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Design, Synthesis and Antitumor Activity of Novel Dispiro[oxindole-cyclohexanone]-pyrrolidines
No full textBackground: Spirooxindoles are privileged scaffolds in medicinal chemistry, which were identified through Wang’s pioneering work as inhibitors of MDM2-p53 interactions. Objective: To design and synthesize 2,6-diarylidenecyclohexanones and dispiro[oxindole-cyclohexanone]-pyrrolidines having potential antitumor effect. Methods: Dispiro[oxindole-cyclohexanone]-pyrrolidines 6a-h were synthesized in a regioselective manner via 1,3-dipolar cycloaddition reaction of 2,6-diarylidenecyclohexanones 3a-h, isatin, and sarcocine. Compounds 6a-h were alkylated to give (7-10)a,b. All compounds were evaluated in vitro for their antitumor activity and cytotoxic selectivity against breast cancer cell lines (MCF-7 and MDA-MB-231), breast fibrosis cell line (MCF10a), and placental cancer cell line (JEG-3). Molecular modeling inside the MDM2 binding site was per-formed using AutoDock4.2. Results: Synthesized compounds showed antitumor activity comparable to tamoxifen and compounds 3a,b,f,g and 9a,b showed selective cytotoxicity against tumor cells but reduced toxicity toward MCF-10a cells. Molecular modelling shows that both classes of synthesized compounds are predicted to fit the deep hydrophobic cleft on the surface of MDM2 and mimic the interactions between p53 and MDM2. Conclusion: The synthesized compounds have antitumor activity against MCF-7, MDA-MB-231, and JEG-3. Few compounds showed a selective cytotoxic effect and may have the potential to inhibit MDM2 and stimulate p53. In the future, studies regarding the optimization of medicinal chemistry as well as mechanistic studies will be conducted to enhance the inhibition effect of identified compounds and elucidate their mechanism of action
Risk factors for opioid toxicity requiring naloxone rescue in adults: a case-control study
No full textBackground: Opioid-induced sedation and respiratory depression (OSRD) is a potentially life-threatening side effect of opioid analgesia. However, little is known about the individual and clinical-related factors associated with OSRD in the New Zealand context. Aim: To identify risk factors for OSRD in patients admitted to a large regional health board in New Zealand—Auckland District Health Board (ADHB). Method: A retrospective matched case-control study design was undertaken among adults who were admitted to ADHB and prescribed opioids in hospital between August 2015 and April 2020. Those who were prescribed opioids and received naloxone for OSRD were defined as cases, whereas those who received opioids but did not experience OSRD were identified as controls. Cases and controls were matched on a 1:1 basis by age (± 10 years). Data were retrieved from the electronic medical records of ADHB. A conditional logistic regression model was used to identify the risk factors for OSRD. Results: We identified 51 cases, and these were matched with 51 control patients. The odds of experiencing OSRD were four times higher among opioid-naïve patients compared to those exposed to opioids prior to hospital admission (OR 4.113; 95% CI 1.14–14.89). Increased risk of OSRD was also associated with higher serum creatinine level prior to OSRD episode (OR 1.015; 95% CI 1.01–1.03) and a higher oral morphine milligram equivalent (OME) (OR 1.023; 95% CI 1.01–1.04). Conclusion: Increased risk of OSRD was associated with a higher OME, a higher serum creatinine level prior to OSRD episode, and opioid naivety. Our findings can inform policies that aim to prevent serious adverse effects related to opioids
Trends in telephonic comprehensive medication review in the United States from 2000 to present: a scoping literature review
No full textBackground: Although comprehensive medication review (CMR) services have been shown to provide value to patients and payers, the extent of uniformity in service delivery is unknown. A variety of standards and recommendations are available from academic and professional sources, but variation in service provision is an important consideration when attempting to measure or compare service quality nationally. Objective: This study aimed to identify and summarize trends in the peer-reviewed and gray literature describing telephonic CMR delivery and content. Methods: A scoping review of peer-reviewed and gray literature was conducted to quantify and qualify trends in CMR service. Two independent reviewers screened abstracts from 9 bibliographic databases and selected gray literature sources in accordance with the Joanna Briggs Institute guidelines and an internally developed protocol. Inclusion criteria for the review were English language; discussion of telephonic CMR service in the United States; research, legislation, or guidelines that describe CMR content coverage requirements for payment; and publication from the year 2000 to the present. Data relating to publication type, study design, setting, region, and themes of CMR content were collated into a Microsoft Excel data extraction form. Qualitative thematic analysis was conducted, and key findings and concepts were reported contextually. Results: Of 374 identified documents screened, 15 were included in this scoping review and thematic analysis. The following characteristics of CMRs were identified: content, coverage, eligibility, frequency, process, and responsiveness. All published documents (n = 15, 100%) included a discussion of CMR content, and 14 sources (93%) addressed process elements of providing a CMR. Discussion of other themes varied in frequency across documents, ranging from 3 articles (20%) addressing organizational goals for CMR to 12 articles (80%) including elements of responsiveness. Within-theme variation was also observed for several CMR content areas. CMR process was the most heterogeneous theme with topics ranging from access to patient health records to pharmacist training. Conclusions: Assessment of telephonic CMR comprised a small but steadily increasing portion of the medication therapy management literature. Publications since 2015 have shown an increasing consensus of CMR content and purpose. Per the identified literature, there is an ongoing demand for higher-quality, more holistic CMRs, but there is no consensus on how to measure CMR quality. Future work should include engaging with CMR experts to understand variability in measures of CMR success
Psychometric evaluation of a comprehensive medication management service experience instrument
No full textBackground: The Health-Systems Alliance for Integrated Medication Management (HAIMM) instrument was developed to estimate patient experience following pharmacist-delivered comprehensive medication management (CMM). Objectives: The objective of this paper was to assess the psychometric properties and factor structure of the HAIMM instrument. Methods: Data were collected from 5 members of the HAIMM collaborative. A one-factor confirmatory factor analysis (CFA) model was used to assess instrument dimensionality. A partial-credit item response theory model was used to assess the psychometric properties of the ten-item HAIMM patient experience instrument, consisting of tests for rating scale functioning, person and item fit, and content validity. Results: Among 516 respondents, there was a strong skew toward high satisfaction, including a strong ceiling effect. CFA results suggest a unidimensional construct. Item difficulty was spread across a low range and content redundancies were identified. The mean-square values for both infit and outfit all fell within the recommended range, whereas the z-standard fit was within the recommended range for most items. The 5-point Likert scale used in the HAIMM instrument did not distinguish between participants’ level of experience following the pharmacist-delivered CMM service. Conclusion: The psychometric analysis showed the HAIMM survey tool does not cover all of the content that should be assessed to fully evaluate CMM experiences. In its current form, the HAIMM instrument should not be used to make comparisons about the quality of CMM services provided, although it may be useful to monitor patient satisfaction for quality improvement purposes. Further research is required to develop an improved instrument that contains expanded content coverage, response options, and aspects of CMM to be useful by health care providers, health systems, and other decision makers
Changes in Adolescent Birth Rates within Appalachian Subregions and Non-Appalachian Counties in the United States, 2012-2018
No full textBACKGROUND: Adolescent births are associated with numerous challenges. While adolescent birth rates have declined across the U.S., disparities persist, and little is known about the extent to which broader declines are seen within Appalachia. PURPOSE: The purpose of this study was to examine the extent to which adolescent birth rates have declined across the subregions of Appalachia relative to non-Appalachia. METHODS: We conducted a retrospective study of adolescent birth rates between 2012 and 2018 using county-level vital records data. Differences were examined across the subregions of Appalachia and among non-Appalachian counties. Multiple regression models were used to examine changes in the rate of decline over time, adjusting for additional covariates of relevance. RESULTS: About 13.4% of all counties in the U.S. are within the Appalachian region. The rate of adolescent births decreased by 12.6 adolescent births per 1,000 females between 2012 and 2018 across the U.S. While all regions experienced declines in the rate of adolescent births, Central Appalachia had the largest reduction in adolescent births (18.5 per 1,000 females), which was also noted in the adjusted models when compared to the counties of non-Appalachia (b= -5.78, CI: -9.58, -1.97). Rates of adolescent birth were markedly higher in counties considered among the most socially and economically vulnerable. IMPLICATIONS: This study demonstrates that the rates of adolescent births vary across the subregions of Appalachia but have declined proportional to rates in non-Appalachia. While adolescent birth rates remain higher in select subregions of Appalachia compared to non-Appalachia, the gap has narrowed considerably
Limited gene flow and pronounced population genetic structure of Eastern Massasauga (Sistrurus catenatus) in a Midwestern prairie remnant
No full textAs anthropogenic changes continue to ecologically stress wildlife, obtaining measures of gene flow and genetic diversity are crucial for evaluating population trends and considering management and conservation strategies for small, imperiled populations. In our study, we conducted a molecular assessment to expand on previous work to elucidate patterns of diversity and connectivity in the remaining disjunct Eastern Massasauga Rattlesnake (Sistrurus catenatus) hibernacula in Illinois. We assayed genetic data for 327 samples collected during 1999-2015 from the Carlyle Lake study area across 21 microsatellite loci. We found hibernacula formed distinct genetic clusters corresponding to the three main study areas (Dam Recreation Areas, Eldon Hazlet State Park, and South Shore State Park). Genetic structuring and low estimates of dispersal indicated that connectivity among these study areas is limited and each is demographically independent. Hibernacula exhibited moderate levels of heterozygosity (0.60-0.73), but estimates of effective population size (5.2-41.0) were low and track census sizes generated via long-term mark-recapture data. Hibernacula at Carlyle Lake, which represent the only Eastern Massasauga remaining in Illinois, are vulnerable to future loss of genetic diversity through lack of gene flow as well as demographic and environmental stochastic processes. Our work highlights the need to include population-level genetic data in recovery planning and suggests that recovery efforts should focus on managing the three major study areas as separate conservation units in order to preserve and maintain long-term adaptive potential of these populations. Specific management goals should include improving connectivity among hibernacula, maintaining existing wet grassland habitat, and minimizing anthropogenic sources of mortality caused by habitat management (e.g., mowing, prescribed fire) and recreational activities. Our molecular study provides additional details about demographic parameters and connectivity at Carlyle Lake that can be used to guide recovery of Eastern Massasauga in Illinois and throughout its range
Computational Modeling for the Oxidation Reactions of the Cysteine Residues with the Superoxide and the Organic Radical Species
No full textThe current computational study analyzes the oxidation reactions of the superoxide and hydroxyl radicals with cysteine residues due to their importance as natural targets to neutralize the harmful reactive oxygen species. Due to the high reactivity of the hydroxyl radicals with the surrounding environment, we also studied the oxidation reactions of organic radicals with cysteine. In addition, we explored the different reaction pathways between cysteine and the superoxide radicals in both anionic and protonated forms. All calculations were performed at the integrated quantum mechanical/molecular mechanical level in an explicit water box under periodic boundary conditions. Higher energy barriers were observed for the organic radicals than the hydroxyl radical, where the chemical nature of the organic radical and the branching pattern are the main factors contributing to the Gibbs energy barriers. The superoxide radical oxidation pathway exhibits a more complex nature due to the complicated interplay of various factors such as the underlying reaction mechanism, the involved oxidizing agent, the kinetic accessibility of the oxidation reaction, and the thermodynamics favorability of those oxidation reactions. We also examined the effect of the solvent-assisted hydrogen atom transfer on the different reaction barriers, which was found to be kinetically unfavorable
An online randomized controlled trial and survey of behavioural factors influencing patients’ willingness to attend a video consultation
No full textObjectives: To examine whether the phrasing of a hospital appointment invitation influences patient preference to attend in person or by video. The study also explores patient capabilities, opportunities, and motivations to attend video consultations. Design: A randomized controlled trial followed by a cross-sectional survey. Methods: Participants (1,481 total, 780 females) were residents of the United Kingdom who self-identified as being diagnosed with a chronic disease. Participants considered one of three hypothetical invitations. In one group, participants were invited to attend in person. Those in another group were invited to attend by video. These participants could either accept the invitation or request the other option. In the final ‘active choice’ group, participants were asked to choose to attend either in-person or by video appointment. Then, all participants responded to open- and closed-ended items about attending video consultations. Results: When the default option was in person, 25% of participants chose video consultation, compared with 41% in the active choice group (RR = 1.65, 95% CI: 1.37–1.99, p \u3c.001) and 65% in the default video group (RR = 2.60, 95% CI: 2.20–2.96, p \u3c.001). Closed-ended responses suggested that younger patients and those with previous experience were more likely to prefer video consultations. Most open-ended responses contained themes about opportunities, followed by motivations and then capabilities. Conclusions: Patients are more likely to express a preference to attend by video when video is the default option. The real-world effectiveness of this intervention is more likely to be realized where hospitals also support patient capabilities, opportunities, and motivations
Exosomes: Biological Pharmaceutical Nanovectors for Theranostics
No full textExosomes are natural cell-derived nanovesicles of endocytic origin that enable cellular crosstalk by transferring encapsulated molecular cargos across biological barriers, thereby holding significantly complex implications in the etiology and progression of diverse disease states. Consequently, the development of exosomes-based nano-theranostic strategies has received immense consideration for advancing therapeutic interventions and disease prognosis. Their favorable biopharmaceutical properties make exosomes a unique nanoparticulate carrier for pharmaceutical drug delivery. This review provides an update on the contemporary strategies utilizing exosomes for theranostic applications in nanomedicine. In addition, we provide a synopsis of exosomal features and insights into strategic modifications that control in vivo biodistribution. We further discuss their opportunities, merits and pitfalls for cell/tissue targeted drug delivery in personalized nanotherapy
Race Does Not Impact Sepsis Outcomes When Considering Socioeconomic Factors in Multilevel Modeling
No full textOBJECTIVES: To determine whether race is a major determinant of sepsis outcomes when controlling for socioeconomic factors. DESIGN: Retrospective cohort study. SETTING: Barnes-Jewish Hospital a 1,350 bed academic medical center. PATIENTS: Eleven-thousand four-hundred thirty-two patients hospitalized between January 2010 and April 2017 with sepsis and septic shock. INTERVENTIONS: Multilevel random effects modeling was employed whereby patients were nested within ZIP codes. Individual patient characteristics and socioeconomic variables aggregated at the ZIP code level (education, employment status, income, poverty level, access to healthcare) were included in the model. MEASUREMENTS AND MAIN RESULTS: In hospital mortality, length of stay, need for vasopressors, and mechanical ventilation were the main endpoints. Black patients had more comorbidities than White patients except for cirrhosis and malignancy. In unadjusted comparisons, White individuals were more likely to require mechanical ventilation and had higher mortality rates and longer hospital stays for both low- and high-income groups. When nesting within ZIP codes and accounting for socioeconomic variables, race did not have a significant effect on mortality. Non-White races had lower odds ratio for mechanical ventilation. CONCLUSIONS: Our study demonstrates that race is not an independent risk factor for sepsis mortality, as well as sepsis-related length of stay. We should expand our inquiry into determinants of sepsis outcomes by including socioeconomic variables