Association of Loneliness and Mindfulness in Substance Use Treatment Retention.

BACKGROUND: Elevated mental illness prevalence complicates efforts designed to address the opioid crisis in Appalachia. The recovery community acknowledges that loneliness impacts mood and engagement in care factors; however, the predictive relationship between loneliness and retention in medication-assisted outpatient treatment programs has not been explored. Our objectives were to identify associations between mental health factors and retention in treatment and elucidate treatment retention odds. Data were collected from eighty participants (n = 57 retained, n = 23 not retained) of a mindfulness-based relapse prevention (MBRP) intervention for individuals receiving medication for opioid use disorder (MOUD) in Appalachia. Loneliness, depression, and anxiety did not differ between the retained and not retained, nor did they predict not being retained; however, mindfulness was significantly lower among those not retained in treatment compared to those retained (OR = 0.956, 95% CI (0.912-1.00), and p < 0.05). Preliminary findings provide evidence for mindfulness training integration as part of effective treatment, with aims to further elucidate the effectiveness of mindfulness therapies on symptom reduction in co-occurring mental health disorders, loneliness, and MOUD treatment retention.

Assessing Loneliness among Adults Receiving Outpatient Treatment with Medication for Opioid Use Disorder (MOUD).

Loneliness is a significant risk factor for substance use, however, impacts of treatments on loneliness are relatively unexplored. Living in a rural location is a greater risk factor for loneliness. This study examined data from a quasi-experimental study in rural Appalachia, comparing the effectiveness of Mindfulness-Based Relapse Prevention (MBRP) versus Treatment as Usual (TAU) among adults receiving MOUD in outpatient therapy. Our objective was to determine whether observed reductions in self-reported craving, anxiety, depression, and increased perceived mindfulness would also improve loneliness reports. Eighty participants (n = 35 MBRP; n = 45 TAU) were included in the analysis from a group-based Comprehensive Opioid Addiction Treatment program. Outcomes tracked included craving, anxiety, depression, mindfulness, and loneliness as measured by the Revised UCLA Loneliness Scale (R-UCLA). A linear mixed model ANOVA determined the significance of the treatments on changes in loneliness scores at baseline, 12 weeks, 24 weeks, and 36 weeks post-recruitment. Both groups reported significantly reduced loneliness over the course of the study (F = 16.07, p < 0.01), however there were no significant differences between groups. Loneliness was also significantly positively (p < 0.01) correlated with anxiety (0.66), depression (0.59), and craving (0.38), and significantly (p < 0.01) inversely correlated (-0.52) with mindfulness. Results suggest that participation in MOUD group-based outpatient therapy has the potential to diminish loneliness and associated poor psychological outcomes. Thus, it is possible that a more targeted intervention for loneliness would further diminish loneliness, which is important as loneliness is linked to risk for relapse.

Candida albicans Infections: a novel porcine wound model to evaluate treatment efficacy.

Candida albicans is a common cause of opportunistic mycoses worldwide and a major contributor in wound infections. The purpose of this study was to establish a fungal wound model and analyze the effects of a common antifungal agent against the proliferation of three C. albicans strains. Second degree burns were created, and then inoculated with one of three different C. albicans ATCC strains: 10261 reference strain, 64550 fluconazole resistant and 26310 fluconazole sensitive. After fungal inoculation, every wound was covered with dressings for 4 h to allow fungal colonization on every wound bed. After 4 h, the dressings were removed, and each wound was treated either once or twice daily with a topical terbinafine hydrochloride or left untreated. On days 2, 4 and 7 post inoculation, three wounds from each treatment group were scrub cultured and quantified. On day 2, wounds infected with the sensitive strains 26310 and 10261 and treated twice showed a significant reduction when compared against those infected wounds receiving once daily treatment. On day 4, wounds which were infected with C. albicans fluconazole sensitive (ATCC 26310) showed a significant reduction in fungal cell counts with treatment applied twice daily. A significant reduction in the colony counts was exhibited in all three strains at the seventh day with active as compared to the non-treated wounds. Twice daily treatment resulted in a lower fungal count than once daily treatment. Neither treatment was able to entirely eradicate C. albicans during the duration of this study. Establishing a reliable fungal wound model will help in the translational goal of identifying new antifungal that could be used clinically by wound care providers.

Considerations when using alpha-glucosidase inhibitors in the treatment of type 2 diabetes.

Introduction: Alpha-glucosidase inhibitors (AGIs) - oral antihyperglycemic drugs, inhibit upper gastrointestinal enzymes that break down complex carbohydrates into glucose. As a result, the absorption of glucose is delayed, postprandial glucose reduced, and glycemic control improved.Areas covered: In this review, the authors describe the current recommendations on the use of the three major approved AGIs (acarbose, miglitol, voglibose). Efficacy and safety parameters together with ethnic considerations have been highlighted throughout the manuscript. The article also discusses potential diabetes prevention and cardiovascular effects of these medications.Expert opinion: The overall safety and efficacy of this class of drug appears to be high: AGIs do not increase the risk of hypoglycemia, do not cause weight gain; they also significantly improve postprandial hyperglycemia, have been associated with the reduction in risk factors for cardiovascular disease and may also delay the progression of prediabetes to T2DM. In general, we continue to believe that acarbose, miglitol, and voglibose should be used as third-line add on treatment options to other anti-hyperglycemic agents. However, this class can have earlier consideration in elderly and/or when metformin is contraindicated.

Chronic nutrient inputs affect stream macroinvertebrate communities more than acute inputs: An experiment manipulating phosphorus, nitrogen and sediment.

Freshwaters worldwide are affected by multiple stressors. Timing of inputs and pathways of delivery can influence the impact stressors have on freshwater communities. In particular, effects of point versus diffuse nutrient inputs on stream macroinvertebrates are poorly understood. Point-source inputs tend to pose a chronic problem, whereas diffuse inputs tend to be acute with short concentration spikes. We manipulated three key agricultural stressors, phosphorus (ambient, chronic, acute), nitrogen (ambient, chronic, acute) and fine sediment (ambient, high), in 112 stream mesocosms (26 days colonisation, 18 days of manipulations) and determined the individual and combined effects of these stressors on stream macroinvertebrate communities (benthos and drift). Chronic nutrient treatments continuously received high concentrations of P and/or N. Acute channels received the same continuous enrichment, but concentrations were doubled during two 3-hour periods (day 6, day 13) to simulate acute nutrient inputs during rainstorms. Sediment was the most pervasive stressor in the benthos, reducing total macroinvertebrate abundance and richness, EPT (mayflies, stoneflies, caddisflies) abundance and richness. By contrast, N or P enrichment did not affect any of the six studied community-level metrics. In the drift assemblage, enrichment effects became more prevalent the longer the experiment went on. Sediment was the dominant driver of drift responses at the beginning of the experiment. After the first acute nutrient pulse, sediment remained the most influential stressor but its effects started to fade. After the second pulse, N became the dominant stressor. In general, impacts of either N or P on the drift were due to chronic exposure, with acute nutrient pulses having no additional effects. Overall, our findings imply that cost-effective management should focus on mitigating sediment inputs first and tackle chronic nutrient inputs second. Freshwater managers should also take into account the length of exposure to high nutrient concentrations, rather than merely the concentrations themselves.

Implementation of a Collaborative HIV and Hepatitis C Screening Program in Appalachian Urgent Care Settings.

INTRODUCTION: With the current hepatitis C (HCV) epidemic in the Appalachian region and the risk of human immunodeficiency virus (HIV) co-infection, there is a need for increased secondary prevention efforts. The purpose of this study was to implement routine HIV and HCV screenings in the urgent care setting through the use of an electronic medical record (EMR) to increase a provider's likelihood of testing eligible patients. METHODS: From June 2017 through May 2018, EMR-based HIV and HCV screenings were implemented in three emergency department-affiliated urgent care settings: a local urgent care walk-in clinic; a university-based student health services center; and an urgent care setting located within a multi-specialty clinic. EMR best practice alerts (BPA) were developed based on Centers for Disease Control and Prevention (CDC) guidelines and populated on registered patients who qualified to receive HIV and/or HCV testing. Patients were excluded from the study if they chose to opt out from testing or the provider deemed it clinically inappropriate. Upon notification of a positive HIV and/or HCV test result through the EMR, patient navigators (PNs) were responsible for linking patients to their first medical appointment. RESULTS: From June 2017 through May 2018, 48,531 patients presented to the three urgent care clinics. Out of 27,230 eligible patients, 1,972 patients (7.2%) agreed to be screened for HIV; for HCV, out of 6,509 eligible patients, 1,895 (29.1%) agreed to be screened. Thirty-one patients (1.6%) screened antibody-positive for HCV, with three being ribonucleic acid confirmed positives. No patients in either setting were confirmed positive for HIV; however, two initially screened HIV-positive. PNs were able to link 17 HCV antibody-positive patients (55%) to their first appointment, with the remainder having a scheduled future appointment. CONCLUSION: Introducing an EMR-based screening program is an effective method to identify and screen eligible patients for HIV and HCV in Appalachian urgent care settings where universal screenings are not routinely implemented.

Multiple-stressor effects of sediment, phosphorus and nitrogen on stream macroinvertebrate communities.

Multiple stressors affect stream ecosystems worldwide and their interactions are of particular concern, with gaps existing in understanding stressor impacts on stream communities. Addressing these knowledge gaps will aid in targeting and designing of appropriate mitigation measures. In this study, the agricultural stressors fine sediment (ambient, low, medium, high), phosphorus (ambient, enriched) and nitrogen (ambient, enriched) were manipulated simultaneously in 64 streamside mesocosms to determine their individual and combined effects on the macroinvertebrate community (benthos and drift). Stressor levels were chosen to reflect those typically observed in European agricultural streams. A 21-day colonisation period was followed by a 14-day manipulative period. Results indicate that added sediment had the most pervasive effects, significantly reducing total macroinvertebrate abundance, total EPT abundance and abundances of three common EPT taxa. The greatest effect was at high sediment cover (90%), with decreasing negative impacts at medium (50%) and low (30%) covers. Added sediment also led to higher drift propensities for nine of the twelve drift variables. The effects of nitrogen and phosphorus were relatively weak compared to sediment. Several complex and unpredictable 2-way or 3-way interactions among stressors were observed. While sediment addition generally reduced total abundance at high levels, this decrease was amplified by P enrichment at low sediment, whereas the opposite effect occurred at medium sediment and little effect at high sediment. These results have direct implications for water management as they highlight the importance of managing sediment inputs while also considering the complex interactions which can occur between sediment and nutrient stressors.

Towards an Understanding of the Interactions between Freshwater Inflows and Phytoplankton Communities in a Subtropical Estuary in the Gulf of Mexico.

Subtropical estuaries worldwide face increased pressure on their ecosystem health and services due to increasing human population growth and associated land use/land cover changes, expansion of ports, and climate change. We investigated freshwater inflows (river discharge) and the physico-chemical characteristics of Galveston Bay (Texas, USA) as mechanisms driving variability in phytoplankton biomass and community composition between February 2008 and December 2009. Results of multivariate analyses (hierarchical cluster analysis, PERMANOVA, Mantel test, and nMDS ordination coupled to environmental vector fitting) revealed that temporal and spatial differences in phytoplankton community structure correlate to differences in hydrographic and water quality parameters. Spatially, phytoplankton biomass and community composition responded to nutrient loading from the San Jacinto River in the northwest region of the bay (consistent with nutrient limitation) while hydraulic displacement (and perhaps other processes) resulted in overall lower biomass in the Trinity River delta (northeast region). The influence of inflows on phytoplankton diminished along a north to south gradient in the bay. Temporally, temperature and variables associated with freshwater inflow (discharge volume, salinity, inorganic nitrogen and phosphorus concentrations) were major influences on phytoplankton dynamics. Dissolved inorganic nitrogen: phosphorus (DIN:DIP) ratios suggest that phytoplankton communities will be predominately nitrogen limited. Diatoms dominated during periods of moderate to high freshwater inflows in winter/spring and were more abundant in the upper bay while cyanobacteria dominated during summer/fall when inflow was low. Given the differential influences of freshwater inflow on the phytoplankton communities of Galveston Bay, alterations upstream (magnitude, timing, frequency) will likely have a profound effect on downstream ecological processes and corresponding ecosystem services.

DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition.

The discovery of incretin-based medications represents a major therapeutic advance in the pharmacological management of type 2 diabetes mellitus (T2DM), as these agents avoid hypoglycemia, weight gain, and simplify the management of T2DM. Dipeptidyl peptidase-4 (CD26, DPP4) inhibitors are the most widely used incretin-based therapy for the treatment of T2DM globally. DPP4 inhibitors are modestly effective in reducing HbA1c (glycated hemoglobin) (≈0.5%) and while these agents were synthesized with the understanding of the role that DPP4 plays in prolonging the half-life of incretins such as glucagon-like peptide-1 and gastric inhibitory peptide, it is now recognized that incretins are only one of many targets of DPP4. The widespread expression of DPP4 on blood vessels, myocardium, and myeloid cells and the nonenzymatic function of CD26 as a signaling and binding protein, across a wide range of species, suggest a teleological role in cardiovascular regulation and inflammation. Indeed, DPP4 is upregulated in proinflammatory states including obesity, T2DM, and atherosclerosis. Consistent with this maladaptive role, the effects of DPP4 inhibition seem to exert a protective role in cardiovascular disease at least in preclinical animal models. Although 2 large clinical trials suggest a neutral effect on cardiovascular end points, current limitations of performing trials in T2DM over a limited time horizon on top of maximal medical therapy must be acknowledged before rendering judgment on the cardiovascular efficacy of these agents. This review will critically review the science of DPP4 and the effects of DPP4 inhibitors on the cardiovascular system.

Antimicrobial dressing efficacy against mature Pseudomonas aeruginosa biofilm on porcine skin explants.

An ex vivo porcine skin explant biofilm model that preserves key properties of biofilm attached to skin at different levels of maturity (0-3 days) was used to assess the efficacy of commercially available antimicrobial dressings and topical treatments. Assays were also performed on the subpopulation of antibiotic tolerant biofilm generated by 24 hours of pre-treatment with gentamicin (120× minimal inhibitory concentration) prior to agent exposure. Five types of antimicrobial agents (iodine, silver, polyhexamethylene biguanide, honey and ethanol) and four types of moisture dressings (cotton gauze, sodium carboxymethylcellulose fibre, calcium alginate fibre and cadexomer beads) were assessed. Time-release silver gel and cadexomer iodine dressings were the most effective in reducing mature biofilm [between 5 and 7 logarithmic (log) of 7-log total], whereas all other dressing formulations reduced biofilm between 0·3 and 2 log in 24 or 72 hours with a single exposure. Similar results were found after 24-hour exposure to silver release dressings using an in vivo pig burn wound model, demonstrating correlation between the ex vivo and in vivo models. Results of this study indicate that commonly used microbicidal wound dressings vary widely in their ability to kill mature biofilm and the efficacy is influenced by time of exposure, number of applications, moisture level and agent formulation (sustained release).

Effect of statin use during hospitalization for intracerebral hemorrhage on mortality and discharge disposition.

IMPORTANCE: Statin use during hospitalization is associated with improved survival and a better discharge disposition among patients with ischemic stroke. It is unclear whether inpatient statin use has a similar effect among patients with intracerebral hemorrhage (ICH). OBJECTIVE: To determine whether inpatient statin use in ICH is associated with improved outcomes and whether the cessation of statin use is associated with worsened outcomes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 3481 patients with ICH admitted to any of 20 hospitals in a large integrated health care delivery system over a 10-year period. Detailed electronic medical and pharmacy records were analyzed to explore the association between inpatient statin use and outcomes. MAIN OUTCOMES AND MEASURES: The primary outcome measures were survival to 30 days after ICH and discharge to home or inpatient rehabilitation facility. We used multivariable logistic regression, controlling for demographics, comorbidities, initial severity, and code status. In addition, we used instrumental variable modeling to control for confounding by unmeasured covariates at the individual patient level. RESULTS: Among patients hospitalized for ICH, inpatient statin users were more likely than nonusers to be alive 30 days after ICH (odds ratio [OR], 4.25 [95% CI, 3.46-5.23]; P < .001) and were more likely than nonusers to be discharged to their home or an acute rehabilitation facility (OR, 2.57 [95% CI, 2.16-3.06]; P < .001). Patients whose statin therapy was discontinued were less likely than statin users to survive to 30 days (OR, 0.16 [95% CI, 0.12-0.21]; P < .001) and were less likely than statin users to be discharged to their home or an acute rehabilitation facility (OR, 0.26 [95% CI, 0.20-0.35]; P < .001). Instrumental variable models of local treatment environment (to control for confounding by unmeasured covariates) confirmed that a higher probability of statin therapy was associated with a higher probability of 30-day survival (with an increase in probability of 0.15 [95% CI, 0.04-0.25]; P = .01) and a better chance of being discharged to home or an acute rehabilitation facility (with an increase in probability of 0.13 [95% CI, 0.02-0.24]; P = .02). CONCLUSIONS AND RELEVANCE: Inpatient statin use is associated with improved outcomes after ICH, and the cessation of statin use is associated with worsened outcomes after ICH. Given the association between statin cessation and substantially worsened outcomes, the risk-benefit balance of discontinuing statin therapy in the acute setting of ICH should be carefully considered.

Intravenous thrombolysis for acute ischaemic stroke in the setting of rivaroxaban use.

The risk of thrombolysis in patients taking novel anticoagulants remains unclear. We describe a patient with a large acute ischaemic stroke, who had a low calibrated anti-factor Xa level, who safely received thrombolysis 15-17 hours after standard dose rivaroxaban without subsequent intracerebral haemorrhage.

An in vitro analysis of the effects of various topical antimicrobial agents on methicillin-resistant and methicillin-sensitive strains of Staphylococcus aureus.

Infections of acute and chronic wounds have a substantial negative impact on patient outcomes. Because bacterial resistance to traditional antimicrobials continues to increase, an in vitro study was conducted to examine current sensitivities of various methicillin-resistant and methicillin-sensitive strains of Staphylococcus aureus (MRSA and MSSA) to commonly used topical antimicrobial agents. Using fresh cultures of eight strains of MRSA and MSSA, the area of the zone of inhibition produced by various topical antimicrobials, including an aminoglycoside antibiotic, monocarboxylic acid antibiotic, pleuromutilin antibiotic, triple antibiotic ointment, and petrolatum ointment, was examined. Six culture plates per antimicrobial were prepared using the Kirby Bauer method; soy blood culture plates were inoculated with the bacteria, incubated for 24 hours at 37˚ C, and their zones of inhibition measured and calculated. Data were analyzed using ANOVA testing. Mupirocin treatment was the most effective antimicrobial, with areas of inhibition ranging from 30.34 cm2 to 61.70 cm2 (P <0.05), as compared to the next most effective, retapamulin, with areas of inhibition ranging from 11.97 cm2 to 23.54 cm2. This study provides current scientific data to help the development of a thoughtful rationale for the use of topical antimicrobials in wounds. Additional in vivo studies to substantiate these findings are needed.

Recurrent involuntary imagery in people who stutter and people who do not stutter.

OBJECTIVE: To compare intrusive memories in groups of people who do (PWS), and who do not (PWNS), stutter. METHOD: Twenty-one participants who stuttered and 21 matched controls were given a semi-structured interview which explored imagery in speaking situations. The data were analyzed using a Content Analysis approach. Other outcome measures were the Beck Anxiety Inventory, the Beck Depression Inventory, the Post Traumatic Stress Disorder, PTSD, Symptom Scale: Self-Report Version. RESULTS: Significantly more stuttering participants than control participants indicated both recurrent imagery and associated memories. Content Analysis revealed themes of disfluency, anxiety, negative social evaluation, self-focus and pressure to speak that were common to both groups' reports. Additional themes of helplessness, shame, sadness and frustration were found only in the images and memories of the stuttering group. No group differences were evident for the number of sensory modalities involved in images and memories, or for ratings of their vividness or strength of associated emotions, or on self-reports of depression, anxiety and trauma. CONCLUSIONS: Recurrent imagery about events in childhood is a potent factor in the memories of PWS. It is worth modifying interventions that have been successfully applied for treating social anxiety for use with people who stutter. EDUCATIONAL OBJECTIVES: After reading this article, participants will be able to: (a) identify the role of intrusive memories in psychiatric disorders and stuttering; (b) investigate how DSM criteria can be employed with people who stutter; (c) employ anxiety instruments used for assessing psychiatric disorders for stuttering; (d) distinguish between the intrusive memories experienced by people who stutter, and people who do not stutter; (e) apply treatments for intrusive memories in psychiatric disorders to work with people who stutter.

A triad of highly divergent polymeric immunoglobulin receptor (PIGR) haplotypes with major effect on IgA concentration in bovine milk.

The aim of this study was to determine a genetic basis for IgA concentration in milk of Bos taurus. We used a Holstein-Friesian x Jersey F2 crossbred pedigree to undertake a genome-wide search for QTL influencing IgA concentration and yield in colostrum and milk. We identified a single genome-wide significant QTL on chromosome 16, maximising at 4.8 Mbp. The polymeric immunoglobulin receptor gene (PIGR) was within the confidence interval of the QTL. In addition, mRNA expression analysis revealed a liver PIGR expression QTL mapping to the same locus as the IgA quantitative trait locus. Sequencing and subsequent genotyping of the PIGR gene revealed three divergent haplotypes that explained the variance of both the IgA QTL and the PIGR expression QTL. Genetic selection based on these markers will facilitate the production of bovine herds producing milk with higher concentrations of IgA.

Efficacy of a bio-electric dressing in healing deep, partial-thickness wounds using a porcine model .

Numerous physical modalities have been used in attempts to augment the healing process, including ultrasound, low- energy light therapy, and electrical stimulation (ES). ES has been shown to benefit tissue repair in a variety of wound types, but variations in study designs, administration, and parameters render its application in clinical practice somewhat unconventional. A dressing was designed to generate an electric potential of 0.6 V to 0.7 V in the presence of moisture, thereby delivering a sustained micro-current without the need for an external power source. The purpose of this study was to examine the effects of this bio-electric dressing (BED) on deep, partial-thickness wounds using six female specific pathogen-free animals and a well established porcine model for wound healing. Wounds (10 mm x 7 mm x 0.5 mm) were created in paravertebral and thoracic areas of these animals using a specialized electrokeratome and covered with the active polyester BED and a polyurethane film dressing (n = 30) (treatment) or an inactive polyester and film dressing (n = 30). Using an epidermal migration assay, wounds were assessed daily from day 4 through day 8 post-wounding. Differences in the proportion of wounds healed were statistically significant (P <0.001) on days 5 and 6 post-wounding. These results show BED is more effective than a control dressing treatment with moisture-retentive dressings in this animal model. Controlled clinical studies are warranted to elucidate the potential clinical implications of this treatment modality.

Effective method to remove wound bacteria: comparison of various debridement modalities in an in vivo porcine model.

BACKGROUND: Debridement is one of the crucial steps for successful wound care. In addition to removing necrotic tissue, debridement has been shown to reduce wound-associated bacteria that delay healing. Using an in vivo porcine model, we compared the effects of various methods of debridement, including hydrosurgery and plasma-mediated bipolar radiofrequency ablation (PBRA), on bacterial removal and wound healing. METHODS: One hundred thirty-five deep dermal wounds were inoculated with methicillin resistant Staphylococcus aureus (MRSA) and covered with a polyurethane dressing for 48 h to allow for biofilm formation. Wounds were then treated with either PBRA (at two settings), hydrosurgery, sharp debridement, or no debridement. Biopsies were collected for microbiology and histologic assessment on d 0, 2, 9, and 21 post-treatment. RESULTS: All treatment groups showed a statistically significant reduction in MRSA counts relative to no debridement at all times points (P < 0.05). PBRA at a maximum setting had the lowest MRSA counts at all recovery times and, compared with all other treatment groups, a statistically significant difference was observed on d 21 (P < 0.05). No detrimental effects on the healing process were noted with any of the debridement methods. CONCLUSION: While sharp debridement has been established as the traditional gold standard for rapid removal of necrotic, infected tissue, our results suggest that novel debridement modalities show clinical promise for the treatment of chronic ulcers and burn wounds, especially when bacteria are present.

Cosmeceuticals and natural products: wound healing.

Despite several technologic and strategic advances in the field, wound care has returned to the roots of medicine and embraced some of the remedies used millennia ago. Some of the many potentially beneficial natural products include the beta-glucans, honey, aloe, cocoa, and oak bark extracts. There has recently been a surge of interest for their possible roles in wound healing.

Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors.

A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3beta.