majority of studies reported mortality outcomes (44 RCTs; 58%), but hospital (27 RCTs; 35%) and intensive care unit (9 RCTs; 12%) length of stay outcomes were less consistently described. CONCLUSION: The ERAS evidence base is growing but contains gaps. Research on preadmission interventions and more consistent reporting of key outcomes is needed.

State Experiences Linking Medicaid Data With Birth Certificates and Other Data Sources.

BACKGROUND: Many states link Medicaid claims with birth certificates or other data, often to inform programs and policies aimed at improving maternal and child health (MCH). OBJECTIVES: To develop an up-to-date understanding of the extent of the use of linked Medicaid claims for MCH research by state. RESEARCH DESIGN: We completed a structured literature review, developed an inventory of linkage efforts, and facilitated semistructured discussions with representatives from 9 states with established Medicaid claims data linkages to understand the technical details of linkages, experiences creating and maintaining linkages, and barriers or facilitators to establishing linkages. RESULTS: We identified 45 peer-reviewed journal articles representing 22 states that used linked Medicaid data to study MCH and 33 states and territories that publicly report on Medicaid data linkages for a total of 39 states with any in-scope linkage. Discussions revealed that linkages often arose from the desire to answer a specific question or evaluate a program but then expanded to other use cases and that most states enable external researchers to access data for analysis. Respondents provided a few examples of where linked birth certificate data were used for health outcomes research. CONCLUSION: Additional resources including technical assistance for identifying best practices along with interagency collaboration could overcome barriers and facilitate a coordinated and consolidated approach across states.

US Military Healthcare Professionals' Practice, Knowledge, and Misconceptions About Concussion.

OBJECTIVE: To determine the US military healthcare professionals' knowledge and training preferences to improve diagnosis and management of concussion sustained in nondeployed settings. PARTICIPANTS: US military healthcare professionals (physicians, physician assistants, and nurse practitioners) completed online surveys to investigate practices, knowledge, and attitudes about concussion diagnosis and treatment, as well as preferences on future training. There were 744 responses from active duty US military healthcare providers, all of whom had cared for at least one patient with mild traumatic brain injury (mTBI) in the previous 24 months. RESULTS: The majority of physicians reported they were confident in their ability to evaluate a patient for a new mTBI (82.1%) and order appropriate imaging for mTBI (78.3%). Accuracy of identifying "red flag" symptoms ranged between 28.2% and 92.6%. A Likert scale from 1 ("not at all confident") to 4 ("very confident") was used to assess providers' confidence in their ability to perform services for patients with mTBI. With respect to barriers to optimal patient care, nurse practitioners consistently reported highest levels of barriers (90.8%). CONCLUSIONS: Although US military providers regularly care for patients with concussion, many report experiencing barriers to providing care, low confidence in basic skills, and inadequate training to diagnose and manage these patients. Customized provider education based on branch of service and occupation, and broader dissemination and utilization of decision support tools or practice guidelines, and patient information tool kits could help improve concussion care.

New York State 1115 Demonstration Independent Evaluation: Interim Report.

The broad goals of New York State's Medicaid Section 1115 Waiver are to enroll a majority of Medicaid beneficiaries into managed care, increase access and service quality, and expand coverage to more low-income New Yorkers. The RAND Corporation was competitively selected as the independent evaluator to assess two components under this 1115 Demonstration Waiver: the Managed Long-Term Care (MLTC) program and the 12-month continuous eligibility policy, which guarantees enrollees Medicaid coverage regardless of changes in income in the 12 months after eligibility determination and enrollment. This final interim evaluation examines whether these two components have helped achieve the program's goals. The RAND team's analyses show that the Demonstration has expanded access to managed care through mandatory MLTC enrollment and 12-month continuous eligibility. The team found no evidence of a significant change in patient safety or quality of care. The authors note that, although this means that there is no evidence the Demonstration achieved the goal of improving quality of care, increasing access without compromising quality of care is a success in its own right.

Differences in lymphoma patients between chimeric antigen receptor T-cell therapy trials and the general population.

Chimeric antigen receptor (CAR)-T cell therapies appear to be promising treatments for non-Hodgkin's and B-cell lymphoma. However, several CAR-T therapies approved by the US Food and Drug Administration have only been tested for efficacy in relatively few single-arm clinical trials with small sample sizes. We sought to examine the differences between patients in these trials and the general population of patients with non-Hodgkin's and B-cell lymphoma. Five hundred and twenty-two patients from 15 CAR-T trials found in a systematic review and 417,492 patients from the Surveillance, Epidemiology, and End Results (SEER) Program database were compared. CAR-T study participants appeared to be younger (46.7% under 70 years old vs. 42.2%), more male (68.0% vs. 55.7%), and followed for a shorter period of time compared to patients in the SEER population (mean [M] 45.6 months, 95% confidence interval [CI] 17.7 to 63.3 months follow-up vs. M 57.1 months, 95% CI 57.0 to 57.3 months survival). CAR-T study participants may differ significantly from the general population of patients with non-Hodgkin's and B-cell lymphoma. Effectiveness of CAR-T therapies in the general population of lymphoma patients may differ from effectiveness demonstrated in trials. Newly created CAR-T patient registries are essential to establishing population-level effectiveness of the therapies.

Effect of patient characteristics on posttraumatic stress disorder treatment retention among veterans: A systematic review.

To identify baseline patient characteristics (i.e., demographic and psychological factors, military background) associated with better posttraumatic stress disorder (PTSD) treatment retention among veterans, we conducted a systematic review. After an electronic database search for studies of PTSD treatment in veterans, two reviewers independently screened the literature for eligibility, abstracted study-level information, and assessed risk of bias. As most studies used multivariate models to assess multiple potential predictors of retention simultaneously, the results were described narratively. The GRADE approach, adapted for prognostic literature, was used to assess the overall quality of evidence (QoE). In total, 19 studies reported in 25 publications met the inclusion criteria (n = 6 good quality, n = 9 fair quality, n = 4 poor quality). Definitions of treatment completion and dropout varied, and some studies lumped different therapy approaches together. Older age and higher treatment expectations were associated with better retention (moderate QoE). In 5 of 6 studies, baseline PTSD severity was not associated with retention, and the remaining study reported an association between better retention and more severe PTSD symptoms; the presence of more co-occurring psychiatric disorders was associated with better retention (moderate QoE). QoE was low or insufficient to support conclusions for any other characteristics due to inconsistent results, imprecision, potential publication bias, possible study population overlap, study limitations, or lack of studies. More research is needed regarding the associations between modifiable factors (e.g., motivation, barriers, expectations) and retention, and consistent definitions of treatment completion and minimally adequate treatment should be adopted throughout the field.

An evidence map of treatments for infantile epilepsy.

Epilepsy prevalence is high among infants, but treatment guidelines are not clear. We conducted a scoping review of interventions to manage epilepsy in infants, and identified 37 studies. Most studies reported that interventions were effective (22 studies; 76 %), but randomized controlled trials were uncommon (7 studies; 19 %) and sample sizes were small (range: 2 to 284 participants; mean: 69.4; 95 % confidence interval: 49.5, 89.2). Additional high quality research and systematic reviews on interventions for infantile epilepsy are needed to establish better treatment guidelines for the disease.

Radiation Therapy for Brain Metastases: A Systematic Review.

PURPOSE: This evidence report synthesizes the available evidence on radiation therapy for brain metastases. METHODS AND MATERIALS: The literature search included PubMed, EMBASE, Web of Science, Scopus, CINAHL, clinicaltrials.gov, and published guidelines in July 2020; independently submitted data, expert consultation, and contacting authors. Included studies were randomized controlled trials (RCTs) and large observational studies (for safety assessments), evaluating whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) alone or in combination, as initial or postoperative treatment, with or without systemic therapy for adults with brain metastases due to lung cancer, breast cancer, or melanoma. RESULTS: Ninety-seven studies reported in 189 publications were identified, but the number of analyses was limited owing to different intervention and comparator combinations as well as insufficient reporting of outcome data. Risk of bias varied, and 25 trials were terminated early, predominantly owing to poor accrual. The combination of SRS plus WBRT compared with SRS alone or WBRT alone showed no statistically significant difference in overall survival (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.69%-1.73%; 4 RCTs) or death owing to brain metastases (relative risk [RR], 0.93; 95% CI, 0.48%-1.81%; 3 RCTs). Radiation therapy after surgery did not improve overall survival compared with surgery alone (HR, 0.98; 95% CI, 0.76%-1.26%; 5 RCTs). Data for quality of life, functional status, and cognitive effects were insufficient to determine effects of WBRT, SRS, or postsurgery interventions. We did not find systematic differences across interventions in serious adverse events, number of adverse events, radiation necrosis, fatigue, or seizures. WBRT plus systemic therapy (RR 1.44; 95% CI, 1.03%-2.00%; 14 studies) was associated with increased risks for vomiting compared with WBRT alone. CONCLUSIONS: Despite the substantial research literature on radiation therapy, comparative effectiveness information is limited. There is a need for more data on patient-relevant outcomes such as quality of life, functional status, and cognitive effects.

The Use of Technology in the Clinical Care of Anxiety: An Evidence Map.

OBJECTIVE: Cost, distance, and stigma may present barriers to face-to-face treatment for anxiety disorders. Technology can help overcome these barriers. The evidence map presented here provides an overview of technology use in clinical care for anxiety. METHODS: Searches in three databases from their inception dates to June 2019 identified published randomized controlled trials (RCTs) examining technology use in anxiety disorder management. Reviewers screened 4,061 records, included 128 RCTs, and extracted data on study characteristics and technology type, function, and effectiveness. RESULTS: In 88% of the 128 RCTs, the authors reported reduced anxiety symptoms postintervention. Studies of computer technology (66%) and patient self-directed psychotherapy (31%) were most common. Many interventions were studied by only a few RCTs, and many studies had small sample sizes. CONCLUSIONS: Almost all interventions reported improved anxiety symptoms, with computer applications having the largest evidence base. More information is needed to evaluate the role of technology in clinical care for anxiety.

An evidence map of randomised controlled trials evaluating genetic therapies.

OBJECTIVES: Genetic therapies replace or inactivate disease-causing genes or introduce new or modified genes. These therapies have the potential to cure in a single application rather than treating symptoms through repeated administrations. This evidence map provides a broad overview of the genetic therapies that have been evaluated in randomised controlled trials (RCTs) for efficacy and safety. ELIGIBILITY CRITERIA: Two independent reviewers screened publications using predetermined eligibility criteria. Study details and data on safety and efficacy were abstracted from included trials. Results were visualised in an evidence map. INFORMATION SOURCES: We searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov and grey literature to November 2018. RISK OF BIAS: Only RCTs were included in this review to reduce the risk of selection bias in the evaluation of genetic therapy safety and efficacy. INCLUDED STUDIES: We identified 119 RCTs evaluating genetic therapies for a variety of clinical conditions. SYNTHESIS OF RESULTS: On average, samples included 107 participants (range: 1-1022), and were followed for 15 months (range: 0-124). Interventions using adenoviruses (40%) to treat cardiovascular diseases (29%) were the most common. DESCRIPTION OF THE EFFECT: In RCTs reporting safety and efficacy outcomes, in the majority (60%) genetic therapies were associated with improved symptoms but in nearly half (45%) serious adverse event (SAEs) were also reported. Improvement was reported in trials treating cancer, cardiovascular, ocular and muscular diseases. However, only 19 trials reported symptom improvement for at least 1 year. STRENGTHS AND LIMITATIONS OF EVIDENCE: This is the first comprehensive evidence map of RCTs evaluating the safety and efficacy of genetic therapies. Evidence for long-term effectiveness and safety is still sparse. This lack of evidence has implications for the use, ethics, pricing and logistics of genetic therapies. INTERPRETATION: This evidence map provides a broad overview of research studies that allow strong evidence statements regarding the safety and efficacy of genetic therapies. Most interventions improve symptoms, but SAE are also common. More research is needed to evaluate genetic therapies with regard to the potential to cure diseases.

Evidence map of ductal carcinoma in situ management options.

OBJECTIVE: Ductal carcinoma in situ (DCIS) has the potential to progress to invasive carcinoma. The optimal management of DCIS and methods for individualizing treatment of DCIS are still being determined. This evidence map depicts the robustness and topical span of research on DCIS management choice on patient-centered and clinical outcomes. METHODS: We searched PubMed, EMBASE, PsycINFO, PubMed Health, PROSPERO, and clinical practice guideline sites to identify systematic reviews of DCIS management options and consulted with topic experts. A bubble plot visualizes the literature volume and research content for patient-centered outcomes. An online decision tree facilitates discussions with patients and guides through the available evidence. RESULTS: In total, 40 systematic reviews met inclusion criteria. The research syntheses addressed DCIS management options, including the role of magnetic resonance imaging, axillary surgery/sentinel lymph node biopsy, and excisional biopsy. The map shows existing evidence for mutually exclusive treatment options including active surveillance, breast-conserving surgery, nipple sparing mastectomy, and simple mastectomy. Research findings for intraoperative radiation, adjuvant radiation therapy, adjuvant hormone therapy, hypofractionation radiotherapy, accelerated partial breast irradiation, radiation therapy plus boost, and combined radiation and hormone therapy, as well as for breast reconstruction after mastectomy and surveillance mammography postsurgery are also displayed. The evidence map highlights a scarcity of robust evidence on patient-centered outcomes. CONCLUSIONS: The evidence map provides an overview of DCIS research showing the range of management options and remaining decisional dilemmas that follow a diagnosis of DCIS. It maps the evidence in accessible tools to guide practice and future research. : Video Summary:http://links.lww.com/MENO/A448.

A multidisciplinary review of the policy, intellectual property rights, and international trade environment for access and affordability to essential cancer medications.

In 2015, the World Health Organization (WHO) Expert Committee approved the addition of 16 cancer medicines to the WHO Model List of Essential Medicines (EML), bringing the total number of cancer medicines on the list to 46. This change represented the first major revision to the EML oncology section in recent history and reinforces international recognition of the need to ensure access and affordability for cancer treatments. Importantly, many low and middle-income countries rely on the EML, as well as the children's EML, as a guide to establish national formularies, and moreover use these lists as tools to negotiate medicine pricing. However, EML inclusion is only one component that impacts cancer treatment access. More specifically, factors such as intellectual property rights and international trade agreements can interact with EML inclusion, drug pricing, and accessibility. To better understand this dynamic, we conducted an interdisciplinary review of the patent status of EML cancer medicines compared to other EML noncommunicable disease medicines using the 17th, 18th, 19th, 20th, and 21st editions of the list. We also explored the interaction of intellectual property rights with the international trade regime and how trade agreements can and do impact cancer treatment access and affordability. Based on this analysis, we conclude that patent status is simply one factor in the complex international environment of health systems, IPR policies, and trade regimes and that aligning these oftentimes disparate interests will require shared global governance across the cancer care continuum.

Impact of Project ECHO Models of Medical Tele-Education: a Systematic Review.

BACKGROUND: Extension for Community Healthcare Outcomes (ECHO) and related models of medical tele-education are rapidly expanding; however, their effectiveness remains unclear. This systematic review examines the effectiveness of ECHO and ECHO-like medical tele-education models of healthcare delivery in terms of improved provider- and patient-related outcomes. METHODS: We searched English-language studies in PubMed, Embase, and PsycINFO databases from 1 January 2007 to 1 December 2018 as well as bibliography review. Two reviewers independently screened citations for peer-reviewed publications reporting provider- and/or patient-related outcomes of technology-enabled collaborative learning models that satisfied six criteria of the ECHO framework. Reviewers then independently abstracted data, assessed study quality, and rated strength of evidence (SOE) based on Cochrane GRADE criteria. RESULTS: Data from 52 peer-reviewed articles were included. Forty-three reported provider-related outcomes; 15 reported patient-related outcomes. Studies on provider-related outcomes suggested favorable results across three domains: satisfaction, increased knowledge, and increased clinical confidence. However, SOE was low, relying primarily on self-reports and surveys with low response rates. One randomized trial has been conducted. For patient-related outcomes, 11 of 15 studies incorporated a comparison group; none involved randomization. Four studies reported care outcomes, while 11 reported changes in care processes. Evidence suggested effectiveness at improving outcomes for patients with hepatitis C, chronic pain, dementia, and type 2 diabetes. Evidence is generally low-quality, retrospective, non-experimental, and subject to social desirability bias and low survey response rates. DISCUSSION: The number of studies examining ECHO and ECHO-like models of medical tele-education has been modest compared with the scope and scale of implementation throughout the USA and internationally. Given the potential of ECHO to broaden access to healthcare in rural, remote, and underserved communities, more studies are needed to evaluate effectiveness. This need for evidence follows similar patterns to other service delivery models in the literature.

Mindfulness meditation for workplace wellness: An evidence map.

BACKGROUND: Mindfulness interventions aim to foster greater attention and awareness of present moment experiences. Uptake of mindfulness programs in the workplace has grown as organizations look to support employee health, wellbeing, and performance. OBJECTIVE: In support of evidence-based decision making in workplace contexts, we created an evidence map summarizing physical and mental health, cognitive, affective, and interpersonal outcomes from systematic reviews of randomized controlled trials (RCTs) of mindfulness interventions. METHODS: We searched nine electronic databases to July 2017, dually-screened all reviews, and consulted topic experts to identify systematic reviews on mindfulness interventions. The distribution of evidence is presented as an evidence map in a bubble plot. RESULTS: In total, 175 systematic reviews met inclusion criteria. Reviews included a variety of mindfulness-based interventions. The largest review included 109 randomized controlled trials. The majority of these addressed general health, psychological conditions, chronic illness, pain, and substance use. Twenty-six systematic reviews assessed studies conducted in workplace settings and with healthcare professionals, educators, and caregivers. The evidence map shows the prevalence of research by the primary area of focus. An outline of promising applications of mindfulness interventions is included. CONCLUSIONS: The evidence map provides an overview of existing mindfulness research. It shows the body of available evidence to inform policy and organizational decision-making supporting employee wellbeing in work contexts.

The Use of Technology in the Clinical Care of Depression: An Evidence Map.

OBJECTIVE: Depression is a highly prevalent clinical condition. The use of technologies in the clinical care of depressive disorders may increase the reach of clinical services for these disorders and support more comprehensive treatment. The objective of this evidence map is to provide an overview of the use of technology in the clinical care of depression. DATA SOURCES: We searched PubMed, PsycINFO, and the Web of Science from inception to June 2017 to identify published randomized controlled trials (RCTs). STUDY SELECTION: Two reviewers used predetermined eligibility criteria to review 4,062 records and include 161 RCTs that met our inclusion criteria. We include studies evaluating any type of treatment-related technology in the clinical care of depression. DATA EXTRACTION: We extracted data on sample sizes, the type of technology examined, the function of that technology, the effectiveness of the technology, and publication year. RESULTS: Out of 161 RCTs, we found the greatest amount of research for psychotherapy by computer (51 RCTs). The majority of studies were published after 2012 (94 RCTs; 58%). Few published studies involved videoconferences or smartphones, or provider feedback or auto-reminders. 145 studies (90%) reported that the intervention had a positive outcome of symptom improvement compared to baseline. CONCLUSIONS: This evidence map provides a broad overview of the existing research evaluating technology in depression care. Computer applications are still most common. Almost all applications yield symptom improvement. More information is needed to evaluate the role of technology in clinical care.

Discovery of 1-{(3R,4R)-3-[({5-Chloro-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]-4-methoxypyrrolidin-1-yl}prop-2-en-1-one (PF-06459988), a Potent, WT Sparing, Irreversible Inhibitor of T790M-Containing EGFR Mutants.

First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.

Targeting small cell lung cancer harboring PIK3CA mutation with a selective oral PI3K inhibitor PF-4989216.

PURPOSE: Constitutive activation of phosphoinositide 3-kinase (PI3K) occurs frequently in many human tumors via either gene mutation in the p110α catalytic subunit of PI3K or functional loss of tumor suppressor PTEN. Patients with small-cell lung cancer (SCLC) have very poor prognosis and survival rates such that an effective targeted therapy is in strong demand for these patients. In this study, we characterized the highly selective oral PI3K inhibitor, PF-4989216, in preclinical SCLC models to investigate whether targeting the PI3K pathway is an effective targeted therapy option for SCLCs that harbor a PIK3CA mutation. EXPERIMENTAL DESIGN: A panel of SCLC cell lines with PIK3CA mutation or PTEN loss were treated with PF-4989216 in several in vitro assays, including PI3K pathway signaling, cell viability, apoptosis, cell-cycle progression, and cell transformation. SCLC cell lines that were sensitive in vitro to PF-4989216 were further evaluated by in vivo animal studies to determine the pharmacokinetic/pharmacodynamic relationship and tumor growth inhibition (TGI) by PF-4989216 treatment. RESULTS: PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation. In SCLCs with PTEN loss, PF-4989216 also inhibited PI3K signaling but did not induce BCL2-interacting mediator (BIM)-mediated apoptosis nor was there any effect on cell viability or transformation. These results implicate differential tumorigenesis and apoptosis mechanisms in SCLCs harboring PIK3CA mutation versus PTEN loss. CONCLUSIONS: Our results suggest that PF-4989216 is a potential cancer drug candidate for patients with SCLC with PIK3CA mutation but not PTEN loss.

miR-221 promotes tumorigenesis in human triple negative breast cancer cells.

Patients with triple-negative breast cancers (TNBCs) typically have a poor prognosis. TNBCs are characterized by their resistance to apoptosis, aggressive cellular proliferation, migration and invasion, and currently lack molecular markers and effective targeted therapy. Recently, miR-221/miR-222 have been shown to regulate ERα expression and ERα-mediated signaling in luminal breast cancer cells, and also to promote EMT in TNBCs. In this study, we characterized the role of miR-221 in a panel of TNBCs as compared to other breast cancer types. miR-221 knockdown not only blocked cell cycle progression, induced cell apoptosis, and inhibited cell proliferation in-vitro but it also inhibited in-vivo tumor growth by targeting p27(kip1). Furthermore, miR-221 knockdown inhibited cell migration and invasion by altering E-cadherin expression, and its regulatory transcription factors Snail and Slug in human TNBC cell lines. Therefore, miR-221 functions as an oncogene and is essential in regulating tumorigenesis in TNBCs both in vitro as well as in vivo.

Highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.

We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity.

Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase.

Optimization of the ADME properties of a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase resulted in the identification of highly selective compounds with properties suitable for use as in vitro and in vivo tools to probe the effects of Sky inhibition.