Design, synthesis, molecular docking, and molecular dynamic studies of novel quinazoline derivatives as phosphodiesterase 7 inhibitors.

Introduction: Phosphodiesterase 7 (PDE7) is a high-affinity cyclic AMP (cAMP)-specific PDE that is expressed in immune and proinflammatory cells. In this work, we explore the possibility that selective small molecule inhibitors of this enzyme family could provide a novel approach to alleviate the inflammation that is associated with many inflammatory diseases. Methods: A series of novel substituted 4-hydrazinoquinazoline derivatives and fused triazoloquinazolines were designed, synthesized, and evaluated in vitro for their PDE7A inhibition activities, in comparison with Theophylline, a non-selective PDE inhibitor, and BRL50481, a selective PDE7A inhibitor. This series of novel quinazoline derivatives were synthesized via multi-step reactions. The reaction sequence began with selective monohydrazinolysis of compounds 2a,b to give 3a,b. Schiff bases 4a-h were synthesized by the reaction of the quinazolylhydrazines 3a,b with various substituted aromatic aldehydes. The reaction of 4a-h with bromine in acetic acid, in turn, gave fused triazoloquinazolines 5a-h. These compounds were characterized by satisfied spectrum analyses mainly including 1HNMR, 13CNMR, and MS together with elemental analyses. Results and discussion: The results of in vitro PDE7A inhibition activity clearly indicated that compounds 4b, 4g, 5c, and 5f exhibited good potency. Molecular docking and molecular dynamic simulation studies further supported our findings and provided the basis of interaction in terms of conventional hydrogen bonds and π-π stacking patterns. The present results lay the groundwork for developing lead compounds with improved phosphodiesterase seven inhibitory activities.

Optimization of Patient Progression in a New Era: A Comprehensive Framework.

PURPOSE/OBJECTIVES: The onset of the coronavirus disease 2019 pandemic increased the demand for inpatient services and led to widespread staffing shortages in the acute and post-acute setting, contributing to delayed inpatient throughput and leading to capacity crises. Novel strategies are needed to facilitate the efficient progression of hospitalized patients when medically ready for lower levels of care. The authors have developed a foundational strategic framework for patient progression to ensure capture of patient progression data, enhance efficiency, and optimal utilization of post-acute resources in increasingly complex and resource-constrained acute and post-acute environments. PRIMARY PRACTICE SETTINGS: Interventions were implemented, and metrics of success tracked as part of an overarching framework to test new models of care or optimize existing assets related to barriers to patient progression. Brigham and Women's Hospital (BWH) and Brigham and Women's Faulkner Hospital (BWFH) comprise an academic medical center and a community hospital, respectively, that are affiliated with Massachusetts General Brigham (MGB), a nonprofit health care system in Massachusetts. Key interventions include (1) screening to prioritize patients needing case management services through a modified early screening for discharge planning tool and process; (2) communicating, documenting, identifying patient progression status, barriers to discharge and post-acute needs through interdisciplinary care optimization rounds, a novel tool in the electronic health record, and an associated dashboard; (3) managing active high-risk patients through a novel complex care team and post-acute strategy development; (4) developing novel transportation and hospice pathways; and (5) establishing community hospital repatriation and a physical therapy "Why Not Home" campaign. FINDINGS: Key metrics of success were (1) modified discharge planning tool resulting in screening out low-risk patients (53%) and impacting length of stay (0.55-day reduction, p = .083) during a 3-month intervention versus control study; (2) documentation adherence in more than 98% of patients 10 months postimplementation; (3) complex care team achieving a 2.5% reduction in Case Mix Index-adjusted length of stay 6 months postimplementation; (4) use of care van offsetting ambulance/chair car in 10% of cases, and earlier discharge time/length of stay in 21% of cases 3 months postimplementation; and (5) implementation of community repatriation impacting delay days to discharge (10-month pilot, 40 patients accounting for 1,000 delay days). CONCLUSIONS: Implementation of a novel comprehensive framework focusing on optimizing patient progression resulted in increased operational efficiency and positively impacted length of stay at our academic and community hospitals. Additional study is actively ongoing to understand long-term benefit of the innovations that the authors have developed. Further interventions are needed to wholly mitigate evolving capacity challenges in the acute and post-acute settings. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: The authors' implementation of the Brigham framework for progression demonstrates that innovative approaches to case management can help address the evolving challenges in care transitions planning. Notable opportunities include approaches that empower case managers as multidisciplinary team leaders, improve workflow, utilize patient progression data, prioritize patients with complex care needs support key patient populations, and promote post-acute collaboration.

What Went Right? A Mixed-Methods Study of Positive Feedback Data in a Hospital-Wide Mortality Review Survey.

BACKGROUND: Toxic work culture contributes to healthcare worker burnout and attrition, but little is known about how healthcare organizations can systematically create and promote a culture of civility and collegiality. OBJECTIVE: To analyze peer-to-peer positive feedback collected as part of a systematized mortality review survey to identify themes and recognition dynamics that can inform positive organizational culture change. DESIGN: Convergent mixed-methods study design. PARTICIPANTS: A total of 388 physicians, 212 registered nurses, 64 advanced practice providers, and 1 respiratory therapist at four non-profit hospitals (2 academic and 2 community). INTERVENTION: Providing optional positive feedback in the mortality review survey. MAIN MEASURES: Key themes and subthemes that emerged from positive feedback data, associations between key themes and positive feedback respondent characteristics, and recognition dynamics between positive feedback respondents and recipients. KEY RESULTS: Approximately 20% of healthcare workers provided positive feedback. Three key themes emerged among responses with free text comments: (1) providing extraordinary patient and family-centered care; (2) demonstrating self-possession and mastery; and (3) exhibiting empathic peer support and effective team collaboration. Compared to other specialties, most positive feedback from medicine (70.2%), neurology (65.2%), hospice and palliative medicine (64.3%), and surgery (58.8%) focused on providing extraordinary patient and family-centered care (p = 0.02), whereas emergency medicine (59.1%) comments predominantly focused on demonstrating self-possession and mastery (p = 0.06). Registered nurses (40.2%) provided multidirectional positive feedback more often than other clinician types in the hospital hierarchy (p < 0.001). CONCLUSIONS: Analysis of positive feedback from a mortality review survey provided meaningful insights into a health system's culture of teamwork and values related to civility and collegiality when providing end-of-life care. Systematic collection and sharing of positive feedback is feasible and has the potential to promote positive culture change and improve healthcare worker well-being.

A Public Health Critical Race Praxis Informed Congestive Heart Failure Quality Improvement Initiative on Inpatient General Medicine.

BACKGROUND: Prior evaluation at our hospital demonstrated that, compared to White patients, Black and Latinx patients with congestive heart failure (CHF) were less likely to be admitted to the cardiology service rather than the general medicine service (GMS). Patients admitted to GMS (compared to cardiology) had inferior rates of cardiology follow-up and 30-day readmission. OBJECTIVE: To develop and test the feasibility and impacts of using quality improvement (QI) methods, in combination with the Public Health Critical Race Praxis (PHCRP) framework, to engage stakeholders in developing an intervention for ensuring guideline-concordant inpatient CHF care across all patient groups. METHODS: We compared measures for all patients admitted with CHF to GMS between September 2019 and March 2020 (intervention group) to CHF patients admitted to GMS in the previous year (pre-intervention group) and those admitted to cardiology during the pre-intervention and intervention periods (cardiology group). Our primary measures were 30-day readmissions and 14- and 30-day post-discharge cardiology follow-up. RESULTS: There were 79 patients admitted with CHF to GMS during the intervention period, all of whom received the intervention. There were similar rates of Black and Latinx patients across the three groups. Compared to pre-intervention, intervention patients had a significantly lower 30-day readmission rate (18.9% vs. 24.8%; p=0.024), though the cardiology group also had a decrease in 30-day readmissions from the pre-intervention to intervention period. Compared to pre-intervention, intervention patients had significantly higher 14-day and 30-day post-discharge follow-up visits scheduled with cardiology (36.7% vs. 24.8%, p=0.005; 55.7% vs. 42.3%, p=0.0029), but no improvement in appointment attendance. CONCLUSION: This study provides a first test of applying the PHCRP framework within a stakeholder-engaged QI initiative for improving CHF care across races and ethnicities. Our study design cannot evaluate causation. However, the improvements in 30-day readmission, as well as in processes of care that may affect it, provide optimism that inclusion of a racism-conscious framework in QI initiatives is feasible and may enhance QI measures.

Evaluation of the Local Anesthetic Activity, Acute Toxicity, and Structure-Toxicity Relationship in Series of Synthesized 1-Aryltetrahydroisoquinoline Alkaloid Derivatives In Vivo and In Silico.

Isoquinoline alkaloids constitute one of the most common classes of alkaloids that have shown a pronounced role in curing various diseases. Finding ways to reduce the toxicity of these molecules and to increase their therapeutic margin is an urgent matter. Here, a one-step method for the synthesis of a series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines was performed in 85-98% yield by the Pictet-Spengler reaction. This was accomplished using the reaction between 3,4-dimethoxyphenylethylamine and substituted benzaldehydes boiling in trifluoroacetic acid. Furthermore, 1-(3'-amino-, 4'-aminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were obtained in 94% and 97% yield by reduction in 1-(3'-nitro-, 4'-nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines with SnCl2 × 2H2O. The structures of the substances obtained were confirmed by infrared (IR) and nuclear magnetic resonance (1H and 13C NMR) spectra. ADMET/TOPKAT in silico study concluded that the synthesized compounds exhibited acceptable pharmacodynamic and pharmacokinetic properties without carcinogenic or mutagenic potential but with variable hepatotoxicity. The acute toxicity and structure-toxicity relationship (STR) in the series of 20 derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (3a-r, 4a, b) was studied via determination of acute toxicity and resorptive action in white mice employing intragastric step-by-step administration. The first compound, 1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3a), showed the highest toxicity with LD50 of 280 mg/kg in contrast to 1-(3'-bromo -4'-hydroxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3e) which proved to be the safest of the compounds studied. Its toxicity was 13.75 times lower than that of the parent compound 3a. All compounds investigated showed high local anesthetic activity on rabbit eyes in the concentrations studied. Only 3r, 3n, and 4a caused eye irritation and redness. All investigated derivatives (except 4b) in 1% concentration were more active than lidocaine, providing longer duration of complete anesthesia. Therefore, based on the obtained results of in silico tests, local anesthesia, and acute toxicity, a conclusion can be drawn that the experimental compounds need further extensive future investigations and possible modifications so that they can act as promising drug candidates.

Ambulatory Medication Safety: Vaccination and Laboratory Screening for Patients Receiving Immunomodulatory Therapies.

OBJECTIVE: Immunomodulatory therapies improve the management of chronic diseases but can be associated with infectious risk. The present study was undertaken to examine the laboratory screening practices for hepatitis B virus (HBV), hepatitis C virus (HCV), and tuberculosis (TB) and rates of vaccination for pneumococcal and influenza in patients prescribed select immunosuppressive agents at our institution. METHODS: A retrospective analysis was conducted to review patients who were prescribed a select immunosuppressive over 3 years. Data were extracted from electronic health records to identify rates of screening and vaccination prior to initiation or at any time. Logistic regression models were developed to identify predictors of screening and vaccination. RESULTS: We identified 2,396 patients prescribed immunosuppressive medications by rheumatology (52.6%) and non-rheumatology specialties. Rates of screening at any time point were 84.5% (2,025 of 2,396) for HBV, 76.7% (1,838 of 2,396) for HCV, and 71.8% (1,720 of 2,396) for TB. Patients who had either in-system primary care providers (PCPs) or rheumatologists were more likely to receive pneumococcal vaccinations (odds ratio [OR] 1.98 [95% confidence interval (95% CI) 1.55-2.54] and OR 4.08 [95% CI 2.76-6.02], respectively). Patients with dermatologic (OR 1.67 [95% CI 1.14-2.45]) or rheumatologic providers (OR 2.5 [95% CI 1.86-3.36]) were more likely to be vaccinated for influenza. CONCLUSION: More than 70% of patients were screened for either HBV, HCV, or TB at some point. Rates of pneumococcal vaccination were better than rates of influenza vaccination. Patients with in-system PCPs were more likely to be screened and vaccinated. Establishing and executing consistent processes for screening and vaccination prior to immunosuppressive treatment remains a priority in ambulatory settings.

pH Responsive Hydrogels for the Delivery of Capecitabine: Development, Optimization and Pharmacokinetic Studies.

The objective of the current study was to achieve a sustained release profile of capecitabine (CAP), an anticancer agent frequently administered in conventional dosage form due to its short plasma half-life. A drug-loaded smart pH responsive chitosan/fenugreek-g-poly (MAA) hydrogel was synthesized by an aqueous free radical polymerization technique. The developed network was evaluated for capecitabine loading %, swelling response, morphology, structural and compositional characteristics, and drug release behavior. Significantly higher swelling and in vitro drug release rate were exhibited by formulations at pH 7.4 than at pH 1.2, demonstrating the pH responsive character of hydrogels. Swelling percentage and CAP loading ranged within 74.45-83.54% and 50.13-72.43%, respectively. Maximum release, up to 93%, was demonstrated over 30 h, evidencing the controlled release pattern of CAP from hydrogels. The optimized formulation was further screened for acute oral toxicity studies. No signs of oral, dermal, or ocular toxicities were noticed, confirming safety evidence of the network. Furthermore, pharmacokinetic analysis demonstrated the sustained release response of CAP from hydrogels as confirmed by a significant increase in plasma half-life (t1/2) (13 h) and AUC (42.88 µg h/mL) of CAP. Based on these findings, fabricated hydrogels are strongly recommended as a biocompatible carrier for colorectal delivery of active agents.

Euclea divinorum Hiern: Chemical Profiling of the Leaf Extract and Its Antioxidant Activity In Silico, In Vitro and in Caenorhabditis elegans Model.

Euclea divinorum Hiern is a medicinal plant widely distributed in the northeast parts of South Africa. This plant has been used to treat miscarriage and to alleviate gastrointestinal problems. It can also be used externally for the treatment of ulcers and gonorrhea. In this study, we investigated the phytochemical composition of E. divinorum leaf extract using LC-MS and explored its antioxidant properties in vitro and in vivo. The total polyphenolic content of the extract was determined by the Folin-Ciocalteu method. DPPH and FRAP assays were employed to confirm the plant's antioxidant potential in vitro. A survival assay in the Caenorhabditis elegans model was used to evaluate the extract's ability to counteract juglone-induced oxidative stress. Moreover, a docking study was performed for the extract's metabolites, in order to predict possible molecular targets that could explain the antioxidant effect of the plant on a molecular level. This in silico approach was accomplished on three different proteins; xanthine oxidase enzyme, heat shock protein 90 (Hsp90), and induced nitric oxide synthase (iNOS). Docking scores of the resulting poses and their interactions with binding sites' residues were explored for each protein and were compared to those of simultaneously docked respective co-crystallized and reference substrates. The extract furnished promising antioxidant activities in vitro and in vivo in the C. elegans model that might be attributed to the presence of 46 compounds, which showed several interactions and low binding scores with the tested enzymes. In conclusion, E. divinorum is a promising, safe, and effective antioxidant candidate that could be used to ameliorate oxidative stress-related disorders.

Design and Synthesis of Coumarin Derivatives as Cytotoxic Agents through PI3K/AKT Signaling Pathway Inhibition in HL60 and HepG2 Cancer Cells.

In this study, a series of coumarin derivatives, either alone or as hybrids with cinnamic acid, were synthesized and evaluated for their cytotoxicity against a panel of cancer cells using the MTT assay. Then, the most active compounds were inspected for their mechanism of cytotoxicity by cell-cycle analysis, RT-PCR, DNA fragmentation, and Western blotting techniques. Cytotoxic results showed that compound (4) had a significant cytotoxic effect against HL60 cells (IC50 = 8.09 µM), while compound (8b) had a noticeable activity against HepG2 cells (IC50 = 13.14 µM). Compounds (4) and (8b) mediated their cytotoxicity via PI3K/AKT pathway inhibition. These results were assured by molecular docking studies. These results support further exploratory research focusing on the therapeutic activity of coumarin derivatives as cytotoxic agents.

The Kidney Failure Risk Equation Score and CKD Care Delivery Measures: A Cross-sectional Study.

RATIONALE & OBJECTIVE: The 4-variable kidney failure risk equation (KFRE) allows for the prediction of chronic kidney disease (CKD) progression using age, sex, estimated glomerular filtration rate, and urine albumin/creatinine ratio. Electronic health records enable KFRE auto-calculation, and registries allow population-level application. We assessed whether 2-year KFRE score categories are associated with CKD care metrics. STUDY DESIGN: Cross-sectional cohort. SETTING & PARTICIPANTS: This study included individuals with CKD in March 2020 who were receiving care within the Partners HealthCare system in Massachusetts. OUTCOMES: The presence of sufficient data to calculate the KFRE and, among those with a KFRE score, performance on CKD clinical care metrics, including (1) prescription of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (2) blood pressure at goal (<140/90 mm Hg) based on clinic measurements; (3) composite metric of hepatitis B virus immunity; (4) composite metric of referral, evaluation, or waitlist status for kidney transplantation; (5) advance directive documentation; (6) yearly influenza vaccination; and (7) pneumonia vaccination. ANALYTICAL APPROACH: Multivariable logistic regression analysis was used to analyze the association of KFRE score category with CKD care metrics. RESULTS: Of 61,546 patients, 18,272 (30%) had auto-calculated 2-year KFRE scores; the remaining patients lacked KFRE scores because of absent albuminuria assessment. Individuals with a KFRE score were more likely to have a primary care provider or nephrologist. Among patients with 2-year KFRE scores, high-risk patients had increased odds of completing advance directives (OR, 1.52; 95% CI, 1.07-2.17), while low-risk patients had decreased odds of influenza vaccination (OR, 0.85; 95% CI, 0.75-0.97). Patients with moderate- and high-risk KFRE scores had lower odds of having blood pressure at goal (OR, 0.77; 95% CI, 0.61-0.96 and OR, 0.63; 95% CI, 0.44-0.88, respectively). LIMITATIONS: Albuminuria data may have been assessed outside of the Partners system. CONCLUSIONS: A higher-risk KFRE score is associated with the delivery of some but not all CKD care measures. An opportunity exists to improve albuminuria measurement.

Characterization, antibacterial, antioxidant, antidiabetic, and anti-inflammatory activities of green synthesized silver nanoparticles using Phragmanthera austroarabica A. G. Mill and J. A. Nyberg extract.

Introduction: Diabetes mellitus is a chronic metabolic disorder that exhibited great expansion all over the world. It is becoming an epidemic disease adding a major burden to the health care system, particularly in developing countries. Methods: The plant under investigation in the current study Phragmanthera austroarabica A. G. Mill and J. A. Nyberg is traditionally used in Saudi Arabia for the treatment of diabetes mellitus. The methanolic extract (200 mg/kg) of the plant and pure gallic acid (40 mg/kg), a major metabolite of the plant, as well as their silver nanoparticle formulae (AgNPs) were evaluated for their antidiabetic activity. Results and Discussion: The results showed a decrease in body fat, obesity, an improvement in lipid profiles, normalization of hyperglycemia, insulin resistance, and hyperinsulinemia, and an improvement in liver tissue structure and function. However, the results obtained from AgNPs for both extract and the pure gallic acid were better in most measured parameters. Additionally, the activity of both the crude extract of the plant and its AgNPs were evaluated against a number of gram-positive, gram-negative bacteria and fungi. Although the activity of the crude extract ranged from moderate to weak or even non-active, the AgNPs of the plant extract clearly enhanced the antimicrobial activity. AgNPs of the extract demonstrated remarkable activity, especially against the Gram-negative pathogens Proteus vulgaris (MIC 2.5 µg/ml) and Pseudomonas aeruginosa (MIC 5 µg/ml). Furthermore, a promising antimicrobial activity was shown against the Gram-positive pathogen Streptococcus mutants (MIC 1.25 µg/ml).

Improving hepatitis B vaccination rates for advanced chronic kidney disease patients: a quality improvement initiative.

INTRODUCTION: Chronic kidney disease (CKD) patients are vulnerable to hepatitis B, and immunization prior to end stage kidney disease is recommended to optimize seroconversion. Our institution undertook a process improvement approach to increase hepatitis B vaccination in stage 4 and 5 CKD patients. METHODS: Four strategies were utilized such as: (1) Electronic health record (EHR)-based CKD registry to identify patients, (2) EHR-based physician/nurse reminders, (3) a co-located nurse appointment for vaccine administration, and (4) information sharing and provider awareness effort. The CKD registry was utilized to identify patients with stage 4 or 5 CKD, with at least two clinic visits in the prior 2 years, who had not received the hepatitis B vaccine or did not have serologic evidence of immunity. Target monthly vaccination rate was set at 75%, based on clinic leadership, nephrologist, and nurse consensus. RESULTS: A total of 239 patients were included in the study period, from November 2018 to January 2019 (observation period) and from February 2019 to September 2019 (intervention period). Monthly vaccination rate improved from 48% in November 2018 to the target rate of 75% by the end of the intervention (August and September 2019). There was a statistically significant increase from the rate of vaccination at a unique patient level in the first month of the baseline period, compared to the last month of the intervention period (51 vs. 75% p = 0.03). CONCLUSIONS: Utilizing a nurse-led approach to hepatitis B vaccination, coupled with EHR-based tools, along with continuous monitoring of performance, helped to improve hepatitis B vaccination among CKD stage 4 and 5 patients.